A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.

CASE CONTINUED

The patient continued to feel sick and reported having three to four loose bowel movements per day and mild abdominal pain. His cough and dyspnea persisted.

He had not had contact with anyone who was ill, denied being exposed to animals or insects, and had not consumed unpasteurized dairy products; he recalled having cleaned his military-issue uniforms and equipment 2 to 3 weeks before the symptoms began. He called a military physician to get advice on what else could be causing his symptoms. This physician recommended tests based on potential exposures in Iraq. Tests for brucellosis, visceral leishmaniasis, and Q fever were ordered.

Over the next several days, he began to feel better, and at 3 to 4 weeks after the onset of his symptoms, he felt that he had returned to normal. All tests were negative.

TESTING FOR ATYPICAL PATHOGENS

2. Which of the following would be the most readily available method to confirm the diagnosis?

• Culture
• Polymerase chain reaction (PCR) testing
• Histopathologic testing
• Serologic testing

Testing for atypical pathogens was reasonable in this patient. In addition to an evaluation for parasitic causes of persistent and chronic diarrhea, an evaluation for Q fever, brucellosis, and visceral leishmaniasis via serologic testing was warranted. A variety of tests exist for all of these infections, but serologic tests are the most readily available.

Leishmaniasis testing

Visceral leishmaniasis was traditionally diagnosed by visualizing organisms in splenic or bone marrow aspirates,²⁸ but now serologic tests are available through commercial and public health laboratories such as the CDC. Immunochromatographic tests using recombinant k39 antigen are highly sensitive and specific and have been used in military cases.^29,30

Brucellosis testing

Brucella can be cultured from blood or tissue samples. The laboratory must be alerted, as special media can be used to increase the yield and precautions must be taken to prevent laboratory-acquired infection. Serologic testing is the method most commonly used for diagnosis.³¹

Q fever testing

Q fever can be diagnosed with serologic testing during its acute and convalescent phases.

PCR testing of blood is useful for diagnosing acute disease and is positive before serologic conversion, thus allowing rapid diagnosis and treatment.³² The Joint Biological Agent Identification and Diagnostic System (JBAIDS) PCR platform was studied in a Combat Support Hospital in Iraq for making the rapid diagnosis of Q fever and has since been approved by the US Food and Drug Administration for military use.³³

Culture is beyond the scope of most clinical laboratories and requires specialized cell culture or egg yolk media. In tissue, usually liver tissue obtained in an effort to evaluate hepatitis, the histologic finding of “doughnut” granulomas, or fibrin-encased granulomas, can be suggestive of C burnetii but may be nonspecific and seen with other infections.^23,34

Serologic testing with an immunofluorescence assay (IFA) remains the most common method of diagnosis. It is based on the detection of immunoglobulin G (IgG) and IgM responses against phase I and phase II antigens of C burnetii. After initial infection, the organism displays phase I antigens and is highly infectious. When grown in culture, the organism undergoes phase shifting to a less infectious form with predominantly phase II antigens. Paradoxically, after initial infection in humans, antibody response against phase II antigens is seen first, whereas in chronic infection, a phase I antibody response dominates.^26,35 Phase II antibodies appear around week 2, and 90% of samples from infected people are positive by week 3. A fourfold rise in titer between the acute-phase and convalescent-phase samples confirms the diagnosis.³⁵

A number of serologic assays are available worldwide, but they have different methods and cutoff values, so questions have arisen about the equivalence of the results.^14,36 Serologic cutoffs have been defined in Europe, where most cases of Q fever have been reported.³⁷

CHRONIC Q FEVER

3. Which of the following would be the most likely chronic manifestation of Q fever?

• Pneumonia
• Hepatitis
• Endocarditis
• Chronic fatigue
• Osteomyelitis

Chronic syndromes can develop years to months after untreated or inadequately treated infection and can be serious. Chronic infection can also result after a clinically silent initial infection.^26,38 Culture-negative endocarditis, which occurs in fewer than 1% of patients diagnosed with acute infection, is the most common chronic manifestation (Table 1). Patients with underlying valvular disease, malignancy, or immunosuppression are at greater risk.^38–40

Challenges and controversies

The diagnosis of chronic Q fever remains challenging. Traditionally, elevated phase I IgG titers were considered highly predictive of chronic disease. A cutoff of 1:800 was set, based on retrospective data from chronic cases in Europe, but its generalizability to different assays and patient populations has been unclear. ^14,36,37 Recent reviews and prospective analysis with serial serologic studies in the Dutch outbreak and other sources suggest the positive predictive value (PPV) of phase I IgG titers greater than 1:800 to be lower than previously estimated, largely due to widespread testing and resultant increased seroprevalence assessments. It has been suggested the cutoff be raised to 1:1,600, which still only carries a 59% positive predictive value.^41,42

Chronic fatigue due to Q fever remains a controversial topic and has only been described in Europe, Asia, and Australia. A direct link has yet to be established.⁴³ Additional research is needed, but small studies of prolonged antibiotic treatment have not shown benefit in these cases.⁴⁴

CASE CONTINUED

This patient did well. During a routine physical while enrolled at the Army War College in Carlisle, PA, 6 months after the original presentation, he mentioned his illness to the physician, who then repeated testing for Q fever; the test was positive (Table 2). Subsequently, serum samples from before and after his deployment were tested along with another convalescent-phase sample, and the results demonstrated Q fever seroconversion. He was well and had no physical complaints. He had no heart murmur, and a complete blood count and tests of liver enzymes and inflammatory markers were normal.

TREATMENT AND PREVENTION OF Q FEVER

4. Which of the following treatments would be appropriate, given his diagnosis of Q fever?

• Doxycycline (Vibramycin) 100 mg twice daily for 14 days
• Levofloxacin (Levaquin) 500 mg daily for 5 days
• Doxycycline 100 mg twice daily for 14 days and hydroxychloroquine (Plaquenil) 200 mg three times per day for 18 months
• No treatment

The treatment goals in Q fever are to hasten the resolution of symptoms and to prevent chronic disease. Generally, if there are no clinical findings or symptoms, treatment is not indicated. If the patient has symptoms, early treatment is preferred, but a response may be seen even when there is a delay in diagnosis.

Doxycycline 100 mg twice a day for 14 days is the treatment of choice. In addition, quinolones have in vitro activity,⁴⁵ and a recent study suggests moxifloxacin (Avelox) may be the preferred antibiotic for those who cannot tolerate doxycycline.⁴⁶ In pregnant women and in children, macrolides and trimethoprim-sulfamethoxazole (Bactrim) are preferred.^47,48

Treatment of chronic Q fever, in particular endocarditis, warrants more intensive therapy. A retrospective review of treated cases of endocarditis suggested that monotherapy with doxycycline often failed, and combination therapy with hydroxychloroquine has been advocated based on in vivo and in vitro experience.⁴⁹

PREVENTING LONG-TERM SEQUELAE OF CHRONIC Q FEVER

5. At this point, what is the next step in the management of this patient?

• No further follow-up is indicated
• Transthoracic echocardiography (TTE)
• Repeat Q fever serologic testing in 3 to 6 months
• Whole-blood PCR testing and transesophageal echocardiography (TEE)

Long-term follow-up of patients with Q fever has been advocated to monitor for the development of chronic Q fever, but recent studies question the previously devised algorithms.⁵⁰

The data the algorithms were based on suggested that preexisting valvular heart disease could be associated with up to a 39% risk of endocarditis, and a two-step approach was devised to prevent and identify early chronic infection.^51,52 Patients with Q fever would undergo TTE at baseline, and if the findings were abnormal (including mild regurgitation), then 12 months of prophylactic treatment with hydroxychloroquine and doxycycline was recommended. If TTE was normal, serial serologic testing every 3 months was recommended. If the anti-phase I IgG titer was greater than 1:800 at any point, TEE and a whole-blood PCR assay were recommended to evaluate for endocarditis.⁵¹

These recommendations were based on data from the French National Reference Center and had not been prospectively evaluated. The 2007–2008 Dutch outbreak provided a large cohort of Q fever cases. After initial screening with TTE and serologic follow-up, 59% of patients were noted to have mild valvular abnormalities, and many had phase I IgG levels greater than 1:800 during follow-up despite being clinically free of disease. The Dutch subsequently stopped screening with TTE as part of routine follow-up and elected to follow patients clinically.

Similar findings have been noted from case follow-up in France and Taiwan, also supporting using serologic cutoffs alone in determining the need for evaluation (with TEE) or treatment of chronic disease.^53,54 The usefulness of serologic testing every 3 months has also been questioned, and some have advocated extending the interval, especially since less emphasis is being placed on the results in favor of more practical clinical follow-up.³⁹

One such clinical approach at follow-up is presented in Figure 1. TTE should be reserved for patients with known valvular disease or a clear murmur. Those with underlying valvular disease and acute Q fever should be managed on an individual basis by a specialist in infectious disease, and antibiotic prophylaxis should be considered. Patients without underlying disease should have regular follow-up examinations and serologic testing every 6 months, and clinical symptoms should guide further testing (eg, with TEE and PCR testing) for chronic disease.

In this patient, phase I and II antibody titers were notably elevated (in TABLE 2, phase I titers > 1:800 and 1:1600 cutoffs). Such high titers have been common in military cases from Iraq and Afghanistan, and to date no cases of endocarditis have been diagnosed despite close follow-up. Most cases in military personnel are in relatively young patients who lack risk factors for endocarditis. Based on emerging data from large overseas outbreaks and the potential toxicity of intensive preemptive dual-antimicrobial therapy, an approach of close follow-up was taken.

PRIMARY PREVENTION OF Q FEVER

Prevention of Q fever remains a challenge, as the organism is highly persistent in the environment. An effective licensed vaccine exists in Australia under the brand name Q-Vax, but no approved vaccine is currently available in the United States.⁵⁵

THE PATIENT’S COURSE

The patient returned for follow-up about 1 year after his first presentation. He noted some ongoing fatigue but attributed this to his course work, and he said he otherwise felt well. He exercises regularly, with no shortness of breath, fevers, chills, or weight loss. He continued to have elevated Q fever titers. Because he had no symptoms, no heart murmur, and normal inflammatory markers, he had no further workup and continued to be followed with serial serologic testing and examinations.

A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.

CASE CONTINUED

The patient continued to feel sick and reported having three to four loose bowel movements per day and mild abdominal pain. His cough and dyspnea persisted.

He had not had contact with anyone who was ill, denied being exposed to animals or insects, and had not consumed unpasteurized dairy products; he recalled having cleaned his military-issue uniforms and equipment 2 to 3 weeks before the symptoms began. He called a military physician to get advice on what else could be causing his symptoms. This physician recommended tests based on potential exposures in Iraq. Tests for brucellosis, visceral leishmaniasis, and Q fever were ordered.

Over the next several days, he began to feel better, and at 3 to 4 weeks after the onset of his symptoms, he felt that he had returned to normal. All tests were negative.

TESTING FOR ATYPICAL PATHOGENS

2. Which of the following would be the most readily available method to confirm the diagnosis?

• Culture
• Polymerase chain reaction (PCR) testing
• Histopathologic testing
• Serologic testing

Testing for atypical pathogens was reasonable in this patient. In addition to an evaluation for parasitic causes of persistent and chronic diarrhea, an evaluation for Q fever, brucellosis, and visceral leishmaniasis via serologic testing was warranted. A variety of tests exist for all of these infections, but serologic tests are the most readily available.

Leishmaniasis testing

Visceral leishmaniasis was traditionally diagnosed by visualizing organisms in splenic or bone marrow aspirates,²⁸ but now serologic tests are available through commercial and public health laboratories such as the CDC. Immunochromatographic tests using recombinant k39 antigen are highly sensitive and specific and have been used in military cases.^29,30

Brucellosis testing

Brucella can be cultured from blood or tissue samples. The laboratory must be alerted, as special media can be used to increase the yield and precautions must be taken to prevent laboratory-acquired infection. Serologic testing is the method most commonly used for diagnosis.³¹

Q fever testing

Q fever can be diagnosed with serologic testing during its acute and convalescent phases.

PCR testing of blood is useful for diagnosing acute disease and is positive before serologic conversion, thus allowing rapid diagnosis and treatment.³² The Joint Biological Agent Identification and Diagnostic System (JBAIDS) PCR platform was studied in a Combat Support Hospital in Iraq for making the rapid diagnosis of Q fever and has since been approved by the US Food and Drug Administration for military use.³³

Culture is beyond the scope of most clinical laboratories and requires specialized cell culture or egg yolk media. In tissue, usually liver tissue obtained in an effort to evaluate hepatitis, the histologic finding of “doughnut” granulomas, or fibrin-encased granulomas, can be suggestive of C burnetii but may be nonspecific and seen with other infections.^23,34

Serologic testing with an immunofluorescence assay (IFA) remains the most common method of diagnosis. It is based on the detection of immunoglobulin G (IgG) and IgM responses against phase I and phase II antigens of C burnetii. After initial infection, the organism displays phase I antigens and is highly infectious. When grown in culture, the organism undergoes phase shifting to a less infectious form with predominantly phase II antigens. Paradoxically, after initial infection in humans, antibody response against phase II antigens is seen first, whereas in chronic infection, a phase I antibody response dominates.^26,35 Phase II antibodies appear around week 2, and 90% of samples from infected people are positive by week 3. A fourfold rise in titer between the acute-phase and convalescent-phase samples confirms the diagnosis.³⁵

A number of serologic assays are available worldwide, but they have different methods and cutoff values, so questions have arisen about the equivalence of the results.^14,36 Serologic cutoffs have been defined in Europe, where most cases of Q fever have been reported.³⁷

CHRONIC Q FEVER

3. Which of the following would be the most likely chronic manifestation of Q fever?

• Pneumonia
• Hepatitis
• Endocarditis
• Chronic fatigue
• Osteomyelitis

Chronic syndromes can develop years to months after untreated or inadequately treated infection and can be serious. Chronic infection can also result after a clinically silent initial infection.^26,38 Culture-negative endocarditis, which occurs in fewer than 1% of patients diagnosed with acute infection, is the most common chronic manifestation (Table 1). Patients with underlying valvular disease, malignancy, or immunosuppression are at greater risk.^38–40

Challenges and controversies

The diagnosis of chronic Q fever remains challenging. Traditionally, elevated phase I IgG titers were considered highly predictive of chronic disease. A cutoff of 1:800 was set, based on retrospective data from chronic cases in Europe, but its generalizability to different assays and patient populations has been unclear. ^14,36,37 Recent reviews and prospective analysis with serial serologic studies in the Dutch outbreak and other sources suggest the positive predictive value (PPV) of phase I IgG titers greater than 1:800 to be lower than previously estimated, largely due to widespread testing and resultant increased seroprevalence assessments. It has been suggested the cutoff be raised to 1:1,600, which still only carries a 59% positive predictive value.^41,42

Chronic fatigue due to Q fever remains a controversial topic and has only been described in Europe, Asia, and Australia. A direct link has yet to be established.⁴³ Additional research is needed, but small studies of prolonged antibiotic treatment have not shown benefit in these cases.⁴⁴

CASE CONTINUED

This patient did well. During a routine physical while enrolled at the Army War College in Carlisle, PA, 6 months after the original presentation, he mentioned his illness to the physician, who then repeated testing for Q fever; the test was positive (Table 2). Subsequently, serum samples from before and after his deployment were tested along with another convalescent-phase sample, and the results demonstrated Q fever seroconversion. He was well and had no physical complaints. He had no heart murmur, and a complete blood count and tests of liver enzymes and inflammatory markers were normal.

TREATMENT AND PREVENTION OF Q FEVER

4. Which of the following treatments would be appropriate, given his diagnosis of Q fever?

• Doxycycline (Vibramycin) 100 mg twice daily for 14 days
• Levofloxacin (Levaquin) 500 mg daily for 5 days
• Doxycycline 100 mg twice daily for 14 days and hydroxychloroquine (Plaquenil) 200 mg three times per day for 18 months
• No treatment

The treatment goals in Q fever are to hasten the resolution of symptoms and to prevent chronic disease. Generally, if there are no clinical findings or symptoms, treatment is not indicated. If the patient has symptoms, early treatment is preferred, but a response may be seen even when there is a delay in diagnosis.

Doxycycline 100 mg twice a day for 14 days is the treatment of choice. In addition, quinolones have in vitro activity,⁴⁵ and a recent study suggests moxifloxacin (Avelox) may be the preferred antibiotic for those who cannot tolerate doxycycline.⁴⁶ In pregnant women and in children, macrolides and trimethoprim-sulfamethoxazole (Bactrim) are preferred.^47,48

Treatment of chronic Q fever, in particular endocarditis, warrants more intensive therapy. A retrospective review of treated cases of endocarditis suggested that monotherapy with doxycycline often failed, and combination therapy with hydroxychloroquine has been advocated based on in vivo and in vitro experience.⁴⁹

PREVENTING LONG-TERM SEQUELAE OF CHRONIC Q FEVER

5. At this point, what is the next step in the management of this patient?

• No further follow-up is indicated
• Transthoracic echocardiography (TTE)
• Repeat Q fever serologic testing in 3 to 6 months
• Whole-blood PCR testing and transesophageal echocardiography (TEE)

Long-term follow-up of patients with Q fever has been advocated to monitor for the development of chronic Q fever, but recent studies question the previously devised algorithms.⁵⁰

The data the algorithms were based on suggested that preexisting valvular heart disease could be associated with up to a 39% risk of endocarditis, and a two-step approach was devised to prevent and identify early chronic infection.^51,52 Patients with Q fever would undergo TTE at baseline, and if the findings were abnormal (including mild regurgitation), then 12 months of prophylactic treatment with hydroxychloroquine and doxycycline was recommended. If TTE was normal, serial serologic testing every 3 months was recommended. If the anti-phase I IgG titer was greater than 1:800 at any point, TEE and a whole-blood PCR assay were recommended to evaluate for endocarditis.⁵¹

These recommendations were based on data from the French National Reference Center and had not been prospectively evaluated. The 2007–2008 Dutch outbreak provided a large cohort of Q fever cases. After initial screening with TTE and serologic follow-up, 59% of patients were noted to have mild valvular abnormalities, and many had phase I IgG levels greater than 1:800 during follow-up despite being clinically free of disease. The Dutch subsequently stopped screening with TTE as part of routine follow-up and elected to follow patients clinically.

Similar findings have been noted from case follow-up in France and Taiwan, also supporting using serologic cutoffs alone in determining the need for evaluation (with TEE) or treatment of chronic disease.^53,54 The usefulness of serologic testing every 3 months has also been questioned, and some have advocated extending the interval, especially since less emphasis is being placed on the results in favor of more practical clinical follow-up.³⁹

One such clinical approach at follow-up is presented in Figure 1. TTE should be reserved for patients with known valvular disease or a clear murmur. Those with underlying valvular disease and acute Q fever should be managed on an individual basis by a specialist in infectious disease, and antibiotic prophylaxis should be considered. Patients without underlying disease should have regular follow-up examinations and serologic testing every 6 months, and clinical symptoms should guide further testing (eg, with TEE and PCR testing) for chronic disease.

In this patient, phase I and II antibody titers were notably elevated (in TABLE 2, phase I titers > 1:800 and 1:1600 cutoffs). Such high titers have been common in military cases from Iraq and Afghanistan, and to date no cases of endocarditis have been diagnosed despite close follow-up. Most cases in military personnel are in relatively young patients who lack risk factors for endocarditis. Based on emerging data from large overseas outbreaks and the potential toxicity of intensive preemptive dual-antimicrobial therapy, an approach of close follow-up was taken.

PRIMARY PREVENTION OF Q FEVER

Prevention of Q fever remains a challenge, as the organism is highly persistent in the environment. An effective licensed vaccine exists in Australia under the brand name Q-Vax, but no approved vaccine is currently available in the United States.⁵⁵

THE PATIENT’S COURSE

The patient returned for follow-up about 1 year after his first presentation. He noted some ongoing fatigue but attributed this to his course work, and he said he otherwise felt well. He exercises regularly, with no shortness of breath, fevers, chills, or weight loss. He continued to have elevated Q fever titers. Because he had no symptoms, no heart murmur, and normal inflammatory markers, he had no further workup and continued to be followed with serial serologic testing and examinations.

A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.

CASE CONTINUED

The patient continued to feel sick and reported having three to four loose bowel movements per day and mild abdominal pain. His cough and dyspnea persisted.

He had not had contact with anyone who was ill, denied being exposed to animals or insects, and had not consumed unpasteurized dairy products; he recalled having cleaned his military-issue uniforms and equipment 2 to 3 weeks before the symptoms began. He called a military physician to get advice on what else could be causing his symptoms. This physician recommended tests based on potential exposures in Iraq. Tests for brucellosis, visceral leishmaniasis, and Q fever were ordered.

Over the next several days, he began to feel better, and at 3 to 4 weeks after the onset of his symptoms, he felt that he had returned to normal. All tests were negative.

TESTING FOR ATYPICAL PATHOGENS

2. Which of the following would be the most readily available method to confirm the diagnosis?

• Culture
• Polymerase chain reaction (PCR) testing
• Histopathologic testing
• Serologic testing

Testing for atypical pathogens was reasonable in this patient. In addition to an evaluation for parasitic causes of persistent and chronic diarrhea, an evaluation for Q fever, brucellosis, and visceral leishmaniasis via serologic testing was warranted. A variety of tests exist for all of these infections, but serologic tests are the most readily available.

Leishmaniasis testing

Visceral leishmaniasis was traditionally diagnosed by visualizing organisms in splenic or bone marrow aspirates,²⁸ but now serologic tests are available through commercial and public health laboratories such as the CDC. Immunochromatographic tests using recombinant k39 antigen are highly sensitive and specific and have been used in military cases.^29,30

Brucellosis testing

Brucella can be cultured from blood or tissue samples. The laboratory must be alerted, as special media can be used to increase the yield and precautions must be taken to prevent laboratory-acquired infection. Serologic testing is the method most commonly used for diagnosis.³¹

Q fever testing

Q fever can be diagnosed with serologic testing during its acute and convalescent phases.

PCR testing of blood is useful for diagnosing acute disease and is positive before serologic conversion, thus allowing rapid diagnosis and treatment.³² The Joint Biological Agent Identification and Diagnostic System (JBAIDS) PCR platform was studied in a Combat Support Hospital in Iraq for making the rapid diagnosis of Q fever and has since been approved by the US Food and Drug Administration for military use.³³

Culture is beyond the scope of most clinical laboratories and requires specialized cell culture or egg yolk media. In tissue, usually liver tissue obtained in an effort to evaluate hepatitis, the histologic finding of “doughnut” granulomas, or fibrin-encased granulomas, can be suggestive of C burnetii but may be nonspecific and seen with other infections.^23,34

Serologic testing with an immunofluorescence assay (IFA) remains the most common method of diagnosis. It is based on the detection of immunoglobulin G (IgG) and IgM responses against phase I and phase II antigens of C burnetii. After initial infection, the organism displays phase I antigens and is highly infectious. When grown in culture, the organism undergoes phase shifting to a less infectious form with predominantly phase II antigens. Paradoxically, after initial infection in humans, antibody response against phase II antigens is seen first, whereas in chronic infection, a phase I antibody response dominates.^26,35 Phase II antibodies appear around week 2, and 90% of samples from infected people are positive by week 3. A fourfold rise in titer between the acute-phase and convalescent-phase samples confirms the diagnosis.³⁵

A number of serologic assays are available worldwide, but they have different methods and cutoff values, so questions have arisen about the equivalence of the results.^14,36 Serologic cutoffs have been defined in Europe, where most cases of Q fever have been reported.³⁷

CHRONIC Q FEVER

3. Which of the following would be the most likely chronic manifestation of Q fever?

• Pneumonia
• Hepatitis
• Endocarditis
• Chronic fatigue
• Osteomyelitis

Chronic syndromes can develop years to months after untreated or inadequately treated infection and can be serious. Chronic infection can also result after a clinically silent initial infection.^26,38 Culture-negative endocarditis, which occurs in fewer than 1% of patients diagnosed with acute infection, is the most common chronic manifestation (Table 1). Patients with underlying valvular disease, malignancy, or immunosuppression are at greater risk.^38–40

Challenges and controversies

The diagnosis of chronic Q fever remains challenging. Traditionally, elevated phase I IgG titers were considered highly predictive of chronic disease. A cutoff of 1:800 was set, based on retrospective data from chronic cases in Europe, but its generalizability to different assays and patient populations has been unclear. ^14,36,37 Recent reviews and prospective analysis with serial serologic studies in the Dutch outbreak and other sources suggest the positive predictive value (PPV) of phase I IgG titers greater than 1:800 to be lower than previously estimated, largely due to widespread testing and resultant increased seroprevalence assessments. It has been suggested the cutoff be raised to 1:1,600, which still only carries a 59% positive predictive value.^41,42

Chronic fatigue due to Q fever remains a controversial topic and has only been described in Europe, Asia, and Australia. A direct link has yet to be established.⁴³ Additional research is needed, but small studies of prolonged antibiotic treatment have not shown benefit in these cases.⁴⁴

CASE CONTINUED

This patient did well. During a routine physical while enrolled at the Army War College in Carlisle, PA, 6 months after the original presentation, he mentioned his illness to the physician, who then repeated testing for Q fever; the test was positive (Table 2). Subsequently, serum samples from before and after his deployment were tested along with another convalescent-phase sample, and the results demonstrated Q fever seroconversion. He was well and had no physical complaints. He had no heart murmur, and a complete blood count and tests of liver enzymes and inflammatory markers were normal.

TREATMENT AND PREVENTION OF Q FEVER

4. Which of the following treatments would be appropriate, given his diagnosis of Q fever?

• Doxycycline (Vibramycin) 100 mg twice daily for 14 days
• Levofloxacin (Levaquin) 500 mg daily for 5 days
• Doxycycline 100 mg twice daily for 14 days and hydroxychloroquine (Plaquenil) 200 mg three times per day for 18 months
• No treatment

The treatment goals in Q fever are to hasten the resolution of symptoms and to prevent chronic disease. Generally, if there are no clinical findings or symptoms, treatment is not indicated. If the patient has symptoms, early treatment is preferred, but a response may be seen even when there is a delay in diagnosis.

Doxycycline 100 mg twice a day for 14 days is the treatment of choice. In addition, quinolones have in vitro activity,⁴⁵ and a recent study suggests moxifloxacin (Avelox) may be the preferred antibiotic for those who cannot tolerate doxycycline.⁴⁶ In pregnant women and in children, macrolides and trimethoprim-sulfamethoxazole (Bactrim) are preferred.^47,48

Treatment of chronic Q fever, in particular endocarditis, warrants more intensive therapy. A retrospective review of treated cases of endocarditis suggested that monotherapy with doxycycline often failed, and combination therapy with hydroxychloroquine has been advocated based on in vivo and in vitro experience.⁴⁹

PREVENTING LONG-TERM SEQUELAE OF CHRONIC Q FEVER

5. At this point, what is the next step in the management of this patient?

• No further follow-up is indicated
• Transthoracic echocardiography (TTE)
• Repeat Q fever serologic testing in 3 to 6 months
• Whole-blood PCR testing and transesophageal echocardiography (TEE)

Long-term follow-up of patients with Q fever has been advocated to monitor for the development of chronic Q fever, but recent studies question the previously devised algorithms.⁵⁰

The data the algorithms were based on suggested that preexisting valvular heart disease could be associated with up to a 39% risk of endocarditis, and a two-step approach was devised to prevent and identify early chronic infection.^51,52 Patients with Q fever would undergo TTE at baseline, and if the findings were abnormal (including mild regurgitation), then 12 months of prophylactic treatment with hydroxychloroquine and doxycycline was recommended. If TTE was normal, serial serologic testing every 3 months was recommended. If the anti-phase I IgG titer was greater than 1:800 at any point, TEE and a whole-blood PCR assay were recommended to evaluate for endocarditis.⁵¹

These recommendations were based on data from the French National Reference Center and had not been prospectively evaluated. The 2007–2008 Dutch outbreak provided a large cohort of Q fever cases. After initial screening with TTE and serologic follow-up, 59% of patients were noted to have mild valvular abnormalities, and many had phase I IgG levels greater than 1:800 during follow-up despite being clinically free of disease. The Dutch subsequently stopped screening with TTE as part of routine follow-up and elected to follow patients clinically.

Similar findings have been noted from case follow-up in France and Taiwan, also supporting using serologic cutoffs alone in determining the need for evaluation (with TEE) or treatment of chronic disease.^53,54 The usefulness of serologic testing every 3 months has also been questioned, and some have advocated extending the interval, especially since less emphasis is being placed on the results in favor of more practical clinical follow-up.³⁹

One such clinical approach at follow-up is presented in Figure 1. TTE should be reserved for patients with known valvular disease or a clear murmur. Those with underlying valvular disease and acute Q fever should be managed on an individual basis by a specialist in infectious disease, and antibiotic prophylaxis should be considered. Patients without underlying disease should have regular follow-up examinations and serologic testing every 6 months, and clinical symptoms should guide further testing (eg, with TEE and PCR testing) for chronic disease.

In this patient, phase I and II antibody titers were notably elevated (in TABLE 2, phase I titers > 1:800 and 1:1600 cutoffs). Such high titers have been common in military cases from Iraq and Afghanistan, and to date no cases of endocarditis have been diagnosed despite close follow-up. Most cases in military personnel are in relatively young patients who lack risk factors for endocarditis. Based on emerging data from large overseas outbreaks and the potential toxicity of intensive preemptive dual-antimicrobial therapy, an approach of close follow-up was taken.

PRIMARY PREVENTION OF Q FEVER

Prevention of Q fever remains a challenge, as the organism is highly persistent in the environment. An effective licensed vaccine exists in Australia under the brand name Q-Vax, but no approved vaccine is currently available in the United States.⁵⁵

THE PATIENT’S COURSE

The patient returned for follow-up about 1 year after his first presentation. He noted some ongoing fatigue but attributed this to his course work, and he said he otherwise felt well. He exercises regularly, with no shortness of breath, fevers, chills, or weight loss. He continued to have elevated Q fever titers. Because he had no symptoms, no heart murmur, and normal inflammatory markers, he had no further workup and continued to be followed with serial serologic testing and examinations.

A 62-year-old woman has had flashing lights and floaters in her left eye with progressive loss of vision over the past month. She has not had recent trauma. She does not smoke.

She was referred for an ophthalmologic evaluation. Her visual acuity was 20/20 in the right eye, but she could only count fingers with the left. The anterior segment appeared normal in both eyes. Funduscopic examination of the left eye revealed numerous lobulated, yellowish, choroidal lesions in the posterior pole with overlying subretinal fluid. The lesions involved the fovea, accounting for the poor visual acuity. There were two similar but smaller lesions in the right eye (Figure 1). Ultrasonography confirmed the choroidal location of the lesions (Figure 2).

Q: Which is the most likely diagnosis?

• Retinal detachment
• Choroidal melanoma
• Uveitis
• Uveal metastatic tumor

A: Uveal metastatic tumor is the correct diagnosis. Funduscopic findings of bilateral yellow choroidal lesions are consistent with metastatic cancer.

The patient was admitted to the hospital for a thorough evaluation. Computed tomography of the chest showed a 2.1-by-4.5-cm mass in the lower lobe of the left lung, highly suspicious for malignancy and associated with left hilar lymphadenopathy and right acute pulmonary embolism. Bronchoscopy showed an endobronchial tumor completely occluding the left lower lobe and the lingular orifices.

Pathologic specimens from the endobronchial tumor confirmed adenocarcinoma, consistent with a primary lung cancer.

THE OTHER DIAGNOSTIC CHOICES

Detachment or separation of the retina from the underlying pigment epithelium is one of the most commonly encountered eye emergencies.¹ It requires urgent attention, since delay in treatment can cause permanent vision loss.

Retinal detachment differs from uveal metastatic tumor in that it presents and progresses rapidly. The common signs and symptoms are floaters in the center of the visual axis, a sensation of flashing lights (related to retinal traction), and, eventually, loss of vision. The detachment most often represents a break or tear (rhegmatogenous retinal detachment), but it is also a common sequela of neglected diabetic retinopathy. Exudative retinal detachment is usually secondary to uveal inflammation or a uveal tumor.

Choroidal melanoma, the most common primary intraocular malignancy, arises from melanocytes within the choroid. In most cases, it develops from preexisting melanocytic nevi.² It may present as blurred vision, a paracentral scotoma, painless and progressive visual field loss, and floaters. Choroidal melanoma is usually pigmented (dark brown) and is invariably unilateral.

Uveitis is an inflammation of the uveal tract, which includes the iris, ciliary body, and choroid. It is classified as anterior, intermediate, or posterior uveitis or as panuveitis.³

Although flashing lights, floaters, and reduced vision can occur in uveitis, its other important presenting symptoms (ie, pain, redness, and photophobia) were absent in this patient. The absence of anterior chamber cells and corneal inflammatory deposits (keratic precipitates) also made uveitis less likely.⁴ However, granulomatous uveitis such as sarcoidosis can present as nodular thickening of the uvea, mimicking an intraocular tumor.⁵

THE MOST COMMON INTRAOCULAR MALIGNANCY

Uveal metastasis is the most common intraocular malignancy⁶ and is found on autopsy in up to 12% of people who die of cancer; it involves both eyes in 4.4% of cases. Multiple metastases are seen in one eye in up to 20% of cases.⁷

The tumors are most often in the choroid, probably because of its extensive blood supply. Breast cancer (in women) and lung cancer (in men) are the most common cancers with uveal metastasis.⁸ Uveal metastasis from cancers of the prostate, kidney, thyroid, and gastrointestinal tract and from lymphoma and leukemia is less common.⁸

Patients with choroidal metastasis can see flashing lights, floating spots, and distortion of their vision. In such patients, a careful history and physical examination can uncover signs and symptoms of the hidden cancer, especially of lung cancer.⁹

Once uveal metastasis is suspected, both eyes and orbits and the central nervous system should be examined, as this disease tends to present bilaterally and to involve the central nervous system.¹⁰ Uveal metastases respond to chemotherapy and radiotherapy, depending on the nature of the primary tumor. In general, treatment is based on the extent of the metastasis, prior treatments, and the patient’s overall functional status.

A 62-year-old woman has had flashing lights and floaters in her left eye with progressive loss of vision over the past month. She has not had recent trauma. She does not smoke.

She was referred for an ophthalmologic evaluation. Her visual acuity was 20/20 in the right eye, but she could only count fingers with the left. The anterior segment appeared normal in both eyes. Funduscopic examination of the left eye revealed numerous lobulated, yellowish, choroidal lesions in the posterior pole with overlying subretinal fluid. The lesions involved the fovea, accounting for the poor visual acuity. There were two similar but smaller lesions in the right eye (Figure 1). Ultrasonography confirmed the choroidal location of the lesions (Figure 2).

Q: Which is the most likely diagnosis?

• Retinal detachment
• Choroidal melanoma
• Uveitis
• Uveal metastatic tumor

A: Uveal metastatic tumor is the correct diagnosis. Funduscopic findings of bilateral yellow choroidal lesions are consistent with metastatic cancer.

The patient was admitted to the hospital for a thorough evaluation. Computed tomography of the chest showed a 2.1-by-4.5-cm mass in the lower lobe of the left lung, highly suspicious for malignancy and associated with left hilar lymphadenopathy and right acute pulmonary embolism. Bronchoscopy showed an endobronchial tumor completely occluding the left lower lobe and the lingular orifices.

Pathologic specimens from the endobronchial tumor confirmed adenocarcinoma, consistent with a primary lung cancer.

THE OTHER DIAGNOSTIC CHOICES

Detachment or separation of the retina from the underlying pigment epithelium is one of the most commonly encountered eye emergencies.¹ It requires urgent attention, since delay in treatment can cause permanent vision loss.

Retinal detachment differs from uveal metastatic tumor in that it presents and progresses rapidly. The common signs and symptoms are floaters in the center of the visual axis, a sensation of flashing lights (related to retinal traction), and, eventually, loss of vision. The detachment most often represents a break or tear (rhegmatogenous retinal detachment), but it is also a common sequela of neglected diabetic retinopathy. Exudative retinal detachment is usually secondary to uveal inflammation or a uveal tumor.

Choroidal melanoma, the most common primary intraocular malignancy, arises from melanocytes within the choroid. In most cases, it develops from preexisting melanocytic nevi.² It may present as blurred vision, a paracentral scotoma, painless and progressive visual field loss, and floaters. Choroidal melanoma is usually pigmented (dark brown) and is invariably unilateral.

Uveitis is an inflammation of the uveal tract, which includes the iris, ciliary body, and choroid. It is classified as anterior, intermediate, or posterior uveitis or as panuveitis.³

Although flashing lights, floaters, and reduced vision can occur in uveitis, its other important presenting symptoms (ie, pain, redness, and photophobia) were absent in this patient. The absence of anterior chamber cells and corneal inflammatory deposits (keratic precipitates) also made uveitis less likely.⁴ However, granulomatous uveitis such as sarcoidosis can present as nodular thickening of the uvea, mimicking an intraocular tumor.⁵

THE MOST COMMON INTRAOCULAR MALIGNANCY

Uveal metastasis is the most common intraocular malignancy⁶ and is found on autopsy in up to 12% of people who die of cancer; it involves both eyes in 4.4% of cases. Multiple metastases are seen in one eye in up to 20% of cases.⁷

The tumors are most often in the choroid, probably because of its extensive blood supply. Breast cancer (in women) and lung cancer (in men) are the most common cancers with uveal metastasis.⁸ Uveal metastasis from cancers of the prostate, kidney, thyroid, and gastrointestinal tract and from lymphoma and leukemia is less common.⁸

Patients with choroidal metastasis can see flashing lights, floating spots, and distortion of their vision. In such patients, a careful history and physical examination can uncover signs and symptoms of the hidden cancer, especially of lung cancer.⁹

Once uveal metastasis is suspected, both eyes and orbits and the central nervous system should be examined, as this disease tends to present bilaterally and to involve the central nervous system.¹⁰ Uveal metastases respond to chemotherapy and radiotherapy, depending on the nature of the primary tumor. In general, treatment is based on the extent of the metastasis, prior treatments, and the patient’s overall functional status.

A 62-year-old woman has had flashing lights and floaters in her left eye with progressive loss of vision over the past month. She has not had recent trauma. She does not smoke.

She was referred for an ophthalmologic evaluation. Her visual acuity was 20/20 in the right eye, but she could only count fingers with the left. The anterior segment appeared normal in both eyes. Funduscopic examination of the left eye revealed numerous lobulated, yellowish, choroidal lesions in the posterior pole with overlying subretinal fluid. The lesions involved the fovea, accounting for the poor visual acuity. There were two similar but smaller lesions in the right eye (Figure 1). Ultrasonography confirmed the choroidal location of the lesions (Figure 2).

Q: Which is the most likely diagnosis?

• Retinal detachment
• Choroidal melanoma
• Uveitis
• Uveal metastatic tumor

A: Uveal metastatic tumor is the correct diagnosis. Funduscopic findings of bilateral yellow choroidal lesions are consistent with metastatic cancer.

The patient was admitted to the hospital for a thorough evaluation. Computed tomography of the chest showed a 2.1-by-4.5-cm mass in the lower lobe of the left lung, highly suspicious for malignancy and associated with left hilar lymphadenopathy and right acute pulmonary embolism. Bronchoscopy showed an endobronchial tumor completely occluding the left lower lobe and the lingular orifices.

Pathologic specimens from the endobronchial tumor confirmed adenocarcinoma, consistent with a primary lung cancer.

THE OTHER DIAGNOSTIC CHOICES

Detachment or separation of the retina from the underlying pigment epithelium is one of the most commonly encountered eye emergencies.¹ It requires urgent attention, since delay in treatment can cause permanent vision loss.

Retinal detachment differs from uveal metastatic tumor in that it presents and progresses rapidly. The common signs and symptoms are floaters in the center of the visual axis, a sensation of flashing lights (related to retinal traction), and, eventually, loss of vision. The detachment most often represents a break or tear (rhegmatogenous retinal detachment), but it is also a common sequela of neglected diabetic retinopathy. Exudative retinal detachment is usually secondary to uveal inflammation or a uveal tumor.

Choroidal melanoma, the most common primary intraocular malignancy, arises from melanocytes within the choroid. In most cases, it develops from preexisting melanocytic nevi.² It may present as blurred vision, a paracentral scotoma, painless and progressive visual field loss, and floaters. Choroidal melanoma is usually pigmented (dark brown) and is invariably unilateral.

Uveitis is an inflammation of the uveal tract, which includes the iris, ciliary body, and choroid. It is classified as anterior, intermediate, or posterior uveitis or as panuveitis.³

Although flashing lights, floaters, and reduced vision can occur in uveitis, its other important presenting symptoms (ie, pain, redness, and photophobia) were absent in this patient. The absence of anterior chamber cells and corneal inflammatory deposits (keratic precipitates) also made uveitis less likely.⁴ However, granulomatous uveitis such as sarcoidosis can present as nodular thickening of the uvea, mimicking an intraocular tumor.⁵

THE MOST COMMON INTRAOCULAR MALIGNANCY

Uveal metastasis is the most common intraocular malignancy⁶ and is found on autopsy in up to 12% of people who die of cancer; it involves both eyes in 4.4% of cases. Multiple metastases are seen in one eye in up to 20% of cases.⁷

The tumors are most often in the choroid, probably because of its extensive blood supply. Breast cancer (in women) and lung cancer (in men) are the most common cancers with uveal metastasis.⁸ Uveal metastasis from cancers of the prostate, kidney, thyroid, and gastrointestinal tract and from lymphoma and leukemia is less common.⁸

Patients with choroidal metastasis can see flashing lights, floating spots, and distortion of their vision. In such patients, a careful history and physical examination can uncover signs and symptoms of the hidden cancer, especially of lung cancer.⁹

Once uveal metastasis is suspected, both eyes and orbits and the central nervous system should be examined, as this disease tends to present bilaterally and to involve the central nervous system.¹⁰ Uveal metastases respond to chemotherapy and radiotherapy, depending on the nature of the primary tumor. In general, treatment is based on the extent of the metastasis, prior treatments, and the patient’s overall functional status.

Health care delivery is perennially resource-constrained, perhaps never more so than in these times of severe economic distress. Yet the introduction of new medical technologies and therapies (some of dubious benefit) continues unabated. Consequently, the search for how best to deploy limited health care resources continues to engender much interest.

In that light, the recent commentary on cost-effectiveness studies by Dr. Vinay Prasad in the June 2012 of this journal,¹ which attempted to highlight some of the pitfalls of such studies, is commendable. Unfortunately, the comments, which largely focused on the methodology of cost-effectiveness studies, end up merely as a straw man debate. To the less well-informed reader, the commentary might appear as an indictment of cost-effectiveness research.

It is thus crucial to correct those potentially misleading comments and to point out that recommendations for the proper conduct of cost-effectiveness studies were published as far back as 1996 by the Panel on Cost-effectiveness in Health and Medicine.² This panel was convened by the US Public Health Service and included members with demonstrated expertise in cost-effectiveness analysis, clinical medicine, ethics, and health outcomes measurement. The recommendations addressed all the issues raised in the commentary and more, and are well worth a read, as they enable readers to understand how to conduct these studies, how to judge the quality of these studies, and how the findings might be applied.² Nonetheless, it is worthwhile to address the logical inaccuracies in the specific examples in the commentary.

IF A TREATMENT IS INEFFECTIVE, IT IS COST-INEFFECTIVE TOO

First, the author discusses the case of vertebroplasty for osteoporotic vertebral fractures. Vertebroplasty had previously been estimated to be cost-effective relative to 12 months of medical therapy. However, a subsequent clinical study found it was no better than a sham procedure, thus setting up the uncomfortable possibility that a sham procedure is more cost-effective than both vertebroplasty and medical therapy.

This can hardly be blamed on the earlier cost-effectiveness study. If any given therapy does not effectively achieve the desired outcomes for the condition for which it is being used, then that therapy ought not to be used at all for that condition. In that context, a cost-effectiveness study is rendered moot in the first place, as the therapy of interest is not effective. Using a more broadly related example, why would anyone conduct a cost-effectiveness study of antibiotics for the treatment of the common cold? Indeed, the vertebroplasty example merely highlights the limitations of the original clinical studies that erroneously deemed it effective for osteoporotic vertebral fractures.

The possibility that a sham procedure might be more cost-effective than vertebroplasty or medical intervention is unsettling to the extent that one has a pro-intervention bias for all diseases. Perhaps the lesson may be that none of the current therapies for this condition is useful, and that until there is a truly beneficial therapy, patients may best be served by doing nothing. To paraphrase one of the author’s rather obvious recommendations, knowing that a therapy is efficacious (toward achieving our desired end point, whatever that may be) should be a prerequisite to adopting it into clinical practice, let alone determining its cost-effectiveness.

Furthermore, cost-effectiveness studies by their nature cannot and should not be static but need to be adjusted over time. For all analyses, it is anticipated that future amendments will be required to adjust for changes in effectiveness (including the disproving of efficacy), changes in relevant strategies available, changes in cost, and changes in population parameters.

WE ALL DIE EVENTUALLY

Secondly, using the example of exemestane (Aromasin) for primary prevention of breast cancer in postmenopausal women, the author raises issues about how to determine the net benefit of preventive therapies in terms of deaths avoided or life-years gained. The particular concern relates to what extent the benefit of deaths avoided by exemestane is negated by deaths that are caused by other non-breast-cancer-related diseases. This implies that using exemestane to prevent death by breast cancer is possibly useless, as those women would go on to die of other causes eventually.

But is that not the case for every preventive or therapeutic intervention? Curing bacterial pneumonia with antibiotics surely saves patients who nonetheless will eventually die some day from another cause. Does this make the use of antibiotics for bacterial pneumonia cost-ineffective? No. The point is that life ultimately ends in death, but along the spectrum of life we utilize various interventions to prolong life and improve its quality as long as is meaningfully possible—either by preventing some diseases or by treating others.

Thus, the implicit assumption ab initio is that prevention or treatment of any particular disease is intrinsically a desirable proposition on its own merits and deserving of some expense of resources. As such, for any given disease, the cost-effectiveness of preventive or therapeutic measures must necessarily be confined to deaths avoided and life-years gained (or other such suitable measures) that are directly attributable to that disease process or to side effects of the particular therapy. Attempting to expand beyond that measure would lead to absurdities such that no intervention would ever be cost-effective because we all eventually die.

REAL-WORLD DATA TAKE YEARS

Finally, using the case of cyclooxygenase 2 inhibitors, the author raises the issue of sourcing data for cost-effectiveness studies.

There is some validity to this point regarding using only real-world experiential data versus data from randomized controlled clinical trials, as vastly different estimates of cost per unit of benefit can be found. However, strict adherence to this recommendation creates a dilemma: real-world data take years to accumulate after an intervention is approved for clinical use based on clinical trial data. But front-line clinicians and payers need to know whether the new intervention is worth adopting into daily clinical practice—particularly because new brand-name, patent-protected therapies generally cost much more early on than later, when patents expire and economies of scale induce drops in prices.

If high acquisition costs without supporting cost-effectiveness data preclude the adoption of the new therapy, then real-world experience cannot be accumulated. On the flip side, unfettered adoption would certainly consume significant resources that may turn out to have been wasted if, years later, real-world experience reveals that the effectiveness was significantly less than estimated by the clinical trial.

However, this is not a problem inherent in cost-effectiveness studies, but rather a result of the uncertainties and difficulties involved in translating findings from clinical trials to the real world, where patients are not as closely monitored to ensure proper compliance and to minimize side effects and uncontrolled interactions. Health economists are well aware of this problem of uncertainty and other limitations of randomized controlled trials.

These limitations have precipitated the development of decision analytic modeling for economic evaluation. This research method is now highly sophisticated and widely accepted as the gold standard. Decision analytic modeling allows data from a trial to be extrapolated beyond the trial period, intermediate clinical outcomes to be linked to final outcomes, clinical trial results to be generalized to other settings, head-to-head comparisons of interventions to be made where relevant clinical trial data do not exist, and economic evaluations to be performed for trials in which economic outcomes were not collected.³

Furthermore, decision analytic modeling in part exists to overcome the data issues raised by the commentary. By using probabilistic sensitivity analyses to account for uncertainties and assure robustness of the results, the reliability of the results is enhanced, regardless of the source of data. In fact, with today’s more powerful computers and software and the limited financial resources available for large randomized controlled clinical trials, the use of economic modeling continues to grow as an indispensable means of economic evaluation.

AN INDISPENSABLE TOOL

In conclusion, properly conducted cost-effectiveness studies are an increasingly important and indispensable tool as we strive to improve the efficiency and effectiveness of health care delivery, particularly in this time of health system changes, the aging of the population, and increasingly limited budgets. Economic modeling allows researchers to explore different scenarios, overcome many of the limitations of clinical trials, identify thresholds at which estimated cost-effectiveness ratios may change, and provide valuable information to health policy makers, providers, and patients to guide the efficient allocation and utilization of health care resources.

Health care delivery is perennially resource-constrained, perhaps never more so than in these times of severe economic distress. Yet the introduction of new medical technologies and therapies (some of dubious benefit) continues unabated. Consequently, the search for how best to deploy limited health care resources continues to engender much interest.

In that light, the recent commentary on cost-effectiveness studies by Dr. Vinay Prasad in the June 2012 of this journal,¹ which attempted to highlight some of the pitfalls of such studies, is commendable. Unfortunately, the comments, which largely focused on the methodology of cost-effectiveness studies, end up merely as a straw man debate. To the less well-informed reader, the commentary might appear as an indictment of cost-effectiveness research.

It is thus crucial to correct those potentially misleading comments and to point out that recommendations for the proper conduct of cost-effectiveness studies were published as far back as 1996 by the Panel on Cost-effectiveness in Health and Medicine.² This panel was convened by the US Public Health Service and included members with demonstrated expertise in cost-effectiveness analysis, clinical medicine, ethics, and health outcomes measurement. The recommendations addressed all the issues raised in the commentary and more, and are well worth a read, as they enable readers to understand how to conduct these studies, how to judge the quality of these studies, and how the findings might be applied.² Nonetheless, it is worthwhile to address the logical inaccuracies in the specific examples in the commentary.

IF A TREATMENT IS INEFFECTIVE, IT IS COST-INEFFECTIVE TOO

First, the author discusses the case of vertebroplasty for osteoporotic vertebral fractures. Vertebroplasty had previously been estimated to be cost-effective relative to 12 months of medical therapy. However, a subsequent clinical study found it was no better than a sham procedure, thus setting up the uncomfortable possibility that a sham procedure is more cost-effective than both vertebroplasty and medical therapy.

This can hardly be blamed on the earlier cost-effectiveness study. If any given therapy does not effectively achieve the desired outcomes for the condition for which it is being used, then that therapy ought not to be used at all for that condition. In that context, a cost-effectiveness study is rendered moot in the first place, as the therapy of interest is not effective. Using a more broadly related example, why would anyone conduct a cost-effectiveness study of antibiotics for the treatment of the common cold? Indeed, the vertebroplasty example merely highlights the limitations of the original clinical studies that erroneously deemed it effective for osteoporotic vertebral fractures.

The possibility that a sham procedure might be more cost-effective than vertebroplasty or medical intervention is unsettling to the extent that one has a pro-intervention bias for all diseases. Perhaps the lesson may be that none of the current therapies for this condition is useful, and that until there is a truly beneficial therapy, patients may best be served by doing nothing. To paraphrase one of the author’s rather obvious recommendations, knowing that a therapy is efficacious (toward achieving our desired end point, whatever that may be) should be a prerequisite to adopting it into clinical practice, let alone determining its cost-effectiveness.

Furthermore, cost-effectiveness studies by their nature cannot and should not be static but need to be adjusted over time. For all analyses, it is anticipated that future amendments will be required to adjust for changes in effectiveness (including the disproving of efficacy), changes in relevant strategies available, changes in cost, and changes in population parameters.

WE ALL DIE EVENTUALLY

Secondly, using the example of exemestane (Aromasin) for primary prevention of breast cancer in postmenopausal women, the author raises issues about how to determine the net benefit of preventive therapies in terms of deaths avoided or life-years gained. The particular concern relates to what extent the benefit of deaths avoided by exemestane is negated by deaths that are caused by other non-breast-cancer-related diseases. This implies that using exemestane to prevent death by breast cancer is possibly useless, as those women would go on to die of other causes eventually.

But is that not the case for every preventive or therapeutic intervention? Curing bacterial pneumonia with antibiotics surely saves patients who nonetheless will eventually die some day from another cause. Does this make the use of antibiotics for bacterial pneumonia cost-ineffective? No. The point is that life ultimately ends in death, but along the spectrum of life we utilize various interventions to prolong life and improve its quality as long as is meaningfully possible—either by preventing some diseases or by treating others.

Thus, the implicit assumption ab initio is that prevention or treatment of any particular disease is intrinsically a desirable proposition on its own merits and deserving of some expense of resources. As such, for any given disease, the cost-effectiveness of preventive or therapeutic measures must necessarily be confined to deaths avoided and life-years gained (or other such suitable measures) that are directly attributable to that disease process or to side effects of the particular therapy. Attempting to expand beyond that measure would lead to absurdities such that no intervention would ever be cost-effective because we all eventually die.

REAL-WORLD DATA TAKE YEARS

Finally, using the case of cyclooxygenase 2 inhibitors, the author raises the issue of sourcing data for cost-effectiveness studies.

There is some validity to this point regarding using only real-world experiential data versus data from randomized controlled clinical trials, as vastly different estimates of cost per unit of benefit can be found. However, strict adherence to this recommendation creates a dilemma: real-world data take years to accumulate after an intervention is approved for clinical use based on clinical trial data. But front-line clinicians and payers need to know whether the new intervention is worth adopting into daily clinical practice—particularly because new brand-name, patent-protected therapies generally cost much more early on than later, when patents expire and economies of scale induce drops in prices.

If high acquisition costs without supporting cost-effectiveness data preclude the adoption of the new therapy, then real-world experience cannot be accumulated. On the flip side, unfettered adoption would certainly consume significant resources that may turn out to have been wasted if, years later, real-world experience reveals that the effectiveness was significantly less than estimated by the clinical trial.

However, this is not a problem inherent in cost-effectiveness studies, but rather a result of the uncertainties and difficulties involved in translating findings from clinical trials to the real world, where patients are not as closely monitored to ensure proper compliance and to minimize side effects and uncontrolled interactions. Health economists are well aware of this problem of uncertainty and other limitations of randomized controlled trials.

These limitations have precipitated the development of decision analytic modeling for economic evaluation. This research method is now highly sophisticated and widely accepted as the gold standard. Decision analytic modeling allows data from a trial to be extrapolated beyond the trial period, intermediate clinical outcomes to be linked to final outcomes, clinical trial results to be generalized to other settings, head-to-head comparisons of interventions to be made where relevant clinical trial data do not exist, and economic evaluations to be performed for trials in which economic outcomes were not collected.³

Furthermore, decision analytic modeling in part exists to overcome the data issues raised by the commentary. By using probabilistic sensitivity analyses to account for uncertainties and assure robustness of the results, the reliability of the results is enhanced, regardless of the source of data. In fact, with today’s more powerful computers and software and the limited financial resources available for large randomized controlled clinical trials, the use of economic modeling continues to grow as an indispensable means of economic evaluation.

AN INDISPENSABLE TOOL

In conclusion, properly conducted cost-effectiveness studies are an increasingly important and indispensable tool as we strive to improve the efficiency and effectiveness of health care delivery, particularly in this time of health system changes, the aging of the population, and increasingly limited budgets. Economic modeling allows researchers to explore different scenarios, overcome many of the limitations of clinical trials, identify thresholds at which estimated cost-effectiveness ratios may change, and provide valuable information to health policy makers, providers, and patients to guide the efficient allocation and utilization of health care resources.

Health care delivery is perennially resource-constrained, perhaps never more so than in these times of severe economic distress. Yet the introduction of new medical technologies and therapies (some of dubious benefit) continues unabated. Consequently, the search for how best to deploy limited health care resources continues to engender much interest.

In that light, the recent commentary on cost-effectiveness studies by Dr. Vinay Prasad in the June 2012 of this journal,¹ which attempted to highlight some of the pitfalls of such studies, is commendable. Unfortunately, the comments, which largely focused on the methodology of cost-effectiveness studies, end up merely as a straw man debate. To the less well-informed reader, the commentary might appear as an indictment of cost-effectiveness research.

It is thus crucial to correct those potentially misleading comments and to point out that recommendations for the proper conduct of cost-effectiveness studies were published as far back as 1996 by the Panel on Cost-effectiveness in Health and Medicine.² This panel was convened by the US Public Health Service and included members with demonstrated expertise in cost-effectiveness analysis, clinical medicine, ethics, and health outcomes measurement. The recommendations addressed all the issues raised in the commentary and more, and are well worth a read, as they enable readers to understand how to conduct these studies, how to judge the quality of these studies, and how the findings might be applied.² Nonetheless, it is worthwhile to address the logical inaccuracies in the specific examples in the commentary.

IF A TREATMENT IS INEFFECTIVE, IT IS COST-INEFFECTIVE TOO

First, the author discusses the case of vertebroplasty for osteoporotic vertebral fractures. Vertebroplasty had previously been estimated to be cost-effective relative to 12 months of medical therapy. However, a subsequent clinical study found it was no better than a sham procedure, thus setting up the uncomfortable possibility that a sham procedure is more cost-effective than both vertebroplasty and medical therapy.

This can hardly be blamed on the earlier cost-effectiveness study. If any given therapy does not effectively achieve the desired outcomes for the condition for which it is being used, then that therapy ought not to be used at all for that condition. In that context, a cost-effectiveness study is rendered moot in the first place, as the therapy of interest is not effective. Using a more broadly related example, why would anyone conduct a cost-effectiveness study of antibiotics for the treatment of the common cold? Indeed, the vertebroplasty example merely highlights the limitations of the original clinical studies that erroneously deemed it effective for osteoporotic vertebral fractures.

The possibility that a sham procedure might be more cost-effective than vertebroplasty or medical intervention is unsettling to the extent that one has a pro-intervention bias for all diseases. Perhaps the lesson may be that none of the current therapies for this condition is useful, and that until there is a truly beneficial therapy, patients may best be served by doing nothing. To paraphrase one of the author’s rather obvious recommendations, knowing that a therapy is efficacious (toward achieving our desired end point, whatever that may be) should be a prerequisite to adopting it into clinical practice, let alone determining its cost-effectiveness.

Furthermore, cost-effectiveness studies by their nature cannot and should not be static but need to be adjusted over time. For all analyses, it is anticipated that future amendments will be required to adjust for changes in effectiveness (including the disproving of efficacy), changes in relevant strategies available, changes in cost, and changes in population parameters.

WE ALL DIE EVENTUALLY

Secondly, using the example of exemestane (Aromasin) for primary prevention of breast cancer in postmenopausal women, the author raises issues about how to determine the net benefit of preventive therapies in terms of deaths avoided or life-years gained. The particular concern relates to what extent the benefit of deaths avoided by exemestane is negated by deaths that are caused by other non-breast-cancer-related diseases. This implies that using exemestane to prevent death by breast cancer is possibly useless, as those women would go on to die of other causes eventually.

But is that not the case for every preventive or therapeutic intervention? Curing bacterial pneumonia with antibiotics surely saves patients who nonetheless will eventually die some day from another cause. Does this make the use of antibiotics for bacterial pneumonia cost-ineffective? No. The point is that life ultimately ends in death, but along the spectrum of life we utilize various interventions to prolong life and improve its quality as long as is meaningfully possible—either by preventing some diseases or by treating others.

Thus, the implicit assumption ab initio is that prevention or treatment of any particular disease is intrinsically a desirable proposition on its own merits and deserving of some expense of resources. As such, for any given disease, the cost-effectiveness of preventive or therapeutic measures must necessarily be confined to deaths avoided and life-years gained (or other such suitable measures) that are directly attributable to that disease process or to side effects of the particular therapy. Attempting to expand beyond that measure would lead to absurdities such that no intervention would ever be cost-effective because we all eventually die.

REAL-WORLD DATA TAKE YEARS

Finally, using the case of cyclooxygenase 2 inhibitors, the author raises the issue of sourcing data for cost-effectiveness studies.

There is some validity to this point regarding using only real-world experiential data versus data from randomized controlled clinical trials, as vastly different estimates of cost per unit of benefit can be found. However, strict adherence to this recommendation creates a dilemma: real-world data take years to accumulate after an intervention is approved for clinical use based on clinical trial data. But front-line clinicians and payers need to know whether the new intervention is worth adopting into daily clinical practice—particularly because new brand-name, patent-protected therapies generally cost much more early on than later, when patents expire and economies of scale induce drops in prices.

If high acquisition costs without supporting cost-effectiveness data preclude the adoption of the new therapy, then real-world experience cannot be accumulated. On the flip side, unfettered adoption would certainly consume significant resources that may turn out to have been wasted if, years later, real-world experience reveals that the effectiveness was significantly less than estimated by the clinical trial.

However, this is not a problem inherent in cost-effectiveness studies, but rather a result of the uncertainties and difficulties involved in translating findings from clinical trials to the real world, where patients are not as closely monitored to ensure proper compliance and to minimize side effects and uncontrolled interactions. Health economists are well aware of this problem of uncertainty and other limitations of randomized controlled trials.

These limitations have precipitated the development of decision analytic modeling for economic evaluation. This research method is now highly sophisticated and widely accepted as the gold standard. Decision analytic modeling allows data from a trial to be extrapolated beyond the trial period, intermediate clinical outcomes to be linked to final outcomes, clinical trial results to be generalized to other settings, head-to-head comparisons of interventions to be made where relevant clinical trial data do not exist, and economic evaluations to be performed for trials in which economic outcomes were not collected.³

Furthermore, decision analytic modeling in part exists to overcome the data issues raised by the commentary. By using probabilistic sensitivity analyses to account for uncertainties and assure robustness of the results, the reliability of the results is enhanced, regardless of the source of data. In fact, with today’s more powerful computers and software and the limited financial resources available for large randomized controlled clinical trials, the use of economic modeling continues to grow as an indispensable means of economic evaluation.

AN INDISPENSABLE TOOL

In conclusion, properly conducted cost-effectiveness studies are an increasingly important and indispensable tool as we strive to improve the efficiency and effectiveness of health care delivery, particularly in this time of health system changes, the aging of the population, and increasingly limited budgets. Economic modeling allows researchers to explore different scenarios, overcome many of the limitations of clinical trials, identify thresholds at which estimated cost-effectiveness ratios may change, and provide valuable information to health policy makers, providers, and patients to guide the efficient allocation and utilization of health care resources.

Drs. Udeh and Udeh attempt to highlight the “straw man” nature of my argument and the inaccuracies of my piece, but they ultimately disprove none of my claims.

Regarding vertebroplasty—a procedure that never worked better than a sham one—the authors do not fault the cost-effectiveness analysis for getting it wrong, but rather early clinical studies that provided false confidence. Yet, as a matter of fact, both were wrong. Cost-effectiveness analyses cannot be excused because they are based on faulty assumptions or poor data. This is precisely the reason they should be faulted. If incorrect cost-effectiveness analyses cannot be blamed because clinical data are flawed, can incorrect clinical research blame its shortcomings on promising preclinical data?

Cost-effectiveness analyses continue to be published regarding interventions that lack even a single randomized controlled trial showing efficacy, despite the authors’ assertion that no one would do that. Favorable cost profiles have been found for diverse, unproven interventions such as transarterial chemoembolization,¹ surgical laminectomy,² and rosiglitazone (Avandia).³ Udeh and Udeh hold an untenable position, arguing that such analyses are ridiculous and would not be performed (such as a study of antibiotics to treat the common cold), while dismissing counterexamples (vertebroplasty), contending they are moot. The fact is that flawed cost-effectiveness studies are performed. They are often in error, and they distort our discussions of funding and approval.

Regarding exemastane (Aromasin), the authors miss the distinction between disease-specific death and overall mortality. Often, therapies lower the death rate from a particular disease but do not increase the overall survival rate. Typically, in these situations, we attribute the discrepancy to a lack of power, but an alternative hypothesis is that some death rates (eg, from cancer) decrease, while others (eg, from cardiovascular disease) increase, resulting in no net benefit. My comment regarding primary prevention studies is that unless the overall mortality rate is improved, one may continue to wonder if this phenomenon—trading death—is occurring. As a result, cost-effective analyses performed on these data may reach false conclusions. The authors’ fatalistic interpretation of my comments is not what I intended and is much more like a straw man.

Lastly, some of the difficulties in reconciling costs from randomized trials and actual clinical practice would be improved if clinical trials included participants who were more like the patients who would ultimately use the therapy. Such pragmatic trials would be a boon to the validity of research science⁴ and the accuracy of cost-effectiveness studies. I doubt that decision analytic modeling alone can overcome the problems I highlight. Two decades ago, we learned—from cost-effectiveness studies of autologous bone marrow transplantation in breast cancer—that decision analysis could not overcome major deficits in evidence.⁵ Autologous bone marrow transplantation is cost-effective—well, assuming it works.

We need cost-effectiveness studies to help us prioritize among countless emerging medical practices. However, we also need those analyses to be accurate. The examples I highlighted show common ways we err. The two rules I propose in my original commentary⁶ are not obvious to all, and they continue to be ignored. As such, cost-effectiveness still resembles like apples and oranges.

Drs. Udeh and Udeh attempt to highlight the “straw man” nature of my argument and the inaccuracies of my piece, but they ultimately disprove none of my claims.

Regarding vertebroplasty—a procedure that never worked better than a sham one—the authors do not fault the cost-effectiveness analysis for getting it wrong, but rather early clinical studies that provided false confidence. Yet, as a matter of fact, both were wrong. Cost-effectiveness analyses cannot be excused because they are based on faulty assumptions or poor data. This is precisely the reason they should be faulted. If incorrect cost-effectiveness analyses cannot be blamed because clinical data are flawed, can incorrect clinical research blame its shortcomings on promising preclinical data?

Cost-effectiveness analyses continue to be published regarding interventions that lack even a single randomized controlled trial showing efficacy, despite the authors’ assertion that no one would do that. Favorable cost profiles have been found for diverse, unproven interventions such as transarterial chemoembolization,¹ surgical laminectomy,² and rosiglitazone (Avandia).³ Udeh and Udeh hold an untenable position, arguing that such analyses are ridiculous and would not be performed (such as a study of antibiotics to treat the common cold), while dismissing counterexamples (vertebroplasty), contending they are moot. The fact is that flawed cost-effectiveness studies are performed. They are often in error, and they distort our discussions of funding and approval.

Regarding exemastane (Aromasin), the authors miss the distinction between disease-specific death and overall mortality. Often, therapies lower the death rate from a particular disease but do not increase the overall survival rate. Typically, in these situations, we attribute the discrepancy to a lack of power, but an alternative hypothesis is that some death rates (eg, from cancer) decrease, while others (eg, from cardiovascular disease) increase, resulting in no net benefit. My comment regarding primary prevention studies is that unless the overall mortality rate is improved, one may continue to wonder if this phenomenon—trading death—is occurring. As a result, cost-effective analyses performed on these data may reach false conclusions. The authors’ fatalistic interpretation of my comments is not what I intended and is much more like a straw man.

Lastly, some of the difficulties in reconciling costs from randomized trials and actual clinical practice would be improved if clinical trials included participants who were more like the patients who would ultimately use the therapy. Such pragmatic trials would be a boon to the validity of research science⁴ and the accuracy of cost-effectiveness studies. I doubt that decision analytic modeling alone can overcome the problems I highlight. Two decades ago, we learned—from cost-effectiveness studies of autologous bone marrow transplantation in breast cancer—that decision analysis could not overcome major deficits in evidence.⁵ Autologous bone marrow transplantation is cost-effective—well, assuming it works.

We need cost-effectiveness studies to help us prioritize among countless emerging medical practices. However, we also need those analyses to be accurate. The examples I highlighted show common ways we err. The two rules I propose in my original commentary⁶ are not obvious to all, and they continue to be ignored. As such, cost-effectiveness still resembles like apples and oranges.

Drs. Udeh and Udeh attempt to highlight the “straw man” nature of my argument and the inaccuracies of my piece, but they ultimately disprove none of my claims.

Regarding vertebroplasty—a procedure that never worked better than a sham one—the authors do not fault the cost-effectiveness analysis for getting it wrong, but rather early clinical studies that provided false confidence. Yet, as a matter of fact, both were wrong. Cost-effectiveness analyses cannot be excused because they are based on faulty assumptions or poor data. This is precisely the reason they should be faulted. If incorrect cost-effectiveness analyses cannot be blamed because clinical data are flawed, can incorrect clinical research blame its shortcomings on promising preclinical data?

Cost-effectiveness analyses continue to be published regarding interventions that lack even a single randomized controlled trial showing efficacy, despite the authors’ assertion that no one would do that. Favorable cost profiles have been found for diverse, unproven interventions such as transarterial chemoembolization,¹ surgical laminectomy,² and rosiglitazone (Avandia).³ Udeh and Udeh hold an untenable position, arguing that such analyses are ridiculous and would not be performed (such as a study of antibiotics to treat the common cold), while dismissing counterexamples (vertebroplasty), contending they are moot. The fact is that flawed cost-effectiveness studies are performed. They are often in error, and they distort our discussions of funding and approval.

Regarding exemastane (Aromasin), the authors miss the distinction between disease-specific death and overall mortality. Often, therapies lower the death rate from a particular disease but do not increase the overall survival rate. Typically, in these situations, we attribute the discrepancy to a lack of power, but an alternative hypothesis is that some death rates (eg, from cancer) decrease, while others (eg, from cardiovascular disease) increase, resulting in no net benefit. My comment regarding primary prevention studies is that unless the overall mortality rate is improved, one may continue to wonder if this phenomenon—trading death—is occurring. As a result, cost-effective analyses performed on these data may reach false conclusions. The authors’ fatalistic interpretation of my comments is not what I intended and is much more like a straw man.

Lastly, some of the difficulties in reconciling costs from randomized trials and actual clinical practice would be improved if clinical trials included participants who were more like the patients who would ultimately use the therapy. Such pragmatic trials would be a boon to the validity of research science⁴ and the accuracy of cost-effectiveness studies. I doubt that decision analytic modeling alone can overcome the problems I highlight. Two decades ago, we learned—from cost-effectiveness studies of autologous bone marrow transplantation in breast cancer—that decision analysis could not overcome major deficits in evidence.⁵ Autologous bone marrow transplantation is cost-effective—well, assuming it works.

We need cost-effectiveness studies to help us prioritize among countless emerging medical practices. However, we also need those analyses to be accurate. The examples I highlighted show common ways we err. The two rules I propose in my original commentary⁶ are not obvious to all, and they continue to be ignored. As such, cost-effectiveness still resembles like apples and oranges.

A 39-year-old woman on patient-controlled analgesia with morphine after cesarean delivery suddenly developed shortness of breath. On examination, the uvula was notably edematous, pale, and translucent, with no sign of erythema (Figure 1). The previous night, when the morphine was started, she had mild pruritus, which responded to treatment with oral diphenhydramine (Benadryl).

Given the extent of the uvular edema, emergency intubation was performed, and epinephrine and corticosteroids were given.

Q: Which is the most likely diagnosis at this point?

• Hereditary angioedema
• Infection causing epiglottitis masquerading as uvular swelling
• Opioid-induced uvular hydrops
• Myxedematous infiltration due to hypothyroidism

A: Opioid-induced uvular hydrops is the most likely diagnosis in this case, although it is rare. The most common side effect of opioids is constipation; others include lethargy, delirium, and sedation.

Hereditary angioedema is unlikely in this patient, as it usually presents in childhood or adolescence and there is usually a family history. Also, her cesarean delivery was done under regional anesthesia, which requires no oral or uvular manipulation and so cannot cause uvular swelling. In the absence of pain, fever, or signs and symptoms of pharyngitis, infection was unlikely. And she had no history of hypothyroidism.

UVULAR HYDROPS

This condition may be caused by opioid-induced direct degranulation of mast cells and basophils, inciting an inflammatory response.

Differential diagnoses include:

• Hereditary angioedema
• Effects of other drugs (angiotensin-converting enzyme inhibitors, cocaine, non-steroidal anti-inflammatory drugs)
• Infection (Haemophilus influenzae, Streptococcus pneumoniae)
• Trauma (intubation during surgery)
• Myxedematous infiltration due to hypothyroidism
• Granulomatous infiltration due to sarcoidosis.

When the patient’s condition has been stabilized, several outpatient tests may help narrow the differential diagnosis:

• Serum complement levels, of which the most reliable and cost-effective screening test for hereditary angioedema is a serum C4 level
• A serum thyroid-stimulating hormone level to rule out hypothyroidism
• Skin and lymph node biopsy (if skin lesions or lymphadenopathy is present), and chest radiograph to rule out sarcoidosis
• A urine drug screen and a skin-prick test for opioids (even though a negative skin test does not exclude opiate sensitivity).

OUR PATIENT’S COURSE

Our patient was discharged and underwent further outpatient evaluation. At discharge, she was advised to avoid opioids in the future.

A 39-year-old woman on patient-controlled analgesia with morphine after cesarean delivery suddenly developed shortness of breath. On examination, the uvula was notably edematous, pale, and translucent, with no sign of erythema (Figure 1). The previous night, when the morphine was started, she had mild pruritus, which responded to treatment with oral diphenhydramine (Benadryl).

Given the extent of the uvular edema, emergency intubation was performed, and epinephrine and corticosteroids were given.

Q: Which is the most likely diagnosis at this point?

• Hereditary angioedema
• Infection causing epiglottitis masquerading as uvular swelling
• Opioid-induced uvular hydrops
• Myxedematous infiltration due to hypothyroidism

A: Opioid-induced uvular hydrops is the most likely diagnosis in this case, although it is rare. The most common side effect of opioids is constipation; others include lethargy, delirium, and sedation.

Hereditary angioedema is unlikely in this patient, as it usually presents in childhood or adolescence and there is usually a family history. Also, her cesarean delivery was done under regional anesthesia, which requires no oral or uvular manipulation and so cannot cause uvular swelling. In the absence of pain, fever, or signs and symptoms of pharyngitis, infection was unlikely. And she had no history of hypothyroidism.

UVULAR HYDROPS

This condition may be caused by opioid-induced direct degranulation of mast cells and basophils, inciting an inflammatory response.

Differential diagnoses include:

• Hereditary angioedema
• Effects of other drugs (angiotensin-converting enzyme inhibitors, cocaine, non-steroidal anti-inflammatory drugs)
• Infection (Haemophilus influenzae, Streptococcus pneumoniae)
• Trauma (intubation during surgery)
• Myxedematous infiltration due to hypothyroidism
• Granulomatous infiltration due to sarcoidosis.

When the patient’s condition has been stabilized, several outpatient tests may help narrow the differential diagnosis:

• Serum complement levels, of which the most reliable and cost-effective screening test for hereditary angioedema is a serum C4 level
• A serum thyroid-stimulating hormone level to rule out hypothyroidism
• Skin and lymph node biopsy (if skin lesions or lymphadenopathy is present), and chest radiograph to rule out sarcoidosis
• A urine drug screen and a skin-prick test for opioids (even though a negative skin test does not exclude opiate sensitivity).

OUR PATIENT’S COURSE

Our patient was discharged and underwent further outpatient evaluation. At discharge, she was advised to avoid opioids in the future.

A 39-year-old woman on patient-controlled analgesia with morphine after cesarean delivery suddenly developed shortness of breath. On examination, the uvula was notably edematous, pale, and translucent, with no sign of erythema (Figure 1). The previous night, when the morphine was started, she had mild pruritus, which responded to treatment with oral diphenhydramine (Benadryl).

Given the extent of the uvular edema, emergency intubation was performed, and epinephrine and corticosteroids were given.

Q: Which is the most likely diagnosis at this point?

• Hereditary angioedema
• Infection causing epiglottitis masquerading as uvular swelling
• Opioid-induced uvular hydrops
• Myxedematous infiltration due to hypothyroidism

A: Opioid-induced uvular hydrops is the most likely diagnosis in this case, although it is rare. The most common side effect of opioids is constipation; others include lethargy, delirium, and sedation.

Hereditary angioedema is unlikely in this patient, as it usually presents in childhood or adolescence and there is usually a family history. Also, her cesarean delivery was done under regional anesthesia, which requires no oral or uvular manipulation and so cannot cause uvular swelling. In the absence of pain, fever, or signs and symptoms of pharyngitis, infection was unlikely. And she had no history of hypothyroidism.

UVULAR HYDROPS

This condition may be caused by opioid-induced direct degranulation of mast cells and basophils, inciting an inflammatory response.

Differential diagnoses include:

• Hereditary angioedema
• Effects of other drugs (angiotensin-converting enzyme inhibitors, cocaine, non-steroidal anti-inflammatory drugs)
• Infection (Haemophilus influenzae, Streptococcus pneumoniae)
• Trauma (intubation during surgery)
• Myxedematous infiltration due to hypothyroidism
• Granulomatous infiltration due to sarcoidosis.

When the patient’s condition has been stabilized, several outpatient tests may help narrow the differential diagnosis:

• Serum complement levels, of which the most reliable and cost-effective screening test for hereditary angioedema is a serum C4 level
• A serum thyroid-stimulating hormone level to rule out hypothyroidism
• Skin and lymph node biopsy (if skin lesions or lymphadenopathy is present), and chest radiograph to rule out sarcoidosis
• A urine drug screen and a skin-prick test for opioids (even though a negative skin test does not exclude opiate sensitivity).

OUR PATIENT’S COURSE

Our patient was discharged and underwent further outpatient evaluation. At discharge, she was advised to avoid opioids in the future.

The “I” has changed its meaning, the “P” is not necessary to make the diagnosis, and the syndrome is not strikingly common in adults. But the disease formerly known as idiopathic thrombocytopenic purpura (ITP) remains important for internists to diagnose because thrombocytopenia is extremely common.

ITP has long been recognized in children (in whom it is often self-limited but severe) and in adults (in whom it is often more insidious and chronic, with a wider differential diagnosis).

The “I” used to stand for “idiopathic” but now it stands for “immune,” following a half decade of work by many investigators. The seminal experimental work of Dr. William J. Harrington and others while the former was a hematology fellow with Carl Moore at Washington University is the stuff of legend and ethical debate. Harrington had himself injected with a pint of serum from a patient with ITP and nearly died, demonstrating that the patient’s blood contained a substance or substances capable of inducing reversible profound thrombocytopenia in the recipient.¹ Today, this classic experiment would probably not be performed, nor would the many more infusions that Harrington subsequently gave himself, other physicians, and support staff.²

Understanding the immunologic basis for ITP has led to treatments that are usually but not uniformly successful. Prednisone remains the main initial therapy, but its myriad side effects have led to the strategy of turning sooner to other therapies, such as intravenous immunoglobulin, splenectomy, rituximab (Rituxan), and, most recently, thrombopoietin agonists, in order to control the disease or even put it into remission.

Treatment decisions are often assigned to the hematologist or rheumatologist, but recognizing ITP and distinguishing it from other causes of thrombocytopenia remain the province of primary care providers, as discussed by Thota et al in this issue of the Journal.³ The diagnosis of ITP does not require the presence of purpura, which most adults ITP patients probably do not have, nor does it always require a bone marrow biopsy. It is important that ITP be distinguished from thrombocytopenia that is induced by drugs (particularly heparin) and myelodysplastic and other marrow processes (potential clues being other cytopenias, an unexplained elevated mean corpuscular volume, or constitutional symptoms). Undiagnosed thyroid disease and HIV infection should be tested for routinely, once drug-associated and other obvious causes are excluded.

The “I” has changed its meaning, the “P” is not necessary to make the diagnosis, and the syndrome is not strikingly common in adults. But the disease formerly known as idiopathic thrombocytopenic purpura (ITP) remains important for internists to diagnose because thrombocytopenia is extremely common.

ITP has long been recognized in children (in whom it is often self-limited but severe) and in adults (in whom it is often more insidious and chronic, with a wider differential diagnosis).

The “I” used to stand for “idiopathic” but now it stands for “immune,” following a half decade of work by many investigators. The seminal experimental work of Dr. William J. Harrington and others while the former was a hematology fellow with Carl Moore at Washington University is the stuff of legend and ethical debate. Harrington had himself injected with a pint of serum from a patient with ITP and nearly died, demonstrating that the patient’s blood contained a substance or substances capable of inducing reversible profound thrombocytopenia in the recipient.¹ Today, this classic experiment would probably not be performed, nor would the many more infusions that Harrington subsequently gave himself, other physicians, and support staff.²

Understanding the immunologic basis for ITP has led to treatments that are usually but not uniformly successful. Prednisone remains the main initial therapy, but its myriad side effects have led to the strategy of turning sooner to other therapies, such as intravenous immunoglobulin, splenectomy, rituximab (Rituxan), and, most recently, thrombopoietin agonists, in order to control the disease or even put it into remission.

Treatment decisions are often assigned to the hematologist or rheumatologist, but recognizing ITP and distinguishing it from other causes of thrombocytopenia remain the province of primary care providers, as discussed by Thota et al in this issue of the Journal.³ The diagnosis of ITP does not require the presence of purpura, which most adults ITP patients probably do not have, nor does it always require a bone marrow biopsy. It is important that ITP be distinguished from thrombocytopenia that is induced by drugs (particularly heparin) and myelodysplastic and other marrow processes (potential clues being other cytopenias, an unexplained elevated mean corpuscular volume, or constitutional symptoms). Undiagnosed thyroid disease and HIV infection should be tested for routinely, once drug-associated and other obvious causes are excluded.

The “I” has changed its meaning, the “P” is not necessary to make the diagnosis, and the syndrome is not strikingly common in adults. But the disease formerly known as idiopathic thrombocytopenic purpura (ITP) remains important for internists to diagnose because thrombocytopenia is extremely common.

ITP has long been recognized in children (in whom it is often self-limited but severe) and in adults (in whom it is often more insidious and chronic, with a wider differential diagnosis).

The “I” used to stand for “idiopathic” but now it stands for “immune,” following a half decade of work by many investigators. The seminal experimental work of Dr. William J. Harrington and others while the former was a hematology fellow with Carl Moore at Washington University is the stuff of legend and ethical debate. Harrington had himself injected with a pint of serum from a patient with ITP and nearly died, demonstrating that the patient’s blood contained a substance or substances capable of inducing reversible profound thrombocytopenia in the recipient.¹ Today, this classic experiment would probably not be performed, nor would the many more infusions that Harrington subsequently gave himself, other physicians, and support staff.²

Understanding the immunologic basis for ITP has led to treatments that are usually but not uniformly successful. Prednisone remains the main initial therapy, but its myriad side effects have led to the strategy of turning sooner to other therapies, such as intravenous immunoglobulin, splenectomy, rituximab (Rituxan), and, most recently, thrombopoietin agonists, in order to control the disease or even put it into remission.

Treatment decisions are often assigned to the hematologist or rheumatologist, but recognizing ITP and distinguishing it from other causes of thrombocytopenia remain the province of primary care providers, as discussed by Thota et al in this issue of the Journal.³ The diagnosis of ITP does not require the presence of purpura, which most adults ITP patients probably do not have, nor does it always require a bone marrow biopsy. It is important that ITP be distinguished from thrombocytopenia that is induced by drugs (particularly heparin) and myelodysplastic and other marrow processes (potential clues being other cytopenias, an unexplained elevated mean corpuscular volume, or constitutional symptoms). Undiagnosed thyroid disease and HIV infection should be tested for routinely, once drug-associated and other obvious causes are excluded.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.