When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

See related editorial

Results of laboratory testing included a positive reactive syphilis immunoglobulin G (IgG) enzyme immunoassay and a positive rapid plasma reagin (RPR) test (titer 1:256). Human immunodeficiency virus (HIV) testing was negative, and serologic testing demonstrated prior immunization to hepatitis B virus. Given the clinical presentation and laboratory findings, secondary syphilis was considered the most probable diagnosis.

The patient was treated with benzathine penicillin G 2.4 million units intramuscularly.

SYPHILIS: A REEMERGING CONDITION

Epidemiology

The rate of reported primary and secondary syphilis cases in the United States has risen since 2001.¹ Most cases occur in men who have sex with men.¹ Additional risk factors include condomless intercourse and drug use.²

Signs and symptoms of the 3 stages

Primary syphilis begins 2 to 3 weeks after inoculation of a mucosal surface.³ This stage is marked by one or more painless chancres and, in some cases, local nontender lymphadenopathy.^3,4 Secondary syphilis presents 4 to 8 weeks later with systemic symptoms including rash, classically involving the palms or soles, lymphadenopathy, myalgia, fever, and weight loss.^2,3 Untreated primary and secondary syphilis may progress to latent or asymptomatic disease.⁵

Tertiary syphilis, defined by the US Centers for Disease Control and Prevention (CDC) as gummas or cardiovascular syphilis, occurs 15 to 30 years after an untreated exposure.^4,6 Neurosyphilis can present at any stage of the disease.⁶

Diagnosis

The diagnosis of syphilis involves a nontreponemal test such as RPR or Venereal Disease Research Laboratory (VDRL) to screen for disease, followed by a treponemal antibody test such as fluorescent treponemal antibody-absorption, Treponema pallidum particle agglutination assay, or syphilis IgG to confirm the diagnosis.⁵ There is no screening test for tertiary disease in patients previously diagnosed with primary or secondary syphilis, but a cerebrospinal fluid (CSF) examination is recommended if neurologic or ocular manifestations are present.⁶

Treatment

Treatment of primary, secondary, and early latent syphilis is a single dose of 2.4 million units of benzathine penicillin G given intramuscularly.⁷ The treatment of late latent and tertiary syphilis is less well defined by the current literature but generally includes penicillin.⁷

Patients with primary and secondary syphilis undergo serologic and clinical evaluation at 6 and 12 months to be assessed for treatment failure or reinfection.⁶ Patients with latent disease require serologic follow-up at 6, 12, and 24 months.⁶ Additionally, CSF analysis should be done if baseline high titers do not fall within 12 to 24 months of treatment or if symptoms suggest syphilis.⁶ Patients with neurosyphilis often require CSF evaluation every 6 months.⁶ Follow-up for patients with tertiary syphilis is less well defined.

Patients coinfected with HIV have special needs and considerations, as outlined in the CDC’s 2015 Sexually Transmitted Diseases Treatment Guidelines.⁶

Sexual contacts of patients with syphilis deserve evaluation. Exposure within 90 days of a patient’s diagnosis with primary, secondary, or latent disease requires treatment regardless of the results of serologic testing.⁶ Persons exposed more than 90 days before diagnosis may undergo serologic testing; however, if results are not immediately available or follow-up is unlikely, the individual should be treated for early syphilis.⁶ If serologic testing results are negative, no treatment is required.⁶

See related editorial

Results of laboratory testing included a positive reactive syphilis immunoglobulin G (IgG) enzyme immunoassay and a positive rapid plasma reagin (RPR) test (titer 1:256). Human immunodeficiency virus (HIV) testing was negative, and serologic testing demonstrated prior immunization to hepatitis B virus. Given the clinical presentation and laboratory findings, secondary syphilis was considered the most probable diagnosis.

The patient was treated with benzathine penicillin G 2.4 million units intramuscularly.

SYPHILIS: A REEMERGING CONDITION

Epidemiology

The rate of reported primary and secondary syphilis cases in the United States has risen since 2001.¹ Most cases occur in men who have sex with men.¹ Additional risk factors include condomless intercourse and drug use.²

Signs and symptoms of the 3 stages

Primary syphilis begins 2 to 3 weeks after inoculation of a mucosal surface.³ This stage is marked by one or more painless chancres and, in some cases, local nontender lymphadenopathy.^3,4 Secondary syphilis presents 4 to 8 weeks later with systemic symptoms including rash, classically involving the palms or soles, lymphadenopathy, myalgia, fever, and weight loss.^2,3 Untreated primary and secondary syphilis may progress to latent or asymptomatic disease.⁵

Tertiary syphilis, defined by the US Centers for Disease Control and Prevention (CDC) as gummas or cardiovascular syphilis, occurs 15 to 30 years after an untreated exposure.^4,6 Neurosyphilis can present at any stage of the disease.⁶

Diagnosis

The diagnosis of syphilis involves a nontreponemal test such as RPR or Venereal Disease Research Laboratory (VDRL) to screen for disease, followed by a treponemal antibody test such as fluorescent treponemal antibody-absorption, Treponema pallidum particle agglutination assay, or syphilis IgG to confirm the diagnosis.⁵ There is no screening test for tertiary disease in patients previously diagnosed with primary or secondary syphilis, but a cerebrospinal fluid (CSF) examination is recommended if neurologic or ocular manifestations are present.⁶

Treatment

Treatment of primary, secondary, and early latent syphilis is a single dose of 2.4 million units of benzathine penicillin G given intramuscularly.⁷ The treatment of late latent and tertiary syphilis is less well defined by the current literature but generally includes penicillin.⁷

Patients with primary and secondary syphilis undergo serologic and clinical evaluation at 6 and 12 months to be assessed for treatment failure or reinfection.⁶ Patients with latent disease require serologic follow-up at 6, 12, and 24 months.⁶ Additionally, CSF analysis should be done if baseline high titers do not fall within 12 to 24 months of treatment or if symptoms suggest syphilis.⁶ Patients with neurosyphilis often require CSF evaluation every 6 months.⁶ Follow-up for patients with tertiary syphilis is less well defined.

Patients coinfected with HIV have special needs and considerations, as outlined in the CDC’s 2015 Sexually Transmitted Diseases Treatment Guidelines.⁶

Sexual contacts of patients with syphilis deserve evaluation. Exposure within 90 days of a patient’s diagnosis with primary, secondary, or latent disease requires treatment regardless of the results of serologic testing.⁶ Persons exposed more than 90 days before diagnosis may undergo serologic testing; however, if results are not immediately available or follow-up is unlikely, the individual should be treated for early syphilis.⁶ If serologic testing results are negative, no treatment is required.⁶

See related editorial

Results of laboratory testing included a positive reactive syphilis immunoglobulin G (IgG) enzyme immunoassay and a positive rapid plasma reagin (RPR) test (titer 1:256). Human immunodeficiency virus (HIV) testing was negative, and serologic testing demonstrated prior immunization to hepatitis B virus. Given the clinical presentation and laboratory findings, secondary syphilis was considered the most probable diagnosis.

The patient was treated with benzathine penicillin G 2.4 million units intramuscularly.

SYPHILIS: A REEMERGING CONDITION

Epidemiology

The rate of reported primary and secondary syphilis cases in the United States has risen since 2001.¹ Most cases occur in men who have sex with men.¹ Additional risk factors include condomless intercourse and drug use.²

Signs and symptoms of the 3 stages

Primary syphilis begins 2 to 3 weeks after inoculation of a mucosal surface.³ This stage is marked by one or more painless chancres and, in some cases, local nontender lymphadenopathy.^3,4 Secondary syphilis presents 4 to 8 weeks later with systemic symptoms including rash, classically involving the palms or soles, lymphadenopathy, myalgia, fever, and weight loss.^2,3 Untreated primary and secondary syphilis may progress to latent or asymptomatic disease.⁵

Tertiary syphilis, defined by the US Centers for Disease Control and Prevention (CDC) as gummas or cardiovascular syphilis, occurs 15 to 30 years after an untreated exposure.^4,6 Neurosyphilis can present at any stage of the disease.⁶

Diagnosis

The diagnosis of syphilis involves a nontreponemal test such as RPR or Venereal Disease Research Laboratory (VDRL) to screen for disease, followed by a treponemal antibody test such as fluorescent treponemal antibody-absorption, Treponema pallidum particle agglutination assay, or syphilis IgG to confirm the diagnosis.⁵ There is no screening test for tertiary disease in patients previously diagnosed with primary or secondary syphilis, but a cerebrospinal fluid (CSF) examination is recommended if neurologic or ocular manifestations are present.⁶

Treatment

Treatment of primary, secondary, and early latent syphilis is a single dose of 2.4 million units of benzathine penicillin G given intramuscularly.⁷ The treatment of late latent and tertiary syphilis is less well defined by the current literature but generally includes penicillin.⁷

Patients with primary and secondary syphilis undergo serologic and clinical evaluation at 6 and 12 months to be assessed for treatment failure or reinfection.⁶ Patients with latent disease require serologic follow-up at 6, 12, and 24 months.⁶ Additionally, CSF analysis should be done if baseline high titers do not fall within 12 to 24 months of treatment or if symptoms suggest syphilis.⁶ Patients with neurosyphilis often require CSF evaluation every 6 months.⁶ Follow-up for patients with tertiary syphilis is less well defined.

Patients coinfected with HIV have special needs and considerations, as outlined in the CDC’s 2015 Sexually Transmitted Diseases Treatment Guidelines.⁶

Sexual contacts of patients with syphilis deserve evaluation. Exposure within 90 days of a patient’s diagnosis with primary, secondary, or latent disease requires treatment regardless of the results of serologic testing.⁶ Persons exposed more than 90 days before diagnosis may undergo serologic testing; however, if results are not immediately available or follow-up is unlikely, the individual should be treated for early syphilis.⁶ If serologic testing results are negative, no treatment is required.⁶

According to a report from the US Centers for Disease Control and Prevention (CDC) on the incidence of sexually transmitted diseases (STDs), “Total combined cases of chlamydia, gonorrhea, and syphilis reported in 2015 reached the highest number ever”¹ since the CDC was founded in July 1946.

See related article

Nearly 24,000 cases of primary and secondary syphilis were reported in 2015, a 19% increase from the previous year. And Dr. Jonathan Mermin, director of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, reported, “We have reached a decisive moment for the nation. STD rates are rising, and many of the country’s systems for preventing STDs have eroded. We must mobilize, rebuild, and expand services—or the human and economic burden will continue to grow.”¹

Dr. Mermin stressed the need to rebuild services because, “In recent years more than half of state and local STD programs have experienced budget cuts, resulting in more than 20 health department STD clinic closures in one year alone. Fewer clinics mean reduced access to STD testing and treatment for those who need these services.”¹

The CDC also reports that STD treatment costs the US healthcare system nearly $16 billion each year.

The CDC has identified several players whose engagement is necessary to stem the tide of this epidemic:

• Providers must make STD screening a standard part of medical care, especially in pregnant women, and integrate STD prevention and treatment into prenatal care and other routine visits.
• People need to talk openly about STDs, get tested regularly, and reduce risk by using condoms or practicing mutual monogamy if sexually active.
• Parents and providers need to offer young people safe, effective ways to get information and services.
• State and local health departments should continue to direct resources to people hardest hit by the STD epidemic and work with community partners to maximize their impact.¹

STD CAMPAIGNS 100 YEARS AGO

This message sounds familiar. Let’s go back 100 years to World War I. The book No Magic Bullet by Allan M. Brandt² provides fascinating details about this period in America’s battle against venereal diseases. While the book is well worth reading in its entirety, I will attempt here to summarize the pertinent facts.

In the late 1910s, antivenereal campaigns were in full swing, with publicly shown movies such as “Fit to Fight” to train soldiers about STD symptoms and prevention to keep them physically healthy for fighting in the war. Similar information was widely available stateside for both men and women in open, matter-of-fact formats to encourage STD prevention.

After the war ended, the national sentiment became split between sexual revolution and social moralism. “Social hygienists” blamed the widespread increase in promiscuity on the newly introduced sexually explicit philosophy of Sigmund Freud, the widespread availability of automobiles (ie, a mobile, private, backseat location for sex), popular “vulgar” dances, and social feminism, among many others. The sexual revolution clearly led to an increased risk of STDs. But the antivenereal campaigns that had been appropriate in wartime came to be considered amoral and unfit for public consumption, and a period of silence about venereal diseases ensued.

By the 1930s, the situation had worsened:

• Approximately 1 out of every 10 Americans suffered from syphilis.
• Each year, Americans contracted almost half a million new syphilis infections (twice as many cases as tuberculosis, and 100 times as many cases as polio).
• 18% of all deaths from organic heart disease could be attributed to syphilis.
• Up to 20% of all mental institution inmates suffered from tertiary syphilis.
• 60,000 children were born each year with congenital syphilis.²

Although penicillin was still a decade or more away from discovery, syphilis could be treated, though likely not cured, with arsenic compounds. A course of treatment from a private physician, however, could cost from $300 to $1,000. Many patients who could not pay these exorbitant prices turned to public clinics for help. However, funding for the Venereal Disease Division of the Public Health Service, originally $4 million in 1920, was cut to less than $60,000 by 1926.² Some hospitals refused to admit patients with syphilis and other venereal diseases, deeming them “morally tainted and less deserving of care.”²

Things couldn’t get much worse.

Dr. Thomas Parran was the New York State health commissioner in 1930, at the start of the Great Depression. Realizing that arguments for moral responsibility to prevent and treat venereal diseases were not effective, Dr. Parran and other public health officials turned to financial arguments. Among the most persuasive arguments, “More than $15 million was spent annually for the ambulatory care of venereal patients…Experts argued that syphilis costs taxpayers between $40 and $50 million each year for the institutional care of the insane, paralyzed, and blind.”² The American Medical Association calculated that “8 to 10 million workers lost 21 million working days each year at an average of $4 a day as a result of infection with these conditions.”² The cost was estimated at more than $100,000,000 annually.²

But the general public was not a part of the larger conversation regarding treatment and prevention of syphilis, thanks to the social hygienists. In November 1934, Dr. Parran was scheduled to give a radio broadcast on future goals for public health in New York. Notified that he would not be able to mention syphilis or gonorrhea by name, he refused to give the speech. Dr. Parran went on to lead the charge to reduce the moral cloud that blocked the ability to address syphilis openly and scientifically. With his extensive experience in public health, he proposed plans that had been effective in controlling other infectious diseases as measures to control the spread of syphilis. He outlined the following:

• Identify cases of syphilis. Offer free diagnostic centers where individuals could obtain confidential blood tests.
• Offer prompt therapy for identified cases.
• Identify, locate, and test all contacts of infected patients, and treat them if they are infected too.
• Make blood testing mandatory before marriage and early in all pregnancies.
• Educate the public concerning syphilis.²

Do these approaches sound familiar?

Appointed US Surgeon General in 1936 by President Franklin Delano Roosevelt, Dr. Parran published “The next great plague to go,”³ an article focusing on the medical approach to treating syphilis and other venereal diseases, while refusing to address the moral and social issues.³ This was widely acclaimed by the public and the press. Two years after he was blocked from mentioning syphilis and gonorrhea on the radio, he was pictured on the cover of Time magazine for his groundbreaking work.

With the advent of penicillin, syphilis became not only treatable but curable. Over the next decades, the number of patients infected with syphilis and the morbidity it caused continually declined until the 1990s, when there were even whispers of eradication in the United States. This likely came in part due to the AIDS epidemic and the increased public discourse on safe sex.

However, the 1990s saw a new rise in cases of syphilis. This clearly could not be blamed on the social hygienists; rather, it was likely due to apathy and a decline in public health spending. We are now in a period of rapid rise in STDs.

We have the benefit of antibiotics. We have the benefit of hindsight. What we need is to heed the call to arms of Dr. Mermin, to be inspired by the wisdom of Dr. Parran, and to act. Identify the case of syphilis, offer treatment, educate the public. Drs. Coleman, Fiahlo, and Brateanu have accomplished all of these in their article in this issue of the Journal.⁴

According to a report from the US Centers for Disease Control and Prevention (CDC) on the incidence of sexually transmitted diseases (STDs), “Total combined cases of chlamydia, gonorrhea, and syphilis reported in 2015 reached the highest number ever”¹ since the CDC was founded in July 1946.

See related article

Nearly 24,000 cases of primary and secondary syphilis were reported in 2015, a 19% increase from the previous year. And Dr. Jonathan Mermin, director of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, reported, “We have reached a decisive moment for the nation. STD rates are rising, and many of the country’s systems for preventing STDs have eroded. We must mobilize, rebuild, and expand services—or the human and economic burden will continue to grow.”¹

Dr. Mermin stressed the need to rebuild services because, “In recent years more than half of state and local STD programs have experienced budget cuts, resulting in more than 20 health department STD clinic closures in one year alone. Fewer clinics mean reduced access to STD testing and treatment for those who need these services.”¹

The CDC also reports that STD treatment costs the US healthcare system nearly $16 billion each year.

The CDC has identified several players whose engagement is necessary to stem the tide of this epidemic:

• Providers must make STD screening a standard part of medical care, especially in pregnant women, and integrate STD prevention and treatment into prenatal care and other routine visits.
• People need to talk openly about STDs, get tested regularly, and reduce risk by using condoms or practicing mutual monogamy if sexually active.
• Parents and providers need to offer young people safe, effective ways to get information and services.
• State and local health departments should continue to direct resources to people hardest hit by the STD epidemic and work with community partners to maximize their impact.¹

STD CAMPAIGNS 100 YEARS AGO

This message sounds familiar. Let’s go back 100 years to World War I. The book No Magic Bullet by Allan M. Brandt² provides fascinating details about this period in America’s battle against venereal diseases. While the book is well worth reading in its entirety, I will attempt here to summarize the pertinent facts.

In the late 1910s, antivenereal campaigns were in full swing, with publicly shown movies such as “Fit to Fight” to train soldiers about STD symptoms and prevention to keep them physically healthy for fighting in the war. Similar information was widely available stateside for both men and women in open, matter-of-fact formats to encourage STD prevention.

After the war ended, the national sentiment became split between sexual revolution and social moralism. “Social hygienists” blamed the widespread increase in promiscuity on the newly introduced sexually explicit philosophy of Sigmund Freud, the widespread availability of automobiles (ie, a mobile, private, backseat location for sex), popular “vulgar” dances, and social feminism, among many others. The sexual revolution clearly led to an increased risk of STDs. But the antivenereal campaigns that had been appropriate in wartime came to be considered amoral and unfit for public consumption, and a period of silence about venereal diseases ensued.

By the 1930s, the situation had worsened:

• Approximately 1 out of every 10 Americans suffered from syphilis.
• Each year, Americans contracted almost half a million new syphilis infections (twice as many cases as tuberculosis, and 100 times as many cases as polio).
• 18% of all deaths from organic heart disease could be attributed to syphilis.
• Up to 20% of all mental institution inmates suffered from tertiary syphilis.
• 60,000 children were born each year with congenital syphilis.²

Although penicillin was still a decade or more away from discovery, syphilis could be treated, though likely not cured, with arsenic compounds. A course of treatment from a private physician, however, could cost from $300 to $1,000. Many patients who could not pay these exorbitant prices turned to public clinics for help. However, funding for the Venereal Disease Division of the Public Health Service, originally $4 million in 1920, was cut to less than $60,000 by 1926.² Some hospitals refused to admit patients with syphilis and other venereal diseases, deeming them “morally tainted and less deserving of care.”²

Things couldn’t get much worse.

Dr. Thomas Parran was the New York State health commissioner in 1930, at the start of the Great Depression. Realizing that arguments for moral responsibility to prevent and treat venereal diseases were not effective, Dr. Parran and other public health officials turned to financial arguments. Among the most persuasive arguments, “More than $15 million was spent annually for the ambulatory care of venereal patients…Experts argued that syphilis costs taxpayers between $40 and $50 million each year for the institutional care of the insane, paralyzed, and blind.”² The American Medical Association calculated that “8 to 10 million workers lost 21 million working days each year at an average of $4 a day as a result of infection with these conditions.”² The cost was estimated at more than $100,000,000 annually.²

But the general public was not a part of the larger conversation regarding treatment and prevention of syphilis, thanks to the social hygienists. In November 1934, Dr. Parran was scheduled to give a radio broadcast on future goals for public health in New York. Notified that he would not be able to mention syphilis or gonorrhea by name, he refused to give the speech. Dr. Parran went on to lead the charge to reduce the moral cloud that blocked the ability to address syphilis openly and scientifically. With his extensive experience in public health, he proposed plans that had been effective in controlling other infectious diseases as measures to control the spread of syphilis. He outlined the following:

• Identify cases of syphilis. Offer free diagnostic centers where individuals could obtain confidential blood tests.
• Offer prompt therapy for identified cases.
• Identify, locate, and test all contacts of infected patients, and treat them if they are infected too.
• Make blood testing mandatory before marriage and early in all pregnancies.
• Educate the public concerning syphilis.²

Do these approaches sound familiar?

Appointed US Surgeon General in 1936 by President Franklin Delano Roosevelt, Dr. Parran published “The next great plague to go,”³ an article focusing on the medical approach to treating syphilis and other venereal diseases, while refusing to address the moral and social issues.³ This was widely acclaimed by the public and the press. Two years after he was blocked from mentioning syphilis and gonorrhea on the radio, he was pictured on the cover of Time magazine for his groundbreaking work.

With the advent of penicillin, syphilis became not only treatable but curable. Over the next decades, the number of patients infected with syphilis and the morbidity it caused continually declined until the 1990s, when there were even whispers of eradication in the United States. This likely came in part due to the AIDS epidemic and the increased public discourse on safe sex.

However, the 1990s saw a new rise in cases of syphilis. This clearly could not be blamed on the social hygienists; rather, it was likely due to apathy and a decline in public health spending. We are now in a period of rapid rise in STDs.

We have the benefit of antibiotics. We have the benefit of hindsight. What we need is to heed the call to arms of Dr. Mermin, to be inspired by the wisdom of Dr. Parran, and to act. Identify the case of syphilis, offer treatment, educate the public. Drs. Coleman, Fiahlo, and Brateanu have accomplished all of these in their article in this issue of the Journal.⁴

According to a report from the US Centers for Disease Control and Prevention (CDC) on the incidence of sexually transmitted diseases (STDs), “Total combined cases of chlamydia, gonorrhea, and syphilis reported in 2015 reached the highest number ever”¹ since the CDC was founded in July 1946.

See related article

Nearly 24,000 cases of primary and secondary syphilis were reported in 2015, a 19% increase from the previous year. And Dr. Jonathan Mermin, director of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, reported, “We have reached a decisive moment for the nation. STD rates are rising, and many of the country’s systems for preventing STDs have eroded. We must mobilize, rebuild, and expand services—or the human and economic burden will continue to grow.”¹

Dr. Mermin stressed the need to rebuild services because, “In recent years more than half of state and local STD programs have experienced budget cuts, resulting in more than 20 health department STD clinic closures in one year alone. Fewer clinics mean reduced access to STD testing and treatment for those who need these services.”¹

The CDC also reports that STD treatment costs the US healthcare system nearly $16 billion each year.

The CDC has identified several players whose engagement is necessary to stem the tide of this epidemic:

• Providers must make STD screening a standard part of medical care, especially in pregnant women, and integrate STD prevention and treatment into prenatal care and other routine visits.
• People need to talk openly about STDs, get tested regularly, and reduce risk by using condoms or practicing mutual monogamy if sexually active.
• Parents and providers need to offer young people safe, effective ways to get information and services.
• State and local health departments should continue to direct resources to people hardest hit by the STD epidemic and work with community partners to maximize their impact.¹

STD CAMPAIGNS 100 YEARS AGO

This message sounds familiar. Let’s go back 100 years to World War I. The book No Magic Bullet by Allan M. Brandt² provides fascinating details about this period in America’s battle against venereal diseases. While the book is well worth reading in its entirety, I will attempt here to summarize the pertinent facts.

In the late 1910s, antivenereal campaigns were in full swing, with publicly shown movies such as “Fit to Fight” to train soldiers about STD symptoms and prevention to keep them physically healthy for fighting in the war. Similar information was widely available stateside for both men and women in open, matter-of-fact formats to encourage STD prevention.

After the war ended, the national sentiment became split between sexual revolution and social moralism. “Social hygienists” blamed the widespread increase in promiscuity on the newly introduced sexually explicit philosophy of Sigmund Freud, the widespread availability of automobiles (ie, a mobile, private, backseat location for sex), popular “vulgar” dances, and social feminism, among many others. The sexual revolution clearly led to an increased risk of STDs. But the antivenereal campaigns that had been appropriate in wartime came to be considered amoral and unfit for public consumption, and a period of silence about venereal diseases ensued.

By the 1930s, the situation had worsened:

• Approximately 1 out of every 10 Americans suffered from syphilis.
• Each year, Americans contracted almost half a million new syphilis infections (twice as many cases as tuberculosis, and 100 times as many cases as polio).
• 18% of all deaths from organic heart disease could be attributed to syphilis.
• Up to 20% of all mental institution inmates suffered from tertiary syphilis.
• 60,000 children were born each year with congenital syphilis.²

Although penicillin was still a decade or more away from discovery, syphilis could be treated, though likely not cured, with arsenic compounds. A course of treatment from a private physician, however, could cost from $300 to $1,000. Many patients who could not pay these exorbitant prices turned to public clinics for help. However, funding for the Venereal Disease Division of the Public Health Service, originally $4 million in 1920, was cut to less than $60,000 by 1926.² Some hospitals refused to admit patients with syphilis and other venereal diseases, deeming them “morally tainted and less deserving of care.”²

Things couldn’t get much worse.

Dr. Thomas Parran was the New York State health commissioner in 1930, at the start of the Great Depression. Realizing that arguments for moral responsibility to prevent and treat venereal diseases were not effective, Dr. Parran and other public health officials turned to financial arguments. Among the most persuasive arguments, “More than $15 million was spent annually for the ambulatory care of venereal patients…Experts argued that syphilis costs taxpayers between $40 and $50 million each year for the institutional care of the insane, paralyzed, and blind.”² The American Medical Association calculated that “8 to 10 million workers lost 21 million working days each year at an average of $4 a day as a result of infection with these conditions.”² The cost was estimated at more than $100,000,000 annually.²

But the general public was not a part of the larger conversation regarding treatment and prevention of syphilis, thanks to the social hygienists. In November 1934, Dr. Parran was scheduled to give a radio broadcast on future goals for public health in New York. Notified that he would not be able to mention syphilis or gonorrhea by name, he refused to give the speech. Dr. Parran went on to lead the charge to reduce the moral cloud that blocked the ability to address syphilis openly and scientifically. With his extensive experience in public health, he proposed plans that had been effective in controlling other infectious diseases as measures to control the spread of syphilis. He outlined the following:

• Identify cases of syphilis. Offer free diagnostic centers where individuals could obtain confidential blood tests.
• Offer prompt therapy for identified cases.
• Identify, locate, and test all contacts of infected patients, and treat them if they are infected too.
• Make blood testing mandatory before marriage and early in all pregnancies.
• Educate the public concerning syphilis.²

Do these approaches sound familiar?

Appointed US Surgeon General in 1936 by President Franklin Delano Roosevelt, Dr. Parran published “The next great plague to go,”³ an article focusing on the medical approach to treating syphilis and other venereal diseases, while refusing to address the moral and social issues.³ This was widely acclaimed by the public and the press. Two years after he was blocked from mentioning syphilis and gonorrhea on the radio, he was pictured on the cover of Time magazine for his groundbreaking work.

With the advent of penicillin, syphilis became not only treatable but curable. Over the next decades, the number of patients infected with syphilis and the morbidity it caused continually declined until the 1990s, when there were even whispers of eradication in the United States. This likely came in part due to the AIDS epidemic and the increased public discourse on safe sex.

However, the 1990s saw a new rise in cases of syphilis. This clearly could not be blamed on the social hygienists; rather, it was likely due to apathy and a decline in public health spending. We are now in a period of rapid rise in STDs.

We have the benefit of antibiotics. We have the benefit of hindsight. What we need is to heed the call to arms of Dr. Mermin, to be inspired by the wisdom of Dr. Parran, and to act. Identify the case of syphilis, offer treatment, educate the public. Drs. Coleman, Fiahlo, and Brateanu have accomplished all of these in their article in this issue of the Journal.⁴

From time to time, all physicians encounter patients whose behavior evokes negative emotions. In 1978, in an article titled “Taking care of the hateful patient,”¹ Groves detailed 4 types of patients—“dependent clingers, entitled demanders, manipulative help-rejecters, and self-destructive deniers”¹—that even the most seasoned physicians dread, and provided suggestions for managing interactions with them. The topic was revisited and updated in 2006 by Strous et al.²

See related editorial

Now, more than 10 years later, the challenge of how to interact with difficult patients is more relevant than ever. A cultural environment in which every patient can become an “expert” via the Internet has added new challenges. Patients who are especially time-consuming and emotionally draining exacerbate the many other pressures physicians face today (eg, increased paperwork, cost-consciousness, shortened appointment times, and the move to electronic medical records), contributing to physician burnout.

This article further updates the topic of managing challenging patients to reflect the current practice climate. We provide a more modern view of challenging patients and provide guidance on handling them. Although it may be tempting to diagnose some of these patients as having a personality disorder, it can often be more helpful to recognize patterns of behavior and have a clear plan for management. We also discuss general coping strategies for avoiding physician burnout.

INTERNET-SEEKING, QUESTIONING

A 45-year-old man carries in an overstuffed briefcase for his first primary care visit. He is a medical editor for a national journal and recently worked on a case study involving a rare cancer. As he edited, he recognized that he had the same symptoms and diagnosed himself with the same disease. He has brought with him a sheaf of articles he found on the Internet detailing clinical trials for experimental treatments. When the doctor begins to ask questions, he says the answers are irrelevant: he explains that he would have gone straight to an oncologist, but his insurance policy requires that he also have a primary care physician. He now expects the doctor to order magnetic resonance imaging, refer him to an oncologist, and support his request for the treatment he has identified as best.

The Internet: A blessing and a curse

Patients now have access to enormous amounts of information of variable accuracy. As in this case, patients may come to an appointment carrying early research studies that the physician has not yet reviewed. Others get their information from patient blogs that frequently offer opinions without evidence. Often, based on an advertisement or Internet reading, a patient requests a particular medication or test that may not be cost-effective or medically justified.

In a survey more than 10 years ago, more than 75% of physicians reported that they had patients who brought in information from online sources.³ Hu et al⁴ reported that 70% of patients who had online information planned to discuss it with their physicians. This practice is only growing, including in older patients.⁵

Physicians may feel confused and frustrated by patients who come armed with information. They may infer that patients do not trust them to diagnose correctly or treat optimally. In addition, discussing such information takes time, causing others on the schedule to wait, adding to the stress of coping with over-booked appointments.

Why so overprepared?

Patients who have or fear that they have cancer may be particularly worried that an important treatment will be overlooked.⁶ Since they feel that their life is hanging in the balance, their search for a definitive cure is understandable.

Internet-seeking, intensely questioning patients clearly want more information about the treatments they are receiving, alternative medical or procedural options, and complementary therapies.⁷ The response to their desire for more information affects their impression of physician empathy.⁸

Adapting to a more informed patient

Approaching these patients as an opportunity to educate may result in a more trusting patient and one more likely to be open to physician guidance and more likely to adhere to an advised treatment plan. Triangulation of the 3 actors—the physician, the patient, and the Web—can help patients to make more-informed choices and foster an attitude of partnership with the physician to lead them to optimal healthcare.

In a review of the impact of Internet use on healthcare and the physician-patient relationship, Wald et al⁹ urged physicians to:

• Adopt a positive attitude toward discussing Internet contributions
• Encourage patients to take an active role in maintaining health
• Acknowledge patient concerns and fears
• Avoid becoming defensive
• Recommend credible Internet sources.

Laing et al¹⁰ urged physicians to recognize rather than deny the effects of patients’ online searching for information and support, and not to ignore the potential impact on treatment. Consumers are gaining autonomy and self-efficacy, and Laing et al encouraged healthcare providers to develop ways to incorporate this new reality into the services they provide.¹⁰

How Web-based interaction can assist in patient decision-making for colorectal cancer screening is being explored.¹¹ Patients at home can use an online tool to learn about screening choices and would be more knowledgable and comfortable discussing the options with their care provider. The hope is to build in an automatic reminder for the clinician, who would better understand the patient’s preference before the office visit.

One approach to our patient is to say, “I can see how worried you are about having the same type of cancer you read about, and I want to help you. It is clear to me that you know a lot about healthcare, and I appreciate your engagement in your health. How about starting over? Let me ask a few questions so I can get a better perspective on your symptoms?” Many times, this strategy can help patients reframe their view and accept help.

A 60-year-old lawyer is admitted to the hospital for evaluation of abdominal pain. His physician recommends placing a nasogastric tube to provide nutrition while the evaluation is completed. His wife, a former nurse practitioner, insists that a nasogastric tube would be too dangerous and demands that he be allowed to eat instead. The couple declares the primary internal medicine physician incompetent, does not want any residents to be involved in his care, and antagonizes the nurses with constant demands. Soon, the entire team avoids the patient’s room.

Why so hostile?

People with demanding behavior often have a hostile and confrontational manner. They may use medical jargon and appear to believe that they know more than their healthcare team. Many demand to know why they have not been offered a particular test, diagnosis, or treatment, especially if they or a family member has a healthcare background. Such patients appear to feel that they are being treated incorrectly and leave us feeling vulnerable, wondering whether the patient might one day come back to haunt us with a lawsuit, especially if the medical outcome is unfavorable.

Understanding the motivation for the behavior can help a physician to empathize with the demanding patient.¹² Although it may seem that the demanding patient is trying to intimidate the physician, the goal is usually the same: to find the best possible treatment. Anger and hostility are often motivated by fear and a sense of losing control.

Ironically, this maladaptive coping style may alienate the very people who can help the patient. Hostile behavior evokes defensiveness and resentment in others. A power struggle may ensue: as the patient makes more unreasonable demands and threats, the physician reacts by asserting his or her views in an attempt to maintain control. Or the physician and the rest of the healthcare team may simply avoid the patient as much as possible.

Collaboration can defuse anger

The best strategy is often to steer the encounter away from a power struggle by legitimizing the patient’s feeling of entitlement to the best possible treatment.¹³ Take a collaborative stance with the patient, with the common goal of finding and implementing the most effective and lowest-risk diagnostic and treatment plan. Empathy and exploration of the patient’s concerns are always in order.

Physicians can try several strategies to improve interactions with demanding patients and caregivers:

Be consistent. All members of the healthcare team, including nurses and specialists, should convey consistent messages regarding diagnostic testing and treatment plans.

Don’t play the game. Demanding patients often complain about being mistreated by other healthcare providers. When confronted with such complaints, acknowledge the patient’s feelings while refraining from blaming or criticizing other members of the healthcare team.

Clarify expectations. Clarifying expectations from the initial patient encounter can prevent conflicts later. Support a patient who must accept a diagnosis of a terminal illness, and then when appropriate, discuss goals moving forward. Collaboration within the framework of reasonable expectations is key.

For our case, the physician could say, “We want to work with you together as a team. We will work hard to address your concerns, but our nurses must have a safe environment in which to help you.” Such a statement highlights shared goals and expression of concern without judgment. The next step is to clarify expectations by describing the hospital routine and how decisions are made.

Offer choices. Offering choices whenever possible can help a demanding patient feel more in control. Rather than dismiss a patient’s ideas, explore the alternatives. While effective patient communication is preferable to repeated referrals to specialists,¹⁴ judicious referral can engender trust in the physician’s competence if a diagnosis is not forthcoming.¹⁵

A unique challenge in teaching hospitals is the patient who refuses to interact with residents and students. It is best to acknowledge the patient’s concerns and offer alternative options:

• If the patient is worried about lack of completed training, then clarify the residents’ roles and reassure the patient that you communicate with residents and supervisors regarding any clinical decisions
• If possible, offer to see the patient alone or have the resident interact only on an as-needed basis
• Consider transferring the patient to a nonteaching service or to another hospital.

Admit failings. Although not easy, admitting to and apologizing for things that have gone wrong can help to calm a demanding patient and even reduce the likelihood of a lawsuit.¹⁶ The physician should not convey defensiveness and instead should acknowledge the limitations of the healthcare system.

Legitimize concerns—to an extent. Legitimizing a demanding patient’s concerns is important, but never be bullied into taking actions that create unnecessary risk. Upsetting a demanding patient is better than ordering tests or providing treatments that are potentially harmful. Good physician-patient communication can go a long way toward preventing adverse outcomes.

A 25-year-old professional presents to a new primary care provider concerned about a mole on her back. She discusses her sun exposure and family history of skin cancer and produces photographs documenting changes in the mole over time. Impressed with this level of detail, the physician takes time to explain his concerns before referring her to a dermatologist. Later that day, she calls to let the doctor know that her procedure has been scheduled and to thank him for his care. A few weeks after the mole is removed, she returns to discuss treatment options for the small remaining scar.

After this appointment, she calls the office repeatedly with a wide array of concerns, including an isolated symptom of fatigue that could indicate cancer and the relative merits of different sunscreens. She also sends the physician frequent e-mail messages through the personal health record system with pictures of inconsequential marks on her skin.

Needing reassurance is normal—to a point

Many patients seek reassurance from their physicians, and this can be done in a healthy and respectful manner. But requests for reassurance may escalate to becoming repeated, insistent, and even aggressive.¹ This can elicit reactions from physicians ranging from feeling annoyed and burdened to feeling angry and overwhelmed.¹⁷ This can lead to significant stress, which, if not managed well, can lead to excessively control of physician behavior and substandard care.¹⁸

Reassurance-seeking behavior can manifest anywhere along the spectrum of health and disease.¹⁹ It may be a symptom of health anxiety (ie, an exaggerated fear of illness) or hypochondria (ie, the persistent conviction that one is currently or likely to become ill).^20,21

Why so needy?

Attachment theory may help explain neediness. Parental bonding during childhood is associated with mental and physical health and health-related behaviors in adults.^22,23 People with insecure-preoccupied attachment styles tend to be overly emotionally dependent on the acceptance of others and may exhibit dependent and care-seeking behaviors with a physician.²⁴

Needy patients are often genuinely grateful for the care and attention from a physician.¹ In the beginning, the doctor may appreciate the patient’s validation of care provided, but this positive feeling wanes as calls and requests become incessant. As the physician’s exhaustion increases with each request, the care and well-being of the patient may no longer be the primary focus.¹

Set boundaries

Be alert to signs that a patient is crossing the line to an unhealthy need for reassurance. Address medical concerns appropriately, then institute clear guidelines for follow-up, which should be reinforced by the entire care team if necessary.²²

                The following strategies can be useful for defining boundaries:

• Instruct the patient to come to the office only for scheduled follow-up visits and to call only during office hours or in an emergency
• Be up-front about the time allowed for each appointment and ask the patient to help focus the discussion according to his or her main concerns²⁵
• Consider telling the patient, “You seem really worried about a lot of physical symptoms. I want to reassure you that I find no evidence of a medical illness that would require intervention. I am concerned about your phone calls and e-mails, and I wonder what would be helpful at this point to address your concerns?”
• Consider treating the patient for anxiety.

It is important to remain responsive to all types of patient concerns. Setting boundaries will guide patients to express health concerns in an appropriate manner so that they can be heard and managed.^18,19               

SELF-INJURY

A 22-year-old woman presents to the emergency department complaining of abdominal pain. After a full workup, the physician clears her medically and orders a few laboratory tests. As the nurse draws blood samples, she notices multiple fresh cuts on the patient’s arm and informs the physician. The patient is questioned and examined again and acknowledges occasional thoughts of self-harm. 

Her parents arrive and appear appropriately concerned. They report that she has been “cutting” for 4 years and is regularly seeing a therapist. However, they say that they are not worried for her safety and that she has an appointment with her therapist this week. Based on this, the emergency department physician discharges her.

Two weeks later, the patient returns to the emergency department with continued cutting and apparent cellulitis, prompting medical admission.

Self-injury presents in many ways

Self-injurious behaviors come in many forms other than the easily recognized one presented in this case: eg, a patient with cirrhosis who continues to drink, a patient with severe epilepsy who forgets to take medications and lands in the emergency department every week for status epilepticus, a patient with diabetes who eats a high-sugar diet, a patient with renal insufficiency who ignores water restrictions, or a patient with an organ transplant who misses medications and relapses.

There is an important psychological difference between patients who knowingly continue to challenge their luck and those who do not fully understand the severity of their condition and the consequences of their actions. The patient who simply does not “get it” can sometimes be managed effectively with education and by working with family members to create an environment to facilitate critical healthy behaviors.

Patients who willfully self-inflict injury are asking for help while doing everything to avoid being helped. They typically come to the office or the emergency department with assorted complaints, not divulging the real reason for their visit until the last minute as they are leaving. Then they drop a clue to the real concern, leaving the physician confused and frustrated.

Why deny an obvious problem?

Fear of the stigma of mental illness can be a major barrier to full disclosure of symptoms of psychological distress, and this especially tends to be the case for patients from some ethnic minorities.²⁶ 

On the other hand, patients with borderline or antisocial personality disorder (and less often, schizotypal or narcissistic personality disorder) frequently use denial as their primary psychological defense. Self-destructive denial is sometimes associated with traumatic memories, feelings of worthlessness, or a desire to reduce self-awareness and rationalize harmful behaviors. Such patients usually need lengthy treatment, and although the likelihood of cure is low, therapy can be helpful.^27–29  

Lessons from psychiatry              

It can be difficult to maintain empathy for patients who intentionally harm themselves. It is helpful to think of these patients as having a terminal illness and to recognize that they are suffering.

Different interventions have been studied for such patients. Dialectical behavior therapy, an approach that teaches patients better coping skills for regulating emotions, can help reduce maladaptive emotional distress and self-destructive behaviors.^30–32 Lessons from this approach can be applied by general practitioners:

• Engage the patient and together establish an effective crisis management plan
• With patient permission, involve the family in the treatment plan
• Set clear limits about self-harm: once the patient values interaction with the doctor, he or she will be less likely to break the agreement.

Patients with severe or continuing issues can be referred to appropriate services that offer dialectical behavior therapy or other intensive outpatient programs.

To handle our patient, one might start by saying, “I am sorry to see you back in the ER. We need to treat the cellulitis and get your outpatient behavioral team on board, so we know the plan.” Then, it is critical that the entire team keep to that plan.

Patients with challenging behaviors will always be part of medical practice. Physicians should be aware of their reactions and feelings towards a patient (known in psychiatry as countertransference), as they can increase physician stress and interfere with providing optimal care. Finding effective ways to work with difficult patients will avoid these outcomes.

Physicians also feel loss of control

Most physicians are resilient, but they can feel overwhelmed under certain circumstances. According to Scudder and Shanafelt,³³ a physician’s sense of well-being is influenced by several factors, including feelings of control in the workplace. It is easy to imagine how one or more difficult patients can create a sense of overwhelming demand and loss of control.

These tips can help maintain a sense of control and improve interactions with patients:

Have a plan for effective communication. Not having a plan for communicating in a difficult situation can contribute to loss of control in a hectic schedule that is already stretched to its limits. Practicing responses with a colleague for especially difficult patients or using a team approach can be helpful. Remaining compassionate while setting boundaries will result in the best outcome for the patient and physician.

Stop to analyze the situation. One of the tenets of cognitive-behavioral therapy is recognizing that negative thoughts can quickly take us down a dangerous path. Feeling angry and resentful without stopping to think and reflect on the causes can lead to the physician feeling victimized (just like many difficult patients feel).

It is important to step back and think, not just feel. While difficult patients present in different ways, all are reacting to losing control of their situation and want support. During a difficult interaction with a patient, pause to consider, “Why is he behaving this way? Is he afraid? Does he feel that no one cares?”

When a patient verbally attacks beyond what is appropriate, recognize that this is probably due less to anything the physician did than to the patient’s internal issues. Identifying the driver of a patient’s behavior makes it easier to control our own emotions.

Practice empathy. Difficult patients usually have something in their background that can help explain their inappropriate behavior, such as a lack of parental support or abuse. Being open to hearing their story facilitates an empathetic connection.

AVOIDING BURNOUT

Discuss problems

Sadly, physicians often neglect to talk with each other and with trainees about issues leading to burnout, thereby missing important opportunities for empathy, objectivity, reflection, and teaching moments.

Lessons can be gleaned from training in psychiatry, a field in which one must learn methods for working effectively in challenging situations. Dozens of scenarios are practiced using videotapes or observation through one-way mirrors. While not everyone has such opportunities, everyone can discuss issues with one another. Regularly scheduled facilitated groups devoted to discussing problems with colleagues can be enormously helpful.

Schedule quiet times

Mindfulness is an excellent way to spend a few minutes out of every 3- to 4-hour block. There are many ways to help facilitate such moments. Residents and students can be provided with a small book, Mindfulness on the Go,³⁷ aimed for the busy person.

Deep, slow breathing can bring rapid relief to intense negative feelings. Not only does it reduce anxiety faster than medication, but it is also free, is easily taught to others, and can be done unobtrusively. A short description of the role of the blood pH in managing the locus ceruleus and vagus nerve’s balance of sympathetic and parasympathetic activity may capture the curiosity of someone who may otherwise be resistant to the exercise.

Increasingly, hospitals are developing mindfulness sessions and offering a variety of skills physicians can put into their toolbox. Lessons from cognitive-behavioral therapy, dialectical behavior therapy, imagery, and muscle relaxation can help physicians in responding to patients. Investing in communication skills training specific to challenging behaviors seen in different specialties better equips physicians with more effective strategies.

From time to time, all physicians encounter patients whose behavior evokes negative emotions. In 1978, in an article titled “Taking care of the hateful patient,”¹ Groves detailed 4 types of patients—“dependent clingers, entitled demanders, manipulative help-rejecters, and self-destructive deniers”¹—that even the most seasoned physicians dread, and provided suggestions for managing interactions with them. The topic was revisited and updated in 2006 by Strous et al.²

See related editorial

Now, more than 10 years later, the challenge of how to interact with difficult patients is more relevant than ever. A cultural environment in which every patient can become an “expert” via the Internet has added new challenges. Patients who are especially time-consuming and emotionally draining exacerbate the many other pressures physicians face today (eg, increased paperwork, cost-consciousness, shortened appointment times, and the move to electronic medical records), contributing to physician burnout.

This article further updates the topic of managing challenging patients to reflect the current practice climate. We provide a more modern view of challenging patients and provide guidance on handling them. Although it may be tempting to diagnose some of these patients as having a personality disorder, it can often be more helpful to recognize patterns of behavior and have a clear plan for management. We also discuss general coping strategies for avoiding physician burnout.

INTERNET-SEEKING, QUESTIONING

A 45-year-old man carries in an overstuffed briefcase for his first primary care visit. He is a medical editor for a national journal and recently worked on a case study involving a rare cancer. As he edited, he recognized that he had the same symptoms and diagnosed himself with the same disease. He has brought with him a sheaf of articles he found on the Internet detailing clinical trials for experimental treatments. When the doctor begins to ask questions, he says the answers are irrelevant: he explains that he would have gone straight to an oncologist, but his insurance policy requires that he also have a primary care physician. He now expects the doctor to order magnetic resonance imaging, refer him to an oncologist, and support his request for the treatment he has identified as best.

The Internet: A blessing and a curse

Patients now have access to enormous amounts of information of variable accuracy. As in this case, patients may come to an appointment carrying early research studies that the physician has not yet reviewed. Others get their information from patient blogs that frequently offer opinions without evidence. Often, based on an advertisement or Internet reading, a patient requests a particular medication or test that may not be cost-effective or medically justified.

In a survey more than 10 years ago, more than 75% of physicians reported that they had patients who brought in information from online sources.³ Hu et al⁴ reported that 70% of patients who had online information planned to discuss it with their physicians. This practice is only growing, including in older patients.⁵

Physicians may feel confused and frustrated by patients who come armed with information. They may infer that patients do not trust them to diagnose correctly or treat optimally. In addition, discussing such information takes time, causing others on the schedule to wait, adding to the stress of coping with over-booked appointments.

Why so overprepared?

Patients who have or fear that they have cancer may be particularly worried that an important treatment will be overlooked.⁶ Since they feel that their life is hanging in the balance, their search for a definitive cure is understandable.

Internet-seeking, intensely questioning patients clearly want more information about the treatments they are receiving, alternative medical or procedural options, and complementary therapies.⁷ The response to their desire for more information affects their impression of physician empathy.⁸

Adapting to a more informed patient

Approaching these patients as an opportunity to educate may result in a more trusting patient and one more likely to be open to physician guidance and more likely to adhere to an advised treatment plan. Triangulation of the 3 actors—the physician, the patient, and the Web—can help patients to make more-informed choices and foster an attitude of partnership with the physician to lead them to optimal healthcare.

In a review of the impact of Internet use on healthcare and the physician-patient relationship, Wald et al⁹ urged physicians to:

• Adopt a positive attitude toward discussing Internet contributions
• Encourage patients to take an active role in maintaining health
• Acknowledge patient concerns and fears
• Avoid becoming defensive
• Recommend credible Internet sources.

Laing et al¹⁰ urged physicians to recognize rather than deny the effects of patients’ online searching for information and support, and not to ignore the potential impact on treatment. Consumers are gaining autonomy and self-efficacy, and Laing et al encouraged healthcare providers to develop ways to incorporate this new reality into the services they provide.¹⁰

How Web-based interaction can assist in patient decision-making for colorectal cancer screening is being explored.¹¹ Patients at home can use an online tool to learn about screening choices and would be more knowledgable and comfortable discussing the options with their care provider. The hope is to build in an automatic reminder for the clinician, who would better understand the patient’s preference before the office visit.

One approach to our patient is to say, “I can see how worried you are about having the same type of cancer you read about, and I want to help you. It is clear to me that you know a lot about healthcare, and I appreciate your engagement in your health. How about starting over? Let me ask a few questions so I can get a better perspective on your symptoms?” Many times, this strategy can help patients reframe their view and accept help.

A 60-year-old lawyer is admitted to the hospital for evaluation of abdominal pain. His physician recommends placing a nasogastric tube to provide nutrition while the evaluation is completed. His wife, a former nurse practitioner, insists that a nasogastric tube would be too dangerous and demands that he be allowed to eat instead. The couple declares the primary internal medicine physician incompetent, does not want any residents to be involved in his care, and antagonizes the nurses with constant demands. Soon, the entire team avoids the patient’s room.

Why so hostile?

People with demanding behavior often have a hostile and confrontational manner. They may use medical jargon and appear to believe that they know more than their healthcare team. Many demand to know why they have not been offered a particular test, diagnosis, or treatment, especially if they or a family member has a healthcare background. Such patients appear to feel that they are being treated incorrectly and leave us feeling vulnerable, wondering whether the patient might one day come back to haunt us with a lawsuit, especially if the medical outcome is unfavorable.

Understanding the motivation for the behavior can help a physician to empathize with the demanding patient.¹² Although it may seem that the demanding patient is trying to intimidate the physician, the goal is usually the same: to find the best possible treatment. Anger and hostility are often motivated by fear and a sense of losing control.

Ironically, this maladaptive coping style may alienate the very people who can help the patient. Hostile behavior evokes defensiveness and resentment in others. A power struggle may ensue: as the patient makes more unreasonable demands and threats, the physician reacts by asserting his or her views in an attempt to maintain control. Or the physician and the rest of the healthcare team may simply avoid the patient as much as possible.

Collaboration can defuse anger

The best strategy is often to steer the encounter away from a power struggle by legitimizing the patient’s feeling of entitlement to the best possible treatment.¹³ Take a collaborative stance with the patient, with the common goal of finding and implementing the most effective and lowest-risk diagnostic and treatment plan. Empathy and exploration of the patient’s concerns are always in order.

Physicians can try several strategies to improve interactions with demanding patients and caregivers:

Be consistent. All members of the healthcare team, including nurses and specialists, should convey consistent messages regarding diagnostic testing and treatment plans.

Don’t play the game. Demanding patients often complain about being mistreated by other healthcare providers. When confronted with such complaints, acknowledge the patient’s feelings while refraining from blaming or criticizing other members of the healthcare team.

Clarify expectations. Clarifying expectations from the initial patient encounter can prevent conflicts later. Support a patient who must accept a diagnosis of a terminal illness, and then when appropriate, discuss goals moving forward. Collaboration within the framework of reasonable expectations is key.

For our case, the physician could say, “We want to work with you together as a team. We will work hard to address your concerns, but our nurses must have a safe environment in which to help you.” Such a statement highlights shared goals and expression of concern without judgment. The next step is to clarify expectations by describing the hospital routine and how decisions are made.

Offer choices. Offering choices whenever possible can help a demanding patient feel more in control. Rather than dismiss a patient’s ideas, explore the alternatives. While effective patient communication is preferable to repeated referrals to specialists,¹⁴ judicious referral can engender trust in the physician’s competence if a diagnosis is not forthcoming.¹⁵

A unique challenge in teaching hospitals is the patient who refuses to interact with residents and students. It is best to acknowledge the patient’s concerns and offer alternative options:

• If the patient is worried about lack of completed training, then clarify the residents’ roles and reassure the patient that you communicate with residents and supervisors regarding any clinical decisions
• If possible, offer to see the patient alone or have the resident interact only on an as-needed basis
• Consider transferring the patient to a nonteaching service or to another hospital.

Admit failings. Although not easy, admitting to and apologizing for things that have gone wrong can help to calm a demanding patient and even reduce the likelihood of a lawsuit.¹⁶ The physician should not convey defensiveness and instead should acknowledge the limitations of the healthcare system.

Legitimize concerns—to an extent. Legitimizing a demanding patient’s concerns is important, but never be bullied into taking actions that create unnecessary risk. Upsetting a demanding patient is better than ordering tests or providing treatments that are potentially harmful. Good physician-patient communication can go a long way toward preventing adverse outcomes.

A 25-year-old professional presents to a new primary care provider concerned about a mole on her back. She discusses her sun exposure and family history of skin cancer and produces photographs documenting changes in the mole over time. Impressed with this level of detail, the physician takes time to explain his concerns before referring her to a dermatologist. Later that day, she calls to let the doctor know that her procedure has been scheduled and to thank him for his care. A few weeks after the mole is removed, she returns to discuss treatment options for the small remaining scar.

After this appointment, she calls the office repeatedly with a wide array of concerns, including an isolated symptom of fatigue that could indicate cancer and the relative merits of different sunscreens. She also sends the physician frequent e-mail messages through the personal health record system with pictures of inconsequential marks on her skin.

Needing reassurance is normal—to a point

Many patients seek reassurance from their physicians, and this can be done in a healthy and respectful manner. But requests for reassurance may escalate to becoming repeated, insistent, and even aggressive.¹ This can elicit reactions from physicians ranging from feeling annoyed and burdened to feeling angry and overwhelmed.¹⁷ This can lead to significant stress, which, if not managed well, can lead to excessively control of physician behavior and substandard care.¹⁸

Reassurance-seeking behavior can manifest anywhere along the spectrum of health and disease.¹⁹ It may be a symptom of health anxiety (ie, an exaggerated fear of illness) or hypochondria (ie, the persistent conviction that one is currently or likely to become ill).^20,21

Why so needy?

Attachment theory may help explain neediness. Parental bonding during childhood is associated with mental and physical health and health-related behaviors in adults.^22,23 People with insecure-preoccupied attachment styles tend to be overly emotionally dependent on the acceptance of others and may exhibit dependent and care-seeking behaviors with a physician.²⁴

Needy patients are often genuinely grateful for the care and attention from a physician.¹ In the beginning, the doctor may appreciate the patient’s validation of care provided, but this positive feeling wanes as calls and requests become incessant. As the physician’s exhaustion increases with each request, the care and well-being of the patient may no longer be the primary focus.¹

Set boundaries

Be alert to signs that a patient is crossing the line to an unhealthy need for reassurance. Address medical concerns appropriately, then institute clear guidelines for follow-up, which should be reinforced by the entire care team if necessary.²²

                The following strategies can be useful for defining boundaries:

• Instruct the patient to come to the office only for scheduled follow-up visits and to call only during office hours or in an emergency
• Be up-front about the time allowed for each appointment and ask the patient to help focus the discussion according to his or her main concerns²⁵
• Consider telling the patient, “You seem really worried about a lot of physical symptoms. I want to reassure you that I find no evidence of a medical illness that would require intervention. I am concerned about your phone calls and e-mails, and I wonder what would be helpful at this point to address your concerns?”
• Consider treating the patient for anxiety.

It is important to remain responsive to all types of patient concerns. Setting boundaries will guide patients to express health concerns in an appropriate manner so that they can be heard and managed.^18,19               

SELF-INJURY

A 22-year-old woman presents to the emergency department complaining of abdominal pain. After a full workup, the physician clears her medically and orders a few laboratory tests. As the nurse draws blood samples, she notices multiple fresh cuts on the patient’s arm and informs the physician. The patient is questioned and examined again and acknowledges occasional thoughts of self-harm. 

Her parents arrive and appear appropriately concerned. They report that she has been “cutting” for 4 years and is regularly seeing a therapist. However, they say that they are not worried for her safety and that she has an appointment with her therapist this week. Based on this, the emergency department physician discharges her.

Two weeks later, the patient returns to the emergency department with continued cutting and apparent cellulitis, prompting medical admission.

Self-injury presents in many ways

Self-injurious behaviors come in many forms other than the easily recognized one presented in this case: eg, a patient with cirrhosis who continues to drink, a patient with severe epilepsy who forgets to take medications and lands in the emergency department every week for status epilepticus, a patient with diabetes who eats a high-sugar diet, a patient with renal insufficiency who ignores water restrictions, or a patient with an organ transplant who misses medications and relapses.

There is an important psychological difference between patients who knowingly continue to challenge their luck and those who do not fully understand the severity of their condition and the consequences of their actions. The patient who simply does not “get it” can sometimes be managed effectively with education and by working with family members to create an environment to facilitate critical healthy behaviors.

Patients who willfully self-inflict injury are asking for help while doing everything to avoid being helped. They typically come to the office or the emergency department with assorted complaints, not divulging the real reason for their visit until the last minute as they are leaving. Then they drop a clue to the real concern, leaving the physician confused and frustrated.

Why deny an obvious problem?

Fear of the stigma of mental illness can be a major barrier to full disclosure of symptoms of psychological distress, and this especially tends to be the case for patients from some ethnic minorities.²⁶ 

On the other hand, patients with borderline or antisocial personality disorder (and less often, schizotypal or narcissistic personality disorder) frequently use denial as their primary psychological defense. Self-destructive denial is sometimes associated with traumatic memories, feelings of worthlessness, or a desire to reduce self-awareness and rationalize harmful behaviors. Such patients usually need lengthy treatment, and although the likelihood of cure is low, therapy can be helpful.^27–29  

Lessons from psychiatry              

It can be difficult to maintain empathy for patients who intentionally harm themselves. It is helpful to think of these patients as having a terminal illness and to recognize that they are suffering.

Different interventions have been studied for such patients. Dialectical behavior therapy, an approach that teaches patients better coping skills for regulating emotions, can help reduce maladaptive emotional distress and self-destructive behaviors.^30–32 Lessons from this approach can be applied by general practitioners:

• Engage the patient and together establish an effective crisis management plan
• With patient permission, involve the family in the treatment plan
• Set clear limits about self-harm: once the patient values interaction with the doctor, he or she will be less likely to break the agreement.

Patients with severe or continuing issues can be referred to appropriate services that offer dialectical behavior therapy or other intensive outpatient programs.

To handle our patient, one might start by saying, “I am sorry to see you back in the ER. We need to treat the cellulitis and get your outpatient behavioral team on board, so we know the plan.” Then, it is critical that the entire team keep to that plan.

Patients with challenging behaviors will always be part of medical practice. Physicians should be aware of their reactions and feelings towards a patient (known in psychiatry as countertransference), as they can increase physician stress and interfere with providing optimal care. Finding effective ways to work with difficult patients will avoid these outcomes.

Physicians also feel loss of control

Most physicians are resilient, but they can feel overwhelmed under certain circumstances. According to Scudder and Shanafelt,³³ a physician’s sense of well-being is influenced by several factors, including feelings of control in the workplace. It is easy to imagine how one or more difficult patients can create a sense of overwhelming demand and loss of control.

These tips can help maintain a sense of control and improve interactions with patients:

Have a plan for effective communication. Not having a plan for communicating in a difficult situation can contribute to loss of control in a hectic schedule that is already stretched to its limits. Practicing responses with a colleague for especially difficult patients or using a team approach can be helpful. Remaining compassionate while setting boundaries will result in the best outcome for the patient and physician.

Stop to analyze the situation. One of the tenets of cognitive-behavioral therapy is recognizing that negative thoughts can quickly take us down a dangerous path. Feeling angry and resentful without stopping to think and reflect on the causes can lead to the physician feeling victimized (just like many difficult patients feel).

It is important to step back and think, not just feel. While difficult patients present in different ways, all are reacting to losing control of their situation and want support. During a difficult interaction with a patient, pause to consider, “Why is he behaving this way? Is he afraid? Does he feel that no one cares?”

When a patient verbally attacks beyond what is appropriate, recognize that this is probably due less to anything the physician did than to the patient’s internal issues. Identifying the driver of a patient’s behavior makes it easier to control our own emotions.

Practice empathy. Difficult patients usually have something in their background that can help explain their inappropriate behavior, such as a lack of parental support or abuse. Being open to hearing their story facilitates an empathetic connection.

AVOIDING BURNOUT

Discuss problems

Sadly, physicians often neglect to talk with each other and with trainees about issues leading to burnout, thereby missing important opportunities for empathy, objectivity, reflection, and teaching moments.

Lessons can be gleaned from training in psychiatry, a field in which one must learn methods for working effectively in challenging situations. Dozens of scenarios are practiced using videotapes or observation through one-way mirrors. While not everyone has such opportunities, everyone can discuss issues with one another. Regularly scheduled facilitated groups devoted to discussing problems with colleagues can be enormously helpful.

Schedule quiet times

Mindfulness is an excellent way to spend a few minutes out of every 3- to 4-hour block. There are many ways to help facilitate such moments. Residents and students can be provided with a small book, Mindfulness on the Go,³⁷ aimed for the busy person.

Deep, slow breathing can bring rapid relief to intense negative feelings. Not only does it reduce anxiety faster than medication, but it is also free, is easily taught to others, and can be done unobtrusively. A short description of the role of the blood pH in managing the locus ceruleus and vagus nerve’s balance of sympathetic and parasympathetic activity may capture the curiosity of someone who may otherwise be resistant to the exercise.

Increasingly, hospitals are developing mindfulness sessions and offering a variety of skills physicians can put into their toolbox. Lessons from cognitive-behavioral therapy, dialectical behavior therapy, imagery, and muscle relaxation can help physicians in responding to patients. Investing in communication skills training specific to challenging behaviors seen in different specialties better equips physicians with more effective strategies.

From time to time, all physicians encounter patients whose behavior evokes negative emotions. In 1978, in an article titled “Taking care of the hateful patient,”¹ Groves detailed 4 types of patients—“dependent clingers, entitled demanders, manipulative help-rejecters, and self-destructive deniers”¹—that even the most seasoned physicians dread, and provided suggestions for managing interactions with them. The topic was revisited and updated in 2006 by Strous et al.²

See related editorial

Now, more than 10 years later, the challenge of how to interact with difficult patients is more relevant than ever. A cultural environment in which every patient can become an “expert” via the Internet has added new challenges. Patients who are especially time-consuming and emotionally draining exacerbate the many other pressures physicians face today (eg, increased paperwork, cost-consciousness, shortened appointment times, and the move to electronic medical records), contributing to physician burnout.

This article further updates the topic of managing challenging patients to reflect the current practice climate. We provide a more modern view of challenging patients and provide guidance on handling them. Although it may be tempting to diagnose some of these patients as having a personality disorder, it can often be more helpful to recognize patterns of behavior and have a clear plan for management. We also discuss general coping strategies for avoiding physician burnout.

INTERNET-SEEKING, QUESTIONING

A 45-year-old man carries in an overstuffed briefcase for his first primary care visit. He is a medical editor for a national journal and recently worked on a case study involving a rare cancer. As he edited, he recognized that he had the same symptoms and diagnosed himself with the same disease. He has brought with him a sheaf of articles he found on the Internet detailing clinical trials for experimental treatments. When the doctor begins to ask questions, he says the answers are irrelevant: he explains that he would have gone straight to an oncologist, but his insurance policy requires that he also have a primary care physician. He now expects the doctor to order magnetic resonance imaging, refer him to an oncologist, and support his request for the treatment he has identified as best.

The Internet: A blessing and a curse

Patients now have access to enormous amounts of information of variable accuracy. As in this case, patients may come to an appointment carrying early research studies that the physician has not yet reviewed. Others get their information from patient blogs that frequently offer opinions without evidence. Often, based on an advertisement or Internet reading, a patient requests a particular medication or test that may not be cost-effective or medically justified.

In a survey more than 10 years ago, more than 75% of physicians reported that they had patients who brought in information from online sources.³ Hu et al⁴ reported that 70% of patients who had online information planned to discuss it with their physicians. This practice is only growing, including in older patients.⁵

Physicians may feel confused and frustrated by patients who come armed with information. They may infer that patients do not trust them to diagnose correctly or treat optimally. In addition, discussing such information takes time, causing others on the schedule to wait, adding to the stress of coping with over-booked appointments.

Why so overprepared?

Patients who have or fear that they have cancer may be particularly worried that an important treatment will be overlooked.⁶ Since they feel that their life is hanging in the balance, their search for a definitive cure is understandable.

Internet-seeking, intensely questioning patients clearly want more information about the treatments they are receiving, alternative medical or procedural options, and complementary therapies.⁷ The response to their desire for more information affects their impression of physician empathy.⁸

Adapting to a more informed patient

Approaching these patients as an opportunity to educate may result in a more trusting patient and one more likely to be open to physician guidance and more likely to adhere to an advised treatment plan. Triangulation of the 3 actors—the physician, the patient, and the Web—can help patients to make more-informed choices and foster an attitude of partnership with the physician to lead them to optimal healthcare.

In a review of the impact of Internet use on healthcare and the physician-patient relationship, Wald et al⁹ urged physicians to:

• Adopt a positive attitude toward discussing Internet contributions
• Encourage patients to take an active role in maintaining health
• Acknowledge patient concerns and fears
• Avoid becoming defensive
• Recommend credible Internet sources.

Laing et al¹⁰ urged physicians to recognize rather than deny the effects of patients’ online searching for information and support, and not to ignore the potential impact on treatment. Consumers are gaining autonomy and self-efficacy, and Laing et al encouraged healthcare providers to develop ways to incorporate this new reality into the services they provide.¹⁰

How Web-based interaction can assist in patient decision-making for colorectal cancer screening is being explored.¹¹ Patients at home can use an online tool to learn about screening choices and would be more knowledgable and comfortable discussing the options with their care provider. The hope is to build in an automatic reminder for the clinician, who would better understand the patient’s preference before the office visit.

One approach to our patient is to say, “I can see how worried you are about having the same type of cancer you read about, and I want to help you. It is clear to me that you know a lot about healthcare, and I appreciate your engagement in your health. How about starting over? Let me ask a few questions so I can get a better perspective on your symptoms?” Many times, this strategy can help patients reframe their view and accept help.

A 60-year-old lawyer is admitted to the hospital for evaluation of abdominal pain. His physician recommends placing a nasogastric tube to provide nutrition while the evaluation is completed. His wife, a former nurse practitioner, insists that a nasogastric tube would be too dangerous and demands that he be allowed to eat instead. The couple declares the primary internal medicine physician incompetent, does not want any residents to be involved in his care, and antagonizes the nurses with constant demands. Soon, the entire team avoids the patient’s room.

Why so hostile?

People with demanding behavior often have a hostile and confrontational manner. They may use medical jargon and appear to believe that they know more than their healthcare team. Many demand to know why they have not been offered a particular test, diagnosis, or treatment, especially if they or a family member has a healthcare background. Such patients appear to feel that they are being treated incorrectly and leave us feeling vulnerable, wondering whether the patient might one day come back to haunt us with a lawsuit, especially if the medical outcome is unfavorable.

Understanding the motivation for the behavior can help a physician to empathize with the demanding patient.¹² Although it may seem that the demanding patient is trying to intimidate the physician, the goal is usually the same: to find the best possible treatment. Anger and hostility are often motivated by fear and a sense of losing control.

Ironically, this maladaptive coping style may alienate the very people who can help the patient. Hostile behavior evokes defensiveness and resentment in others. A power struggle may ensue: as the patient makes more unreasonable demands and threats, the physician reacts by asserting his or her views in an attempt to maintain control. Or the physician and the rest of the healthcare team may simply avoid the patient as much as possible.

Collaboration can defuse anger

The best strategy is often to steer the encounter away from a power struggle by legitimizing the patient’s feeling of entitlement to the best possible treatment.¹³ Take a collaborative stance with the patient, with the common goal of finding and implementing the most effective and lowest-risk diagnostic and treatment plan. Empathy and exploration of the patient’s concerns are always in order.

Physicians can try several strategies to improve interactions with demanding patients and caregivers:

Be consistent. All members of the healthcare team, including nurses and specialists, should convey consistent messages regarding diagnostic testing and treatment plans.

Don’t play the game. Demanding patients often complain about being mistreated by other healthcare providers. When confronted with such complaints, acknowledge the patient’s feelings while refraining from blaming or criticizing other members of the healthcare team.

Clarify expectations. Clarifying expectations from the initial patient encounter can prevent conflicts later. Support a patient who must accept a diagnosis of a terminal illness, and then when appropriate, discuss goals moving forward. Collaboration within the framework of reasonable expectations is key.

For our case, the physician could say, “We want to work with you together as a team. We will work hard to address your concerns, but our nurses must have a safe environment in which to help you.” Such a statement highlights shared goals and expression of concern without judgment. The next step is to clarify expectations by describing the hospital routine and how decisions are made.

Offer choices. Offering choices whenever possible can help a demanding patient feel more in control. Rather than dismiss a patient’s ideas, explore the alternatives. While effective patient communication is preferable to repeated referrals to specialists,¹⁴ judicious referral can engender trust in the physician’s competence if a diagnosis is not forthcoming.¹⁵

A unique challenge in teaching hospitals is the patient who refuses to interact with residents and students. It is best to acknowledge the patient’s concerns and offer alternative options:

• If the patient is worried about lack of completed training, then clarify the residents’ roles and reassure the patient that you communicate with residents and supervisors regarding any clinical decisions
• If possible, offer to see the patient alone or have the resident interact only on an as-needed basis
• Consider transferring the patient to a nonteaching service or to another hospital.

Admit failings. Although not easy, admitting to and apologizing for things that have gone wrong can help to calm a demanding patient and even reduce the likelihood of a lawsuit.¹⁶ The physician should not convey defensiveness and instead should acknowledge the limitations of the healthcare system.

Legitimize concerns—to an extent. Legitimizing a demanding patient’s concerns is important, but never be bullied into taking actions that create unnecessary risk. Upsetting a demanding patient is better than ordering tests or providing treatments that are potentially harmful. Good physician-patient communication can go a long way toward preventing adverse outcomes.

A 25-year-old professional presents to a new primary care provider concerned about a mole on her back. She discusses her sun exposure and family history of skin cancer and produces photographs documenting changes in the mole over time. Impressed with this level of detail, the physician takes time to explain his concerns before referring her to a dermatologist. Later that day, she calls to let the doctor know that her procedure has been scheduled and to thank him for his care. A few weeks after the mole is removed, she returns to discuss treatment options for the small remaining scar.

After this appointment, she calls the office repeatedly with a wide array of concerns, including an isolated symptom of fatigue that could indicate cancer and the relative merits of different sunscreens. She also sends the physician frequent e-mail messages through the personal health record system with pictures of inconsequential marks on her skin.

Needing reassurance is normal—to a point

Many patients seek reassurance from their physicians, and this can be done in a healthy and respectful manner. But requests for reassurance may escalate to becoming repeated, insistent, and even aggressive.¹ This can elicit reactions from physicians ranging from feeling annoyed and burdened to feeling angry and overwhelmed.¹⁷ This can lead to significant stress, which, if not managed well, can lead to excessively control of physician behavior and substandard care.¹⁸

Reassurance-seeking behavior can manifest anywhere along the spectrum of health and disease.¹⁹ It may be a symptom of health anxiety (ie, an exaggerated fear of illness) or hypochondria (ie, the persistent conviction that one is currently or likely to become ill).^20,21

Why so needy?

Attachment theory may help explain neediness. Parental bonding during childhood is associated with mental and physical health and health-related behaviors in adults.^22,23 People with insecure-preoccupied attachment styles tend to be overly emotionally dependent on the acceptance of others and may exhibit dependent and care-seeking behaviors with a physician.²⁴

Needy patients are often genuinely grateful for the care and attention from a physician.¹ In the beginning, the doctor may appreciate the patient’s validation of care provided, but this positive feeling wanes as calls and requests become incessant. As the physician’s exhaustion increases with each request, the care and well-being of the patient may no longer be the primary focus.¹

Set boundaries

Be alert to signs that a patient is crossing the line to an unhealthy need for reassurance. Address medical concerns appropriately, then institute clear guidelines for follow-up, which should be reinforced by the entire care team if necessary.²²

                The following strategies can be useful for defining boundaries:

• Instruct the patient to come to the office only for scheduled follow-up visits and to call only during office hours or in an emergency
• Be up-front about the time allowed for each appointment and ask the patient to help focus the discussion according to his or her main concerns²⁵
• Consider telling the patient, “You seem really worried about a lot of physical symptoms. I want to reassure you that I find no evidence of a medical illness that would require intervention. I am concerned about your phone calls and e-mails, and I wonder what would be helpful at this point to address your concerns?”
• Consider treating the patient for anxiety.

It is important to remain responsive to all types of patient concerns. Setting boundaries will guide patients to express health concerns in an appropriate manner so that they can be heard and managed.^18,19               

SELF-INJURY

A 22-year-old woman presents to the emergency department complaining of abdominal pain. After a full workup, the physician clears her medically and orders a few laboratory tests. As the nurse draws blood samples, she notices multiple fresh cuts on the patient’s arm and informs the physician. The patient is questioned and examined again and acknowledges occasional thoughts of self-harm. 

Her parents arrive and appear appropriately concerned. They report that she has been “cutting” for 4 years and is regularly seeing a therapist. However, they say that they are not worried for her safety and that she has an appointment with her therapist this week. Based on this, the emergency department physician discharges her.

Two weeks later, the patient returns to the emergency department with continued cutting and apparent cellulitis, prompting medical admission.

Self-injury presents in many ways

Self-injurious behaviors come in many forms other than the easily recognized one presented in this case: eg, a patient with cirrhosis who continues to drink, a patient with severe epilepsy who forgets to take medications and lands in the emergency department every week for status epilepticus, a patient with diabetes who eats a high-sugar diet, a patient with renal insufficiency who ignores water restrictions, or a patient with an organ transplant who misses medications and relapses.

There is an important psychological difference between patients who knowingly continue to challenge their luck and those who do not fully understand the severity of their condition and the consequences of their actions. The patient who simply does not “get it” can sometimes be managed effectively with education and by working with family members to create an environment to facilitate critical healthy behaviors.

Patients who willfully self-inflict injury are asking for help while doing everything to avoid being helped. They typically come to the office or the emergency department with assorted complaints, not divulging the real reason for their visit until the last minute as they are leaving. Then they drop a clue to the real concern, leaving the physician confused and frustrated.

Why deny an obvious problem?

Fear of the stigma of mental illness can be a major barrier to full disclosure of symptoms of psychological distress, and this especially tends to be the case for patients from some ethnic minorities.²⁶ 

On the other hand, patients with borderline or antisocial personality disorder (and less often, schizotypal or narcissistic personality disorder) frequently use denial as their primary psychological defense. Self-destructive denial is sometimes associated with traumatic memories, feelings of worthlessness, or a desire to reduce self-awareness and rationalize harmful behaviors. Such patients usually need lengthy treatment, and although the likelihood of cure is low, therapy can be helpful.^27–29  

Lessons from psychiatry              

It can be difficult to maintain empathy for patients who intentionally harm themselves. It is helpful to think of these patients as having a terminal illness and to recognize that they are suffering.

Different interventions have been studied for such patients. Dialectical behavior therapy, an approach that teaches patients better coping skills for regulating emotions, can help reduce maladaptive emotional distress and self-destructive behaviors.^30–32 Lessons from this approach can be applied by general practitioners:

• Engage the patient and together establish an effective crisis management plan
• With patient permission, involve the family in the treatment plan
• Set clear limits about self-harm: once the patient values interaction with the doctor, he or she will be less likely to break the agreement.

Patients with severe or continuing issues can be referred to appropriate services that offer dialectical behavior therapy or other intensive outpatient programs.

To handle our patient, one might start by saying, “I am sorry to see you back in the ER. We need to treat the cellulitis and get your outpatient behavioral team on board, so we know the plan.” Then, it is critical that the entire team keep to that plan.

Patients with challenging behaviors will always be part of medical practice. Physicians should be aware of their reactions and feelings towards a patient (known in psychiatry as countertransference), as they can increase physician stress and interfere with providing optimal care. Finding effective ways to work with difficult patients will avoid these outcomes.

Physicians also feel loss of control

Most physicians are resilient, but they can feel overwhelmed under certain circumstances. According to Scudder and Shanafelt,³³ a physician’s sense of well-being is influenced by several factors, including feelings of control in the workplace. It is easy to imagine how one or more difficult patients can create a sense of overwhelming demand and loss of control.

These tips can help maintain a sense of control and improve interactions with patients:

Have a plan for effective communication. Not having a plan for communicating in a difficult situation can contribute to loss of control in a hectic schedule that is already stretched to its limits. Practicing responses with a colleague for especially difficult patients or using a team approach can be helpful. Remaining compassionate while setting boundaries will result in the best outcome for the patient and physician.

Stop to analyze the situation. One of the tenets of cognitive-behavioral therapy is recognizing that negative thoughts can quickly take us down a dangerous path. Feeling angry and resentful without stopping to think and reflect on the causes can lead to the physician feeling victimized (just like many difficult patients feel).

It is important to step back and think, not just feel. While difficult patients present in different ways, all are reacting to losing control of their situation and want support. During a difficult interaction with a patient, pause to consider, “Why is he behaving this way? Is he afraid? Does he feel that no one cares?”

When a patient verbally attacks beyond what is appropriate, recognize that this is probably due less to anything the physician did than to the patient’s internal issues. Identifying the driver of a patient’s behavior makes it easier to control our own emotions.

Practice empathy. Difficult patients usually have something in their background that can help explain their inappropriate behavior, such as a lack of parental support or abuse. Being open to hearing their story facilitates an empathetic connection.

AVOIDING BURNOUT

Discuss problems

Sadly, physicians often neglect to talk with each other and with trainees about issues leading to burnout, thereby missing important opportunities for empathy, objectivity, reflection, and teaching moments.

Lessons can be gleaned from training in psychiatry, a field in which one must learn methods for working effectively in challenging situations. Dozens of scenarios are practiced using videotapes or observation through one-way mirrors. While not everyone has such opportunities, everyone can discuss issues with one another. Regularly scheduled facilitated groups devoted to discussing problems with colleagues can be enormously helpful.

Schedule quiet times

Mindfulness is an excellent way to spend a few minutes out of every 3- to 4-hour block. There are many ways to help facilitate such moments. Residents and students can be provided with a small book, Mindfulness on the Go,³⁷ aimed for the busy person.

Deep, slow breathing can bring rapid relief to intense negative feelings. Not only does it reduce anxiety faster than medication, but it is also free, is easily taught to others, and can be done unobtrusively. A short description of the role of the blood pH in managing the locus ceruleus and vagus nerve’s balance of sympathetic and parasympathetic activity may capture the curiosity of someone who may otherwise be resistant to the exercise.

Increasingly, hospitals are developing mindfulness sessions and offering a variety of skills physicians can put into their toolbox. Lessons from cognitive-behavioral therapy, dialectical behavior therapy, imagery, and muscle relaxation can help physicians in responding to patients. Investing in communication skills training specific to challenging behaviors seen in different specialties better equips physicians with more effective strategies.

Anyone who has tried to appreciate the challenges we face in medicine has probably read the 1978 article by Groves, “Taking care of the hateful patient.”¹ This and a later article by Strous et al² label and group patients according to specific behaviors and, perhaps more importantly, how they make the clinician on the other end of the conversation feel.

See related article

How patients make us feel should not be underappreciated. Taking care of other human beings is a complex, intricate, intimate privilege. To characterize it as anything else—to simply consumerize it—is to not fully understand it.

Yet, now more than ever, the impact of challenges—not just with patients but in healthcare today—is staggering: 54% of US physicians report burnout,³ and significant numbers would not choose medicine again as a career. Too much time spent charting (up to 2 hours in a recent study⁴) and less time spent connecting as human beings are driving the meaning out of medicine. Calls are growing for more empathy in medicine and better services to meet the needs of patients and caregivers alike.

WORDS CAN STIGMATIZE, VALIDATE, DAMAGE, OR HEAL

As we read in the article by Schuermeyer et al in this issue of the Journal,⁵ there are steps forward and also continued opportunities. The article begins to shift us from labeling patients as “dependent clingers” and “entitled demanders” to a much needed and more meaningful discussion about difficult patient behaviors and how we might more effectively respond to them.

Even if we need to apply them in medicine at times, our labeling the type of person a patient is or how the patient behaves carries tremendous significance to our patients and should not be applied lightly. Depending on the words or labels we choose, our words can stigmatize, validate, damage, or heal. Have no doubt, however, that our words will be remembered.

PATIENTS LABEL US, TOO

As a chief experience officer, I review thousands of patient comments every month. And what patients say is that although their medical care may be spectacular, their emotional needs and expectations are not always met. Despite both valid and less-valid criticisms of patient satisfaction surveys, we have an obligation to listen and learn. We too are fallible.

We too could be—and most certainly are—labeled by patients. “Insensitive,” “uncaring,” and “rude” are words I too often hear from patients as they comment on the care they received from their physicians. These labels certainly do not embody the profound caring at the core of the healthcare profession, just as they do not embody our patients.

An additional and unforeseen risk to labeling is the end of meaningful reflection. When we label, we stop asking who this person is. What trauma did the person suffer that makes trust so difficult? What is he or she most afraid of? What am I contributing to this ineffective dialogue, and how can I adapt my own language and behavior? We have a professional responsibility to respond to frustration or challenges with patients, not with labeling in return, but with humility, listening, and reflection.

BEYOND LABELS

To truly enhance communication and the experience of our patients, we must model empathic curiosity. People are not the label we give them. They are not the disease they have. The richness of their lives, experiences, and emotions cannot possibly be embodied in a single word that we have assigned. Our role as healers requires not judgment but the willingness to know more about who they are and the skill to more effectively express our intention and meaning. Only then will our patients feel truly “seen” and known by us.

To that end, there are a few models of effective communication. One of them, the Relationship: Establishment, Development, and Engagement (REDE) model, was developed at Cleveland Clinic,⁶ and a recent study found that when physicians were trained in it, patient satisfaction, physician empathy, and burnout improved.⁷ Another, the Four Habit model, has been effectively used by Kaiser Permanente for decades.⁸ These models provide a framework and detailed skills that can be used with any patient, loved one, or colleague, especially those we find “challenging.”

In addition, Groves and Schuermeyer et al highlight the impact these difficult conversations have on the clinician. Because most clinicians care deeply about the patients they serve, they are haunted by conversations that don’t go well. When patients are unhappy or angry with our care, we often feel that it is our fault or that we have failed in some way. Alternatively, we seek to distance ourselves from the patient we find challenging.

EMPATHY IS HARD WORK

The most difficult work actually goes on in the space between withdrawing from our patients in anger and continuing to enable inappropriate behavior at an emotional cost to ourselves and our colleagues. That in-between space is an opportunity for the clinician to set boundaries and be consistent, while also seeking to build relationships based on empathy and trust. Otherwise, both parties walk away labeling each other, which prevents us from building relationships with the patients whom we find difficult. Relationships still matter in healthcare and have therapeutic benefits for our patients and ourselves.

Empathy is hard work. When we connect with the patient in front of us, empathy may be easy. Yet the real need for empathy is when we don’t connect with the person in front of us—when we feel frustrated, tired, and angry. And I believe as healers—not just doctors—we are absolutely up for the challenge.

Anyone who has tried to appreciate the challenges we face in medicine has probably read the 1978 article by Groves, “Taking care of the hateful patient.”¹ This and a later article by Strous et al² label and group patients according to specific behaviors and, perhaps more importantly, how they make the clinician on the other end of the conversation feel.

See related article

How patients make us feel should not be underappreciated. Taking care of other human beings is a complex, intricate, intimate privilege. To characterize it as anything else—to simply consumerize it—is to not fully understand it.

Yet, now more than ever, the impact of challenges—not just with patients but in healthcare today—is staggering: 54% of US physicians report burnout,³ and significant numbers would not choose medicine again as a career. Too much time spent charting (up to 2 hours in a recent study⁴) and less time spent connecting as human beings are driving the meaning out of medicine. Calls are growing for more empathy in medicine and better services to meet the needs of patients and caregivers alike.

WORDS CAN STIGMATIZE, VALIDATE, DAMAGE, OR HEAL

As we read in the article by Schuermeyer et al in this issue of the Journal,⁵ there are steps forward and also continued opportunities. The article begins to shift us from labeling patients as “dependent clingers” and “entitled demanders” to a much needed and more meaningful discussion about difficult patient behaviors and how we might more effectively respond to them.

Even if we need to apply them in medicine at times, our labeling the type of person a patient is or how the patient behaves carries tremendous significance to our patients and should not be applied lightly. Depending on the words or labels we choose, our words can stigmatize, validate, damage, or heal. Have no doubt, however, that our words will be remembered.

PATIENTS LABEL US, TOO

As a chief experience officer, I review thousands of patient comments every month. And what patients say is that although their medical care may be spectacular, their emotional needs and expectations are not always met. Despite both valid and less-valid criticisms of patient satisfaction surveys, we have an obligation to listen and learn. We too are fallible.

We too could be—and most certainly are—labeled by patients. “Insensitive,” “uncaring,” and “rude” are words I too often hear from patients as they comment on the care they received from their physicians. These labels certainly do not embody the profound caring at the core of the healthcare profession, just as they do not embody our patients.

An additional and unforeseen risk to labeling is the end of meaningful reflection. When we label, we stop asking who this person is. What trauma did the person suffer that makes trust so difficult? What is he or she most afraid of? What am I contributing to this ineffective dialogue, and how can I adapt my own language and behavior? We have a professional responsibility to respond to frustration or challenges with patients, not with labeling in return, but with humility, listening, and reflection.

BEYOND LABELS

To truly enhance communication and the experience of our patients, we must model empathic curiosity. People are not the label we give them. They are not the disease they have. The richness of their lives, experiences, and emotions cannot possibly be embodied in a single word that we have assigned. Our role as healers requires not judgment but the willingness to know more about who they are and the skill to more effectively express our intention and meaning. Only then will our patients feel truly “seen” and known by us.

To that end, there are a few models of effective communication. One of them, the Relationship: Establishment, Development, and Engagement (REDE) model, was developed at Cleveland Clinic,⁶ and a recent study found that when physicians were trained in it, patient satisfaction, physician empathy, and burnout improved.⁷ Another, the Four Habit model, has been effectively used by Kaiser Permanente for decades.⁸ These models provide a framework and detailed skills that can be used with any patient, loved one, or colleague, especially those we find “challenging.”

In addition, Groves and Schuermeyer et al highlight the impact these difficult conversations have on the clinician. Because most clinicians care deeply about the patients they serve, they are haunted by conversations that don’t go well. When patients are unhappy or angry with our care, we often feel that it is our fault or that we have failed in some way. Alternatively, we seek to distance ourselves from the patient we find challenging.

EMPATHY IS HARD WORK

The most difficult work actually goes on in the space between withdrawing from our patients in anger and continuing to enable inappropriate behavior at an emotional cost to ourselves and our colleagues. That in-between space is an opportunity for the clinician to set boundaries and be consistent, while also seeking to build relationships based on empathy and trust. Otherwise, both parties walk away labeling each other, which prevents us from building relationships with the patients whom we find difficult. Relationships still matter in healthcare and have therapeutic benefits for our patients and ourselves.

Empathy is hard work. When we connect with the patient in front of us, empathy may be easy. Yet the real need for empathy is when we don’t connect with the person in front of us—when we feel frustrated, tired, and angry. And I believe as healers—not just doctors—we are absolutely up for the challenge.

Anyone who has tried to appreciate the challenges we face in medicine has probably read the 1978 article by Groves, “Taking care of the hateful patient.”¹ This and a later article by Strous et al² label and group patients according to specific behaviors and, perhaps more importantly, how they make the clinician on the other end of the conversation feel.

See related article

How patients make us feel should not be underappreciated. Taking care of other human beings is a complex, intricate, intimate privilege. To characterize it as anything else—to simply consumerize it—is to not fully understand it.

Yet, now more than ever, the impact of challenges—not just with patients but in healthcare today—is staggering: 54% of US physicians report burnout,³ and significant numbers would not choose medicine again as a career. Too much time spent charting (up to 2 hours in a recent study⁴) and less time spent connecting as human beings are driving the meaning out of medicine. Calls are growing for more empathy in medicine and better services to meet the needs of patients and caregivers alike.

WORDS CAN STIGMATIZE, VALIDATE, DAMAGE, OR HEAL

As we read in the article by Schuermeyer et al in this issue of the Journal,⁵ there are steps forward and also continued opportunities. The article begins to shift us from labeling patients as “dependent clingers” and “entitled demanders” to a much needed and more meaningful discussion about difficult patient behaviors and how we might more effectively respond to them.

Even if we need to apply them in medicine at times, our labeling the type of person a patient is or how the patient behaves carries tremendous significance to our patients and should not be applied lightly. Depending on the words or labels we choose, our words can stigmatize, validate, damage, or heal. Have no doubt, however, that our words will be remembered.

PATIENTS LABEL US, TOO

As a chief experience officer, I review thousands of patient comments every month. And what patients say is that although their medical care may be spectacular, their emotional needs and expectations are not always met. Despite both valid and less-valid criticisms of patient satisfaction surveys, we have an obligation to listen and learn. We too are fallible.

We too could be—and most certainly are—labeled by patients. “Insensitive,” “uncaring,” and “rude” are words I too often hear from patients as they comment on the care they received from their physicians. These labels certainly do not embody the profound caring at the core of the healthcare profession, just as they do not embody our patients.

An additional and unforeseen risk to labeling is the end of meaningful reflection. When we label, we stop asking who this person is. What trauma did the person suffer that makes trust so difficult? What is he or she most afraid of? What am I contributing to this ineffective dialogue, and how can I adapt my own language and behavior? We have a professional responsibility to respond to frustration or challenges with patients, not with labeling in return, but with humility, listening, and reflection.

BEYOND LABELS

To truly enhance communication and the experience of our patients, we must model empathic curiosity. People are not the label we give them. They are not the disease they have. The richness of their lives, experiences, and emotions cannot possibly be embodied in a single word that we have assigned. Our role as healers requires not judgment but the willingness to know more about who they are and the skill to more effectively express our intention and meaning. Only then will our patients feel truly “seen” and known by us.

To that end, there are a few models of effective communication. One of them, the Relationship: Establishment, Development, and Engagement (REDE) model, was developed at Cleveland Clinic,⁶ and a recent study found that when physicians were trained in it, patient satisfaction, physician empathy, and burnout improved.⁷ Another, the Four Habit model, has been effectively used by Kaiser Permanente for decades.⁸ These models provide a framework and detailed skills that can be used with any patient, loved one, or colleague, especially those we find “challenging.”

In addition, Groves and Schuermeyer et al highlight the impact these difficult conversations have on the clinician. Because most clinicians care deeply about the patients they serve, they are haunted by conversations that don’t go well. When patients are unhappy or angry with our care, we often feel that it is our fault or that we have failed in some way. Alternatively, we seek to distance ourselves from the patient we find challenging.

EMPATHY IS HARD WORK

The most difficult work actually goes on in the space between withdrawing from our patients in anger and continuing to enable inappropriate behavior at an emotional cost to ourselves and our colleagues. That in-between space is an opportunity for the clinician to set boundaries and be consistent, while also seeking to build relationships based on empathy and trust. Otherwise, both parties walk away labeling each other, which prevents us from building relationships with the patients whom we find difficult. Relationships still matter in healthcare and have therapeutic benefits for our patients and ourselves.

Empathy is hard work. When we connect with the patient in front of us, empathy may be easy. Yet the real need for empathy is when we don’t connect with the person in front of us—when we feel frustrated, tired, and angry. And I believe as healers—not just doctors—we are absolutely up for the challenge.

A 69-year-old woman with hypertension, diabetes mellitus, and chronic kidney disease presented with a 1-month history of worsening episodic dyspnea, lower-extremity edema, and dizziness. Two months earlier, she had been diagnosed with poorly differentiated pelvic adnexal sarcoma associated with a mature teratoma of the left ovary, and she had undergone bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and omentectomy.

Examination revealed tachypnea (23 breaths per minute) and bilateral pitting pedal edema. The neck veins were distended. There was no hepatomegaly. Results of laboratory testing were unremarkable.

EVALUATING A CARDIAC MASS

Thrombus, tumor, or vegetation?

If an intracardiac mass is discovered, we need to determine what it is.

Thrombosis is more likely if contrast echocardiography shows the mass has no stalk (thrombi almost never have a stalk), the atrial chamber is enlarged, cardiac output is low, there is stasis, the mass is avascular, and it responds to thrombolytic therapy. A giant organized thrombus can clinically mimic a tumor if it is immobile, is located close to the wall, and responds poorly to thrombolysis. A wall-motion abnormality adjacent to the mass, global hypokinesis, or a concomitant autoimmune condition such as lupus erythematosus or antiphospholipid antibody syndrome may also favor thrombosis.

Tumors in the heart are uncommon. The prevalence of primary cardiac tumors has been reported as 0.01% to 0.1% in autopsy studies. Metastases to the pericardium, myocardium, coronary arteries, or great vessels have been found at autopsy in 0.7% to 3.5% of the general population and in 9.1% of patients with known malignancy.¹

Vegetations from infective endocarditis should also be considered early in the evaluation of an intracardiac mass. They can result from bacterial, fungal, or parasitic infection. Vegetations are generally irregular in appearance, mobile, and attached to a valve. Left-sided valves are generally involved, and a larger mass may indicate fungal origin. Abscess from tuberculosis may need to be considered in the appropriate setting. Whenever feasible, tissue diagnosis is desirable.

Occasionally, there may be an inflammatory component to masses detected in the setting of autoimmune disease.

If echocardiography cannot clearly distinguish whether the mass is a tumor or a thrombus, MRI with gadolinium contrast is useful. MRI is superior to CT in depicting anatomic details and does not involve radiation.

Cardiac CT is increasingly used when other imaging findings are equivocal or to study a calcified mass. CT with contrast carries a small risk of contrast-induced nephropathy and has lower soft-tissue and temporal resolution. CT without contrast can detect the mass and reveal calcifications within the mass, but contrast is needed to assess the vascularity of the tumor. New-generation CT with electrocardiographic gating nearly matches MRI imaging, and CT is preferred for patients with contraindications to MRI.

CT provides additional information on the global assessment of the chest, lung and vascular structures.² Cardiac CT and MRI help in precise anatomic delineation, characterization, and preoperative planning of treatment of a large cardiac mass.

TYPES OF CARDIAC TUMORS

Metastases account for most cardiac tumors and are often from primary cancers of the lung, breast, skin, thyroid, and kidney.

Primary cardiac tumors are most often myxomas, which are benign and generally found in the atrial chamber, solitary, with a stalk attached to the area of the fossa ovalis. Other primary cardiac tumors include sarcomas, angiosarcomas, rhabdomyosarcomas, papillary fibroelastomas, lipomas, hemangiomas, mesotheliomas, and rhabdomyomas.

TREATMENT OF CARDIAC TUMORS

For primary and secondary cardiac tumors, complete resection should be considered, provided there is no other organ involvement.³ For suspected lymphomas, image-guided biopsy should be performed before treatment.

For uncertain and diagnostically challenging cases, guided biopsy of the lesions using intracardiac echocardiography or transesophageal echocardiography has been reported to be helpful.⁴

Most often, the workup and management of cardiac masses calls for a team involving an internist, cardiologist, cardiothoracic surgeon, and vascular medicine specialist. Depending on the nature of the mass, the team may also include an oncologist, radiotherapist, and infectious disease specialist.

Because our patient had significant kidney disease, CT was done without contrast. However, it was not able to clearly delineate the mass in the right ventricle. Cardiac MRI was not performed. Biopsy with transesophageal or intracardiac echocardiographic guidance was not an option, as the patient’s condition was poor.

TAKE-HOME POINTS

The differential diagnosis of an intracardiac mass includes thrombus, benign or malignant tumors, and masses of infectious or inflammatory origin. While noninvasive imaging tests provide clues that can help narrow the differential diagnosis, tissue biopsy with histologic study is necessary to confirm the diagnosis. A team approach is paramount in managing cardiac masses.

A 69-year-old woman with hypertension, diabetes mellitus, and chronic kidney disease presented with a 1-month history of worsening episodic dyspnea, lower-extremity edema, and dizziness. Two months earlier, she had been diagnosed with poorly differentiated pelvic adnexal sarcoma associated with a mature teratoma of the left ovary, and she had undergone bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and omentectomy.

Examination revealed tachypnea (23 breaths per minute) and bilateral pitting pedal edema. The neck veins were distended. There was no hepatomegaly. Results of laboratory testing were unremarkable.

EVALUATING A CARDIAC MASS

Thrombus, tumor, or vegetation?

If an intracardiac mass is discovered, we need to determine what it is.

Thrombosis is more likely if contrast echocardiography shows the mass has no stalk (thrombi almost never have a stalk), the atrial chamber is enlarged, cardiac output is low, there is stasis, the mass is avascular, and it responds to thrombolytic therapy. A giant organized thrombus can clinically mimic a tumor if it is immobile, is located close to the wall, and responds poorly to thrombolysis. A wall-motion abnormality adjacent to the mass, global hypokinesis, or a concomitant autoimmune condition such as lupus erythematosus or antiphospholipid antibody syndrome may also favor thrombosis.

Tumors in the heart are uncommon. The prevalence of primary cardiac tumors has been reported as 0.01% to 0.1% in autopsy studies. Metastases to the pericardium, myocardium, coronary arteries, or great vessels have been found at autopsy in 0.7% to 3.5% of the general population and in 9.1% of patients with known malignancy.¹

Vegetations from infective endocarditis should also be considered early in the evaluation of an intracardiac mass. They can result from bacterial, fungal, or parasitic infection. Vegetations are generally irregular in appearance, mobile, and attached to a valve. Left-sided valves are generally involved, and a larger mass may indicate fungal origin. Abscess from tuberculosis may need to be considered in the appropriate setting. Whenever feasible, tissue diagnosis is desirable.

Occasionally, there may be an inflammatory component to masses detected in the setting of autoimmune disease.

If echocardiography cannot clearly distinguish whether the mass is a tumor or a thrombus, MRI with gadolinium contrast is useful. MRI is superior to CT in depicting anatomic details and does not involve radiation.

Cardiac CT is increasingly used when other imaging findings are equivocal or to study a calcified mass. CT with contrast carries a small risk of contrast-induced nephropathy and has lower soft-tissue and temporal resolution. CT without contrast can detect the mass and reveal calcifications within the mass, but contrast is needed to assess the vascularity of the tumor. New-generation CT with electrocardiographic gating nearly matches MRI imaging, and CT is preferred for patients with contraindications to MRI.

CT provides additional information on the global assessment of the chest, lung and vascular structures.² Cardiac CT and MRI help in precise anatomic delineation, characterization, and preoperative planning of treatment of a large cardiac mass.

TYPES OF CARDIAC TUMORS

Metastases account for most cardiac tumors and are often from primary cancers of the lung, breast, skin, thyroid, and kidney.

Primary cardiac tumors are most often myxomas, which are benign and generally found in the atrial chamber, solitary, with a stalk attached to the area of the fossa ovalis. Other primary cardiac tumors include sarcomas, angiosarcomas, rhabdomyosarcomas, papillary fibroelastomas, lipomas, hemangiomas, mesotheliomas, and rhabdomyomas.

TREATMENT OF CARDIAC TUMORS

For primary and secondary cardiac tumors, complete resection should be considered, provided there is no other organ involvement.³ For suspected lymphomas, image-guided biopsy should be performed before treatment.

For uncertain and diagnostically challenging cases, guided biopsy of the lesions using intracardiac echocardiography or transesophageal echocardiography has been reported to be helpful.⁴

Most often, the workup and management of cardiac masses calls for a team involving an internist, cardiologist, cardiothoracic surgeon, and vascular medicine specialist. Depending on the nature of the mass, the team may also include an oncologist, radiotherapist, and infectious disease specialist.

Because our patient had significant kidney disease, CT was done without contrast. However, it was not able to clearly delineate the mass in the right ventricle. Cardiac MRI was not performed. Biopsy with transesophageal or intracardiac echocardiographic guidance was not an option, as the patient’s condition was poor.

TAKE-HOME POINTS

The differential diagnosis of an intracardiac mass includes thrombus, benign or malignant tumors, and masses of infectious or inflammatory origin. While noninvasive imaging tests provide clues that can help narrow the differential diagnosis, tissue biopsy with histologic study is necessary to confirm the diagnosis. A team approach is paramount in managing cardiac masses.

A 69-year-old woman with hypertension, diabetes mellitus, and chronic kidney disease presented with a 1-month history of worsening episodic dyspnea, lower-extremity edema, and dizziness. Two months earlier, she had been diagnosed with poorly differentiated pelvic adnexal sarcoma associated with a mature teratoma of the left ovary, and she had undergone bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and omentectomy.

Examination revealed tachypnea (23 breaths per minute) and bilateral pitting pedal edema. The neck veins were distended. There was no hepatomegaly. Results of laboratory testing were unremarkable.

EVALUATING A CARDIAC MASS

Thrombus, tumor, or vegetation?

If an intracardiac mass is discovered, we need to determine what it is.

Thrombosis is more likely if contrast echocardiography shows the mass has no stalk (thrombi almost never have a stalk), the atrial chamber is enlarged, cardiac output is low, there is stasis, the mass is avascular, and it responds to thrombolytic therapy. A giant organized thrombus can clinically mimic a tumor if it is immobile, is located close to the wall, and responds poorly to thrombolysis. A wall-motion abnormality adjacent to the mass, global hypokinesis, or a concomitant autoimmune condition such as lupus erythematosus or antiphospholipid antibody syndrome may also favor thrombosis.

Tumors in the heart are uncommon. The prevalence of primary cardiac tumors has been reported as 0.01% to 0.1% in autopsy studies. Metastases to the pericardium, myocardium, coronary arteries, or great vessels have been found at autopsy in 0.7% to 3.5% of the general population and in 9.1% of patients with known malignancy.¹

Vegetations from infective endocarditis should also be considered early in the evaluation of an intracardiac mass. They can result from bacterial, fungal, or parasitic infection. Vegetations are generally irregular in appearance, mobile, and attached to a valve. Left-sided valves are generally involved, and a larger mass may indicate fungal origin. Abscess from tuberculosis may need to be considered in the appropriate setting. Whenever feasible, tissue diagnosis is desirable.

Occasionally, there may be an inflammatory component to masses detected in the setting of autoimmune disease.

If echocardiography cannot clearly distinguish whether the mass is a tumor or a thrombus, MRI with gadolinium contrast is useful. MRI is superior to CT in depicting anatomic details and does not involve radiation.

Cardiac CT is increasingly used when other imaging findings are equivocal or to study a calcified mass. CT with contrast carries a small risk of contrast-induced nephropathy and has lower soft-tissue and temporal resolution. CT without contrast can detect the mass and reveal calcifications within the mass, but contrast is needed to assess the vascularity of the tumor. New-generation CT with electrocardiographic gating nearly matches MRI imaging, and CT is preferred for patients with contraindications to MRI.

CT provides additional information on the global assessment of the chest, lung and vascular structures.² Cardiac CT and MRI help in precise anatomic delineation, characterization, and preoperative planning of treatment of a large cardiac mass.

TYPES OF CARDIAC TUMORS

Metastases account for most cardiac tumors and are often from primary cancers of the lung, breast, skin, thyroid, and kidney.

Primary cardiac tumors are most often myxomas, which are benign and generally found in the atrial chamber, solitary, with a stalk attached to the area of the fossa ovalis. Other primary cardiac tumors include sarcomas, angiosarcomas, rhabdomyosarcomas, papillary fibroelastomas, lipomas, hemangiomas, mesotheliomas, and rhabdomyomas.

TREATMENT OF CARDIAC TUMORS

For primary and secondary cardiac tumors, complete resection should be considered, provided there is no other organ involvement.³ For suspected lymphomas, image-guided biopsy should be performed before treatment.

For uncertain and diagnostically challenging cases, guided biopsy of the lesions using intracardiac echocardiography or transesophageal echocardiography has been reported to be helpful.⁴

Most often, the workup and management of cardiac masses calls for a team involving an internist, cardiologist, cardiothoracic surgeon, and vascular medicine specialist. Depending on the nature of the mass, the team may also include an oncologist, radiotherapist, and infectious disease specialist.

Because our patient had significant kidney disease, CT was done without contrast. However, it was not able to clearly delineate the mass in the right ventricle. Cardiac MRI was not performed. Biopsy with transesophageal or intracardiac echocardiographic guidance was not an option, as the patient’s condition was poor.

TAKE-HOME POINTS

The differential diagnosis of an intracardiac mass includes thrombus, benign or malignant tumors, and masses of infectious or inflammatory origin. While noninvasive imaging tests provide clues that can help narrow the differential diagnosis, tissue biopsy with histologic study is necessary to confirm the diagnosis. A team approach is paramount in managing cardiac masses.

Each year, millions of women undergo mammography in the hope of decreasing their risk of dying of breast cancer. The effectiveness of screening mammography, however, continues to be debated.

While most randomized controlled trials have demonstrated significantly lower mortality rates in women who undergo screening, not all trials have. Most experts agree that screening mammography programs decrease breast cancer mortality rates by 12% to 33%.^1,2 But some point out that although mammography programs clearly detect more cases of breast cancer, some proportion of this detection may include “overdiagnosis” of cancers that would not have caused morbidity or mortality, including ductal carcinoma in situ. Also, although deaths from breast cancer have decreased in the United States, at least some of the decrease may be due to more effective treatment rather than early detection.

Moreover, screening has well-documented harms. False-positive results cause alarm and expose women to needless follow-up imaging and biopsies, with their attendant inconvenience, discomfort, risks, and costs. Conversely, false-negative results (especially common in women with dense breasts) lead to missed diagnosis and a false sense of security.

How could programs and technology be improved to make screening more beneficial, both for patients and for society as a whole? A major improvement would be if mammography could be made more sensitive and specific for detecting invasive cancers, with fewer false-positive results. Lower cost and less frequent screening would also be major improvements.

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, may be a way to improve the value of breast cancer screening programs. In 2011, the US Food and Drug Administration (FDA) approved DBT for all mammographic indications, including screening.

WHAT IS TOMOSYNTHESIS?

In DBT, the x-ray source is rotated in an arc around the patient’s breast (Figure 1), generating a 3D image.³ DBT is now routinely built into newer-generation mammography units. The 3D projections of DBT are obtained during the same breast compression required for standard 2D digital mammography. Thus, DBT requires minimal additional time on the part of the patient and the technologist.⁴

The 3D images are processed and sent to a viewing station, where a radiologist can interpret them next to 2D images. The radiologist has the ability to scroll through the DBT projections slice by slice, as in other cross-sectional imaging examinations. However, given the larger number of images compared with digital mammography, DBT requires more time for interpretation, interrupting the workflow. A population-based observational study suggested that combined digital mammography and DBT screening examinations take twice as long to interpret.⁵

The main advantage of DBT is that it can mitigate the problem of overlapping breast tissue on standard digital projections. These areas of focal asymmetry may represent suspicious masses—or merely overlapping breast parenchyma. When areas of focal asymmetry are found on 2D digital mammography without DBT, patients need to come back for further diagnostic imaging to resolve the finding.⁶ In addition, especially in women with dense breasts, areas of overlapping tissue can have a masking effect, obscuring small breast cancers.⁷

Images courtesy of Diana L. Lam, MD, University of Washington, Seattle.

For breast cancer screening, DBT is read in conjunction with standard digital mammography. By allowing examination of the breast parenchyma in thin slices, DBT decreases the interpretive issue of overlapping breast parenchyma and the masking effect, potentially leading to fewer false-positive results and higher rates of cancer detection (Figure 2).

EFFECTIVENESS OF TOMOSYNTHESIS

There is limited evidence at this time to support the addition of DBT to digital mammography for primary breast cancer screening, with no published randomized trials that assessed outcomes. However, 2 population-based trials in Europe have prospectively assessed DBT plus digital mammography as a primary screening strategy: the Screening With Tomosynthesis or Standard Mammography (STORM) trial⁸ and the Oslo tomosynthesis screening trial.⁵ Only the STORM trial reported first-year interval cancer rates, from which the sensitivity and specificity of DBT plus 2D digital mammography could be calculated and compared with those of 2D digital mammography alone.⁸

In April 2013, the Oslo tomosynthesis screening trial published interim results of its prospective cohort study of 12,631 Norwegian women ages 50 to 69.⁵ Women were invited to participate based on the availability of technical staff and imaging systems at the time of screening, and all participants underwent digital mammography and DBT. Images were read independently by 4 radiologists using a double-reader protocol.

The interim results suggest that adding DBT to digital mammography increased cancer detection rates by 31% and decreased the false-positive rate by 13% compared with 2D digital mammography alone (Table 1). However, the double-reader protocol in this study differs from typical single-reader protocols in the United States, limiting the applicability of the findings.

The STORM trial: Low sensitivity

The STORM trial is a prospective cohort study that included 7,292 women without symptoms, at average risk, age 48 and older, who participated in national breast cancer screening services in northern Italy. Each participant underwent digital mammography and DBT. The examinations were read sequentially (digital mammography first, then DBT plus digital mammography) either by a single radiologist, as is most common in the United States, or by 2 radiologists, as is standard in Europe.

Using the single-reader strategy, adding DBT significantly increased cancer detection rates and reduced the total recall rate (Table 1). Sensitivity was 85% vs 54%, and specificity was 97% vs 96%.^8,9

Of note, the sensitivity of 54% for digital mammography in the STORM trial is substantially lower than the sensitivity of digital mammography reported in the United States.¹⁰

Friedewald et al confirmed Oslo and STORM

To date, the largest US study of DBT plus digital mammography for breast cancer screening was a multicenter retrospective cohort study by Friedewald et al in 2014.¹¹ This study compared cancer detection and recall rates before and after the implementation of DBT at 13 breast centers and evaluated a total of 454,850 examinations (173,663 with DBT plus digital mammography and 281,187 with digital mammography only).

Overall, the recall rate decreased significantly after DBT was adopted and the cancer detection rate increased, findings consistent with those of the STORM and Oslo trials (Table 1). Adding DBT detected invasive cancers at a higher rate than 2D digital mammography alone (4.1/1000 vs 2.9/1,000), while there was no significant difference in ductal carcinoma in situ detection rates. This suggests that the additional cancers detected by DBT may be more clinically important. Nevertheless, the number of biopsies with negative results also increased, suggesting that adding DBT may pose potential harms.

In 2016, Rafferty et al¹² published an additional analysis of the data from Friedewald et al, concluding that adding DBT to 2D digital mammography increased the cancer detection rate more in women with heterogeneously dense breasts than in those with either nondense breasts or extremely dense breasts.¹² The reduction in recall rate was also greatest in the heterogeneously dense subgroup.

Insufficient evidence to recommend

Most other cohort studies comparing DBT and digital mammography have had findings similar to those of the European prospective studies and the large US retrospective cohort study, with the addition of DBT to mammography reducing recall rates and increasing cancer detection rates.¹³ However, many of these studies were subject to potential selection bias and did not provide information on the cancer risk of the participants. In addition, no studies have assessed clinical outcomes such as breast cancer stage at diagnosis or interval cancers, let alone breast cancer mortality.

Rigorous studies need to be done in the United States, using the standard single-reader protocol most often used in this country, to ascertain the clinical outcomes of DBT plus digital mammography for breast cancer screening for women at average risk. A 2016 review cited a dearth of high-quality US studies assessing the role of DBT in primary breast cancer.¹³

The US Preventive Services Task Force, in its 2016 guidelines for breast cancer screening, concluded that there was insufficient evidence to assess the harms and benefits of DBT as a method of breast cancer screening, including adjunctive screening in women with dense breasts.¹

Similarly, the American College of Physicians has advised against screening average-risk women for breast cancer using DBT.¹⁴

APPROVAL, DISSEMINATION, COSTS, AND CHOICE FOR PATIENTS

Even with early promising data suggesting that DBT can increase cancer detection rates and decrease false-positive results when added to routine screening mammography, the rapid diffusion of DBT into clinical practice is outpacing evidence of its effectiveness.⁴ This adoption was spurred in January 2015 when the Centers for Medicare and Medicaid Services added a Current Procedural Terminology code for DBT, allowing for additional reimbursement for it for all mammography indications.¹⁵ Still, the use of DBT in community settings is inconsistent, given the significant up-front costs associated with equipment purchases and variable reimbursement by private insurers who consider the technology experimental.

For the US healthcare system as a whole, it is uncertain whether the purported benefits of DBT will outweigh the additional costs associated with its use. The average reimbursement for a routine digital mammography examination is $135; adding DBT adds an average of $56 to the cost.¹⁵

Using an established, discrete-event breast cancer simulation model, a team of investigators evaluated the cost-effectiveness of combined biennial digital mammography and DBT screening compared with biennial digital mammography screening alone in US women with dense breasts.¹⁶ They found that biennial combined screening is likely to be cost-effective in US women with dense breasts. They also found that for every 2,000 women screened from age 50 to age 74, adding DBT would prevent 1 breast cancer death and 810 false-positive screening examinations.¹⁶

In addition, some have expressed concern that adding DBT to standard digital mammography increases radiation exposure. In fact, the radiation dose with DBT is similar to that with standard 2D digital mammography. Thus, when acquired together, combined digital mammography and DBT screening leads to twice the radiation dose compared with digital mammography alone.¹⁷ Nevertheless, this increased dose remains well below the FDA limits for a screening examination. In addition, the FDA has approved software that allows reconstruction of 2D synthetic views from the 3D data set, which will eventually bring radiation dose levels down to levels comparable to those of conventional digital mammography.¹⁷

Given that DBT is built into newer mammography units and is available as an add-on feature for existing units, its use is likely to increase even faster than digital mammography did when it replaced screen-film mammography in the previous decade.⁴ Its adoption by screening facilities, however, remains variable, and patients wishing to obtain combined DBT and digital mammography screening may have to travel to a different facility from their usual place of screening.¹⁸

Moreover, not all insurance companies cover DBT, resulting in additional out-of-pocket costs to the patient. It is currently unclear how individual facilities are offering DBT services, including how patients are selected for additional DBT and if they are offered the choice to add or forego DBT screening in combination with standard digital mammography.

SUMMARY: AN EMERGING TECHNOLOGY

DBT is an emerging imaging technology that allows the radiologist to view breast images in slices, as in computed tomography. DBT images can be obtained using the same breast compression that women already undergo for 2D digital mammography for breast cancer screening.

At this time, adding DBT to digital mammography screening nearly doubles the radiation exposure to the patient. However, new software is available that allows creation of synthetic 2D views from the 3D data set, resulting in radiation exposure that is similar to conventional digital mammography.

Although there are no published randomized controlled trials assessing the benefit of DBT over 2D digital mammography for breast cancer screening, prospective observational studies suggest that DBT may reduce false-positive recall rates and increase cancer detection rates when used in population-based screening programs. Assuming that additional breast cancer detection contributes to improved clinical outcomes, women with dense breasts may benefit more than women without dense breasts.

No national organizations currently recommend DBT for primary breast cancer screening. Ideally, future studies would determine whether DBT screening reduces breast cancer mortality. Since this research may not be feasible, surrogate clinical outcomes, such as a decrease in interval breast cancer rates and impact on stage at time of diagnosis, would allow us to more confidently recommend this new technology.

Each year, millions of women undergo mammography in the hope of decreasing their risk of dying of breast cancer. The effectiveness of screening mammography, however, continues to be debated.

While most randomized controlled trials have demonstrated significantly lower mortality rates in women who undergo screening, not all trials have. Most experts agree that screening mammography programs decrease breast cancer mortality rates by 12% to 33%.^1,2 But some point out that although mammography programs clearly detect more cases of breast cancer, some proportion of this detection may include “overdiagnosis” of cancers that would not have caused morbidity or mortality, including ductal carcinoma in situ. Also, although deaths from breast cancer have decreased in the United States, at least some of the decrease may be due to more effective treatment rather than early detection.

Moreover, screening has well-documented harms. False-positive results cause alarm and expose women to needless follow-up imaging and biopsies, with their attendant inconvenience, discomfort, risks, and costs. Conversely, false-negative results (especially common in women with dense breasts) lead to missed diagnosis and a false sense of security.

How could programs and technology be improved to make screening more beneficial, both for patients and for society as a whole? A major improvement would be if mammography could be made more sensitive and specific for detecting invasive cancers, with fewer false-positive results. Lower cost and less frequent screening would also be major improvements.

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, may be a way to improve the value of breast cancer screening programs. In 2011, the US Food and Drug Administration (FDA) approved DBT for all mammographic indications, including screening.

WHAT IS TOMOSYNTHESIS?

In DBT, the x-ray source is rotated in an arc around the patient’s breast (Figure 1), generating a 3D image.³ DBT is now routinely built into newer-generation mammography units. The 3D projections of DBT are obtained during the same breast compression required for standard 2D digital mammography. Thus, DBT requires minimal additional time on the part of the patient and the technologist.⁴

The 3D images are processed and sent to a viewing station, where a radiologist can interpret them next to 2D images. The radiologist has the ability to scroll through the DBT projections slice by slice, as in other cross-sectional imaging examinations. However, given the larger number of images compared with digital mammography, DBT requires more time for interpretation, interrupting the workflow. A population-based observational study suggested that combined digital mammography and DBT screening examinations take twice as long to interpret.⁵

The main advantage of DBT is that it can mitigate the problem of overlapping breast tissue on standard digital projections. These areas of focal asymmetry may represent suspicious masses—or merely overlapping breast parenchyma. When areas of focal asymmetry are found on 2D digital mammography without DBT, patients need to come back for further diagnostic imaging to resolve the finding.⁶ In addition, especially in women with dense breasts, areas of overlapping tissue can have a masking effect, obscuring small breast cancers.⁷

Images courtesy of Diana L. Lam, MD, University of Washington, Seattle.

For breast cancer screening, DBT is read in conjunction with standard digital mammography. By allowing examination of the breast parenchyma in thin slices, DBT decreases the interpretive issue of overlapping breast parenchyma and the masking effect, potentially leading to fewer false-positive results and higher rates of cancer detection (Figure 2).

EFFECTIVENESS OF TOMOSYNTHESIS

There is limited evidence at this time to support the addition of DBT to digital mammography for primary breast cancer screening, with no published randomized trials that assessed outcomes. However, 2 population-based trials in Europe have prospectively assessed DBT plus digital mammography as a primary screening strategy: the Screening With Tomosynthesis or Standard Mammography (STORM) trial⁸ and the Oslo tomosynthesis screening trial.⁵ Only the STORM trial reported first-year interval cancer rates, from which the sensitivity and specificity of DBT plus 2D digital mammography could be calculated and compared with those of 2D digital mammography alone.⁸

In April 2013, the Oslo tomosynthesis screening trial published interim results of its prospective cohort study of 12,631 Norwegian women ages 50 to 69.⁵ Women were invited to participate based on the availability of technical staff and imaging systems at the time of screening, and all participants underwent digital mammography and DBT. Images were read independently by 4 radiologists using a double-reader protocol.

The interim results suggest that adding DBT to digital mammography increased cancer detection rates by 31% and decreased the false-positive rate by 13% compared with 2D digital mammography alone (Table 1). However, the double-reader protocol in this study differs from typical single-reader protocols in the United States, limiting the applicability of the findings.

The STORM trial: Low sensitivity

The STORM trial is a prospective cohort study that included 7,292 women without symptoms, at average risk, age 48 and older, who participated in national breast cancer screening services in northern Italy. Each participant underwent digital mammography and DBT. The examinations were read sequentially (digital mammography first, then DBT plus digital mammography) either by a single radiologist, as is most common in the United States, or by 2 radiologists, as is standard in Europe.

Using the single-reader strategy, adding DBT significantly increased cancer detection rates and reduced the total recall rate (Table 1). Sensitivity was 85% vs 54%, and specificity was 97% vs 96%.^8,9

Of note, the sensitivity of 54% for digital mammography in the STORM trial is substantially lower than the sensitivity of digital mammography reported in the United States.¹⁰

Friedewald et al confirmed Oslo and STORM

To date, the largest US study of DBT plus digital mammography for breast cancer screening was a multicenter retrospective cohort study by Friedewald et al in 2014.¹¹ This study compared cancer detection and recall rates before and after the implementation of DBT at 13 breast centers and evaluated a total of 454,850 examinations (173,663 with DBT plus digital mammography and 281,187 with digital mammography only).

Overall, the recall rate decreased significantly after DBT was adopted and the cancer detection rate increased, findings consistent with those of the STORM and Oslo trials (Table 1). Adding DBT detected invasive cancers at a higher rate than 2D digital mammography alone (4.1/1000 vs 2.9/1,000), while there was no significant difference in ductal carcinoma in situ detection rates. This suggests that the additional cancers detected by DBT may be more clinically important. Nevertheless, the number of biopsies with negative results also increased, suggesting that adding DBT may pose potential harms.

In 2016, Rafferty et al¹² published an additional analysis of the data from Friedewald et al, concluding that adding DBT to 2D digital mammography increased the cancer detection rate more in women with heterogeneously dense breasts than in those with either nondense breasts or extremely dense breasts.¹² The reduction in recall rate was also greatest in the heterogeneously dense subgroup.

Insufficient evidence to recommend

Most other cohort studies comparing DBT and digital mammography have had findings similar to those of the European prospective studies and the large US retrospective cohort study, with the addition of DBT to mammography reducing recall rates and increasing cancer detection rates.¹³ However, many of these studies were subject to potential selection bias and did not provide information on the cancer risk of the participants. In addition, no studies have assessed clinical outcomes such as breast cancer stage at diagnosis or interval cancers, let alone breast cancer mortality.

Rigorous studies need to be done in the United States, using the standard single-reader protocol most often used in this country, to ascertain the clinical outcomes of DBT plus digital mammography for breast cancer screening for women at average risk. A 2016 review cited a dearth of high-quality US studies assessing the role of DBT in primary breast cancer.¹³

The US Preventive Services Task Force, in its 2016 guidelines for breast cancer screening, concluded that there was insufficient evidence to assess the harms and benefits of DBT as a method of breast cancer screening, including adjunctive screening in women with dense breasts.¹

Similarly, the American College of Physicians has advised against screening average-risk women for breast cancer using DBT.¹⁴

APPROVAL, DISSEMINATION, COSTS, AND CHOICE FOR PATIENTS

Even with early promising data suggesting that DBT can increase cancer detection rates and decrease false-positive results when added to routine screening mammography, the rapid diffusion of DBT into clinical practice is outpacing evidence of its effectiveness.⁴ This adoption was spurred in January 2015 when the Centers for Medicare and Medicaid Services added a Current Procedural Terminology code for DBT, allowing for additional reimbursement for it for all mammography indications.¹⁵ Still, the use of DBT in community settings is inconsistent, given the significant up-front costs associated with equipment purchases and variable reimbursement by private insurers who consider the technology experimental.

For the US healthcare system as a whole, it is uncertain whether the purported benefits of DBT will outweigh the additional costs associated with its use. The average reimbursement for a routine digital mammography examination is $135; adding DBT adds an average of $56 to the cost.¹⁵

Using an established, discrete-event breast cancer simulation model, a team of investigators evaluated the cost-effectiveness of combined biennial digital mammography and DBT screening compared with biennial digital mammography screening alone in US women with dense breasts.¹⁶ They found that biennial combined screening is likely to be cost-effective in US women with dense breasts. They also found that for every 2,000 women screened from age 50 to age 74, adding DBT would prevent 1 breast cancer death and 810 false-positive screening examinations.¹⁶

In addition, some have expressed concern that adding DBT to standard digital mammography increases radiation exposure. In fact, the radiation dose with DBT is similar to that with standard 2D digital mammography. Thus, when acquired together, combined digital mammography and DBT screening leads to twice the radiation dose compared with digital mammography alone.¹⁷ Nevertheless, this increased dose remains well below the FDA limits for a screening examination. In addition, the FDA has approved software that allows reconstruction of 2D synthetic views from the 3D data set, which will eventually bring radiation dose levels down to levels comparable to those of conventional digital mammography.¹⁷

Given that DBT is built into newer mammography units and is available as an add-on feature for existing units, its use is likely to increase even faster than digital mammography did when it replaced screen-film mammography in the previous decade.⁴ Its adoption by screening facilities, however, remains variable, and patients wishing to obtain combined DBT and digital mammography screening may have to travel to a different facility from their usual place of screening.¹⁸

Moreover, not all insurance companies cover DBT, resulting in additional out-of-pocket costs to the patient. It is currently unclear how individual facilities are offering DBT services, including how patients are selected for additional DBT and if they are offered the choice to add or forego DBT screening in combination with standard digital mammography.

SUMMARY: AN EMERGING TECHNOLOGY

DBT is an emerging imaging technology that allows the radiologist to view breast images in slices, as in computed tomography. DBT images can be obtained using the same breast compression that women already undergo for 2D digital mammography for breast cancer screening.

At this time, adding DBT to digital mammography screening nearly doubles the radiation exposure to the patient. However, new software is available that allows creation of synthetic 2D views from the 3D data set, resulting in radiation exposure that is similar to conventional digital mammography.

Although there are no published randomized controlled trials assessing the benefit of DBT over 2D digital mammography for breast cancer screening, prospective observational studies suggest that DBT may reduce false-positive recall rates and increase cancer detection rates when used in population-based screening programs. Assuming that additional breast cancer detection contributes to improved clinical outcomes, women with dense breasts may benefit more than women without dense breasts.

No national organizations currently recommend DBT for primary breast cancer screening. Ideally, future studies would determine whether DBT screening reduces breast cancer mortality. Since this research may not be feasible, surrogate clinical outcomes, such as a decrease in interval breast cancer rates and impact on stage at time of diagnosis, would allow us to more confidently recommend this new technology.

Each year, millions of women undergo mammography in the hope of decreasing their risk of dying of breast cancer. The effectiveness of screening mammography, however, continues to be debated.

While most randomized controlled trials have demonstrated significantly lower mortality rates in women who undergo screening, not all trials have. Most experts agree that screening mammography programs decrease breast cancer mortality rates by 12% to 33%.^1,2 But some point out that although mammography programs clearly detect more cases of breast cancer, some proportion of this detection may include “overdiagnosis” of cancers that would not have caused morbidity or mortality, including ductal carcinoma in situ. Also, although deaths from breast cancer have decreased in the United States, at least some of the decrease may be due to more effective treatment rather than early detection.

Moreover, screening has well-documented harms. False-positive results cause alarm and expose women to needless follow-up imaging and biopsies, with their attendant inconvenience, discomfort, risks, and costs. Conversely, false-negative results (especially common in women with dense breasts) lead to missed diagnosis and a false sense of security.

How could programs and technology be improved to make screening more beneficial, both for patients and for society as a whole? A major improvement would be if mammography could be made more sensitive and specific for detecting invasive cancers, with fewer false-positive results. Lower cost and less frequent screening would also be major improvements.

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, may be a way to improve the value of breast cancer screening programs. In 2011, the US Food and Drug Administration (FDA) approved DBT for all mammographic indications, including screening.

WHAT IS TOMOSYNTHESIS?

In DBT, the x-ray source is rotated in an arc around the patient’s breast (Figure 1), generating a 3D image.³ DBT is now routinely built into newer-generation mammography units. The 3D projections of DBT are obtained during the same breast compression required for standard 2D digital mammography. Thus, DBT requires minimal additional time on the part of the patient and the technologist.⁴

The 3D images are processed and sent to a viewing station, where a radiologist can interpret them next to 2D images. The radiologist has the ability to scroll through the DBT projections slice by slice, as in other cross-sectional imaging examinations. However, given the larger number of images compared with digital mammography, DBT requires more time for interpretation, interrupting the workflow. A population-based observational study suggested that combined digital mammography and DBT screening examinations take twice as long to interpret.⁵

The main advantage of DBT is that it can mitigate the problem of overlapping breast tissue on standard digital projections. These areas of focal asymmetry may represent suspicious masses—or merely overlapping breast parenchyma. When areas of focal asymmetry are found on 2D digital mammography without DBT, patients need to come back for further diagnostic imaging to resolve the finding.⁶ In addition, especially in women with dense breasts, areas of overlapping tissue can have a masking effect, obscuring small breast cancers.⁷

Images courtesy of Diana L. Lam, MD, University of Washington, Seattle.

For breast cancer screening, DBT is read in conjunction with standard digital mammography. By allowing examination of the breast parenchyma in thin slices, DBT decreases the interpretive issue of overlapping breast parenchyma and the masking effect, potentially leading to fewer false-positive results and higher rates of cancer detection (Figure 2).

EFFECTIVENESS OF TOMOSYNTHESIS

There is limited evidence at this time to support the addition of DBT to digital mammography for primary breast cancer screening, with no published randomized trials that assessed outcomes. However, 2 population-based trials in Europe have prospectively assessed DBT plus digital mammography as a primary screening strategy: the Screening With Tomosynthesis or Standard Mammography (STORM) trial⁸ and the Oslo tomosynthesis screening trial.⁵ Only the STORM trial reported first-year interval cancer rates, from which the sensitivity and specificity of DBT plus 2D digital mammography could be calculated and compared with those of 2D digital mammography alone.⁸

In April 2013, the Oslo tomosynthesis screening trial published interim results of its prospective cohort study of 12,631 Norwegian women ages 50 to 69.⁵ Women were invited to participate based on the availability of technical staff and imaging systems at the time of screening, and all participants underwent digital mammography and DBT. Images were read independently by 4 radiologists using a double-reader protocol.

The interim results suggest that adding DBT to digital mammography increased cancer detection rates by 31% and decreased the false-positive rate by 13% compared with 2D digital mammography alone (Table 1). However, the double-reader protocol in this study differs from typical single-reader protocols in the United States, limiting the applicability of the findings.

The STORM trial: Low sensitivity

The STORM trial is a prospective cohort study that included 7,292 women without symptoms, at average risk, age 48 and older, who participated in national breast cancer screening services in northern Italy. Each participant underwent digital mammography and DBT. The examinations were read sequentially (digital mammography first, then DBT plus digital mammography) either by a single radiologist, as is most common in the United States, or by 2 radiologists, as is standard in Europe.

Using the single-reader strategy, adding DBT significantly increased cancer detection rates and reduced the total recall rate (Table 1). Sensitivity was 85% vs 54%, and specificity was 97% vs 96%.^8,9

Of note, the sensitivity of 54% for digital mammography in the STORM trial is substantially lower than the sensitivity of digital mammography reported in the United States.¹⁰

Friedewald et al confirmed Oslo and STORM

To date, the largest US study of DBT plus digital mammography for breast cancer screening was a multicenter retrospective cohort study by Friedewald et al in 2014.¹¹ This study compared cancer detection and recall rates before and after the implementation of DBT at 13 breast centers and evaluated a total of 454,850 examinations (173,663 with DBT plus digital mammography and 281,187 with digital mammography only).

Overall, the recall rate decreased significantly after DBT was adopted and the cancer detection rate increased, findings consistent with those of the STORM and Oslo trials (Table 1). Adding DBT detected invasive cancers at a higher rate than 2D digital mammography alone (4.1/1000 vs 2.9/1,000), while there was no significant difference in ductal carcinoma in situ detection rates. This suggests that the additional cancers detected by DBT may be more clinically important. Nevertheless, the number of biopsies with negative results also increased, suggesting that adding DBT may pose potential harms.

In 2016, Rafferty et al¹² published an additional analysis of the data from Friedewald et al, concluding that adding DBT to 2D digital mammography increased the cancer detection rate more in women with heterogeneously dense breasts than in those with either nondense breasts or extremely dense breasts.¹² The reduction in recall rate was also greatest in the heterogeneously dense subgroup.

Insufficient evidence to recommend

Most other cohort studies comparing DBT and digital mammography have had findings similar to those of the European prospective studies and the large US retrospective cohort study, with the addition of DBT to mammography reducing recall rates and increasing cancer detection rates.¹³ However, many of these studies were subject to potential selection bias and did not provide information on the cancer risk of the participants. In addition, no studies have assessed clinical outcomes such as breast cancer stage at diagnosis or interval cancers, let alone breast cancer mortality.

Rigorous studies need to be done in the United States, using the standard single-reader protocol most often used in this country, to ascertain the clinical outcomes of DBT plus digital mammography for breast cancer screening for women at average risk. A 2016 review cited a dearth of high-quality US studies assessing the role of DBT in primary breast cancer.¹³

The US Preventive Services Task Force, in its 2016 guidelines for breast cancer screening, concluded that there was insufficient evidence to assess the harms and benefits of DBT as a method of breast cancer screening, including adjunctive screening in women with dense breasts.¹

Similarly, the American College of Physicians has advised against screening average-risk women for breast cancer using DBT.¹⁴

APPROVAL, DISSEMINATION, COSTS, AND CHOICE FOR PATIENTS

Even with early promising data suggesting that DBT can increase cancer detection rates and decrease false-positive results when added to routine screening mammography, the rapid diffusion of DBT into clinical practice is outpacing evidence of its effectiveness.⁴ This adoption was spurred in January 2015 when the Centers for Medicare and Medicaid Services added a Current Procedural Terminology code for DBT, allowing for additional reimbursement for it for all mammography indications.¹⁵ Still, the use of DBT in community settings is inconsistent, given the significant up-front costs associated with equipment purchases and variable reimbursement by private insurers who consider the technology experimental.

For the US healthcare system as a whole, it is uncertain whether the purported benefits of DBT will outweigh the additional costs associated with its use. The average reimbursement for a routine digital mammography examination is $135; adding DBT adds an average of $56 to the cost.¹⁵

Using an established, discrete-event breast cancer simulation model, a team of investigators evaluated the cost-effectiveness of combined biennial digital mammography and DBT screening compared with biennial digital mammography screening alone in US women with dense breasts.¹⁶ They found that biennial combined screening is likely to be cost-effective in US women with dense breasts. They also found that for every 2,000 women screened from age 50 to age 74, adding DBT would prevent 1 breast cancer death and 810 false-positive screening examinations.¹⁶

In addition, some have expressed concern that adding DBT to standard digital mammography increases radiation exposure. In fact, the radiation dose with DBT is similar to that with standard 2D digital mammography. Thus, when acquired together, combined digital mammography and DBT screening leads to twice the radiation dose compared with digital mammography alone.¹⁷ Nevertheless, this increased dose remains well below the FDA limits for a screening examination. In addition, the FDA has approved software that allows reconstruction of 2D synthetic views from the 3D data set, which will eventually bring radiation dose levels down to levels comparable to those of conventional digital mammography.¹⁷

Given that DBT is built into newer mammography units and is available as an add-on feature for existing units, its use is likely to increase even faster than digital mammography did when it replaced screen-film mammography in the previous decade.⁴ Its adoption by screening facilities, however, remains variable, and patients wishing to obtain combined DBT and digital mammography screening may have to travel to a different facility from their usual place of screening.¹⁸

Moreover, not all insurance companies cover DBT, resulting in additional out-of-pocket costs to the patient. It is currently unclear how individual facilities are offering DBT services, including how patients are selected for additional DBT and if they are offered the choice to add or forego DBT screening in combination with standard digital mammography.

SUMMARY: AN EMERGING TECHNOLOGY

DBT is an emerging imaging technology that allows the radiologist to view breast images in slices, as in computed tomography. DBT images can be obtained using the same breast compression that women already undergo for 2D digital mammography for breast cancer screening.

At this time, adding DBT to digital mammography screening nearly doubles the radiation exposure to the patient. However, new software is available that allows creation of synthetic 2D views from the 3D data set, resulting in radiation exposure that is similar to conventional digital mammography.

Although there are no published randomized controlled trials assessing the benefit of DBT over 2D digital mammography for breast cancer screening, prospective observational studies suggest that DBT may reduce false-positive recall rates and increase cancer detection rates when used in population-based screening programs. Assuming that additional breast cancer detection contributes to improved clinical outcomes, women with dense breasts may benefit more than women without dense breasts.

No national organizations currently recommend DBT for primary breast cancer screening. Ideally, future studies would determine whether DBT screening reduces breast cancer mortality. Since this research may not be feasible, surrogate clinical outcomes, such as a decrease in interval breast cancer rates and impact on stage at time of diagnosis, would allow us to more confidently recommend this new technology.

Adults with leukemia, lymphoma, multiple myeloma, and other hematologic cancers are living longer, and more than 1.2 million patients with these cancers are alive in the United States.¹ Most adults with nonpediatric cancers are diagnosed in the fifth to seventh decade, and many now survive more than 5 years. The survival rate of patients with most hematologic cancers has doubled since 1974, transforming once-terminal diagnoses into chronic conditions. According to one estimate, there will be 18 million cancer survivors (all types of cancer) by 2022, and nearly 2 million of these will be survivors of hematologic cancers.²

Although survivors of hematologic cancers are at risk of complications of their cancer treatment, they often do not receive routine health maintenance and see their primary care providers only for acute issues.

Primary care providers can play a major role in monitoring the health of hematologic cancer survivors. This requires staying up-to-date on diagnosis, management, and surveillance in this group and being able to address their survivorship issues.³

In this article, we focus on survivorship considerations in patients with previously treated hematologic cancers, including childhood, adolescent, and young-adult cancers. We discuss the role of primary care in the multidisciplinary approach to the continuing care of these patients, and we review innovative technologic solutions to the challenges of delivering care to this group.

SURVIVORSHIP BEGINS AT DIAGNOSIS

The definition of cancer survivorship has changed in the last decade, particularly with hematologic cancers.⁴

Survivorship was once considered the time after the patient successfully completed cancer treatment. But most patients with hematologic cancers will likely need to continue treatment until they die, with essentially unpredictable and intermittent periods of remission and relapse. Advances in cancer treatment and supportive care have led to longer life. Thus, a commonly recognized definition of survivorship begins at diagnosis rather than later in the disease course and continues through the balance of the patient’s life.⁵

The survivorship care plan

In 2005, the Institute of Medicine released a report⁶ calling attention to cancer survivors and their special needs. At that time, a growing number of patients were not returning to their primary care physicians to receive health maintenance after completing their cancer treatment. A proposed solution was for the oncologist to develop a personalized survivorship care plan, which would help the patient understand the treatments received, the importance of health maintenance, and the need for follow-up surveillance.⁵

The survivorship care plan was originally intended for patients who had completed their cancer treatment. But patients with hematologic cancers tend to need lifelong treatment. Nevertheless, major organizations such as the American Society of Hematology and the American Society of Clinical Oncology consider a survivorship care plan an essential part of cancer care for all patients and not just those with solid tumors.⁷ The plan should consist of a written treatment summary and recommendations for follow-up care.

EFFECTS OF HEMATOLOGIC CANCER AND ITS TREATMENT

Hematologic cancers and their treatment put patients at risk of many complications, including endocrinopathies, such as hypothyroidism or diabetes secondary to chronic steroid and immunosuppressant use, and cardiovascular events, such as congestive heart failure and stroke due to high-dose chemotherapy. Survivors are also at risk of secondary cancers and recurrence of the primary cancer.^8–15

Despite the gravity of a cancer diagnosis, cancer patients do not always adhere to a healthy lifestyle. A survey of over 400,000 cancer survivors found that 15% were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in physical activity during the previous 30 days.¹⁶

THE PRIMARY CARE CLINICIAN AND SURVIVORSHIP CARE

Many hematologic oncology practices include not only medical oncologists but also ancillary team members such as nurse practitioners, nurse specialists, physician assistants, registered nurses, and in some cases a social worker or nutritionist. Patients with hematologic cancers often rely on this team for most of their care while undergoing cancer treatment.

Depending on the type of cancer, and especially after a period of stable disease or remission, some patients transition away from the oncology team, particularly if they live far away, and receive care from their local primary care clinician.

Although the Institute for Medicine intended the survivorship care plan⁶ to be a patient-focused tool, primary care providers can benefit from it too. In survey of oncologists and primary care providers in the United States,¹⁷ 49% of the 1,130 oncologists said they almost always provided care plans to patients, and 85% perceived a greater benefit for primary care providers to have these plans than for cancer survivors. However, only 13% of the 1,120 primary care providers surveyed said they consistently received a care plan from the oncologist. The study suggests that oncologists should make a better effort to share these plans with primary care providers to enhance the coordination of care.

COMPONENTS OF A SURVIVORSHIP CARE PLAN AND SELF-MANAGEMENT

Although personalized survivorship care plans are not routinely used in patients with blood cancers,¹⁸ they are as important in hematologic cancer survivors as in patients with solid tumors.

The plan should consist of a treatment summary and information on essential components of a healthy lifestyle and should take into consideration coordination of care among primary and other providers, health maintenance recommendations, information on early detection and screening, and psychosocial welfare. Guidance on preventive screening for physical, financial, and psychosocial well-being should be generated by the oncology team or primary care provider and can be helpful to patients and caregivers as they navigate the healthcare system. (See https://cancercontrol.cancer.gov/pdf/ASCO-Survivorship-Care-Plan.pdf for a sample survivorship care plan.)

Although patients with hematologic cancer often have a highly variable course with multiple periods of remission and relapse, the survivorship care plan and treatment summary are essential components of their ongoing care.

Self-management of chronic illness refers to daily activities to keep the illness under control, minimize its impact on physical health and function, and help the patient cope with the psychosocial sequelae of the illness.¹⁹ Empowering patients and their caregivers to take control of their health is an essential component of survivorship care. Patients and caregivers can be valuable partners to primary care providers and the oncology team in ongoing care to ensure proper testing and monitoring for secondary illnesses.

Implementation of a survivorship care plan can be facilitated by integrating the plan and treatment summaries into the patient’s electronic medical record and encouraging the patient to be a part of the process.²⁰ Many electronic medical record systems such as Epic can automatically fill in treatment summaries and provide patients access to a survivorship care plan tailored to their needs, but these features are not routinely used, and output can be lengthy and hard to follow.^21,22

There has been a surge in research in information technology and care plan delivery since the Health Information Technology for Economic and Clinical Health (HITECH) Act was passed in 2009,²³ specifically in innovative strategies to proactively screen for, assess, and manage disease- and treatment-related symptoms in cancer survivors. As a result, patients and families can be more engaged in their care, and providers can better guide survivorship concerns.

Providers can create their own survivorship care plans or use electronic resources to generate one. The American Society of Clinical Oncology and the National Comprehensive Cancer Network provide printed templates in which the patient, primary care provider, or oncology team can complete a care plan. Newer electronic platforms such as the Carevive system are also available. Brief electronic outcome questionnaires can be completed by the patient at home or in the waiting room to assess symptoms, evaluate health maintenance practices, and generate a plan of care to review with the patient.

EMERGING TECHNOLOGY: TELEMEDICINE, VIRTUAL VISITS

Technology can help patients and the healthcare team in survivorship monitoring. Telemedicine, the exchange of medical information via electronic communication, includes video conferencing for patient consultations, transmission of still images, patient portals, and remote monitoring of vital signs.²⁴

This technology is critical to deliver high-quality acute and chronic care to patients in remote or rural areas, locally to patients unable to travel to the clinic, and internationally.^25–28 As patients become more technologically savvy, providers can try novel strategies to provide patients access to care. As of September 2015, there were at least 165,000 health applications (apps) for smartphones to help patients better manage aspects of their care such as diet, exercise, blood pressure, and blood sugar levels.²⁹

Video technology such as Express Care Online allows patients to connect with their healthcare providers for video and virtual visits without having to leave home or take time off from work. It also allows oncology providers to have virtual face-to-face contact with patients undergoing treatment phases, and primary care providers to have easier contact with patients during maintenance and remission phases. This technology allows for earlier detection of illness and provides broader access to care. Virtual visits may even prevent needless hospitalization in some cases or, conversely, alert the physician to tell the patient with alarming symptoms of an acute event, that it is time to go to the hospital.

SURVEILLANCE FOR LATE TREATMENT EFFECTS

Guidelines for surveillance for late treatment effects include the following:

• Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer³⁰
• National Comprehensive Cancer Network Guidelines for Age-Related Recommendations: Adolescent and Young Adult Oncology³¹
• National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site and Survivorship³¹
• American Society for Blood and Marrow Transplantation, for survivors of hematopoietic cell transplantation.³²

Survivors of childhood blood cancers are at increased risk of cardiac effects of high-dose or anthracycline chemotherapy (eg, doxorubicin for lymphoma, idarubicin for leukemia), skin cancer, sex-specific cancers (breast cancer, cervical cancer, prostate cancer), and osteoporosis.^5,30,33,34

For adult survivors of childhood cancers, it is generally recommended to screen for secondary conditions according to the US Preventive Services Task Force. The clinician must also consider the age at cancer diagnosis (child, young adult, or adult), the length of time since chemotherapy (months vs years), and the type of chemotherapy received.

A myriad of recommendations exist according to cancer type, location, stage, and age at diagnosis, but no clear consensus for screening exists. The major survivorship surveillance guidelines of the Children’s Oncology Group, National Comprehensive Cancer Network, and American Society for Blood and Marrow Transplantation are very detailed and lengthy and therefore not user-friendly for the busy clinician. While these guidelines contain minor differences as to what to test for and when to test, they differ mainly in considerations of the length of exposure to chemotherapy and radiation (eg, children, young adults, and older adults), length of time from completion of treatment to assessment of late complications, and whether the patient underwent hematopoietic stem cell transplant.^35,36

Table 1 reviews hematologic malignancies and conditions that blood cancer survivors are at risk for and general routine screening recommendations.^{5,22,30,33,34,36–39} In general, an assessment by a healthcare provider is recommended annually to screen for late effects of cancer and its treatment. Most important are screening for cardiac toxicity, giving immunizations, and preventing second cancers.

Table 1 reflects general recommendations for healthcare screening in childhood, adolescent, or young adult cancer survivors who see adult primary care physicians and for adult cancer survivors (acute leukemias, lymphomas, and multiple myeloma).

Table 2 focuses on screening and prevention specifically after hematopoietic cell transplantation.^30,32 These tables are not meant to be all-inclusive but to provide evidence-based recommendations for health surveillance at a glance.

SURVIVORS NEED ONGOING CARE

Recent successes in the treatment of hematologic cancers have led to dramatic changes in the overall health of these patients. In many instances, cancer survivors in the United States are considered to have a chronic illness with survival rates surpassing those in the past. A longer life span is counterbalanced by cumulative physical, financial, and psychosocial issues that require a multidisciplinary team to monitor and manage.

Childhood cancer survivors face the same psychosocial and financial issues as survivors of adult-onset cancers and are at heightened risk of preventable conditions. Ultimately, it is up to the survivor to self-manage many long-term treatment-related symptoms.

A survivorship care plan and treatment summary to guide the patient, primary provider, and oncology team is an essential component of quality care. Screening guidelines vary according to the age at treatment and length of time from therapy, but general screening and the use of technology and information technology solutions to deliver care can help survivors. These solutions have the potential to transform healthcare delivery in the future and provide the opportunity for ongoing, comprehensive care.

Adults with leukemia, lymphoma, multiple myeloma, and other hematologic cancers are living longer, and more than 1.2 million patients with these cancers are alive in the United States.¹ Most adults with nonpediatric cancers are diagnosed in the fifth to seventh decade, and many now survive more than 5 years. The survival rate of patients with most hematologic cancers has doubled since 1974, transforming once-terminal diagnoses into chronic conditions. According to one estimate, there will be 18 million cancer survivors (all types of cancer) by 2022, and nearly 2 million of these will be survivors of hematologic cancers.²

Although survivors of hematologic cancers are at risk of complications of their cancer treatment, they often do not receive routine health maintenance and see their primary care providers only for acute issues.

Primary care providers can play a major role in monitoring the health of hematologic cancer survivors. This requires staying up-to-date on diagnosis, management, and surveillance in this group and being able to address their survivorship issues.³

In this article, we focus on survivorship considerations in patients with previously treated hematologic cancers, including childhood, adolescent, and young-adult cancers. We discuss the role of primary care in the multidisciplinary approach to the continuing care of these patients, and we review innovative technologic solutions to the challenges of delivering care to this group.

SURVIVORSHIP BEGINS AT DIAGNOSIS

The definition of cancer survivorship has changed in the last decade, particularly with hematologic cancers.⁴

Survivorship was once considered the time after the patient successfully completed cancer treatment. But most patients with hematologic cancers will likely need to continue treatment until they die, with essentially unpredictable and intermittent periods of remission and relapse. Advances in cancer treatment and supportive care have led to longer life. Thus, a commonly recognized definition of survivorship begins at diagnosis rather than later in the disease course and continues through the balance of the patient’s life.⁵

The survivorship care plan

In 2005, the Institute of Medicine released a report⁶ calling attention to cancer survivors and their special needs. At that time, a growing number of patients were not returning to their primary care physicians to receive health maintenance after completing their cancer treatment. A proposed solution was for the oncologist to develop a personalized survivorship care plan, which would help the patient understand the treatments received, the importance of health maintenance, and the need for follow-up surveillance.⁵

The survivorship care plan was originally intended for patients who had completed their cancer treatment. But patients with hematologic cancers tend to need lifelong treatment. Nevertheless, major organizations such as the American Society of Hematology and the American Society of Clinical Oncology consider a survivorship care plan an essential part of cancer care for all patients and not just those with solid tumors.⁷ The plan should consist of a written treatment summary and recommendations for follow-up care.

EFFECTS OF HEMATOLOGIC CANCER AND ITS TREATMENT

Hematologic cancers and their treatment put patients at risk of many complications, including endocrinopathies, such as hypothyroidism or diabetes secondary to chronic steroid and immunosuppressant use, and cardiovascular events, such as congestive heart failure and stroke due to high-dose chemotherapy. Survivors are also at risk of secondary cancers and recurrence of the primary cancer.^8–15

Despite the gravity of a cancer diagnosis, cancer patients do not always adhere to a healthy lifestyle. A survey of over 400,000 cancer survivors found that 15% were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in physical activity during the previous 30 days.¹⁶

THE PRIMARY CARE CLINICIAN AND SURVIVORSHIP CARE

Many hematologic oncology practices include not only medical oncologists but also ancillary team members such as nurse practitioners, nurse specialists, physician assistants, registered nurses, and in some cases a social worker or nutritionist. Patients with hematologic cancers often rely on this team for most of their care while undergoing cancer treatment.

Depending on the type of cancer, and especially after a period of stable disease or remission, some patients transition away from the oncology team, particularly if they live far away, and receive care from their local primary care clinician.

Although the Institute for Medicine intended the survivorship care plan⁶ to be a patient-focused tool, primary care providers can benefit from it too. In survey of oncologists and primary care providers in the United States,¹⁷ 49% of the 1,130 oncologists said they almost always provided care plans to patients, and 85% perceived a greater benefit for primary care providers to have these plans than for cancer survivors. However, only 13% of the 1,120 primary care providers surveyed said they consistently received a care plan from the oncologist. The study suggests that oncologists should make a better effort to share these plans with primary care providers to enhance the coordination of care.

COMPONENTS OF A SURVIVORSHIP CARE PLAN AND SELF-MANAGEMENT

Although personalized survivorship care plans are not routinely used in patients with blood cancers,¹⁸ they are as important in hematologic cancer survivors as in patients with solid tumors.

The plan should consist of a treatment summary and information on essential components of a healthy lifestyle and should take into consideration coordination of care among primary and other providers, health maintenance recommendations, information on early detection and screening, and psychosocial welfare. Guidance on preventive screening for physical, financial, and psychosocial well-being should be generated by the oncology team or primary care provider and can be helpful to patients and caregivers as they navigate the healthcare system. (See https://cancercontrol.cancer.gov/pdf/ASCO-Survivorship-Care-Plan.pdf for a sample survivorship care plan.)

Although patients with hematologic cancer often have a highly variable course with multiple periods of remission and relapse, the survivorship care plan and treatment summary are essential components of their ongoing care.

Self-management of chronic illness refers to daily activities to keep the illness under control, minimize its impact on physical health and function, and help the patient cope with the psychosocial sequelae of the illness.¹⁹ Empowering patients and their caregivers to take control of their health is an essential component of survivorship care. Patients and caregivers can be valuable partners to primary care providers and the oncology team in ongoing care to ensure proper testing and monitoring for secondary illnesses.

Implementation of a survivorship care plan can be facilitated by integrating the plan and treatment summaries into the patient’s electronic medical record and encouraging the patient to be a part of the process.²⁰ Many electronic medical record systems such as Epic can automatically fill in treatment summaries and provide patients access to a survivorship care plan tailored to their needs, but these features are not routinely used, and output can be lengthy and hard to follow.^21,22

There has been a surge in research in information technology and care plan delivery since the Health Information Technology for Economic and Clinical Health (HITECH) Act was passed in 2009,²³ specifically in innovative strategies to proactively screen for, assess, and manage disease- and treatment-related symptoms in cancer survivors. As a result, patients and families can be more engaged in their care, and providers can better guide survivorship concerns.

Providers can create their own survivorship care plans or use electronic resources to generate one. The American Society of Clinical Oncology and the National Comprehensive Cancer Network provide printed templates in which the patient, primary care provider, or oncology team can complete a care plan. Newer electronic platforms such as the Carevive system are also available. Brief electronic outcome questionnaires can be completed by the patient at home or in the waiting room to assess symptoms, evaluate health maintenance practices, and generate a plan of care to review with the patient.

EMERGING TECHNOLOGY: TELEMEDICINE, VIRTUAL VISITS

Technology can help patients and the healthcare team in survivorship monitoring. Telemedicine, the exchange of medical information via electronic communication, includes video conferencing for patient consultations, transmission of still images, patient portals, and remote monitoring of vital signs.²⁴

This technology is critical to deliver high-quality acute and chronic care to patients in remote or rural areas, locally to patients unable to travel to the clinic, and internationally.^25–28 As patients become more technologically savvy, providers can try novel strategies to provide patients access to care. As of September 2015, there were at least 165,000 health applications (apps) for smartphones to help patients better manage aspects of their care such as diet, exercise, blood pressure, and blood sugar levels.²⁹

Video technology such as Express Care Online allows patients to connect with their healthcare providers for video and virtual visits without having to leave home or take time off from work. It also allows oncology providers to have virtual face-to-face contact with patients undergoing treatment phases, and primary care providers to have easier contact with patients during maintenance and remission phases. This technology allows for earlier detection of illness and provides broader access to care. Virtual visits may even prevent needless hospitalization in some cases or, conversely, alert the physician to tell the patient with alarming symptoms of an acute event, that it is time to go to the hospital.

SURVEILLANCE FOR LATE TREATMENT EFFECTS

Guidelines for surveillance for late treatment effects include the following:

• Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer³⁰
• National Comprehensive Cancer Network Guidelines for Age-Related Recommendations: Adolescent and Young Adult Oncology³¹
• National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site and Survivorship³¹
• American Society for Blood and Marrow Transplantation, for survivors of hematopoietic cell transplantation.³²

Survivors of childhood blood cancers are at increased risk of cardiac effects of high-dose or anthracycline chemotherapy (eg, doxorubicin for lymphoma, idarubicin for leukemia), skin cancer, sex-specific cancers (breast cancer, cervical cancer, prostate cancer), and osteoporosis.^5,30,33,34

For adult survivors of childhood cancers, it is generally recommended to screen for secondary conditions according to the US Preventive Services Task Force. The clinician must also consider the age at cancer diagnosis (child, young adult, or adult), the length of time since chemotherapy (months vs years), and the type of chemotherapy received.

A myriad of recommendations exist according to cancer type, location, stage, and age at diagnosis, but no clear consensus for screening exists. The major survivorship surveillance guidelines of the Children’s Oncology Group, National Comprehensive Cancer Network, and American Society for Blood and Marrow Transplantation are very detailed and lengthy and therefore not user-friendly for the busy clinician. While these guidelines contain minor differences as to what to test for and when to test, they differ mainly in considerations of the length of exposure to chemotherapy and radiation (eg, children, young adults, and older adults), length of time from completion of treatment to assessment of late complications, and whether the patient underwent hematopoietic stem cell transplant.^35,36

Table 1 reviews hematologic malignancies and conditions that blood cancer survivors are at risk for and general routine screening recommendations.^{5,22,30,33,34,36–39} In general, an assessment by a healthcare provider is recommended annually to screen for late effects of cancer and its treatment. Most important are screening for cardiac toxicity, giving immunizations, and preventing second cancers.

Table 1 reflects general recommendations for healthcare screening in childhood, adolescent, or young adult cancer survivors who see adult primary care physicians and for adult cancer survivors (acute leukemias, lymphomas, and multiple myeloma).

Table 2 focuses on screening and prevention specifically after hematopoietic cell transplantation.^30,32 These tables are not meant to be all-inclusive but to provide evidence-based recommendations for health surveillance at a glance.

SURVIVORS NEED ONGOING CARE

Recent successes in the treatment of hematologic cancers have led to dramatic changes in the overall health of these patients. In many instances, cancer survivors in the United States are considered to have a chronic illness with survival rates surpassing those in the past. A longer life span is counterbalanced by cumulative physical, financial, and psychosocial issues that require a multidisciplinary team to monitor and manage.

Childhood cancer survivors face the same psychosocial and financial issues as survivors of adult-onset cancers and are at heightened risk of preventable conditions. Ultimately, it is up to the survivor to self-manage many long-term treatment-related symptoms.

A survivorship care plan and treatment summary to guide the patient, primary provider, and oncology team is an essential component of quality care. Screening guidelines vary according to the age at treatment and length of time from therapy, but general screening and the use of technology and information technology solutions to deliver care can help survivors. These solutions have the potential to transform healthcare delivery in the future and provide the opportunity for ongoing, comprehensive care.

Adults with leukemia, lymphoma, multiple myeloma, and other hematologic cancers are living longer, and more than 1.2 million patients with these cancers are alive in the United States.¹ Most adults with nonpediatric cancers are diagnosed in the fifth to seventh decade, and many now survive more than 5 years. The survival rate of patients with most hematologic cancers has doubled since 1974, transforming once-terminal diagnoses into chronic conditions. According to one estimate, there will be 18 million cancer survivors (all types of cancer) by 2022, and nearly 2 million of these will be survivors of hematologic cancers.²

Although survivors of hematologic cancers are at risk of complications of their cancer treatment, they often do not receive routine health maintenance and see their primary care providers only for acute issues.

Primary care providers can play a major role in monitoring the health of hematologic cancer survivors. This requires staying up-to-date on diagnosis, management, and surveillance in this group and being able to address their survivorship issues.³

In this article, we focus on survivorship considerations in patients with previously treated hematologic cancers, including childhood, adolescent, and young-adult cancers. We discuss the role of primary care in the multidisciplinary approach to the continuing care of these patients, and we review innovative technologic solutions to the challenges of delivering care to this group.

SURVIVORSHIP BEGINS AT DIAGNOSIS

The definition of cancer survivorship has changed in the last decade, particularly with hematologic cancers.⁴

Survivorship was once considered the time after the patient successfully completed cancer treatment. But most patients with hematologic cancers will likely need to continue treatment until they die, with essentially unpredictable and intermittent periods of remission and relapse. Advances in cancer treatment and supportive care have led to longer life. Thus, a commonly recognized definition of survivorship begins at diagnosis rather than later in the disease course and continues through the balance of the patient’s life.⁵

The survivorship care plan

In 2005, the Institute of Medicine released a report⁶ calling attention to cancer survivors and their special needs. At that time, a growing number of patients were not returning to their primary care physicians to receive health maintenance after completing their cancer treatment. A proposed solution was for the oncologist to develop a personalized survivorship care plan, which would help the patient understand the treatments received, the importance of health maintenance, and the need for follow-up surveillance.⁵

The survivorship care plan was originally intended for patients who had completed their cancer treatment. But patients with hematologic cancers tend to need lifelong treatment. Nevertheless, major organizations such as the American Society of Hematology and the American Society of Clinical Oncology consider a survivorship care plan an essential part of cancer care for all patients and not just those with solid tumors.⁷ The plan should consist of a written treatment summary and recommendations for follow-up care.

EFFECTS OF HEMATOLOGIC CANCER AND ITS TREATMENT

Hematologic cancers and their treatment put patients at risk of many complications, including endocrinopathies, such as hypothyroidism or diabetes secondary to chronic steroid and immunosuppressant use, and cardiovascular events, such as congestive heart failure and stroke due to high-dose chemotherapy. Survivors are also at risk of secondary cancers and recurrence of the primary cancer.^8–15

Despite the gravity of a cancer diagnosis, cancer patients do not always adhere to a healthy lifestyle. A survey of over 400,000 cancer survivors found that 15% were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in physical activity during the previous 30 days.¹⁶

THE PRIMARY CARE CLINICIAN AND SURVIVORSHIP CARE

Many hematologic oncology practices include not only medical oncologists but also ancillary team members such as nurse practitioners, nurse specialists, physician assistants, registered nurses, and in some cases a social worker or nutritionist. Patients with hematologic cancers often rely on this team for most of their care while undergoing cancer treatment.

Depending on the type of cancer, and especially after a period of stable disease or remission, some patients transition away from the oncology team, particularly if they live far away, and receive care from their local primary care clinician.

Although the Institute for Medicine intended the survivorship care plan⁶ to be a patient-focused tool, primary care providers can benefit from it too. In survey of oncologists and primary care providers in the United States,¹⁷ 49% of the 1,130 oncologists said they almost always provided care plans to patients, and 85% perceived a greater benefit for primary care providers to have these plans than for cancer survivors. However, only 13% of the 1,120 primary care providers surveyed said they consistently received a care plan from the oncologist. The study suggests that oncologists should make a better effort to share these plans with primary care providers to enhance the coordination of care.

COMPONENTS OF A SURVIVORSHIP CARE PLAN AND SELF-MANAGEMENT

Although personalized survivorship care plans are not routinely used in patients with blood cancers,¹⁸ they are as important in hematologic cancer survivors as in patients with solid tumors.

The plan should consist of a treatment summary and information on essential components of a healthy lifestyle and should take into consideration coordination of care among primary and other providers, health maintenance recommendations, information on early detection and screening, and psychosocial welfare. Guidance on preventive screening for physical, financial, and psychosocial well-being should be generated by the oncology team or primary care provider and can be helpful to patients and caregivers as they navigate the healthcare system. (See https://cancercontrol.cancer.gov/pdf/ASCO-Survivorship-Care-Plan.pdf for a sample survivorship care plan.)

Although patients with hematologic cancer often have a highly variable course with multiple periods of remission and relapse, the survivorship care plan and treatment summary are essential components of their ongoing care.

Self-management of chronic illness refers to daily activities to keep the illness under control, minimize its impact on physical health and function, and help the patient cope with the psychosocial sequelae of the illness.¹⁹ Empowering patients and their caregivers to take control of their health is an essential component of survivorship care. Patients and caregivers can be valuable partners to primary care providers and the oncology team in ongoing care to ensure proper testing and monitoring for secondary illnesses.

Implementation of a survivorship care plan can be facilitated by integrating the plan and treatment summaries into the patient’s electronic medical record and encouraging the patient to be a part of the process.²⁰ Many electronic medical record systems such as Epic can automatically fill in treatment summaries and provide patients access to a survivorship care plan tailored to their needs, but these features are not routinely used, and output can be lengthy and hard to follow.^21,22

There has been a surge in research in information technology and care plan delivery since the Health Information Technology for Economic and Clinical Health (HITECH) Act was passed in 2009,²³ specifically in innovative strategies to proactively screen for, assess, and manage disease- and treatment-related symptoms in cancer survivors. As a result, patients and families can be more engaged in their care, and providers can better guide survivorship concerns.

Providers can create their own survivorship care plans or use electronic resources to generate one. The American Society of Clinical Oncology and the National Comprehensive Cancer Network provide printed templates in which the patient, primary care provider, or oncology team can complete a care plan. Newer electronic platforms such as the Carevive system are also available. Brief electronic outcome questionnaires can be completed by the patient at home or in the waiting room to assess symptoms, evaluate health maintenance practices, and generate a plan of care to review with the patient.

EMERGING TECHNOLOGY: TELEMEDICINE, VIRTUAL VISITS

Technology can help patients and the healthcare team in survivorship monitoring. Telemedicine, the exchange of medical information via electronic communication, includes video conferencing for patient consultations, transmission of still images, patient portals, and remote monitoring of vital signs.²⁴

This technology is critical to deliver high-quality acute and chronic care to patients in remote or rural areas, locally to patients unable to travel to the clinic, and internationally.^25–28 As patients become more technologically savvy, providers can try novel strategies to provide patients access to care. As of September 2015, there were at least 165,000 health applications (apps) for smartphones to help patients better manage aspects of their care such as diet, exercise, blood pressure, and blood sugar levels.²⁹

Video technology such as Express Care Online allows patients to connect with their healthcare providers for video and virtual visits without having to leave home or take time off from work. It also allows oncology providers to have virtual face-to-face contact with patients undergoing treatment phases, and primary care providers to have easier contact with patients during maintenance and remission phases. This technology allows for earlier detection of illness and provides broader access to care. Virtual visits may even prevent needless hospitalization in some cases or, conversely, alert the physician to tell the patient with alarming symptoms of an acute event, that it is time to go to the hospital.

SURVEILLANCE FOR LATE TREATMENT EFFECTS

Guidelines for surveillance for late treatment effects include the following:

• Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer³⁰
• National Comprehensive Cancer Network Guidelines for Age-Related Recommendations: Adolescent and Young Adult Oncology³¹
• National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site and Survivorship³¹
• American Society for Blood and Marrow Transplantation, for survivors of hematopoietic cell transplantation.³²

Survivors of childhood blood cancers are at increased risk of cardiac effects of high-dose or anthracycline chemotherapy (eg, doxorubicin for lymphoma, idarubicin for leukemia), skin cancer, sex-specific cancers (breast cancer, cervical cancer, prostate cancer), and osteoporosis.^5,30,33,34

For adult survivors of childhood cancers, it is generally recommended to screen for secondary conditions according to the US Preventive Services Task Force. The clinician must also consider the age at cancer diagnosis (child, young adult, or adult), the length of time since chemotherapy (months vs years), and the type of chemotherapy received.

A myriad of recommendations exist according to cancer type, location, stage, and age at diagnosis, but no clear consensus for screening exists. The major survivorship surveillance guidelines of the Children’s Oncology Group, National Comprehensive Cancer Network, and American Society for Blood and Marrow Transplantation are very detailed and lengthy and therefore not user-friendly for the busy clinician. While these guidelines contain minor differences as to what to test for and when to test, they differ mainly in considerations of the length of exposure to chemotherapy and radiation (eg, children, young adults, and older adults), length of time from completion of treatment to assessment of late complications, and whether the patient underwent hematopoietic stem cell transplant.^35,36

Table 1 reviews hematologic malignancies and conditions that blood cancer survivors are at risk for and general routine screening recommendations.^{5,22,30,33,34,36–39} In general, an assessment by a healthcare provider is recommended annually to screen for late effects of cancer and its treatment. Most important are screening for cardiac toxicity, giving immunizations, and preventing second cancers.

Table 1 reflects general recommendations for healthcare screening in childhood, adolescent, or young adult cancer survivors who see adult primary care physicians and for adult cancer survivors (acute leukemias, lymphomas, and multiple myeloma).

Table 2 focuses on screening and prevention specifically after hematopoietic cell transplantation.^30,32 These tables are not meant to be all-inclusive but to provide evidence-based recommendations for health surveillance at a glance.

SURVIVORS NEED ONGOING CARE

Recent successes in the treatment of hematologic cancers have led to dramatic changes in the overall health of these patients. In many instances, cancer survivors in the United States are considered to have a chronic illness with survival rates surpassing those in the past. A longer life span is counterbalanced by cumulative physical, financial, and psychosocial issues that require a multidisciplinary team to monitor and manage.

Childhood cancer survivors face the same psychosocial and financial issues as survivors of adult-onset cancers and are at heightened risk of preventable conditions. Ultimately, it is up to the survivor to self-manage many long-term treatment-related symptoms.

A survivorship care plan and treatment summary to guide the patient, primary provider, and oncology team is an essential component of quality care. Screening guidelines vary according to the age at treatment and length of time from therapy, but general screening and the use of technology and information technology solutions to deliver care can help survivors. These solutions have the potential to transform healthcare delivery in the future and provide the opportunity for ongoing, comprehensive care.

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.