Imaging

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

Biologics improved coronary inflammation as well as psoriasis symptoms, according to data from the perivascular fat attenuation index in 134 adults identified using coronary CT angiography.

Oxford Academic Cardiovascular CT Core Lab and Lab of Inflammation and Cardiometabolic Diseases at NHLBI

“The perivascular fat attenuation index [FAI] is a [CT]-based, novel, noninvasive imaging technique that allows for direct visualization and quantification of coronary inflammation using differential mapping of attenuation gradients in pericoronary fat,” wrote Youssef A. Elnabawi, MD, of the National Heart, Lung, and Blood Institute and colleagues. Biologics have been associated with reduced noncalcified coronary plaques in psoriasis patients, which suggests possible reduction in coronary inflammation as well.

In a study published in JAMA Cardiology, the researchers analyzed data from 134 adults with moderate to severe psoriasis who received no biologic therapy for at least 3 months before starting the study. Of these, 52 chose not to receive biologics, and served as controls while being treated with topical or light therapies. The participants are part of the Psoriasis Atherosclerosis Cardiometabolic Initiative, an ongoing, prospective cohort study. The average age of the patients was 51 years, and 63% were male.

The 82 patients given biologics received anti–tumor necrosis factor–alpha, anti–interleukin-12/23, or anti-IL-17 for 1 year. Overall, patients on biologics showed a significant decrease in FAI from a median of –71.22 Hounsfield units (HU) at baseline to a median of –76.06 at 1 year. These patients also showed significant improvement in Psoriasis Area and Severity Index scores, from a median of 7.7 at baseline to a median of 3.2 at 1 year. The control patients not on biologics showed no significant changes in FAI, with a median of –71.98 HU at baseline and –72.66 HU at 1 year.

The changes were consistent among the various biologics used, and The median FAI for patients on anti–tumor necrosis factor–alpha changed from –71.25 at baseline to –75.49 at 1 year; median FAI for both IL-12/23 and anti-IL-17 treatment groups changed from –71.18 HU at baseline to –76.92 at 1 year.

In addition, only patients treated with biologics showed a significant reduction in median C-reactive protein levels from baseline (2.2 mg/L vs. 1.3 mg/L). The changes in FAI were not associated with the presence of coronary plaques, the researchers noted.

The study findings were limited by several factors, including the observational design, small size, and lack of data on cardiovascular endpoints. “Future studies will be needed to explore whether the residual CV risk detected by perivascular FAI can be attenuated using targeted anti-inflammatory interventions,” they wrote.

However, the results suggest that biologics impact coronary vasculature at the microenvironmental level, and that FAI can be a noninvasive, cost-effective way to stratify patients at increased risk for cardiovascular disease, the researchers noted.


“We believe that the strength of perivascular FAI in risk stratifying patients with increased coronary inflammation will allow for better identification of patients at increased risk of future myocardial events that are not captured by traditional CV risk factors,” they wrote.

The study was funded by the National Institutes of Health, several research foundations, Elsevier, Colgate-Palmolive, and Genentech. Dr. Elnabawi had no financial conflicts to disclose; several coauthors reported relationships with multiple companies. One coauthor disclosed a pending and licensed patent to a novel tool for cardiovascular risk stratification based on the CT attenuation of perivascular tissue (OxScore) and a pending and licensed patent to perivascular texture index.

SOURCE: Elnabawi YA et al. JAMA Cardiol. 2019 Jul 31. doi: 10.1001/jamacardio.2019.2589.

Biologics improved coronary inflammation as well as psoriasis symptoms, according to data from the perivascular fat attenuation index in 134 adults identified using coronary CT angiography.

Oxford Academic Cardiovascular CT Core Lab and Lab of Inflammation and Cardiometabolic Diseases at NHLBI

“The perivascular fat attenuation index [FAI] is a [CT]-based, novel, noninvasive imaging technique that allows for direct visualization and quantification of coronary inflammation using differential mapping of attenuation gradients in pericoronary fat,” wrote Youssef A. Elnabawi, MD, of the National Heart, Lung, and Blood Institute and colleagues. Biologics have been associated with reduced noncalcified coronary plaques in psoriasis patients, which suggests possible reduction in coronary inflammation as well.

In a study published in JAMA Cardiology, the researchers analyzed data from 134 adults with moderate to severe psoriasis who received no biologic therapy for at least 3 months before starting the study. Of these, 52 chose not to receive biologics, and served as controls while being treated with topical or light therapies. The participants are part of the Psoriasis Atherosclerosis Cardiometabolic Initiative, an ongoing, prospective cohort study. The average age of the patients was 51 years, and 63% were male.

The 82 patients given biologics received anti–tumor necrosis factor–alpha, anti–interleukin-12/23, or anti-IL-17 for 1 year. Overall, patients on biologics showed a significant decrease in FAI from a median of –71.22 Hounsfield units (HU) at baseline to a median of –76.06 at 1 year. These patients also showed significant improvement in Psoriasis Area and Severity Index scores, from a median of 7.7 at baseline to a median of 3.2 at 1 year. The control patients not on biologics showed no significant changes in FAI, with a median of –71.98 HU at baseline and –72.66 HU at 1 year.

The changes were consistent among the various biologics used, and The median FAI for patients on anti–tumor necrosis factor–alpha changed from –71.25 at baseline to –75.49 at 1 year; median FAI for both IL-12/23 and anti-IL-17 treatment groups changed from –71.18 HU at baseline to –76.92 at 1 year.

In addition, only patients treated with biologics showed a significant reduction in median C-reactive protein levels from baseline (2.2 mg/L vs. 1.3 mg/L). The changes in FAI were not associated with the presence of coronary plaques, the researchers noted.

The study findings were limited by several factors, including the observational design, small size, and lack of data on cardiovascular endpoints. “Future studies will be needed to explore whether the residual CV risk detected by perivascular FAI can be attenuated using targeted anti-inflammatory interventions,” they wrote.

However, the results suggest that biologics impact coronary vasculature at the microenvironmental level, and that FAI can be a noninvasive, cost-effective way to stratify patients at increased risk for cardiovascular disease, the researchers noted.


“We believe that the strength of perivascular FAI in risk stratifying patients with increased coronary inflammation will allow for better identification of patients at increased risk of future myocardial events that are not captured by traditional CV risk factors,” they wrote.

The study was funded by the National Institutes of Health, several research foundations, Elsevier, Colgate-Palmolive, and Genentech. Dr. Elnabawi had no financial conflicts to disclose; several coauthors reported relationships with multiple companies. One coauthor disclosed a pending and licensed patent to a novel tool for cardiovascular risk stratification based on the CT attenuation of perivascular tissue (OxScore) and a pending and licensed patent to perivascular texture index.

SOURCE: Elnabawi YA et al. JAMA Cardiol. 2019 Jul 31. doi: 10.1001/jamacardio.2019.2589.

Biologics improved coronary inflammation as well as psoriasis symptoms, according to data from the perivascular fat attenuation index in 134 adults identified using coronary CT angiography.

Oxford Academic Cardiovascular CT Core Lab and Lab of Inflammation and Cardiometabolic Diseases at NHLBI

“The perivascular fat attenuation index [FAI] is a [CT]-based, novel, noninvasive imaging technique that allows for direct visualization and quantification of coronary inflammation using differential mapping of attenuation gradients in pericoronary fat,” wrote Youssef A. Elnabawi, MD, of the National Heart, Lung, and Blood Institute and colleagues. Biologics have been associated with reduced noncalcified coronary plaques in psoriasis patients, which suggests possible reduction in coronary inflammation as well.

In a study published in JAMA Cardiology, the researchers analyzed data from 134 adults with moderate to severe psoriasis who received no biologic therapy for at least 3 months before starting the study. Of these, 52 chose not to receive biologics, and served as controls while being treated with topical or light therapies. The participants are part of the Psoriasis Atherosclerosis Cardiometabolic Initiative, an ongoing, prospective cohort study. The average age of the patients was 51 years, and 63% were male.

The 82 patients given biologics received anti–tumor necrosis factor–alpha, anti–interleukin-12/23, or anti-IL-17 for 1 year. Overall, patients on biologics showed a significant decrease in FAI from a median of –71.22 Hounsfield units (HU) at baseline to a median of –76.06 at 1 year. These patients also showed significant improvement in Psoriasis Area and Severity Index scores, from a median of 7.7 at baseline to a median of 3.2 at 1 year. The control patients not on biologics showed no significant changes in FAI, with a median of –71.98 HU at baseline and –72.66 HU at 1 year.

The changes were consistent among the various biologics used, and The median FAI for patients on anti–tumor necrosis factor–alpha changed from –71.25 at baseline to –75.49 at 1 year; median FAI for both IL-12/23 and anti-IL-17 treatment groups changed from –71.18 HU at baseline to –76.92 at 1 year.

In addition, only patients treated with biologics showed a significant reduction in median C-reactive protein levels from baseline (2.2 mg/L vs. 1.3 mg/L). The changes in FAI were not associated with the presence of coronary plaques, the researchers noted.

The study findings were limited by several factors, including the observational design, small size, and lack of data on cardiovascular endpoints. “Future studies will be needed to explore whether the residual CV risk detected by perivascular FAI can be attenuated using targeted anti-inflammatory interventions,” they wrote.

However, the results suggest that biologics impact coronary vasculature at the microenvironmental level, and that FAI can be a noninvasive, cost-effective way to stratify patients at increased risk for cardiovascular disease, the researchers noted.


“We believe that the strength of perivascular FAI in risk stratifying patients with increased coronary inflammation will allow for better identification of patients at increased risk of future myocardial events that are not captured by traditional CV risk factors,” they wrote.

The study was funded by the National Institutes of Health, several research foundations, Elsevier, Colgate-Palmolive, and Genentech. Dr. Elnabawi had no financial conflicts to disclose; several coauthors reported relationships with multiple companies. One coauthor disclosed a pending and licensed patent to a novel tool for cardiovascular risk stratification based on the CT attenuation of perivascular tissue (OxScore) and a pending and licensed patent to perivascular texture index.

SOURCE: Elnabawi YA et al. JAMA Cardiol. 2019 Jul 31. doi: 10.1001/jamacardio.2019.2589.

Prompt diagnois of infective endocarditis is critical. Potential consequences of missed or delayed diagnosis, including heart failure, stroke, intracardiac abscess, conduction delays, prosthesis dysfunction, and cerebral emboli, are often catastrophic. Echocardiography is the test used most frequently to evaluate for infective endocarditis, but it misses the diagnosis in almost one-third of cases, and even more often if the patient has a prosthetic valve.

But now, several sophisticated imaging tests are available that complement echocardiography in diagnosing and assessing infective endocarditis; these include 4-dimensional computed tomography (4D CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and leukocyte scintigraphy. These tests have greatly improved our ability not only to diagnose infective endocarditis, but also to determine the extent and spread of infection, and they aid in perioperative assessment. Abnormal findings on these tests have been incorporated into the European Society of Cardiology’s 2015 modified diagnostic criteria for infective endocarditis.¹

This article details the indications, advantages, and limitations of the various imaging tests for diagnosing and evaluating infective endocarditis (Table 1).

INFECTIVE ENDOCARDITIS IS DIFFICULT TO DIAGNOSE AND TREAT

Infective endocarditis is difficult to diagnose and treat. Clinical and imaging clues can be subtle, and the diagnosis requires a high level of suspicion and visualization of cardiac structures.

Further, the incidence of infective endocarditis is on the rise in the United States, particularly in women and young adults, likely due to intravenous drug use.^2,3

ECHOCARDIOGRAPHY HAS AN IMPORTANT ROLE, BUT IS LIMITED

Echocardiography remains the most commonly performed study for diagnosing infective endocarditis, as it is fast, widely accessible, and less expensive than other imaging tests.

Transthoracic echocardiography (TTE) is often the first choice for testing. However, its sensitivity is only about 70% for detecting vegetations on native valves and 50% for detecting vegetations on prosthetic valves.¹ It is inherently constrained by the limited number of views by which a comprehensive external evaluation of the heart can be achieved. Using a 2-dimensional instrument to view a 3-dimensional object is difficult, and depending on several factors, it can be hard to see vegetations and abscesses that are associated with infective endocarditis. Further, TTE is impeded by obesity and by hyperinflated lungs from obstructive pulmonary disease or mechanical ventilation. It has poor sensitivity for detecting small vegetations and for detecting vegetations and paravalvular complications in patients who have a prosthetic valve or a cardiac implanted electronic device.

Transesophageal echocardiography (TEE) is the recommended first-line imaging test for patients with prosthetic valves and no contraindications to the test. Otherwise, it should be done after TTE if the results of TTE are negative but clinical suspicion for infective endocarditis remains high (eg, because the patient uses intravenous drugs). But although TEE has a higher sensitivity than TTE (up to 96% for vegetations on native valves and 92% for those on prosthetic valves, if performed by an experienced sonographer), it can still miss infective endocarditis. Also, TEE does not provide a significant advantage over TTE in patients who have a cardiac implanted electronic device.^1,4,5

Regardless of whether TTE or TEE is used, they are estimated to miss up to 30% of cases of infective endocarditis and its sequelae.⁴ False-negative findings are likelier in patients who have preexisting severe valvular lesions, prosthetic valves, cardiac implanted electronic devices, small vegetations, or abscesses, or if a vegetation has already broken free and embolized. Furthermore, distinguishing between vegetations and thrombi, cardiac tumors, and myxomatous changes using echocardiography is difficult.

For patients who have inconclusive results on echocardiography, contraindications to TEE, or poor sonic windows, cardiac CT can be an excellent alternative. It is especially useful in the setting of a prosthetic valve.

Synchronized (“gated”) with the patient’s heart rate and rhythm, CT machines can acquire images during diastole, reducing motion artifact, and can create 3D images of the heart. In addition, newer machines can acquire several images at different points in the heart cycle to add a fourth dimension—time. The resulting 4D images play like short video loops of the beating heart and allow noninvasive assessment of cardiac anatomy with remarkable detail and resolution.

4D CT is increasingly being used in infective endocarditis, and growing evidence indicates that its accuracy is similar to that of TEE in the preoperative evaluation of patients with aortic prosthetic valve endocarditis.⁶ In a study of 28 patients, complementary use of CT angiography led to a change in treatment strategy in 7 (25%) compared with routine clinical workup.⁷ Several studies have found no difference between 4D CT and preoperative TEE in detecting pseudoaneurysm, abscess, or valve dehiscence. TEE and 4D CT also have similar sensitivities for detecting infective endocarditis in native and prosthetic valves.^8,9

Coupled with CT angiography, 4D CT is also an excellent noninvasive way to perioperatively evaluate the coronary arteries without the risks associated with catheterization in those requiring nonemergency surgery (Figure 1A, B, and C).

4D CT performs well for detecting abscess and pseudoaneurysm but has slightly lower sensitivity for vegetations than TEE (91% vs 99%).⁹

Gated CT, PET, or both may be useful in cases of suspected prosthetic aortic valve endocarditis when TEE is negative. Pseudoaneurysms are not well visualized with TEE, and the atrial mitral curtain area is often thickened on TEE in cases of aortic prosthetic valve infective endocarditis that do not definitely involve abscesses. Gated CT and PET show this area better.⁸ This information is important in cases in which a surgeon may be unconvinced that the patient has prosthetic valve endocarditis.

Limitations of 4D cardiac CT

4D CT with or without angiography has limitations. It requires a wide-volume scanner and an experienced reader.

Patients with irregular heart rhythms or uncontrolled tachycardia pose technical problems for image acquisition. Cardiac CT is typically gated (ie, images are obtained within a defined time period) to acquire images during diastole. Ideally, images are acquired when the heart is in mid to late diastole, a time of minimal cardiac motion, so that motion artifact is minimized. To estimate the timing of image acquisition, the cardiac cycle must be predictable, and its duration should be as long as possible. Tachycardia or irregular rhythms such as frequent ectopic beats or atrial fibrillation make acquisition timing difficult, and thus make it nearly impossible to accurately obtain images when the heart is at minimum motion, limiting assessment of cardiac structures or the coronary tree.^4,10

Extensive coronary calcification can hinder assessment of the coronary tree by CT coronary angiography.

Contrast exposure may limit the use of CT in some patients (eg, those with contrast allergies or renal dysfunction). However, modern scanners allow for much smaller contrast boluses without decreasing sensitivity.

4D CT involves radiation exposure, especially when done with angiography, although modern scanners have greatly reduced exposure. The average radiation dose in CT coronary angiography is 2.9 to 5.9 mSv¹¹ compared with 7 mSv in diagnostic cardiac catheterization (without angioplasty or stenting) or 16 mSv in routine CT of the abdomen and pelvis with contrast.^12,13 In view of the morbidity and mortality risks associated with infective endocarditis, especially if the diagnosis is delayed, this small radiation exposure may be justifiable.

Bottom line for cardiac CT

4D CT is an excellent alternative to echocardiography for select patients. Clinicians should strongly consider this study in the following situations:

• Patients with a prosthetic valve
• Patients who are strongly suspected of having infective endocarditis but who have a poor sonic window on TTE or TEE, as can occur with chronic obstructive lung disease, morbid obesity, or previous thoracic or cardiovascular surgery
• Patients who meet clinical indications for TEE, such as having a prosthetic valve or a high suspicion for native valve infective endocarditis with negative TTE, but who have contraindications to TEE
• As an alternative to TEE for preoperative evaluation in patients with known infective endocarditis.

Patients with tachycardia or irregular heart rhythms are not good candidates for this test.

FDG-PET AND LEUKOCYTE SCINTIGRAPHY

FDG-PET and leukocyte scintigraphy are other options for diagnosing infective endocarditis and determining the presence and extent of intra- and extracardiac infection. They are more sensitive than echocardiography for detecting infection of cardiac implanted electronic devices such as ventricular assist devices, pacemakers, implanted cardiac defibrillators, and cardiac resynchronization therapy devices.^14–16

The utility of FDG-PET is founded on the uptake of ¹⁸F-fluorodeoxyglucose by cells, with higher uptake taking place in cells with higher metabolic activity (such as in areas of inflammation). Similarly, leukocyte scintigraphy relies on the use of radiolabeled leukocytes (ie, leukocytes previously extracted from the patient, labelled, and re-introduced into the patient) to allow for localization of inflamed tissue.

The most significant contribution of FDG-PET may be the ability to detect infective endocarditis early, when echocardiography is initially negative. When abnormal FDG uptake was included in the modified Duke criteria, it increased the sensitivity to 97% for detecting infective endocarditis on admission, leading some to propose its incorporation as a major criterion.¹⁷ In patients with prosthetic valves and suspected infective endocarditis, FDG-PET was found in one study to have a sensitivity of up to 91% and a specificity of up to 95%.¹⁸

Both FDG-PET and leukocyte scintigraphy have a high sensitivity, specificity, and negative predictive value for cardiac implanted electronic device infection, and should be strongly considered in patients in whom it is suspected but who have negative or inconclusive findings on echocardiography.^14,15

In addition, a common conundrum faced by clinicians with use of echocardiography is the difficulty of differentiating thrombus from infected vegetation on valves or device lead wires. Some evidence indicates that FDG-PET may help to discriminate between vegetation and thrombus, although more rigorous studies are needed before its use for that purpose can be recommended.¹⁹

Both FDG-PET and leukocyte scintigraphy perform poorly for detecting native-valve infective endocarditis. In a study in which 90% of the patients had native-valve infective endocarditis according to the Duke criteria, FDG-PET had a specificity of 93% but a sensitivity of only 39%.²⁰

Both studies can be cumbersome, laborious, and time-consuming for patients. FDG-PET requires a fasting or glucose-restricted diet before testing, and the test itself can be complicated by development of hyperglycemia, although this is rare.

While FDG-PET is most effective in detecting infections of prosthetic valves and cardiac implanted electronic devices, the results can be falsely positive in patients with a history of recent cardiac surgery (due to ongoing tissue healing), as well as maladies other than infective endocarditis that lead to inflammation, such as vasculitis or malignancy. Similarly, for unclear reasons, leukocyte scintigraphy can yield false-negative results in patients with enterococcal or candidal infective endocarditis.²¹

FDG-PET and leukocyte scintigraphy are more expensive than TEE and cardiac CT²² and are not widely available.

Both tests entail radiation exposure, with the average dose ranging from 7 to 14 mSv. However, this is less than the average amount acquired during percutaneous coronary intervention (16 mSv), and overlaps with the amount in chest CT with contrast when assessing for pulmonary embolism (7 to 9 mSv). Lower doses are possible with optimized protocols.^12,13,15,23

Bottom line for nuclear studies

FDG-PET and leukocyte scintigraphy are especially useful for patients with a prosthetic valve or cardiac implanted electronic device. However, limitations must be kept in mind.

A suggested algorithm for testing with nuclear imaging is shown in Figure 2.^1,4

CEREBRAL MAGNETIC RESONANCE IMAGING

Cerebral magnetic resonance imaging (MRI) is more sensitive than cerebral CT for detecting emboli in the brain. According to American Heart Association guidelines, cerebral MRI should be done in patients with known or suspected infective endocarditis and neurologic impairment, defined as headaches, meningeal symptoms, or neurologic deficits. It is also often used in neurologically asymptomatic patients with infective endocarditis who have indications for valve surgery to assess for mycotic aneurysms, which are associated with increased intracranial bleeding during surgery.

MRI use in other asymptomatic patients remains controversial.²⁴ In cases with high clinical suspicion for infective endocarditis and no findings on echocardiography, cerebral MRI can increase the sensitivity of the Duke criteria by adding a minor criterion. Some have argued that, in patients with definite infective endocarditis, detecting silent cerebral complications can lead to management changes. However, more studies are needed to determine if there is indeed a group of neurologically asymptomatic infective endocarditis patients for whom cerebral MRI leads to improved outcomes.

Limitations of cerebral MRI

Cerebral MRI cannot be used in patients with non-MRI-compatible implanted hardware.

Gadolinium, the contrast agent typically used, can cause nephrogenic systemic fibrosis in patients who have poor renal function. This rare but serious adverse effect is characterized by irreversible systemic fibrosis affecting skin, muscles, and even visceral tissue such as lungs. The American College of Radiology allows for gadolinium use in patients without acute kidney injury and patients with stable chronic kidney disease with a glomerular filtration rate of at least 30 mL/min/1.73 m². Its use should be avoided in patients with renal failure on replacement therapy, with advanced chronic kidney disease (glomerular filtration rate < 30 mL/min/1.73 m²), or with acute kidney injury, even if they do not need renal replacement therapy.²⁵

Concerns have also been raised about gadolinium retention in the brain, even in patients with normal renal function.^26–28 Thus far, no conclusive clinical adverse effects of retention have been found, although more study is warranted. Nevertheless, the US Food and Drug Administration now requires a black-box warning about this possibility and advises clinicians to counsel patients appropriately.

Bottom line on cerebral MRI

Cerebral MRI should be obtained when a patient presents with definite or possible infective endocarditis with neurologic impairment, such as new headaches, meningismus, or focal neurologic deficits. Routine brain MRI in patients with confirmed infective endocarditis without neurologic symptoms, or those without definite infective endocarditis, is discouraged.

CARDIAC MRI

Cardiac MRI, typically obtained with gadolinium contrast, allows for better 3D assessment of cardiac structures and morphology than echocardiography or CT, and can detect infiltrative cardiac disease, myopericarditis, and much more. It is increasingly used in the field of structural cardiology, but its role for evaluating infective endocarditis remains unclear.

Cardiac MRI does not appear to be better than echocardiography for diagnosing infective endocarditis. However, it may prove helpful in the evaluation of patients known to have infective endocarditis but who cannot be properly evaluated for disease extent because of poor image quality on echocardiography and contraindications to CT.^1,29 Its role is limited in patients with cardiac implanted electronic devices, as most devices are incompatible with MRI use, although newer devices obviate this concern. But even for devices that are MRI-compatible, results are diminished due to an eclipsing effect, wherein the device parts can make it hard to see structures clearly because the “brightness” basically eclipses the surrounding area.⁴

Concerns regarding use of gadolinium as described above need also be considered.

The role of cardiac MRI in diagnosing and managing infective endocarditis may evolve, but at present, the 2017 American College of Cardiology and American Heart Association appropriate-use criteria discourage its use for these purposes.¹⁶

Bottom line for cardiac MRI

Cardiac MRI to evaluate a patient for suspected infective endocarditis is not recommended due to lack of superiority compared with echocardiography or CT, and the risk of nephrogenic systemic fibrosis from gadolinium in patients with renal compromise.

Prompt diagnois of infective endocarditis is critical. Potential consequences of missed or delayed diagnosis, including heart failure, stroke, intracardiac abscess, conduction delays, prosthesis dysfunction, and cerebral emboli, are often catastrophic. Echocardiography is the test used most frequently to evaluate for infective endocarditis, but it misses the diagnosis in almost one-third of cases, and even more often if the patient has a prosthetic valve.

But now, several sophisticated imaging tests are available that complement echocardiography in diagnosing and assessing infective endocarditis; these include 4-dimensional computed tomography (4D CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and leukocyte scintigraphy. These tests have greatly improved our ability not only to diagnose infective endocarditis, but also to determine the extent and spread of infection, and they aid in perioperative assessment. Abnormal findings on these tests have been incorporated into the European Society of Cardiology’s 2015 modified diagnostic criteria for infective endocarditis.¹

This article details the indications, advantages, and limitations of the various imaging tests for diagnosing and evaluating infective endocarditis (Table 1).

INFECTIVE ENDOCARDITIS IS DIFFICULT TO DIAGNOSE AND TREAT

Infective endocarditis is difficult to diagnose and treat. Clinical and imaging clues can be subtle, and the diagnosis requires a high level of suspicion and visualization of cardiac structures.

Further, the incidence of infective endocarditis is on the rise in the United States, particularly in women and young adults, likely due to intravenous drug use.^2,3

ECHOCARDIOGRAPHY HAS AN IMPORTANT ROLE, BUT IS LIMITED

Echocardiography remains the most commonly performed study for diagnosing infective endocarditis, as it is fast, widely accessible, and less expensive than other imaging tests.

Transthoracic echocardiography (TTE) is often the first choice for testing. However, its sensitivity is only about 70% for detecting vegetations on native valves and 50% for detecting vegetations on prosthetic valves.¹ It is inherently constrained by the limited number of views by which a comprehensive external evaluation of the heart can be achieved. Using a 2-dimensional instrument to view a 3-dimensional object is difficult, and depending on several factors, it can be hard to see vegetations and abscesses that are associated with infective endocarditis. Further, TTE is impeded by obesity and by hyperinflated lungs from obstructive pulmonary disease or mechanical ventilation. It has poor sensitivity for detecting small vegetations and for detecting vegetations and paravalvular complications in patients who have a prosthetic valve or a cardiac implanted electronic device.

Transesophageal echocardiography (TEE) is the recommended first-line imaging test for patients with prosthetic valves and no contraindications to the test. Otherwise, it should be done after TTE if the results of TTE are negative but clinical suspicion for infective endocarditis remains high (eg, because the patient uses intravenous drugs). But although TEE has a higher sensitivity than TTE (up to 96% for vegetations on native valves and 92% for those on prosthetic valves, if performed by an experienced sonographer), it can still miss infective endocarditis. Also, TEE does not provide a significant advantage over TTE in patients who have a cardiac implanted electronic device.^1,4,5

Regardless of whether TTE or TEE is used, they are estimated to miss up to 30% of cases of infective endocarditis and its sequelae.⁴ False-negative findings are likelier in patients who have preexisting severe valvular lesions, prosthetic valves, cardiac implanted electronic devices, small vegetations, or abscesses, or if a vegetation has already broken free and embolized. Furthermore, distinguishing between vegetations and thrombi, cardiac tumors, and myxomatous changes using echocardiography is difficult.

For patients who have inconclusive results on echocardiography, contraindications to TEE, or poor sonic windows, cardiac CT can be an excellent alternative. It is especially useful in the setting of a prosthetic valve.

Synchronized (“gated”) with the patient’s heart rate and rhythm, CT machines can acquire images during diastole, reducing motion artifact, and can create 3D images of the heart. In addition, newer machines can acquire several images at different points in the heart cycle to add a fourth dimension—time. The resulting 4D images play like short video loops of the beating heart and allow noninvasive assessment of cardiac anatomy with remarkable detail and resolution.

4D CT is increasingly being used in infective endocarditis, and growing evidence indicates that its accuracy is similar to that of TEE in the preoperative evaluation of patients with aortic prosthetic valve endocarditis.⁶ In a study of 28 patients, complementary use of CT angiography led to a change in treatment strategy in 7 (25%) compared with routine clinical workup.⁷ Several studies have found no difference between 4D CT and preoperative TEE in detecting pseudoaneurysm, abscess, or valve dehiscence. TEE and 4D CT also have similar sensitivities for detecting infective endocarditis in native and prosthetic valves.^8,9

Coupled with CT angiography, 4D CT is also an excellent noninvasive way to perioperatively evaluate the coronary arteries without the risks associated with catheterization in those requiring nonemergency surgery (Figure 1A, B, and C).

4D CT performs well for detecting abscess and pseudoaneurysm but has slightly lower sensitivity for vegetations than TEE (91% vs 99%).⁹

Gated CT, PET, or both may be useful in cases of suspected prosthetic aortic valve endocarditis when TEE is negative. Pseudoaneurysms are not well visualized with TEE, and the atrial mitral curtain area is often thickened on TEE in cases of aortic prosthetic valve infective endocarditis that do not definitely involve abscesses. Gated CT and PET show this area better.⁸ This information is important in cases in which a surgeon may be unconvinced that the patient has prosthetic valve endocarditis.

Limitations of 4D cardiac CT

4D CT with or without angiography has limitations. It requires a wide-volume scanner and an experienced reader.

Patients with irregular heart rhythms or uncontrolled tachycardia pose technical problems for image acquisition. Cardiac CT is typically gated (ie, images are obtained within a defined time period) to acquire images during diastole. Ideally, images are acquired when the heart is in mid to late diastole, a time of minimal cardiac motion, so that motion artifact is minimized. To estimate the timing of image acquisition, the cardiac cycle must be predictable, and its duration should be as long as possible. Tachycardia or irregular rhythms such as frequent ectopic beats or atrial fibrillation make acquisition timing difficult, and thus make it nearly impossible to accurately obtain images when the heart is at minimum motion, limiting assessment of cardiac structures or the coronary tree.^4,10

Extensive coronary calcification can hinder assessment of the coronary tree by CT coronary angiography.

Contrast exposure may limit the use of CT in some patients (eg, those with contrast allergies or renal dysfunction). However, modern scanners allow for much smaller contrast boluses without decreasing sensitivity.

4D CT involves radiation exposure, especially when done with angiography, although modern scanners have greatly reduced exposure. The average radiation dose in CT coronary angiography is 2.9 to 5.9 mSv¹¹ compared with 7 mSv in diagnostic cardiac catheterization (without angioplasty or stenting) or 16 mSv in routine CT of the abdomen and pelvis with contrast.^12,13 In view of the morbidity and mortality risks associated with infective endocarditis, especially if the diagnosis is delayed, this small radiation exposure may be justifiable.

Bottom line for cardiac CT

4D CT is an excellent alternative to echocardiography for select patients. Clinicians should strongly consider this study in the following situations:

• Patients with a prosthetic valve
• Patients who are strongly suspected of having infective endocarditis but who have a poor sonic window on TTE or TEE, as can occur with chronic obstructive lung disease, morbid obesity, or previous thoracic or cardiovascular surgery
• Patients who meet clinical indications for TEE, such as having a prosthetic valve or a high suspicion for native valve infective endocarditis with negative TTE, but who have contraindications to TEE
• As an alternative to TEE for preoperative evaluation in patients with known infective endocarditis.

Patients with tachycardia or irregular heart rhythms are not good candidates for this test.

FDG-PET AND LEUKOCYTE SCINTIGRAPHY

FDG-PET and leukocyte scintigraphy are other options for diagnosing infective endocarditis and determining the presence and extent of intra- and extracardiac infection. They are more sensitive than echocardiography for detecting infection of cardiac implanted electronic devices such as ventricular assist devices, pacemakers, implanted cardiac defibrillators, and cardiac resynchronization therapy devices.^14–16

The utility of FDG-PET is founded on the uptake of ¹⁸F-fluorodeoxyglucose by cells, with higher uptake taking place in cells with higher metabolic activity (such as in areas of inflammation). Similarly, leukocyte scintigraphy relies on the use of radiolabeled leukocytes (ie, leukocytes previously extracted from the patient, labelled, and re-introduced into the patient) to allow for localization of inflamed tissue.

The most significant contribution of FDG-PET may be the ability to detect infective endocarditis early, when echocardiography is initially negative. When abnormal FDG uptake was included in the modified Duke criteria, it increased the sensitivity to 97% for detecting infective endocarditis on admission, leading some to propose its incorporation as a major criterion.¹⁷ In patients with prosthetic valves and suspected infective endocarditis, FDG-PET was found in one study to have a sensitivity of up to 91% and a specificity of up to 95%.¹⁸

Both FDG-PET and leukocyte scintigraphy have a high sensitivity, specificity, and negative predictive value for cardiac implanted electronic device infection, and should be strongly considered in patients in whom it is suspected but who have negative or inconclusive findings on echocardiography.^14,15

In addition, a common conundrum faced by clinicians with use of echocardiography is the difficulty of differentiating thrombus from infected vegetation on valves or device lead wires. Some evidence indicates that FDG-PET may help to discriminate between vegetation and thrombus, although more rigorous studies are needed before its use for that purpose can be recommended.¹⁹

Both FDG-PET and leukocyte scintigraphy perform poorly for detecting native-valve infective endocarditis. In a study in which 90% of the patients had native-valve infective endocarditis according to the Duke criteria, FDG-PET had a specificity of 93% but a sensitivity of only 39%.²⁰

Both studies can be cumbersome, laborious, and time-consuming for patients. FDG-PET requires a fasting or glucose-restricted diet before testing, and the test itself can be complicated by development of hyperglycemia, although this is rare.

While FDG-PET is most effective in detecting infections of prosthetic valves and cardiac implanted electronic devices, the results can be falsely positive in patients with a history of recent cardiac surgery (due to ongoing tissue healing), as well as maladies other than infective endocarditis that lead to inflammation, such as vasculitis or malignancy. Similarly, for unclear reasons, leukocyte scintigraphy can yield false-negative results in patients with enterococcal or candidal infective endocarditis.²¹

FDG-PET and leukocyte scintigraphy are more expensive than TEE and cardiac CT²² and are not widely available.

Both tests entail radiation exposure, with the average dose ranging from 7 to 14 mSv. However, this is less than the average amount acquired during percutaneous coronary intervention (16 mSv), and overlaps with the amount in chest CT with contrast when assessing for pulmonary embolism (7 to 9 mSv). Lower doses are possible with optimized protocols.^12,13,15,23

Bottom line for nuclear studies

FDG-PET and leukocyte scintigraphy are especially useful for patients with a prosthetic valve or cardiac implanted electronic device. However, limitations must be kept in mind.

A suggested algorithm for testing with nuclear imaging is shown in Figure 2.^1,4

CEREBRAL MAGNETIC RESONANCE IMAGING

Cerebral magnetic resonance imaging (MRI) is more sensitive than cerebral CT for detecting emboli in the brain. According to American Heart Association guidelines, cerebral MRI should be done in patients with known or suspected infective endocarditis and neurologic impairment, defined as headaches, meningeal symptoms, or neurologic deficits. It is also often used in neurologically asymptomatic patients with infective endocarditis who have indications for valve surgery to assess for mycotic aneurysms, which are associated with increased intracranial bleeding during surgery.

MRI use in other asymptomatic patients remains controversial.²⁴ In cases with high clinical suspicion for infective endocarditis and no findings on echocardiography, cerebral MRI can increase the sensitivity of the Duke criteria by adding a minor criterion. Some have argued that, in patients with definite infective endocarditis, detecting silent cerebral complications can lead to management changes. However, more studies are needed to determine if there is indeed a group of neurologically asymptomatic infective endocarditis patients for whom cerebral MRI leads to improved outcomes.

Limitations of cerebral MRI

Cerebral MRI cannot be used in patients with non-MRI-compatible implanted hardware.

Gadolinium, the contrast agent typically used, can cause nephrogenic systemic fibrosis in patients who have poor renal function. This rare but serious adverse effect is characterized by irreversible systemic fibrosis affecting skin, muscles, and even visceral tissue such as lungs. The American College of Radiology allows for gadolinium use in patients without acute kidney injury and patients with stable chronic kidney disease with a glomerular filtration rate of at least 30 mL/min/1.73 m². Its use should be avoided in patients with renal failure on replacement therapy, with advanced chronic kidney disease (glomerular filtration rate < 30 mL/min/1.73 m²), or with acute kidney injury, even if they do not need renal replacement therapy.²⁵

Concerns have also been raised about gadolinium retention in the brain, even in patients with normal renal function.^26–28 Thus far, no conclusive clinical adverse effects of retention have been found, although more study is warranted. Nevertheless, the US Food and Drug Administration now requires a black-box warning about this possibility and advises clinicians to counsel patients appropriately.

Bottom line on cerebral MRI

Cerebral MRI should be obtained when a patient presents with definite or possible infective endocarditis with neurologic impairment, such as new headaches, meningismus, or focal neurologic deficits. Routine brain MRI in patients with confirmed infective endocarditis without neurologic symptoms, or those without definite infective endocarditis, is discouraged.

CARDIAC MRI

Cardiac MRI, typically obtained with gadolinium contrast, allows for better 3D assessment of cardiac structures and morphology than echocardiography or CT, and can detect infiltrative cardiac disease, myopericarditis, and much more. It is increasingly used in the field of structural cardiology, but its role for evaluating infective endocarditis remains unclear.

Cardiac MRI does not appear to be better than echocardiography for diagnosing infective endocarditis. However, it may prove helpful in the evaluation of patients known to have infective endocarditis but who cannot be properly evaluated for disease extent because of poor image quality on echocardiography and contraindications to CT.^1,29 Its role is limited in patients with cardiac implanted electronic devices, as most devices are incompatible with MRI use, although newer devices obviate this concern. But even for devices that are MRI-compatible, results are diminished due to an eclipsing effect, wherein the device parts can make it hard to see structures clearly because the “brightness” basically eclipses the surrounding area.⁴

Concerns regarding use of gadolinium as described above need also be considered.

The role of cardiac MRI in diagnosing and managing infective endocarditis may evolve, but at present, the 2017 American College of Cardiology and American Heart Association appropriate-use criteria discourage its use for these purposes.¹⁶

Bottom line for cardiac MRI

Cardiac MRI to evaluate a patient for suspected infective endocarditis is not recommended due to lack of superiority compared with echocardiography or CT, and the risk of nephrogenic systemic fibrosis from gadolinium in patients with renal compromise.

Prompt diagnois of infective endocarditis is critical. Potential consequences of missed or delayed diagnosis, including heart failure, stroke, intracardiac abscess, conduction delays, prosthesis dysfunction, and cerebral emboli, are often catastrophic. Echocardiography is the test used most frequently to evaluate for infective endocarditis, but it misses the diagnosis in almost one-third of cases, and even more often if the patient has a prosthetic valve.

But now, several sophisticated imaging tests are available that complement echocardiography in diagnosing and assessing infective endocarditis; these include 4-dimensional computed tomography (4D CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and leukocyte scintigraphy. These tests have greatly improved our ability not only to diagnose infective endocarditis, but also to determine the extent and spread of infection, and they aid in perioperative assessment. Abnormal findings on these tests have been incorporated into the European Society of Cardiology’s 2015 modified diagnostic criteria for infective endocarditis.¹

This article details the indications, advantages, and limitations of the various imaging tests for diagnosing and evaluating infective endocarditis (Table 1).

INFECTIVE ENDOCARDITIS IS DIFFICULT TO DIAGNOSE AND TREAT

Infective endocarditis is difficult to diagnose and treat. Clinical and imaging clues can be subtle, and the diagnosis requires a high level of suspicion and visualization of cardiac structures.

Further, the incidence of infective endocarditis is on the rise in the United States, particularly in women and young adults, likely due to intravenous drug use.^2,3

ECHOCARDIOGRAPHY HAS AN IMPORTANT ROLE, BUT IS LIMITED

Echocardiography remains the most commonly performed study for diagnosing infective endocarditis, as it is fast, widely accessible, and less expensive than other imaging tests.

Transthoracic echocardiography (TTE) is often the first choice for testing. However, its sensitivity is only about 70% for detecting vegetations on native valves and 50% for detecting vegetations on prosthetic valves.¹ It is inherently constrained by the limited number of views by which a comprehensive external evaluation of the heart can be achieved. Using a 2-dimensional instrument to view a 3-dimensional object is difficult, and depending on several factors, it can be hard to see vegetations and abscesses that are associated with infective endocarditis. Further, TTE is impeded by obesity and by hyperinflated lungs from obstructive pulmonary disease or mechanical ventilation. It has poor sensitivity for detecting small vegetations and for detecting vegetations and paravalvular complications in patients who have a prosthetic valve or a cardiac implanted electronic device.

Transesophageal echocardiography (TEE) is the recommended first-line imaging test for patients with prosthetic valves and no contraindications to the test. Otherwise, it should be done after TTE if the results of TTE are negative but clinical suspicion for infective endocarditis remains high (eg, because the patient uses intravenous drugs). But although TEE has a higher sensitivity than TTE (up to 96% for vegetations on native valves and 92% for those on prosthetic valves, if performed by an experienced sonographer), it can still miss infective endocarditis. Also, TEE does not provide a significant advantage over TTE in patients who have a cardiac implanted electronic device.^1,4,5

Regardless of whether TTE or TEE is used, they are estimated to miss up to 30% of cases of infective endocarditis and its sequelae.⁴ False-negative findings are likelier in patients who have preexisting severe valvular lesions, prosthetic valves, cardiac implanted electronic devices, small vegetations, or abscesses, or if a vegetation has already broken free and embolized. Furthermore, distinguishing between vegetations and thrombi, cardiac tumors, and myxomatous changes using echocardiography is difficult.

For patients who have inconclusive results on echocardiography, contraindications to TEE, or poor sonic windows, cardiac CT can be an excellent alternative. It is especially useful in the setting of a prosthetic valve.

Synchronized (“gated”) with the patient’s heart rate and rhythm, CT machines can acquire images during diastole, reducing motion artifact, and can create 3D images of the heart. In addition, newer machines can acquire several images at different points in the heart cycle to add a fourth dimension—time. The resulting 4D images play like short video loops of the beating heart and allow noninvasive assessment of cardiac anatomy with remarkable detail and resolution.

4D CT is increasingly being used in infective endocarditis, and growing evidence indicates that its accuracy is similar to that of TEE in the preoperative evaluation of patients with aortic prosthetic valve endocarditis.⁶ In a study of 28 patients, complementary use of CT angiography led to a change in treatment strategy in 7 (25%) compared with routine clinical workup.⁷ Several studies have found no difference between 4D CT and preoperative TEE in detecting pseudoaneurysm, abscess, or valve dehiscence. TEE and 4D CT also have similar sensitivities for detecting infective endocarditis in native and prosthetic valves.^8,9

Coupled with CT angiography, 4D CT is also an excellent noninvasive way to perioperatively evaluate the coronary arteries without the risks associated with catheterization in those requiring nonemergency surgery (Figure 1A, B, and C).

4D CT performs well for detecting abscess and pseudoaneurysm but has slightly lower sensitivity for vegetations than TEE (91% vs 99%).⁹

Gated CT, PET, or both may be useful in cases of suspected prosthetic aortic valve endocarditis when TEE is negative. Pseudoaneurysms are not well visualized with TEE, and the atrial mitral curtain area is often thickened on TEE in cases of aortic prosthetic valve infective endocarditis that do not definitely involve abscesses. Gated CT and PET show this area better.⁸ This information is important in cases in which a surgeon may be unconvinced that the patient has prosthetic valve endocarditis.

Limitations of 4D cardiac CT

4D CT with or without angiography has limitations. It requires a wide-volume scanner and an experienced reader.

Patients with irregular heart rhythms or uncontrolled tachycardia pose technical problems for image acquisition. Cardiac CT is typically gated (ie, images are obtained within a defined time period) to acquire images during diastole. Ideally, images are acquired when the heart is in mid to late diastole, a time of minimal cardiac motion, so that motion artifact is minimized. To estimate the timing of image acquisition, the cardiac cycle must be predictable, and its duration should be as long as possible. Tachycardia or irregular rhythms such as frequent ectopic beats or atrial fibrillation make acquisition timing difficult, and thus make it nearly impossible to accurately obtain images when the heart is at minimum motion, limiting assessment of cardiac structures or the coronary tree.^4,10

Extensive coronary calcification can hinder assessment of the coronary tree by CT coronary angiography.

Contrast exposure may limit the use of CT in some patients (eg, those with contrast allergies or renal dysfunction). However, modern scanners allow for much smaller contrast boluses without decreasing sensitivity.

4D CT involves radiation exposure, especially when done with angiography, although modern scanners have greatly reduced exposure. The average radiation dose in CT coronary angiography is 2.9 to 5.9 mSv¹¹ compared with 7 mSv in diagnostic cardiac catheterization (without angioplasty or stenting) or 16 mSv in routine CT of the abdomen and pelvis with contrast.^12,13 In view of the morbidity and mortality risks associated with infective endocarditis, especially if the diagnosis is delayed, this small radiation exposure may be justifiable.

Bottom line for cardiac CT

4D CT is an excellent alternative to echocardiography for select patients. Clinicians should strongly consider this study in the following situations:

• Patients with a prosthetic valve
• Patients who are strongly suspected of having infective endocarditis but who have a poor sonic window on TTE or TEE, as can occur with chronic obstructive lung disease, morbid obesity, or previous thoracic or cardiovascular surgery
• Patients who meet clinical indications for TEE, such as having a prosthetic valve or a high suspicion for native valve infective endocarditis with negative TTE, but who have contraindications to TEE
• As an alternative to TEE for preoperative evaluation in patients with known infective endocarditis.

Patients with tachycardia or irregular heart rhythms are not good candidates for this test.

FDG-PET AND LEUKOCYTE SCINTIGRAPHY

FDG-PET and leukocyte scintigraphy are other options for diagnosing infective endocarditis and determining the presence and extent of intra- and extracardiac infection. They are more sensitive than echocardiography for detecting infection of cardiac implanted electronic devices such as ventricular assist devices, pacemakers, implanted cardiac defibrillators, and cardiac resynchronization therapy devices.^14–16

The utility of FDG-PET is founded on the uptake of ¹⁸F-fluorodeoxyglucose by cells, with higher uptake taking place in cells with higher metabolic activity (such as in areas of inflammation). Similarly, leukocyte scintigraphy relies on the use of radiolabeled leukocytes (ie, leukocytes previously extracted from the patient, labelled, and re-introduced into the patient) to allow for localization of inflamed tissue.

The most significant contribution of FDG-PET may be the ability to detect infective endocarditis early, when echocardiography is initially negative. When abnormal FDG uptake was included in the modified Duke criteria, it increased the sensitivity to 97% for detecting infective endocarditis on admission, leading some to propose its incorporation as a major criterion.¹⁷ In patients with prosthetic valves and suspected infective endocarditis, FDG-PET was found in one study to have a sensitivity of up to 91% and a specificity of up to 95%.¹⁸

Both FDG-PET and leukocyte scintigraphy have a high sensitivity, specificity, and negative predictive value for cardiac implanted electronic device infection, and should be strongly considered in patients in whom it is suspected but who have negative or inconclusive findings on echocardiography.^14,15

In addition, a common conundrum faced by clinicians with use of echocardiography is the difficulty of differentiating thrombus from infected vegetation on valves or device lead wires. Some evidence indicates that FDG-PET may help to discriminate between vegetation and thrombus, although more rigorous studies are needed before its use for that purpose can be recommended.¹⁹

Both FDG-PET and leukocyte scintigraphy perform poorly for detecting native-valve infective endocarditis. In a study in which 90% of the patients had native-valve infective endocarditis according to the Duke criteria, FDG-PET had a specificity of 93% but a sensitivity of only 39%.²⁰

Both studies can be cumbersome, laborious, and time-consuming for patients. FDG-PET requires a fasting or glucose-restricted diet before testing, and the test itself can be complicated by development of hyperglycemia, although this is rare.

While FDG-PET is most effective in detecting infections of prosthetic valves and cardiac implanted electronic devices, the results can be falsely positive in patients with a history of recent cardiac surgery (due to ongoing tissue healing), as well as maladies other than infective endocarditis that lead to inflammation, such as vasculitis or malignancy. Similarly, for unclear reasons, leukocyte scintigraphy can yield false-negative results in patients with enterococcal or candidal infective endocarditis.²¹

FDG-PET and leukocyte scintigraphy are more expensive than TEE and cardiac CT²² and are not widely available.

Both tests entail radiation exposure, with the average dose ranging from 7 to 14 mSv. However, this is less than the average amount acquired during percutaneous coronary intervention (16 mSv), and overlaps with the amount in chest CT with contrast when assessing for pulmonary embolism (7 to 9 mSv). Lower doses are possible with optimized protocols.^12,13,15,23

Bottom line for nuclear studies

FDG-PET and leukocyte scintigraphy are especially useful for patients with a prosthetic valve or cardiac implanted electronic device. However, limitations must be kept in mind.

A suggested algorithm for testing with nuclear imaging is shown in Figure 2.^1,4

CEREBRAL MAGNETIC RESONANCE IMAGING

Cerebral magnetic resonance imaging (MRI) is more sensitive than cerebral CT for detecting emboli in the brain. According to American Heart Association guidelines, cerebral MRI should be done in patients with known or suspected infective endocarditis and neurologic impairment, defined as headaches, meningeal symptoms, or neurologic deficits. It is also often used in neurologically asymptomatic patients with infective endocarditis who have indications for valve surgery to assess for mycotic aneurysms, which are associated with increased intracranial bleeding during surgery.

MRI use in other asymptomatic patients remains controversial.²⁴ In cases with high clinical suspicion for infective endocarditis and no findings on echocardiography, cerebral MRI can increase the sensitivity of the Duke criteria by adding a minor criterion. Some have argued that, in patients with definite infective endocarditis, detecting silent cerebral complications can lead to management changes. However, more studies are needed to determine if there is indeed a group of neurologically asymptomatic infective endocarditis patients for whom cerebral MRI leads to improved outcomes.

Limitations of cerebral MRI

Cerebral MRI cannot be used in patients with non-MRI-compatible implanted hardware.

Gadolinium, the contrast agent typically used, can cause nephrogenic systemic fibrosis in patients who have poor renal function. This rare but serious adverse effect is characterized by irreversible systemic fibrosis affecting skin, muscles, and even visceral tissue such as lungs. The American College of Radiology allows for gadolinium use in patients without acute kidney injury and patients with stable chronic kidney disease with a glomerular filtration rate of at least 30 mL/min/1.73 m². Its use should be avoided in patients with renal failure on replacement therapy, with advanced chronic kidney disease (glomerular filtration rate < 30 mL/min/1.73 m²), or with acute kidney injury, even if they do not need renal replacement therapy.²⁵

Concerns have also been raised about gadolinium retention in the brain, even in patients with normal renal function.^26–28 Thus far, no conclusive clinical adverse effects of retention have been found, although more study is warranted. Nevertheless, the US Food and Drug Administration now requires a black-box warning about this possibility and advises clinicians to counsel patients appropriately.

Bottom line on cerebral MRI

Cerebral MRI should be obtained when a patient presents with definite or possible infective endocarditis with neurologic impairment, such as new headaches, meningismus, or focal neurologic deficits. Routine brain MRI in patients with confirmed infective endocarditis without neurologic symptoms, or those without definite infective endocarditis, is discouraged.

CARDIAC MRI

Cardiac MRI, typically obtained with gadolinium contrast, allows for better 3D assessment of cardiac structures and morphology than echocardiography or CT, and can detect infiltrative cardiac disease, myopericarditis, and much more. It is increasingly used in the field of structural cardiology, but its role for evaluating infective endocarditis remains unclear.

Cardiac MRI does not appear to be better than echocardiography for diagnosing infective endocarditis. However, it may prove helpful in the evaluation of patients known to have infective endocarditis but who cannot be properly evaluated for disease extent because of poor image quality on echocardiography and contraindications to CT.^1,29 Its role is limited in patients with cardiac implanted electronic devices, as most devices are incompatible with MRI use, although newer devices obviate this concern. But even for devices that are MRI-compatible, results are diminished due to an eclipsing effect, wherein the device parts can make it hard to see structures clearly because the “brightness” basically eclipses the surrounding area.⁴

Concerns regarding use of gadolinium as described above need also be considered.

The role of cardiac MRI in diagnosing and managing infective endocarditis may evolve, but at present, the 2017 American College of Cardiology and American Heart Association appropriate-use criteria discourage its use for these purposes.¹⁶

Bottom line for cardiac MRI

Cardiac MRI to evaluate a patient for suspected infective endocarditis is not recommended due to lack of superiority compared with echocardiography or CT, and the risk of nephrogenic systemic fibrosis from gadolinium in patients with renal compromise.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

A 45-year-old woman with a history of multiple organ transplants presented with a 1-month history of anterior left hip pain with insidious onset. Although she was able to perform activities of daily living, she reported increasing difficulty with weight-bearing activities.

RISK FACTORS

Osteonecrosis of the hip is caused by prolonged interruption of blood flow to the femoral head.² While idiopathic osteonecrosis is not uncommon, the condition is often associated with alcohol abuse or, as in our patient, long-term corticosteroid use after organ transplant.³ Corticosteroid use is also the most frequently reported risk factor for multifocal osteonecrosis.

Less common risk factors include systemic lupus erythematosus, antiphospholipid antibodies, coagulopathies, sickle cell disease, Gaucher disease, trauma, and external-beam therapy.

Young age is also associated with osteonecrosis, as nearly 75% of patients are between age 30 and 60.⁴

APPROACH TO DIAGNOSIS

Our patient had a typical clinical presentation of this disease: she was relatively young, was on long-term corticosteroids, and had acute anterior groin pain followed by progressive functional impairment.

The diagnostic evaluation consists of a detailed history, with attention to specific risk factors, and a thorough clinical examination followed by imaging, usually with plain radiography. However, plain radiographs are often unremarkable when the condition is in the early stages. In such cases, magnetic resonance imaging is recommended if clinical suspicion for osteonecrosis is high. It is far more sensitive (> 99%) and specific (> 99%) than plain radiography, and it detects early changes in the femoral head such as focal lesions and bone marrow edema.⁵

TREATMENT OPTIONS

Treatment of osteonecrosis is surgical and depends on the stage of disease.⁶ 

Joint preservation may be an option for small to medium-sized lesions before subchondral collapse has occurred; options include core decompression, bone grafting, and femoral osteotomy to preserve the native femoral head. These procedures have a higher success rate in young patients.

Subchondral collapse usually warrants hip replacement.

OUR PATIENT’S TREATMENT

A 45-year-old woman with a history of multiple organ transplants presented with a 1-month history of anterior left hip pain with insidious onset. Although she was able to perform activities of daily living, she reported increasing difficulty with weight-bearing activities.

RISK FACTORS

Osteonecrosis of the hip is caused by prolonged interruption of blood flow to the femoral head.² While idiopathic osteonecrosis is not uncommon, the condition is often associated with alcohol abuse or, as in our patient, long-term corticosteroid use after organ transplant.³ Corticosteroid use is also the most frequently reported risk factor for multifocal osteonecrosis.

Less common risk factors include systemic lupus erythematosus, antiphospholipid antibodies, coagulopathies, sickle cell disease, Gaucher disease, trauma, and external-beam therapy.

Young age is also associated with osteonecrosis, as nearly 75% of patients are between age 30 and 60.⁴

APPROACH TO DIAGNOSIS

Our patient had a typical clinical presentation of this disease: she was relatively young, was on long-term corticosteroids, and had acute anterior groin pain followed by progressive functional impairment.

The diagnostic evaluation consists of a detailed history, with attention to specific risk factors, and a thorough clinical examination followed by imaging, usually with plain radiography. However, plain radiographs are often unremarkable when the condition is in the early stages. In such cases, magnetic resonance imaging is recommended if clinical suspicion for osteonecrosis is high. It is far more sensitive (> 99%) and specific (> 99%) than plain radiography, and it detects early changes in the femoral head such as focal lesions and bone marrow edema.⁵

TREATMENT OPTIONS

Treatment of osteonecrosis is surgical and depends on the stage of disease.⁶ 

Joint preservation may be an option for small to medium-sized lesions before subchondral collapse has occurred; options include core decompression, bone grafting, and femoral osteotomy to preserve the native femoral head. These procedures have a higher success rate in young patients.

Subchondral collapse usually warrants hip replacement.

OUR PATIENT’S TREATMENT

A 45-year-old woman with a history of multiple organ transplants presented with a 1-month history of anterior left hip pain with insidious onset. Although she was able to perform activities of daily living, she reported increasing difficulty with weight-bearing activities.

RISK FACTORS

Osteonecrosis of the hip is caused by prolonged interruption of blood flow to the femoral head.² While idiopathic osteonecrosis is not uncommon, the condition is often associated with alcohol abuse or, as in our patient, long-term corticosteroid use after organ transplant.³ Corticosteroid use is also the most frequently reported risk factor for multifocal osteonecrosis.

Less common risk factors include systemic lupus erythematosus, antiphospholipid antibodies, coagulopathies, sickle cell disease, Gaucher disease, trauma, and external-beam therapy.

Young age is also associated with osteonecrosis, as nearly 75% of patients are between age 30 and 60.⁴

APPROACH TO DIAGNOSIS

Our patient had a typical clinical presentation of this disease: she was relatively young, was on long-term corticosteroids, and had acute anterior groin pain followed by progressive functional impairment.

The diagnostic evaluation consists of a detailed history, with attention to specific risk factors, and a thorough clinical examination followed by imaging, usually with plain radiography. However, plain radiographs are often unremarkable when the condition is in the early stages. In such cases, magnetic resonance imaging is recommended if clinical suspicion for osteonecrosis is high. It is far more sensitive (> 99%) and specific (> 99%) than plain radiography, and it detects early changes in the femoral head such as focal lesions and bone marrow edema.⁵

TREATMENT OPTIONS

Treatment of osteonecrosis is surgical and depends on the stage of disease.⁶ 

Joint preservation may be an option for small to medium-sized lesions before subchondral collapse has occurred; options include core decompression, bone grafting, and femoral osteotomy to preserve the native femoral head. These procedures have a higher success rate in young patients.

Subchondral collapse usually warrants hip replacement.

OUR PATIENT’S TREATMENT

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

The Food and Drug Administration has approved gadobutrol (Gadavist) injections, for use in conjunction with magnetic resonance angiography (MRA), to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients.

Olivier Le Moal/Getty Images

Approval was based on a pair of open-label, phase 3 studies in which the efficacy of gadobutrol was assessed, based on visualization and performance for distinguishing between normal and abnormal anatomy. MRA with gadobutrol improved visualization by 88%-98%, compared with unenhanced MRA, in which visualization was improved by 24%-82%. Sensitivity and specificity were noninferior to unenhanced MRA.

Gadobutrol was previously indicated for use in diagnostic MRI in both adults and children to detect areas with disrupted blood-brain barrier and/or abnormal vascularity of the central nervous system, and for MRI of the breast to assess the presence and extent of malignant breast disease. The safety profile in the two current trials matched data previously gathered, with the most common adverse events including headache, nausea, and dizziness.

“Until now, no contrast agents were FDA approved for use with MRA of the supra-aortic arteries. With FDA’s action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack,” Elias Melhem, MD, chair of the department of diagnostic radiology and nuclear medicine at the University of Maryland, Baltimore, said in the press release.

Find the full release on the Bayer website.

[email protected]

The Food and Drug Administration has approved gadobutrol (Gadavist) injections, for use in conjunction with magnetic resonance angiography (MRA), to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients.

Olivier Le Moal/Getty Images

Approval was based on a pair of open-label, phase 3 studies in which the efficacy of gadobutrol was assessed, based on visualization and performance for distinguishing between normal and abnormal anatomy. MRA with gadobutrol improved visualization by 88%-98%, compared with unenhanced MRA, in which visualization was improved by 24%-82%. Sensitivity and specificity were noninferior to unenhanced MRA.

Gadobutrol was previously indicated for use in diagnostic MRI in both adults and children to detect areas with disrupted blood-brain barrier and/or abnormal vascularity of the central nervous system, and for MRI of the breast to assess the presence and extent of malignant breast disease. The safety profile in the two current trials matched data previously gathered, with the most common adverse events including headache, nausea, and dizziness.

“Until now, no contrast agents were FDA approved for use with MRA of the supra-aortic arteries. With FDA’s action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack,” Elias Melhem, MD, chair of the department of diagnostic radiology and nuclear medicine at the University of Maryland, Baltimore, said in the press release.

Find the full release on the Bayer website.

[email protected]

The Food and Drug Administration has approved gadobutrol (Gadavist) injections, for use in conjunction with magnetic resonance angiography (MRA), to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients.

Olivier Le Moal/Getty Images

Approval was based on a pair of open-label, phase 3 studies in which the efficacy of gadobutrol was assessed, based on visualization and performance for distinguishing between normal and abnormal anatomy. MRA with gadobutrol improved visualization by 88%-98%, compared with unenhanced MRA, in which visualization was improved by 24%-82%. Sensitivity and specificity were noninferior to unenhanced MRA.

Gadobutrol was previously indicated for use in diagnostic MRI in both adults and children to detect areas with disrupted blood-brain barrier and/or abnormal vascularity of the central nervous system, and for MRI of the breast to assess the presence and extent of malignant breast disease. The safety profile in the two current trials matched data previously gathered, with the most common adverse events including headache, nausea, and dizziness.

“Until now, no contrast agents were FDA approved for use with MRA of the supra-aortic arteries. With FDA’s action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack,” Elias Melhem, MD, chair of the department of diagnostic radiology and nuclear medicine at the University of Maryland, Baltimore, said in the press release.

Find the full release on the Bayer website.

[email protected]

Giant cell arteritis (GCA) is a systemic vasculitis involving medium-sized and large arteries, most commonly the temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Moreover, involvement of the ophthalmic artery and its branches results in loss of vision. GCA can also involve the aorta and its proximal branches, especially in the upper extremities.

GCA is the most common systemic vasculitis in adults. It occurs almost exclusively in patients over age 50 and affects women more than men. It is most frequent in populations of northern European ancestry, especially Scandinavian. In a retrospective cohort study in Norway, the average annual cumulative incidence rate of GCA was 16.7 per 100,000 people over age 50.¹ Risk factors include older age, history of smoking, current smoking, early menopause, and, possibly, stress-related disorders.²

PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD

The pathogenesis of GCA is not completely understood, but there is evidence of immune activation in the arterial wall leading to activation of macrophages and formation of multinucleated giant cells (which may not always be present in biopsies).

The most relevant cytokines in the ongoing pathogenesis are still being defined, but the presence of interferon gamma and interleukin 6 (IL-6) seem to be critical for the expression of the disease. The primary immunogenic triggers for the elaboration of these cytokines and the arteritis remain elusive.

A SPECTRUM OF PRESENTATIONS

The initial symptoms of GCA may be vague, such as malaise, fever, and night sweats, and are likely due to systemic inflammation. Features of vascular involvement include headache, scalp tenderness, and jaw claudication (cramping pain in the jaw while chewing).

A less common but serious feature associated with GCA is partial or complete vision loss affecting 1 or both eyes.³ Some patients suddenly go completely blind without any visual prodrome.

Overlapping GCA phenotypes exist, with a spectrum of presentations that include classic cranial arteritis, extracranial GCA (also called large-vessel GCA), and polymyalgia rheumatica.²

Cranial GCA, the best-characterized clinical presentation, causes symptoms such as headache or signs such as tenderness of the temporal artery. On examination, the temporal arteries may be tender or nodular, and the pulses may be felt above the zygomatic arch, above and in front of the tragus of the ear. About two-thirds of patients with cranial GCA present with new-onset headache, most often in the temporal area, but possibly anywhere throughout the head.

Visual disturbance, jaw claudication, and tongue pain are less common but, if present, increase the likelihood of this diagnosis.²

Large-vessel involvement in GCA is common and refers to involvement of the aorta and its proximal branches. Imaging methods used in diagnosing large-vessel GCA include color Doppler ultrasonography, computed tomography with angiography, magnetic resonance imaging with angiography, and positron emission tomography. In some centers, such imaging is performed in all patients diagnosed with GCA to survey for large-vessel involvement.

Depending on the imaging study, large-vessel involvement has been found in 30% to 80% of cases of GCA.^4,5 It is often associated with nonspecific symptoms such as fever, weight loss, chills, and malaise, but it can also cause more specific symptoms such as unilateral extremity claudication. In contrast to patients with cranial GCA, patients with large-vessel GCA were younger at onset, less likely to have headaches, and more likely to have arm claudication at presentation.⁶ Aortitis of the ascending aorta can occur with a histopathologic pattern of GCA but without the clinical stigmata of GCA.

The finding of aortitis should prompt the clinician to question the patient about other symptoms of GCA and to order imaging of the whole vascular tree. Ultrasonography and biopsy of the temporal arteries can be considered. Whether idiopathic aortitis is part of the GCA spectrum remains to be seen.

Laboratory tests often show anemia, leukocytosis, and thrombocytosis. Acute-phase reactants such as C-reactive protein and the erythrocyte sedimentation rate are often elevated. The sedimentation rate often exceeds 50 mm/hour and sometimes 100 mm/hour.

In 2 retrospective studies, the number of patients with GCA whose sedimentation rate was less than 50 mm/hour ranged between 5% and 11%.^7,8 However, a small percentage of patients with GCA have normal inflammatory markers. Therefore, if the suspicion for GCA is high, treatment should be started and biopsy pursued.⁹ In patients with paraproteinemia or other causes of a spuriously elevated or low erythrocyte sedimentation rate, C-reactive protein is a more reliable test.

Polymyalgia rheumatica is another rheumatologic condition that can occur independently or in conjunction with GCA. It is characterized by stiffness and pain in the proximal joints such as the hips and shoulders, typically worse in the morning and better with activity. Although the patient may subjectively feel weak, a close neurologic examination will reveal normal muscle strength.

Polymyalgia rheumatica is observed in 40% to 60% of patients with GCA at the time of diagnosis; 16% to 21% of patients with polymyalgia rheumatica may develop GCA, especially if untreated.^2,10

Differential diagnosis

Other vasculitides (eg, Takayasu arteritis) can also present with unexplained fever, anemia, and constitutional symptoms.

Infection should be considered if fever is present. An infectious disease accompanied by fever, headache, and elevated inflammatory markers can mimic GCA.

Nonarteritic anterior ischemic optic neuropathy can present with sudden vision loss, prompting concern for underlying GCA. Risk factors include hypertension and diabetes mellitus; other features of GCA, including elevated inflammatory markers, are generally absent.

Temporal artery biopsy remains the standard to confirm the diagnosis. However, because inflammation in the temporal arteries can affect some segments but not others, biopsy results on conventional hematoxylin and eosin staining can be falsely negative in patients with GCA. In one study,¹¹ the mean sensitivity of unilateral temporal artery biopsy was 86.9%.

Typical positive histologic findings are inflammation with panarteritis, CD4-positive lymphocytes, macrophages, giant cells, and fragmentation of the internal elastic lamina.¹²

When GCA is suspected, treatment with glucocorticoids should be started immediately and biopsy performed as soon as possible. Delaying biopsy for 14 days or more may not affect the accuracy of biopsy study.¹³ Treatment should never be withheld while awaiting the results of biopsy study.

Biopsy is usually performed unilaterally, on the same side as the symptoms or abnormal findings on examination. Bilateral temporal artery biopsy is also performed and compared with unilateral biopsy; this approach increases the diagnostic yield by about 5%.¹⁴

IMAGING

In patients with suspected GCA, imaging is recommended early to complement the clinical criteria for the diagnosis of GCA.¹⁵ Positron emission tomography, computed tomography angiography, magnetic resonance angiography, or Doppler ultrasonography can reveal inflammation of the arteries in the proximal upper or lower limbs or the aorta.²

In patients with suspected cranial GCA, ultrasonography of the temporal and axillary arteries is recommended first. If ultrasonography is not available or is inconclusive, high-resolution magnetic resonance imaging of the cranial arteries can be used as an alternative. Computed tomography and positron emission tomography of the cranial arteries are not recommended.

In patients with suspected large-vessel GCA, ultrasonography, positron emission tomography, computed tomography, and magnetic resonance imaging may be used to screen for vessel wall inflammation, edema, and luminal narrowing in extracranial arteries. Ultrasonography is of limited value in assessing aortitis.

Color duplex ultrasonography can be applied to assess for vascular inflammation of the temporal or large arteries. The typical finding of the “halo” sign, a hypoechoic ring around the arterial lumen, represents the inflammation-induced thickening of the arterial wall. The “compression sign,” the persistence of the “halo” during compression of the vessel lumen by the ultrasound probe, has high specificity for the diagnosis.¹⁶

Ultrasonography of suspected GCA has yielded sensitivities of 55% to 100% and specificities of 78% to 100%. However, its sensitivity depends on the user’s level of expertise, so it should be done only in medical centers with a high number of GCA cases and with highly experienced sonographers. High-resolution magnetic resonance imaging is an alternative to ultrasonography and has shown similar sensitivity and specificity.³

TREATMENT WITH GLUCOCORTICOIDS

Glucocorticoids remain the standard for treatment of GCA. The therapeutic effect of glucocorticoids in GCA has been established by years of clinical experience, but has never been proven in a placebo-controlled trial. When started appropriately and expeditiously, glucocorticoids produce exquisite resolution of signs and symptoms and prevent the serious complication of vision loss. Rapid resolution of symptoms is so typical of GCA that if the patient’s symptoms persist more than a few days after starting a glucocorticoid, the diagnosis of GCA should be reconsidered.

In a retrospective study of 245 patients with biopsy-proven GCA treated with glucocorticoids, 34 had permanent loss of sight.¹⁷ In 32 (94%) of the 34, the vision loss occurred before glucocorticoids were started. Of the remaining 2 patients, 1 lost vision 8 days into treatment, and the other lost vision 3 years after diagnosis and 1 year after discontinuation of glucocorticoids.

In a series of 144 patients with biopsy-proven GCA, 51 had no vision loss at presentation and no vision loss after starting glucocorticoids, and 93 had vision loss at presentation. In the latter group, symptoms worsened within 5 days of starting glucocorticoids in 9 patients.¹⁸ If vision was intact at the time of presentation, prompt initiation of glucocorticoids reduced the risk of vision loss to less than 1%.

High doses, slowly tapered

The European League Against Rheumatism recommends early initiation of high-dose glucocorticoids for patients with large-vessel vasculitis,¹⁹ and it also recommends glucocorticoids for patients with polymyalgia rheumatica.²⁰ The optimal initial and tapering dosage has never been formally evaluated, but regimens have been devised on the basis of expert opinion.²¹

For patients with GCA who do not have vision loss at the time of diagnosis, the initial dose is prednisone 1 mg/kg or its equivalent daily for 2 to 4 weeks, after which it is tapered.²¹ If the initial dosage is prednisone 60 mg orally daily for 2 to 4 weeks, our practice is to taper it to 50 mg daily for 2 weeks, then 40 mg daily for 2 weeks. Then, it  is decreased by 5 mg every 2 weeks until it is 20 mg daily, and then by 2.5 mg every 2 weeks until it is 10 mg orally daily. Thereafter, the dosage is decreased by 1 mg every 2 to 4 weeks.

For patients with GCA who experience transient vision loss or diplopia at the time of diagnosis, intravenous pulse glucocorticoid therapy should be initiated to reduce the risk of vision loss as rapidly as possible.²² A typical pulse regimen is methylprednisolone 1 g intravenously daily for 3 days. Though not rigorously validated in studies, such an approach is used to avoid vision impairment due to GCA, which is rarely reversible.

Suspect a relapse of GCA if the patient’s initial symptoms recur, if inflammatory markers become elevated, or if classic symptoms of GCA or polymyalgia rheumatica occur. Elevations in inflammatory markers do not definitely indicate a flare of GCA, but they should trigger close monitoring of the patient’s symptoms.

Relapse is treated by increasing the glucocorticoid dosage as appropriate to the nature of the relapse. If vision is affected or the patient has symptoms of GCA, then increments of 30 to 60 mg of prednisone are warranted, whereas if the patient has symptoms of polymyalgia rheumatica, then increments of 5 to 10 mg of prednisone are usually used.

The incidence of relapses of GCA in multiple tertiary care centers has been reported to vary between 34% and 75%.^23,24 Most relapses occur at prednisone dosages of less than 20 mg orally daily and within the first year after diagnosis. The most common symptoms are limb ischemia, jaw claudication, constitutional symptoms, headaches, and polymyalgia rheumatica. In a review of 286 patients,²⁵ 213 (74%) had at least 1 relapse. The first relapse occurred in the first year in 50%, by 2 years in 68%, and by 5 years in 79%.

ADVERSE EFFECTS OF GLUCOCORTICOIDS

In high doses, glucocorticoids have well-known adverse effects. In a population-based study of 120 patients, each patient treated with glucocorticoids experienced at least 1 adverse effect (cataract, fracture, infection, osteonecrosis, diabetes, hypertension, weight gain, capillary fragility, or hair loss).²⁶ The effects were related to aging and cumulative dosage of prednisone but not to the initial dosage.

Glucocorticoids can affect many organs and systems:

• Eyes (cataracts, increased intraocular pressure, exophthalmos)
• Heart (premature atherosclerotic disease, hypertension, fluid retention, hyperlipidemia, arrhythmias)
• Gastrointestinal system (ulcer, gastrointestinal bleeding, gastritis, visceral perforation, hepatic steatosis, acute pancreatitis)
• Bone and muscle (osteopenia, osteoporosis, osteonecrosis, myopathy)
• Brain (mood disorder, psychosis, memory impairment)
• Endocrine system (hyperglycemia, hypothalamic-pituitary-adrenal axis suppression)
• Immune system (immunosuppression, leading to infection and leukocytosis).

Patients receiving a glucocorticoid dose equivalent to 20 mg or more of prednisone daily for 1 month or more who also have another cause of immunocompromise need prophylaxis against Pneumocystis jirovecii pneumonia.²⁷ They should also receive appropriate immunizations before starting glucocorticoids. Live-virus vaccines should not be given to these patients until they have been off glucocorticoids for 1 month.

Glucocorticoids and bone loss

Glucocorticoids are associated with bone loss and fracture, which can occur within the first few months of use and with dosages as low as 2.5 to 7.5 mg orally daily.²⁸ Therefore, glucocorticoid-induced bone loss has to be treated aggressively, particularly in patients who are older and have a history of fragility fracture.

For patients with GCA who need glucocorticoids in doses greater than 5 mg orally daily for more than 3 months, the following measures are advised to decrease the risk of bone loss:

• Weight-bearing exercise
• Smoking cessation
• Moderation in alcohol intake
• Measures to prevent falls²⁹
• Supplementation with 1,200 mg of calcium and 800 IU of vitamin D.³⁰

Pharmacologic therapy should be initiated in men over age 50 who have established osteoporosis and in postmenopausal women with established osteoporosis or osteopenia. For men over age 50 with established osteopenia, risk assessment with the glucocorticoid-corrected FRAX score (www.sheffield.ac.uk/FRAX) should be performed to identify those at high risk in whom pharmacologic therapy is warranted.³¹

Bisphosphonates are the first-line therapy for glucocorticoid-induced osteoporosis.³²

Teriparatide is the second-line therapy and is used in patients who cannot tolerate bis­phosphonates or other osteoporosis therapies, and in those who have severe osteoporosis, with T scores of –3.5 and below if they have not had a fracture, and –2.5 and below if they have had a fragility fracture.³³

Denosumab, a monoclonal antibody to an osteoclast differentiating factor, may be beneficial for some patients with glucocorticoid-induced osteoporosis.³⁴

To assess the efficacy of therapy, measuring bone mineral density at baseline and at 1 year of therapy is recommended. If density is stable or improved, then repeating the measurement at 2- to 3-year intervals is suggested.

Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.

The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.¹⁹ In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.^35,36

Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.^37,38

Advances in treatment for GCA have stagnated, but recent trials^39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.^41,42

Villiger et al³⁹ performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.

The GiACTA trial. Stone et al⁴⁰ studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:

• Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
• Tocilizumab every other week plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 52 weeks.

The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:

• 56% with tocilizumab weekly
• 53% with tocilizumab every other week
• 14% with placebo plus 26-week prednisone taper
• 18% with placebo plus 52-week taper.

Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).

The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.

However, the study also raised questions about tocilizumab’s toxic effect profile and its  long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.⁴³ As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.

Tocilizumab and lower gastrointestinal tract perforation

One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.

Xie et al,⁴⁴ in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall,  roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.

Does tocilizumab prevent blindness?

Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.⁴⁰ Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.

Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.

No guidelines on tocilizumab yet

Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.

Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.

The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.

Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.⁴³ Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.

The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.

Giant cell arteritis (GCA) is a systemic vasculitis involving medium-sized and large arteries, most commonly the temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Moreover, involvement of the ophthalmic artery and its branches results in loss of vision. GCA can also involve the aorta and its proximal branches, especially in the upper extremities.

GCA is the most common systemic vasculitis in adults. It occurs almost exclusively in patients over age 50 and affects women more than men. It is most frequent in populations of northern European ancestry, especially Scandinavian. In a retrospective cohort study in Norway, the average annual cumulative incidence rate of GCA was 16.7 per 100,000 people over age 50.¹ Risk factors include older age, history of smoking, current smoking, early menopause, and, possibly, stress-related disorders.²

PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD

The pathogenesis of GCA is not completely understood, but there is evidence of immune activation in the arterial wall leading to activation of macrophages and formation of multinucleated giant cells (which may not always be present in biopsies).

The most relevant cytokines in the ongoing pathogenesis are still being defined, but the presence of interferon gamma and interleukin 6 (IL-6) seem to be critical for the expression of the disease. The primary immunogenic triggers for the elaboration of these cytokines and the arteritis remain elusive.

A SPECTRUM OF PRESENTATIONS

The initial symptoms of GCA may be vague, such as malaise, fever, and night sweats, and are likely due to systemic inflammation. Features of vascular involvement include headache, scalp tenderness, and jaw claudication (cramping pain in the jaw while chewing).

A less common but serious feature associated with GCA is partial or complete vision loss affecting 1 or both eyes.³ Some patients suddenly go completely blind without any visual prodrome.

Overlapping GCA phenotypes exist, with a spectrum of presentations that include classic cranial arteritis, extracranial GCA (also called large-vessel GCA), and polymyalgia rheumatica.²

Cranial GCA, the best-characterized clinical presentation, causes symptoms such as headache or signs such as tenderness of the temporal artery. On examination, the temporal arteries may be tender or nodular, and the pulses may be felt above the zygomatic arch, above and in front of the tragus of the ear. About two-thirds of patients with cranial GCA present with new-onset headache, most often in the temporal area, but possibly anywhere throughout the head.

Visual disturbance, jaw claudication, and tongue pain are less common but, if present, increase the likelihood of this diagnosis.²

Large-vessel involvement in GCA is common and refers to involvement of the aorta and its proximal branches. Imaging methods used in diagnosing large-vessel GCA include color Doppler ultrasonography, computed tomography with angiography, magnetic resonance imaging with angiography, and positron emission tomography. In some centers, such imaging is performed in all patients diagnosed with GCA to survey for large-vessel involvement.

Depending on the imaging study, large-vessel involvement has been found in 30% to 80% of cases of GCA.^4,5 It is often associated with nonspecific symptoms such as fever, weight loss, chills, and malaise, but it can also cause more specific symptoms such as unilateral extremity claudication. In contrast to patients with cranial GCA, patients with large-vessel GCA were younger at onset, less likely to have headaches, and more likely to have arm claudication at presentation.⁶ Aortitis of the ascending aorta can occur with a histopathologic pattern of GCA but without the clinical stigmata of GCA.

The finding of aortitis should prompt the clinician to question the patient about other symptoms of GCA and to order imaging of the whole vascular tree. Ultrasonography and biopsy of the temporal arteries can be considered. Whether idiopathic aortitis is part of the GCA spectrum remains to be seen.

Laboratory tests often show anemia, leukocytosis, and thrombocytosis. Acute-phase reactants such as C-reactive protein and the erythrocyte sedimentation rate are often elevated. The sedimentation rate often exceeds 50 mm/hour and sometimes 100 mm/hour.

In 2 retrospective studies, the number of patients with GCA whose sedimentation rate was less than 50 mm/hour ranged between 5% and 11%.^7,8 However, a small percentage of patients with GCA have normal inflammatory markers. Therefore, if the suspicion for GCA is high, treatment should be started and biopsy pursued.⁹ In patients with paraproteinemia or other causes of a spuriously elevated or low erythrocyte sedimentation rate, C-reactive protein is a more reliable test.

Polymyalgia rheumatica is another rheumatologic condition that can occur independently or in conjunction with GCA. It is characterized by stiffness and pain in the proximal joints such as the hips and shoulders, typically worse in the morning and better with activity. Although the patient may subjectively feel weak, a close neurologic examination will reveal normal muscle strength.

Polymyalgia rheumatica is observed in 40% to 60% of patients with GCA at the time of diagnosis; 16% to 21% of patients with polymyalgia rheumatica may develop GCA, especially if untreated.^2,10

Differential diagnosis

Other vasculitides (eg, Takayasu arteritis) can also present with unexplained fever, anemia, and constitutional symptoms.

Infection should be considered if fever is present. An infectious disease accompanied by fever, headache, and elevated inflammatory markers can mimic GCA.

Nonarteritic anterior ischemic optic neuropathy can present with sudden vision loss, prompting concern for underlying GCA. Risk factors include hypertension and diabetes mellitus; other features of GCA, including elevated inflammatory markers, are generally absent.

Temporal artery biopsy remains the standard to confirm the diagnosis. However, because inflammation in the temporal arteries can affect some segments but not others, biopsy results on conventional hematoxylin and eosin staining can be falsely negative in patients with GCA. In one study,¹¹ the mean sensitivity of unilateral temporal artery biopsy was 86.9%.

Typical positive histologic findings are inflammation with panarteritis, CD4-positive lymphocytes, macrophages, giant cells, and fragmentation of the internal elastic lamina.¹²

When GCA is suspected, treatment with glucocorticoids should be started immediately and biopsy performed as soon as possible. Delaying biopsy for 14 days or more may not affect the accuracy of biopsy study.¹³ Treatment should never be withheld while awaiting the results of biopsy study.

Biopsy is usually performed unilaterally, on the same side as the symptoms or abnormal findings on examination. Bilateral temporal artery biopsy is also performed and compared with unilateral biopsy; this approach increases the diagnostic yield by about 5%.¹⁴

IMAGING

In patients with suspected GCA, imaging is recommended early to complement the clinical criteria for the diagnosis of GCA.¹⁵ Positron emission tomography, computed tomography angiography, magnetic resonance angiography, or Doppler ultrasonography can reveal inflammation of the arteries in the proximal upper or lower limbs or the aorta.²

In patients with suspected cranial GCA, ultrasonography of the temporal and axillary arteries is recommended first. If ultrasonography is not available or is inconclusive, high-resolution magnetic resonance imaging of the cranial arteries can be used as an alternative. Computed tomography and positron emission tomography of the cranial arteries are not recommended.

In patients with suspected large-vessel GCA, ultrasonography, positron emission tomography, computed tomography, and magnetic resonance imaging may be used to screen for vessel wall inflammation, edema, and luminal narrowing in extracranial arteries. Ultrasonography is of limited value in assessing aortitis.

Color duplex ultrasonography can be applied to assess for vascular inflammation of the temporal or large arteries. The typical finding of the “halo” sign, a hypoechoic ring around the arterial lumen, represents the inflammation-induced thickening of the arterial wall. The “compression sign,” the persistence of the “halo” during compression of the vessel lumen by the ultrasound probe, has high specificity for the diagnosis.¹⁶

Ultrasonography of suspected GCA has yielded sensitivities of 55% to 100% and specificities of 78% to 100%. However, its sensitivity depends on the user’s level of expertise, so it should be done only in medical centers with a high number of GCA cases and with highly experienced sonographers. High-resolution magnetic resonance imaging is an alternative to ultrasonography and has shown similar sensitivity and specificity.³

TREATMENT WITH GLUCOCORTICOIDS

Glucocorticoids remain the standard for treatment of GCA. The therapeutic effect of glucocorticoids in GCA has been established by years of clinical experience, but has never been proven in a placebo-controlled trial. When started appropriately and expeditiously, glucocorticoids produce exquisite resolution of signs and symptoms and prevent the serious complication of vision loss. Rapid resolution of symptoms is so typical of GCA that if the patient’s symptoms persist more than a few days after starting a glucocorticoid, the diagnosis of GCA should be reconsidered.

In a retrospective study of 245 patients with biopsy-proven GCA treated with glucocorticoids, 34 had permanent loss of sight.¹⁷ In 32 (94%) of the 34, the vision loss occurred before glucocorticoids were started. Of the remaining 2 patients, 1 lost vision 8 days into treatment, and the other lost vision 3 years after diagnosis and 1 year after discontinuation of glucocorticoids.

In a series of 144 patients with biopsy-proven GCA, 51 had no vision loss at presentation and no vision loss after starting glucocorticoids, and 93 had vision loss at presentation. In the latter group, symptoms worsened within 5 days of starting glucocorticoids in 9 patients.¹⁸ If vision was intact at the time of presentation, prompt initiation of glucocorticoids reduced the risk of vision loss to less than 1%.

High doses, slowly tapered

The European League Against Rheumatism recommends early initiation of high-dose glucocorticoids for patients with large-vessel vasculitis,¹⁹ and it also recommends glucocorticoids for patients with polymyalgia rheumatica.²⁰ The optimal initial and tapering dosage has never been formally evaluated, but regimens have been devised on the basis of expert opinion.²¹

For patients with GCA who do not have vision loss at the time of diagnosis, the initial dose is prednisone 1 mg/kg or its equivalent daily for 2 to 4 weeks, after which it is tapered.²¹ If the initial dosage is prednisone 60 mg orally daily for 2 to 4 weeks, our practice is to taper it to 50 mg daily for 2 weeks, then 40 mg daily for 2 weeks. Then, it  is decreased by 5 mg every 2 weeks until it is 20 mg daily, and then by 2.5 mg every 2 weeks until it is 10 mg orally daily. Thereafter, the dosage is decreased by 1 mg every 2 to 4 weeks.

For patients with GCA who experience transient vision loss or diplopia at the time of diagnosis, intravenous pulse glucocorticoid therapy should be initiated to reduce the risk of vision loss as rapidly as possible.²² A typical pulse regimen is methylprednisolone 1 g intravenously daily for 3 days. Though not rigorously validated in studies, such an approach is used to avoid vision impairment due to GCA, which is rarely reversible.

Suspect a relapse of GCA if the patient’s initial symptoms recur, if inflammatory markers become elevated, or if classic symptoms of GCA or polymyalgia rheumatica occur. Elevations in inflammatory markers do not definitely indicate a flare of GCA, but they should trigger close monitoring of the patient’s symptoms.

Relapse is treated by increasing the glucocorticoid dosage as appropriate to the nature of the relapse. If vision is affected or the patient has symptoms of GCA, then increments of 30 to 60 mg of prednisone are warranted, whereas if the patient has symptoms of polymyalgia rheumatica, then increments of 5 to 10 mg of prednisone are usually used.

The incidence of relapses of GCA in multiple tertiary care centers has been reported to vary between 34% and 75%.^23,24 Most relapses occur at prednisone dosages of less than 20 mg orally daily and within the first year after diagnosis. The most common symptoms are limb ischemia, jaw claudication, constitutional symptoms, headaches, and polymyalgia rheumatica. In a review of 286 patients,²⁵ 213 (74%) had at least 1 relapse. The first relapse occurred in the first year in 50%, by 2 years in 68%, and by 5 years in 79%.

ADVERSE EFFECTS OF GLUCOCORTICOIDS

In high doses, glucocorticoids have well-known adverse effects. In a population-based study of 120 patients, each patient treated with glucocorticoids experienced at least 1 adverse effect (cataract, fracture, infection, osteonecrosis, diabetes, hypertension, weight gain, capillary fragility, or hair loss).²⁶ The effects were related to aging and cumulative dosage of prednisone but not to the initial dosage.

Glucocorticoids can affect many organs and systems:

• Eyes (cataracts, increased intraocular pressure, exophthalmos)
• Heart (premature atherosclerotic disease, hypertension, fluid retention, hyperlipidemia, arrhythmias)
• Gastrointestinal system (ulcer, gastrointestinal bleeding, gastritis, visceral perforation, hepatic steatosis, acute pancreatitis)
• Bone and muscle (osteopenia, osteoporosis, osteonecrosis, myopathy)
• Brain (mood disorder, psychosis, memory impairment)
• Endocrine system (hyperglycemia, hypothalamic-pituitary-adrenal axis suppression)
• Immune system (immunosuppression, leading to infection and leukocytosis).

Patients receiving a glucocorticoid dose equivalent to 20 mg or more of prednisone daily for 1 month or more who also have another cause of immunocompromise need prophylaxis against Pneumocystis jirovecii pneumonia.²⁷ They should also receive appropriate immunizations before starting glucocorticoids. Live-virus vaccines should not be given to these patients until they have been off glucocorticoids for 1 month.

Glucocorticoids and bone loss

Glucocorticoids are associated with bone loss and fracture, which can occur within the first few months of use and with dosages as low as 2.5 to 7.5 mg orally daily.²⁸ Therefore, glucocorticoid-induced bone loss has to be treated aggressively, particularly in patients who are older and have a history of fragility fracture.

For patients with GCA who need glucocorticoids in doses greater than 5 mg orally daily for more than 3 months, the following measures are advised to decrease the risk of bone loss:

• Weight-bearing exercise
• Smoking cessation
• Moderation in alcohol intake
• Measures to prevent falls²⁹
• Supplementation with 1,200 mg of calcium and 800 IU of vitamin D.³⁰

Pharmacologic therapy should be initiated in men over age 50 who have established osteoporosis and in postmenopausal women with established osteoporosis or osteopenia. For men over age 50 with established osteopenia, risk assessment with the glucocorticoid-corrected FRAX score (www.sheffield.ac.uk/FRAX) should be performed to identify those at high risk in whom pharmacologic therapy is warranted.³¹

Bisphosphonates are the first-line therapy for glucocorticoid-induced osteoporosis.³²

Teriparatide is the second-line therapy and is used in patients who cannot tolerate bis­phosphonates or other osteoporosis therapies, and in those who have severe osteoporosis, with T scores of –3.5 and below if they have not had a fracture, and –2.5 and below if they have had a fragility fracture.³³

Denosumab, a monoclonal antibody to an osteoclast differentiating factor, may be beneficial for some patients with glucocorticoid-induced osteoporosis.³⁴

To assess the efficacy of therapy, measuring bone mineral density at baseline and at 1 year of therapy is recommended. If density is stable or improved, then repeating the measurement at 2- to 3-year intervals is suggested.

Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.

The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.¹⁹ In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.^35,36

Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.^37,38

Advances in treatment for GCA have stagnated, but recent trials^39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.^41,42

Villiger et al³⁹ performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.

The GiACTA trial. Stone et al⁴⁰ studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:

• Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
• Tocilizumab every other week plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 52 weeks.

The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:

• 56% with tocilizumab weekly
• 53% with tocilizumab every other week
• 14% with placebo plus 26-week prednisone taper
• 18% with placebo plus 52-week taper.

Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).

The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.

However, the study also raised questions about tocilizumab’s toxic effect profile and its  long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.⁴³ As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.

Tocilizumab and lower gastrointestinal tract perforation

One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.

Xie et al,⁴⁴ in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall,  roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.

Does tocilizumab prevent blindness?

Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.⁴⁰ Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.

Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.

No guidelines on tocilizumab yet

Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.

Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.

The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.

Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.⁴³ Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.

The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.

Giant cell arteritis (GCA) is a systemic vasculitis involving medium-sized and large arteries, most commonly the temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Moreover, involvement of the ophthalmic artery and its branches results in loss of vision. GCA can also involve the aorta and its proximal branches, especially in the upper extremities.

GCA is the most common systemic vasculitis in adults. It occurs almost exclusively in patients over age 50 and affects women more than men. It is most frequent in populations of northern European ancestry, especially Scandinavian. In a retrospective cohort study in Norway, the average annual cumulative incidence rate of GCA was 16.7 per 100,000 people over age 50.¹ Risk factors include older age, history of smoking, current smoking, early menopause, and, possibly, stress-related disorders.²

PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD

The pathogenesis of GCA is not completely understood, but there is evidence of immune activation in the arterial wall leading to activation of macrophages and formation of multinucleated giant cells (which may not always be present in biopsies).

The most relevant cytokines in the ongoing pathogenesis are still being defined, but the presence of interferon gamma and interleukin 6 (IL-6) seem to be critical for the expression of the disease. The primary immunogenic triggers for the elaboration of these cytokines and the arteritis remain elusive.

A SPECTRUM OF PRESENTATIONS

The initial symptoms of GCA may be vague, such as malaise, fever, and night sweats, and are likely due to systemic inflammation. Features of vascular involvement include headache, scalp tenderness, and jaw claudication (cramping pain in the jaw while chewing).

A less common but serious feature associated with GCA is partial or complete vision loss affecting 1 or both eyes.³ Some patients suddenly go completely blind without any visual prodrome.

Overlapping GCA phenotypes exist, with a spectrum of presentations that include classic cranial arteritis, extracranial GCA (also called large-vessel GCA), and polymyalgia rheumatica.²

Cranial GCA, the best-characterized clinical presentation, causes symptoms such as headache or signs such as tenderness of the temporal artery. On examination, the temporal arteries may be tender or nodular, and the pulses may be felt above the zygomatic arch, above and in front of the tragus of the ear. About two-thirds of patients with cranial GCA present with new-onset headache, most often in the temporal area, but possibly anywhere throughout the head.

Visual disturbance, jaw claudication, and tongue pain are less common but, if present, increase the likelihood of this diagnosis.²

Large-vessel involvement in GCA is common and refers to involvement of the aorta and its proximal branches. Imaging methods used in diagnosing large-vessel GCA include color Doppler ultrasonography, computed tomography with angiography, magnetic resonance imaging with angiography, and positron emission tomography. In some centers, such imaging is performed in all patients diagnosed with GCA to survey for large-vessel involvement.

Depending on the imaging study, large-vessel involvement has been found in 30% to 80% of cases of GCA.^4,5 It is often associated with nonspecific symptoms such as fever, weight loss, chills, and malaise, but it can also cause more specific symptoms such as unilateral extremity claudication. In contrast to patients with cranial GCA, patients with large-vessel GCA were younger at onset, less likely to have headaches, and more likely to have arm claudication at presentation.⁶ Aortitis of the ascending aorta can occur with a histopathologic pattern of GCA but without the clinical stigmata of GCA.

The finding of aortitis should prompt the clinician to question the patient about other symptoms of GCA and to order imaging of the whole vascular tree. Ultrasonography and biopsy of the temporal arteries can be considered. Whether idiopathic aortitis is part of the GCA spectrum remains to be seen.

Laboratory tests often show anemia, leukocytosis, and thrombocytosis. Acute-phase reactants such as C-reactive protein and the erythrocyte sedimentation rate are often elevated. The sedimentation rate often exceeds 50 mm/hour and sometimes 100 mm/hour.

In 2 retrospective studies, the number of patients with GCA whose sedimentation rate was less than 50 mm/hour ranged between 5% and 11%.^7,8 However, a small percentage of patients with GCA have normal inflammatory markers. Therefore, if the suspicion for GCA is high, treatment should be started and biopsy pursued.⁹ In patients with paraproteinemia or other causes of a spuriously elevated or low erythrocyte sedimentation rate, C-reactive protein is a more reliable test.

Polymyalgia rheumatica is another rheumatologic condition that can occur independently or in conjunction with GCA. It is characterized by stiffness and pain in the proximal joints such as the hips and shoulders, typically worse in the morning and better with activity. Although the patient may subjectively feel weak, a close neurologic examination will reveal normal muscle strength.

Polymyalgia rheumatica is observed in 40% to 60% of patients with GCA at the time of diagnosis; 16% to 21% of patients with polymyalgia rheumatica may develop GCA, especially if untreated.^2,10

Differential diagnosis

Other vasculitides (eg, Takayasu arteritis) can also present with unexplained fever, anemia, and constitutional symptoms.

Infection should be considered if fever is present. An infectious disease accompanied by fever, headache, and elevated inflammatory markers can mimic GCA.

Nonarteritic anterior ischemic optic neuropathy can present with sudden vision loss, prompting concern for underlying GCA. Risk factors include hypertension and diabetes mellitus; other features of GCA, including elevated inflammatory markers, are generally absent.

Temporal artery biopsy remains the standard to confirm the diagnosis. However, because inflammation in the temporal arteries can affect some segments but not others, biopsy results on conventional hematoxylin and eosin staining can be falsely negative in patients with GCA. In one study,¹¹ the mean sensitivity of unilateral temporal artery biopsy was 86.9%.

Typical positive histologic findings are inflammation with panarteritis, CD4-positive lymphocytes, macrophages, giant cells, and fragmentation of the internal elastic lamina.¹²

When GCA is suspected, treatment with glucocorticoids should be started immediately and biopsy performed as soon as possible. Delaying biopsy for 14 days or more may not affect the accuracy of biopsy study.¹³ Treatment should never be withheld while awaiting the results of biopsy study.

Biopsy is usually performed unilaterally, on the same side as the symptoms or abnormal findings on examination. Bilateral temporal artery biopsy is also performed and compared with unilateral biopsy; this approach increases the diagnostic yield by about 5%.¹⁴

IMAGING

In patients with suspected GCA, imaging is recommended early to complement the clinical criteria for the diagnosis of GCA.¹⁵ Positron emission tomography, computed tomography angiography, magnetic resonance angiography, or Doppler ultrasonography can reveal inflammation of the arteries in the proximal upper or lower limbs or the aorta.²

In patients with suspected cranial GCA, ultrasonography of the temporal and axillary arteries is recommended first. If ultrasonography is not available or is inconclusive, high-resolution magnetic resonance imaging of the cranial arteries can be used as an alternative. Computed tomography and positron emission tomography of the cranial arteries are not recommended.

In patients with suspected large-vessel GCA, ultrasonography, positron emission tomography, computed tomography, and magnetic resonance imaging may be used to screen for vessel wall inflammation, edema, and luminal narrowing in extracranial arteries. Ultrasonography is of limited value in assessing aortitis.

Color duplex ultrasonography can be applied to assess for vascular inflammation of the temporal or large arteries. The typical finding of the “halo” sign, a hypoechoic ring around the arterial lumen, represents the inflammation-induced thickening of the arterial wall. The “compression sign,” the persistence of the “halo” during compression of the vessel lumen by the ultrasound probe, has high specificity for the diagnosis.¹⁶

Ultrasonography of suspected GCA has yielded sensitivities of 55% to 100% and specificities of 78% to 100%. However, its sensitivity depends on the user’s level of expertise, so it should be done only in medical centers with a high number of GCA cases and with highly experienced sonographers. High-resolution magnetic resonance imaging is an alternative to ultrasonography and has shown similar sensitivity and specificity.³

TREATMENT WITH GLUCOCORTICOIDS

Glucocorticoids remain the standard for treatment of GCA. The therapeutic effect of glucocorticoids in GCA has been established by years of clinical experience, but has never been proven in a placebo-controlled trial. When started appropriately and expeditiously, glucocorticoids produce exquisite resolution of signs and symptoms and prevent the serious complication of vision loss. Rapid resolution of symptoms is so typical of GCA that if the patient’s symptoms persist more than a few days after starting a glucocorticoid, the diagnosis of GCA should be reconsidered.

In a retrospective study of 245 patients with biopsy-proven GCA treated with glucocorticoids, 34 had permanent loss of sight.¹⁷ In 32 (94%) of the 34, the vision loss occurred before glucocorticoids were started. Of the remaining 2 patients, 1 lost vision 8 days into treatment, and the other lost vision 3 years after diagnosis and 1 year after discontinuation of glucocorticoids.

In a series of 144 patients with biopsy-proven GCA, 51 had no vision loss at presentation and no vision loss after starting glucocorticoids, and 93 had vision loss at presentation. In the latter group, symptoms worsened within 5 days of starting glucocorticoids in 9 patients.¹⁸ If vision was intact at the time of presentation, prompt initiation of glucocorticoids reduced the risk of vision loss to less than 1%.

High doses, slowly tapered

The European League Against Rheumatism recommends early initiation of high-dose glucocorticoids for patients with large-vessel vasculitis,¹⁹ and it also recommends glucocorticoids for patients with polymyalgia rheumatica.²⁰ The optimal initial and tapering dosage has never been formally evaluated, but regimens have been devised on the basis of expert opinion.²¹

For patients with GCA who do not have vision loss at the time of diagnosis, the initial dose is prednisone 1 mg/kg or its equivalent daily for 2 to 4 weeks, after which it is tapered.²¹ If the initial dosage is prednisone 60 mg orally daily for 2 to 4 weeks, our practice is to taper it to 50 mg daily for 2 weeks, then 40 mg daily for 2 weeks. Then, it  is decreased by 5 mg every 2 weeks until it is 20 mg daily, and then by 2.5 mg every 2 weeks until it is 10 mg orally daily. Thereafter, the dosage is decreased by 1 mg every 2 to 4 weeks.

For patients with GCA who experience transient vision loss or diplopia at the time of diagnosis, intravenous pulse glucocorticoid therapy should be initiated to reduce the risk of vision loss as rapidly as possible.²² A typical pulse regimen is methylprednisolone 1 g intravenously daily for 3 days. Though not rigorously validated in studies, such an approach is used to avoid vision impairment due to GCA, which is rarely reversible.

Suspect a relapse of GCA if the patient’s initial symptoms recur, if inflammatory markers become elevated, or if classic symptoms of GCA or polymyalgia rheumatica occur. Elevations in inflammatory markers do not definitely indicate a flare of GCA, but they should trigger close monitoring of the patient’s symptoms.

Relapse is treated by increasing the glucocorticoid dosage as appropriate to the nature of the relapse. If vision is affected or the patient has symptoms of GCA, then increments of 30 to 60 mg of prednisone are warranted, whereas if the patient has symptoms of polymyalgia rheumatica, then increments of 5 to 10 mg of prednisone are usually used.

The incidence of relapses of GCA in multiple tertiary care centers has been reported to vary between 34% and 75%.^23,24 Most relapses occur at prednisone dosages of less than 20 mg orally daily and within the first year after diagnosis. The most common symptoms are limb ischemia, jaw claudication, constitutional symptoms, headaches, and polymyalgia rheumatica. In a review of 286 patients,²⁵ 213 (74%) had at least 1 relapse. The first relapse occurred in the first year in 50%, by 2 years in 68%, and by 5 years in 79%.

ADVERSE EFFECTS OF GLUCOCORTICOIDS

In high doses, glucocorticoids have well-known adverse effects. In a population-based study of 120 patients, each patient treated with glucocorticoids experienced at least 1 adverse effect (cataract, fracture, infection, osteonecrosis, diabetes, hypertension, weight gain, capillary fragility, or hair loss).²⁶ The effects were related to aging and cumulative dosage of prednisone but not to the initial dosage.

Glucocorticoids can affect many organs and systems:

• Eyes (cataracts, increased intraocular pressure, exophthalmos)
• Heart (premature atherosclerotic disease, hypertension, fluid retention, hyperlipidemia, arrhythmias)
• Gastrointestinal system (ulcer, gastrointestinal bleeding, gastritis, visceral perforation, hepatic steatosis, acute pancreatitis)
• Bone and muscle (osteopenia, osteoporosis, osteonecrosis, myopathy)
• Brain (mood disorder, psychosis, memory impairment)
• Endocrine system (hyperglycemia, hypothalamic-pituitary-adrenal axis suppression)
• Immune system (immunosuppression, leading to infection and leukocytosis).

Patients receiving a glucocorticoid dose equivalent to 20 mg or more of prednisone daily for 1 month or more who also have another cause of immunocompromise need prophylaxis against Pneumocystis jirovecii pneumonia.²⁷ They should also receive appropriate immunizations before starting glucocorticoids. Live-virus vaccines should not be given to these patients until they have been off glucocorticoids for 1 month.

Glucocorticoids and bone loss

Glucocorticoids are associated with bone loss and fracture, which can occur within the first few months of use and with dosages as low as 2.5 to 7.5 mg orally daily.²⁸ Therefore, glucocorticoid-induced bone loss has to be treated aggressively, particularly in patients who are older and have a history of fragility fracture.

For patients with GCA who need glucocorticoids in doses greater than 5 mg orally daily for more than 3 months, the following measures are advised to decrease the risk of bone loss:

• Weight-bearing exercise
• Smoking cessation
• Moderation in alcohol intake
• Measures to prevent falls²⁹
• Supplementation with 1,200 mg of calcium and 800 IU of vitamin D.³⁰

Pharmacologic therapy should be initiated in men over age 50 who have established osteoporosis and in postmenopausal women with established osteoporosis or osteopenia. For men over age 50 with established osteopenia, risk assessment with the glucocorticoid-corrected FRAX score (www.sheffield.ac.uk/FRAX) should be performed to identify those at high risk in whom pharmacologic therapy is warranted.³¹

Bisphosphonates are the first-line therapy for glucocorticoid-induced osteoporosis.³²

Teriparatide is the second-line therapy and is used in patients who cannot tolerate bis­phosphonates or other osteoporosis therapies, and in those who have severe osteoporosis, with T scores of –3.5 and below if they have not had a fracture, and –2.5 and below if they have had a fragility fracture.³³

Denosumab, a monoclonal antibody to an osteoclast differentiating factor, may be beneficial for some patients with glucocorticoid-induced osteoporosis.³⁴

To assess the efficacy of therapy, measuring bone mineral density at baseline and at 1 year of therapy is recommended. If density is stable or improved, then repeating the measurement at 2- to 3-year intervals is suggested.

Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.

The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.¹⁹ In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.^35,36

Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.^37,38

Advances in treatment for GCA have stagnated, but recent trials^39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.^41,42

Villiger et al³⁹ performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.

The GiACTA trial. Stone et al⁴⁰ studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:

• Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
• Tocilizumab every other week plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 52 weeks.

The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:

• 56% with tocilizumab weekly
• 53% with tocilizumab every other week
• 14% with placebo plus 26-week prednisone taper
• 18% with placebo plus 52-week taper.

Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).

The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.

However, the study also raised questions about tocilizumab’s toxic effect profile and its  long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.⁴³ As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.

Tocilizumab and lower gastrointestinal tract perforation

One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.

Xie et al,⁴⁴ in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall,  roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.

Does tocilizumab prevent blindness?

Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.⁴⁰ Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.

Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.

No guidelines on tocilizumab yet

Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.

Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.

The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.

Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.⁴³ Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.

The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.

The clinical update of giant cell arteritis (GCA) by Rinden et al in this issue of the Journal reminded me of just how much of our management of this disease has, for decades, been based on retrospective studies (we owe a lot to clinicians from the Mayo Clinic for their compiled observations) tempered by our own recalled experiences, which we may at times twist a bit to fit prevailing paradigms. Several prospective interventional studies, perhaps most importantly the Giant-Cell Arteritis Actemra (GIACTA) trial,¹ evaluated the ability of the interleukin 6 (IL-6) antagonist tocilizumab to supplant the protracted use of glucocorticoids in the treatment of GCA. But I learned much more from this trial, in the form of collected clinical tidbits, than just the bottom-line abstract conclusion that IL-6 antagonism is at least a promising approach in many patients with GCA.

As teachers, we tell students to read the entire published clinical trial report, not just the abstract and conclusions. Over the years, I have been impatient with those who violated this dictum, but I now often find myself among the ranks of those who would have been targets of my disapproval. Usually, the articles that I merely skim lie outside my subsubspecialty areas of interest, as time constraints make this abridged reading a necessity for survival, but that excuse does not diminish the self-recognition of my often less-than-complete understanding of the clinical condition being reported. Delving into the nuances of GIACTA truly emphasized that point.

The external validity of any trial rests on understanding the trial’s methods. In the case of GIACTA, there was much more to be learned and affirmed from the trial¹ than that 1 year of tocilizumab treatment met the primary end point of increasing the percent of patients achieving sustained remission at week 52 after a rapid 26-week tapering off of prednisone compared with placebo.

One treatment group in the GIACTA trial underwent an aggressive 6-month tapering of prednisone, while another underwent a more protracted tapering over 12 months (more in line with common practice). Patients tapered over 6 months also received either the IL-6 antagonist or placebo for the full year. The concept was that if IL-6 blockade is a correct approach, then it will maintain remission in more patients, and significantly reduce the total amount of steroid needed to control the disease, despite rapid, aggressive steroid tapering. This turned out to be correct, although more than 20% of the drug-treated patients still experienced a flare of GCA (vs 68% of the placebo-treated group).

Somewhat surprising was that almost 20% of the entered patients did not achieve an initial remission despite receiving high-dose prednisone. The traditional teaching is that if a patient diagnosed with GCA does not respond to high-dose steroids, the diagnosis should be questioned.

Another interesting facet of the study relates to the diagnosis. We are becoming more aware of the different GCA phenotypes, which include prominent polymyalgia rheumatica or constitutional features, “classic” GCA with cranial symptoms, and dominant large-vessel vasculitis (aortitis and major aortic branch disease). In GIACTA, even though imaging was not mandated, 37% of participants were enrolled based in part on imaging results (CT, MRI, angiography, or PET-CT), not on the results of temporal artery biopsy. This forces us to think more broadly about diagnosing and staging GCA, and to wonder if we should even modify our approach to other clinical challenges, including unexplained fever and wasting in older patients.

Another tidbit that came out of the study relates to the relationship between the acute-phase response and clinical flares. We already knew that a rise in the erythrocyte sedimentation rate is a nonspecific sign and does not equate with a flare. In this trial one-third of patients in the placebo group who had a flare had a normal sedimentation rate or C-reactive protein during the flare, and about one-third of patients in the placebo group were receiving more than 10 mg of prednisone. In preliminary reports of follow-up after  52 weeks of treatment,² patients who had achieved complete remission with the IL-6 antagonist and were off of prednisone were still not out of the woods; when the drug was discontinued, many flares continued to occur over the 2-year study extension. We have more to learn about what triggers and drives flares in this disease.

Thus, in addition to informing us of a successful “steroid-sparing” and rescue drug option for our patients with GCA, the details of this well-conducted trial both challenge and reaffirm some of our clinical impressions. Clearly, GCA must be defined for many patients as a very chronic disease, perhaps with occult vascular reservoirs, the biologic basis of which remains to be defined.

The clinical update of giant cell arteritis (GCA) by Rinden et al in this issue of the Journal reminded me of just how much of our management of this disease has, for decades, been based on retrospective studies (we owe a lot to clinicians from the Mayo Clinic for their compiled observations) tempered by our own recalled experiences, which we may at times twist a bit to fit prevailing paradigms. Several prospective interventional studies, perhaps most importantly the Giant-Cell Arteritis Actemra (GIACTA) trial,¹ evaluated the ability of the interleukin 6 (IL-6) antagonist tocilizumab to supplant the protracted use of glucocorticoids in the treatment of GCA. But I learned much more from this trial, in the form of collected clinical tidbits, than just the bottom-line abstract conclusion that IL-6 antagonism is at least a promising approach in many patients with GCA.

As teachers, we tell students to read the entire published clinical trial report, not just the abstract and conclusions. Over the years, I have been impatient with those who violated this dictum, but I now often find myself among the ranks of those who would have been targets of my disapproval. Usually, the articles that I merely skim lie outside my subsubspecialty areas of interest, as time constraints make this abridged reading a necessity for survival, but that excuse does not diminish the self-recognition of my often less-than-complete understanding of the clinical condition being reported. Delving into the nuances of GIACTA truly emphasized that point.

The external validity of any trial rests on understanding the trial’s methods. In the case of GIACTA, there was much more to be learned and affirmed from the trial¹ than that 1 year of tocilizumab treatment met the primary end point of increasing the percent of patients achieving sustained remission at week 52 after a rapid 26-week tapering off of prednisone compared with placebo.

One treatment group in the GIACTA trial underwent an aggressive 6-month tapering of prednisone, while another underwent a more protracted tapering over 12 months (more in line with common practice). Patients tapered over 6 months also received either the IL-6 antagonist or placebo for the full year. The concept was that if IL-6 blockade is a correct approach, then it will maintain remission in more patients, and significantly reduce the total amount of steroid needed to control the disease, despite rapid, aggressive steroid tapering. This turned out to be correct, although more than 20% of the drug-treated patients still experienced a flare of GCA (vs 68% of the placebo-treated group).

Somewhat surprising was that almost 20% of the entered patients did not achieve an initial remission despite receiving high-dose prednisone. The traditional teaching is that if a patient diagnosed with GCA does not respond to high-dose steroids, the diagnosis should be questioned.

Another interesting facet of the study relates to the diagnosis. We are becoming more aware of the different GCA phenotypes, which include prominent polymyalgia rheumatica or constitutional features, “classic” GCA with cranial symptoms, and dominant large-vessel vasculitis (aortitis and major aortic branch disease). In GIACTA, even though imaging was not mandated, 37% of participants were enrolled based in part on imaging results (CT, MRI, angiography, or PET-CT), not on the results of temporal artery biopsy. This forces us to think more broadly about diagnosing and staging GCA, and to wonder if we should even modify our approach to other clinical challenges, including unexplained fever and wasting in older patients.

Another tidbit that came out of the study relates to the relationship between the acute-phase response and clinical flares. We already knew that a rise in the erythrocyte sedimentation rate is a nonspecific sign and does not equate with a flare. In this trial one-third of patients in the placebo group who had a flare had a normal sedimentation rate or C-reactive protein during the flare, and about one-third of patients in the placebo group were receiving more than 10 mg of prednisone. In preliminary reports of follow-up after  52 weeks of treatment,² patients who had achieved complete remission with the IL-6 antagonist and were off of prednisone were still not out of the woods; when the drug was discontinued, many flares continued to occur over the 2-year study extension. We have more to learn about what triggers and drives flares in this disease.

Thus, in addition to informing us of a successful “steroid-sparing” and rescue drug option for our patients with GCA, the details of this well-conducted trial both challenge and reaffirm some of our clinical impressions. Clearly, GCA must be defined for many patients as a very chronic disease, perhaps with occult vascular reservoirs, the biologic basis of which remains to be defined.

The clinical update of giant cell arteritis (GCA) by Rinden et al in this issue of the Journal reminded me of just how much of our management of this disease has, for decades, been based on retrospective studies (we owe a lot to clinicians from the Mayo Clinic for their compiled observations) tempered by our own recalled experiences, which we may at times twist a bit to fit prevailing paradigms. Several prospective interventional studies, perhaps most importantly the Giant-Cell Arteritis Actemra (GIACTA) trial,¹ evaluated the ability of the interleukin 6 (IL-6) antagonist tocilizumab to supplant the protracted use of glucocorticoids in the treatment of GCA. But I learned much more from this trial, in the form of collected clinical tidbits, than just the bottom-line abstract conclusion that IL-6 antagonism is at least a promising approach in many patients with GCA.

As teachers, we tell students to read the entire published clinical trial report, not just the abstract and conclusions. Over the years, I have been impatient with those who violated this dictum, but I now often find myself among the ranks of those who would have been targets of my disapproval. Usually, the articles that I merely skim lie outside my subsubspecialty areas of interest, as time constraints make this abridged reading a necessity for survival, but that excuse does not diminish the self-recognition of my often less-than-complete understanding of the clinical condition being reported. Delving into the nuances of GIACTA truly emphasized that point.

The external validity of any trial rests on understanding the trial’s methods. In the case of GIACTA, there was much more to be learned and affirmed from the trial¹ than that 1 year of tocilizumab treatment met the primary end point of increasing the percent of patients achieving sustained remission at week 52 after a rapid 26-week tapering off of prednisone compared with placebo.

One treatment group in the GIACTA trial underwent an aggressive 6-month tapering of prednisone, while another underwent a more protracted tapering over 12 months (more in line with common practice). Patients tapered over 6 months also received either the IL-6 antagonist or placebo for the full year. The concept was that if IL-6 blockade is a correct approach, then it will maintain remission in more patients, and significantly reduce the total amount of steroid needed to control the disease, despite rapid, aggressive steroid tapering. This turned out to be correct, although more than 20% of the drug-treated patients still experienced a flare of GCA (vs 68% of the placebo-treated group).

Somewhat surprising was that almost 20% of the entered patients did not achieve an initial remission despite receiving high-dose prednisone. The traditional teaching is that if a patient diagnosed with GCA does not respond to high-dose steroids, the diagnosis should be questioned.

Another interesting facet of the study relates to the diagnosis. We are becoming more aware of the different GCA phenotypes, which include prominent polymyalgia rheumatica or constitutional features, “classic” GCA with cranial symptoms, and dominant large-vessel vasculitis (aortitis and major aortic branch disease). In GIACTA, even though imaging was not mandated, 37% of participants were enrolled based in part on imaging results (CT, MRI, angiography, or PET-CT), not on the results of temporal artery biopsy. This forces us to think more broadly about diagnosing and staging GCA, and to wonder if we should even modify our approach to other clinical challenges, including unexplained fever and wasting in older patients.

Another tidbit that came out of the study relates to the relationship between the acute-phase response and clinical flares. We already knew that a rise in the erythrocyte sedimentation rate is a nonspecific sign and does not equate with a flare. In this trial one-third of patients in the placebo group who had a flare had a normal sedimentation rate or C-reactive protein during the flare, and about one-third of patients in the placebo group were receiving more than 10 mg of prednisone. In preliminary reports of follow-up after  52 weeks of treatment,² patients who had achieved complete remission with the IL-6 antagonist and were off of prednisone were still not out of the woods; when the drug was discontinued, many flares continued to occur over the 2-year study extension. We have more to learn about what triggers and drives flares in this disease.

Thus, in addition to informing us of a successful “steroid-sparing” and rescue drug option for our patients with GCA, the details of this well-conducted trial both challenge and reaffirm some of our clinical impressions. Clearly, GCA must be defined for many patients as a very chronic disease, perhaps with occult vascular reservoirs, the biologic basis of which remains to be defined.