Case Reports

Neck and shoulder pain are common presenting symptoms in the general adult population with a 41.7% and 50.9% lifetime incidence in males and females, respectively.¹ Generally, a single diagnosis is sought to explain a patient’s signs and symptoms, but occasionally 2 or more different causes are responsible. Only by conducting a thorough history and physical examination with proper follow-up will all contributing diseases be discovered. The following case illustrates 2 distinct etiologies responsible for the patient’s pain, one with an extremely unusual presentation.

Case Presentation

A 23-year-old male presented with a 3-month history of pain, spasm, and tightness of his right upper extremity along his posterior neck, shoulder, and triceps area. The patient reported no history of trauma, but he revealed increasing the amount of weight lifting, and his symptoms were especially worse when bench pressing or performing overhead exercises. No paresthesias were reported.

The initial examination revealed a well-developed muscular male with no visible atrophy or tenderness to palpation. He had full range of motion (ROM) of his neck, a normal motor and sensory examination of the C5-T1 nerve roots, and a negative Spurling maneuver. The patient had full ROM of both shoulders but had pain with right shoulder abduction starting at about 120° to 140°. He had pain with resisted supraspinatus muscle testing as well as pain with the liftoff test. The results of the patient’s Hawkins and Neer tests were negative (Table, Figures 1 to 6).^2-4 A point-of-care shoulder ultrasound examination revealed no abnormalities.

The working diagnosis was external shoulder impingement with a differential diagnosis of internal impingement and/or cervical radiculopathy. A diagnostic/therapeutic injection of 40 mg of triamcinolone and 4 mL of 1% xylocaine without epinephrine was administered into the right subacromial bursa. The patient experienced immediate and complete relief of pain with repeat shoulder abduction, supraspinatus muscle testing, and the liftoff test. Although this procedure temporarily relieved the pain with movement, a sensation of tightness, pain, and spasm in the posterior shoulder and right posterior arm was still present. The patient was asked to perform therapeutic rotator cuff and scapular strengthening exercises, annotated on a patient information handout, for 15 minutes a day, every other day and to follow-up in 4 weeks.

At follow-up the external impingement symptoms (pain with shoulder abduction, resisted supraspinatus testing and the liftoff test) were fully resolved, but the patient reported persistent pain, spasm, and sensation of tightness in his right posterior shoulder and arm with intermittent extension into forearm and hand. A review of the history reminded the patient of a wrestling episode that caused neck pain months earlier. The patient reported that his current symptoms began after the wrestling episode.

Physical examination at this time revealed pain in the right posterior arm with left lateral neck movement but no neck pain with right lateral neck movement or flexion and extension. There was again a normal motor and sensory examination in the C5-T1 nerve distribution. Of note, there was full painless abduction in the right shoulder, which had improved from the previous examination, and there was no pain with resisted supraspinatus testing or the liftoff test, both of which had been abnormal at the initial encounter.

Due to the patient’s persistent posterior shoulder pain and exacerbation of symptoms with neck movement and the now revealed antecedent event of neck trauma, a higher concern for cervical disc pathology was entertained. A cervical magnetic resonance imaging examination (MRI) was ordered. A moderately sized left paracentral herniation of the disk at C5-C6 was found. The disk herniation was compressing the left ventral hemi-cord with narrowing of the left neuronal foramina. Additionally, there was a mild posterior disc osteophyte complex that caused mild left foraminal narrowing at C6-C7.

Neurosurgical consultation was obtained. Extensive discussion of nonsurgical vs surgical options were conducted, and a trial of nonsurgical therapy was agreed on. Physical therapy with cervical traction was prescribed with 2 sessions a week for 4 weeks. The patient also continued his therapeutic rotator cuff and scapular stabilizing exercises and decreased the amount and intensity of his weight lifting.

At the next 4-week follow-up, his symptoms were greatly reduced. He was discharged from supervised physical therapy and continued his at-home neck and shoulder strengthening regimen. At the 1-year follow-up, the patient reported that the radiating pain had essentially resolved—only occasionally being present with heavy upper-extremity weight lifting or grappling activities. He continues to be symptom free of his external impingement symptoms as well.

The final diagnosis was cervical radiculopathy of C5/6 nerve root due to left paracentral disc herniation with concomitant cord compression as well as external impingement (rotator cuff dysfunction) of the right shoulder. It is unclear whether the disc herniation contributed to the external shoulder impingement due to alterations in biomechanics or whether the 2 diseases were unrelated.

Discussion

The patient’s cervical disc herniation most likely was due to his earlier grappling episode when he had acute trauma to the neck or an exacerbation of an older asymptomatic herniation. His external shoulder impingement likely was due to overuse with heavy weight lifting, which also caused enough mechanical strain to exacerbate the patient’s cervical disc herniation symptoms. What is most unusual about this case is the right-sided cervical radicular symptoms due to a left-sided cervical disc herniation.

With an annual incidence of 107.3 in men and 63.5 in women per 100,000 patients, cervical radiculopathy is caused by compression or irritation of the cervical nerve roots as they exit the spine. The most common cause of cervical radiculopathy is spondylosis followed by disc herniation, but both can be present in the same patient. Spondylosis refers to degeneration of the discs and facet joints but generally without frank disc herniation.⁵

External shoulder impingement and cervical radiculopathy can have nearly identical symptoms of shoulder and upper arm pain as in this illustrated case. Patients with cervical radiculopathy generally present with neck, shoulder, and arm pain or neurologic deficits. These symptoms alone are very broad and present a wide differential diagnosis. One must determine whether the pain is from the neck or shoulder region.¹ The Table and Figures 1 to 6 describe the physical examination maneuvers used to differentiate the etiology.

The decision to pursue imaging should be based on injury severity and patient treatment goals. Although plain radiographic imaging may reveal spondylotic changes, such as degenerative joint changes at the vertebral facets and uncovertebral joints as well as decreased disc space, MRI is the imaging modality of choice for viewing disc herniations.⁶Nonoperative management of cervical radiculopathy focuses on restoration of full pain-free neck ROM, cervical muscle strengthening, and consideration for cervical traction. The use of either topical or oral medications can be considered if needed to aid in sleep and/or participation in active rehabilitation. Complimentary methods, such as acupuncture, yoga, or therapeutic massage also should be considered. Additionally, corticosteroid epidural injections can be considered, but these have increased risk compared with lumbar epidural injections.⁷ Surgical indications include persistent symptoms after 6 to 12 weeks of conservative therapy with no improvement of symptoms or progressively worsening motor/neurologic deficits.⁸

Conclusion

This case illustrates how 2 different conditions can present similarly and lead to diagnostic uncertainty. In this case, both the shoulder impingement and cervical radiculopathy manifested as shoulder and upper arm pain and could be separated only once the impingement had been treated. In addition the left-sided disc herniation causing right-sided symptoms was very unusual. To the best of the authors’ knowledge, this is only the second report of cervical disc herniation causing contralateral symptoms. In the only other available case report on cervical disc herniation with contralateral symptoms, the symptoms occurred in both the contralateral arm and leg.⁹

Neck and shoulder pain are common presenting symptoms in the general adult population with a 41.7% and 50.9% lifetime incidence in males and females, respectively.¹ Generally, a single diagnosis is sought to explain a patient’s signs and symptoms, but occasionally 2 or more different causes are responsible. Only by conducting a thorough history and physical examination with proper follow-up will all contributing diseases be discovered. The following case illustrates 2 distinct etiologies responsible for the patient’s pain, one with an extremely unusual presentation.

Case Presentation

A 23-year-old male presented with a 3-month history of pain, spasm, and tightness of his right upper extremity along his posterior neck, shoulder, and triceps area. The patient reported no history of trauma, but he revealed increasing the amount of weight lifting, and his symptoms were especially worse when bench pressing or performing overhead exercises. No paresthesias were reported.

The initial examination revealed a well-developed muscular male with no visible atrophy or tenderness to palpation. He had full range of motion (ROM) of his neck, a normal motor and sensory examination of the C5-T1 nerve roots, and a negative Spurling maneuver. The patient had full ROM of both shoulders but had pain with right shoulder abduction starting at about 120° to 140°. He had pain with resisted supraspinatus muscle testing as well as pain with the liftoff test. The results of the patient’s Hawkins and Neer tests were negative (Table, Figures 1 to 6).^2-4 A point-of-care shoulder ultrasound examination revealed no abnormalities.

The working diagnosis was external shoulder impingement with a differential diagnosis of internal impingement and/or cervical radiculopathy. A diagnostic/therapeutic injection of 40 mg of triamcinolone and 4 mL of 1% xylocaine without epinephrine was administered into the right subacromial bursa. The patient experienced immediate and complete relief of pain with repeat shoulder abduction, supraspinatus muscle testing, and the liftoff test. Although this procedure temporarily relieved the pain with movement, a sensation of tightness, pain, and spasm in the posterior shoulder and right posterior arm was still present. The patient was asked to perform therapeutic rotator cuff and scapular strengthening exercises, annotated on a patient information handout, for 15 minutes a day, every other day and to follow-up in 4 weeks.

At follow-up the external impingement symptoms (pain with shoulder abduction, resisted supraspinatus testing and the liftoff test) were fully resolved, but the patient reported persistent pain, spasm, and sensation of tightness in his right posterior shoulder and arm with intermittent extension into forearm and hand. A review of the history reminded the patient of a wrestling episode that caused neck pain months earlier. The patient reported that his current symptoms began after the wrestling episode.

Physical examination at this time revealed pain in the right posterior arm with left lateral neck movement but no neck pain with right lateral neck movement or flexion and extension. There was again a normal motor and sensory examination in the C5-T1 nerve distribution. Of note, there was full painless abduction in the right shoulder, which had improved from the previous examination, and there was no pain with resisted supraspinatus testing or the liftoff test, both of which had been abnormal at the initial encounter.

Due to the patient’s persistent posterior shoulder pain and exacerbation of symptoms with neck movement and the now revealed antecedent event of neck trauma, a higher concern for cervical disc pathology was entertained. A cervical magnetic resonance imaging examination (MRI) was ordered. A moderately sized left paracentral herniation of the disk at C5-C6 was found. The disk herniation was compressing the left ventral hemi-cord with narrowing of the left neuronal foramina. Additionally, there was a mild posterior disc osteophyte complex that caused mild left foraminal narrowing at C6-C7.

Neurosurgical consultation was obtained. Extensive discussion of nonsurgical vs surgical options were conducted, and a trial of nonsurgical therapy was agreed on. Physical therapy with cervical traction was prescribed with 2 sessions a week for 4 weeks. The patient also continued his therapeutic rotator cuff and scapular stabilizing exercises and decreased the amount and intensity of his weight lifting.

At the next 4-week follow-up, his symptoms were greatly reduced. He was discharged from supervised physical therapy and continued his at-home neck and shoulder strengthening regimen. At the 1-year follow-up, the patient reported that the radiating pain had essentially resolved—only occasionally being present with heavy upper-extremity weight lifting or grappling activities. He continues to be symptom free of his external impingement symptoms as well.

The final diagnosis was cervical radiculopathy of C5/6 nerve root due to left paracentral disc herniation with concomitant cord compression as well as external impingement (rotator cuff dysfunction) of the right shoulder. It is unclear whether the disc herniation contributed to the external shoulder impingement due to alterations in biomechanics or whether the 2 diseases were unrelated.

Discussion

The patient’s cervical disc herniation most likely was due to his earlier grappling episode when he had acute trauma to the neck or an exacerbation of an older asymptomatic herniation. His external shoulder impingement likely was due to overuse with heavy weight lifting, which also caused enough mechanical strain to exacerbate the patient’s cervical disc herniation symptoms. What is most unusual about this case is the right-sided cervical radicular symptoms due to a left-sided cervical disc herniation.

With an annual incidence of 107.3 in men and 63.5 in women per 100,000 patients, cervical radiculopathy is caused by compression or irritation of the cervical nerve roots as they exit the spine. The most common cause of cervical radiculopathy is spondylosis followed by disc herniation, but both can be present in the same patient. Spondylosis refers to degeneration of the discs and facet joints but generally without frank disc herniation.⁵

External shoulder impingement and cervical radiculopathy can have nearly identical symptoms of shoulder and upper arm pain as in this illustrated case. Patients with cervical radiculopathy generally present with neck, shoulder, and arm pain or neurologic deficits. These symptoms alone are very broad and present a wide differential diagnosis. One must determine whether the pain is from the neck or shoulder region.¹ The Table and Figures 1 to 6 describe the physical examination maneuvers used to differentiate the etiology.

The decision to pursue imaging should be based on injury severity and patient treatment goals. Although plain radiographic imaging may reveal spondylotic changes, such as degenerative joint changes at the vertebral facets and uncovertebral joints as well as decreased disc space, MRI is the imaging modality of choice for viewing disc herniations.⁶Nonoperative management of cervical radiculopathy focuses on restoration of full pain-free neck ROM, cervical muscle strengthening, and consideration for cervical traction. The use of either topical or oral medications can be considered if needed to aid in sleep and/or participation in active rehabilitation. Complimentary methods, such as acupuncture, yoga, or therapeutic massage also should be considered. Additionally, corticosteroid epidural injections can be considered, but these have increased risk compared with lumbar epidural injections.⁷ Surgical indications include persistent symptoms after 6 to 12 weeks of conservative therapy with no improvement of symptoms or progressively worsening motor/neurologic deficits.⁸

Conclusion

This case illustrates how 2 different conditions can present similarly and lead to diagnostic uncertainty. In this case, both the shoulder impingement and cervical radiculopathy manifested as shoulder and upper arm pain and could be separated only once the impingement had been treated. In addition the left-sided disc herniation causing right-sided symptoms was very unusual. To the best of the authors’ knowledge, this is only the second report of cervical disc herniation causing contralateral symptoms. In the only other available case report on cervical disc herniation with contralateral symptoms, the symptoms occurred in both the contralateral arm and leg.⁹

Neck and shoulder pain are common presenting symptoms in the general adult population with a 41.7% and 50.9% lifetime incidence in males and females, respectively.¹ Generally, a single diagnosis is sought to explain a patient’s signs and symptoms, but occasionally 2 or more different causes are responsible. Only by conducting a thorough history and physical examination with proper follow-up will all contributing diseases be discovered. The following case illustrates 2 distinct etiologies responsible for the patient’s pain, one with an extremely unusual presentation.

Case Presentation

A 23-year-old male presented with a 3-month history of pain, spasm, and tightness of his right upper extremity along his posterior neck, shoulder, and triceps area. The patient reported no history of trauma, but he revealed increasing the amount of weight lifting, and his symptoms were especially worse when bench pressing or performing overhead exercises. No paresthesias were reported.

The initial examination revealed a well-developed muscular male with no visible atrophy or tenderness to palpation. He had full range of motion (ROM) of his neck, a normal motor and sensory examination of the C5-T1 nerve roots, and a negative Spurling maneuver. The patient had full ROM of both shoulders but had pain with right shoulder abduction starting at about 120° to 140°. He had pain with resisted supraspinatus muscle testing as well as pain with the liftoff test. The results of the patient’s Hawkins and Neer tests were negative (Table, Figures 1 to 6).^2-4 A point-of-care shoulder ultrasound examination revealed no abnormalities.

The working diagnosis was external shoulder impingement with a differential diagnosis of internal impingement and/or cervical radiculopathy. A diagnostic/therapeutic injection of 40 mg of triamcinolone and 4 mL of 1% xylocaine without epinephrine was administered into the right subacromial bursa. The patient experienced immediate and complete relief of pain with repeat shoulder abduction, supraspinatus muscle testing, and the liftoff test. Although this procedure temporarily relieved the pain with movement, a sensation of tightness, pain, and spasm in the posterior shoulder and right posterior arm was still present. The patient was asked to perform therapeutic rotator cuff and scapular strengthening exercises, annotated on a patient information handout, for 15 minutes a day, every other day and to follow-up in 4 weeks.

At follow-up the external impingement symptoms (pain with shoulder abduction, resisted supraspinatus testing and the liftoff test) were fully resolved, but the patient reported persistent pain, spasm, and sensation of tightness in his right posterior shoulder and arm with intermittent extension into forearm and hand. A review of the history reminded the patient of a wrestling episode that caused neck pain months earlier. The patient reported that his current symptoms began after the wrestling episode.

Physical examination at this time revealed pain in the right posterior arm with left lateral neck movement but no neck pain with right lateral neck movement or flexion and extension. There was again a normal motor and sensory examination in the C5-T1 nerve distribution. Of note, there was full painless abduction in the right shoulder, which had improved from the previous examination, and there was no pain with resisted supraspinatus testing or the liftoff test, both of which had been abnormal at the initial encounter.

Due to the patient’s persistent posterior shoulder pain and exacerbation of symptoms with neck movement and the now revealed antecedent event of neck trauma, a higher concern for cervical disc pathology was entertained. A cervical magnetic resonance imaging examination (MRI) was ordered. A moderately sized left paracentral herniation of the disk at C5-C6 was found. The disk herniation was compressing the left ventral hemi-cord with narrowing of the left neuronal foramina. Additionally, there was a mild posterior disc osteophyte complex that caused mild left foraminal narrowing at C6-C7.

Neurosurgical consultation was obtained. Extensive discussion of nonsurgical vs surgical options were conducted, and a trial of nonsurgical therapy was agreed on. Physical therapy with cervical traction was prescribed with 2 sessions a week for 4 weeks. The patient also continued his therapeutic rotator cuff and scapular stabilizing exercises and decreased the amount and intensity of his weight lifting.

At the next 4-week follow-up, his symptoms were greatly reduced. He was discharged from supervised physical therapy and continued his at-home neck and shoulder strengthening regimen. At the 1-year follow-up, the patient reported that the radiating pain had essentially resolved—only occasionally being present with heavy upper-extremity weight lifting or grappling activities. He continues to be symptom free of his external impingement symptoms as well.

The final diagnosis was cervical radiculopathy of C5/6 nerve root due to left paracentral disc herniation with concomitant cord compression as well as external impingement (rotator cuff dysfunction) of the right shoulder. It is unclear whether the disc herniation contributed to the external shoulder impingement due to alterations in biomechanics or whether the 2 diseases were unrelated.

Discussion

The patient’s cervical disc herniation most likely was due to his earlier grappling episode when he had acute trauma to the neck or an exacerbation of an older asymptomatic herniation. His external shoulder impingement likely was due to overuse with heavy weight lifting, which also caused enough mechanical strain to exacerbate the patient’s cervical disc herniation symptoms. What is most unusual about this case is the right-sided cervical radicular symptoms due to a left-sided cervical disc herniation.

With an annual incidence of 107.3 in men and 63.5 in women per 100,000 patients, cervical radiculopathy is caused by compression or irritation of the cervical nerve roots as they exit the spine. The most common cause of cervical radiculopathy is spondylosis followed by disc herniation, but both can be present in the same patient. Spondylosis refers to degeneration of the discs and facet joints but generally without frank disc herniation.⁵

External shoulder impingement and cervical radiculopathy can have nearly identical symptoms of shoulder and upper arm pain as in this illustrated case. Patients with cervical radiculopathy generally present with neck, shoulder, and arm pain or neurologic deficits. These symptoms alone are very broad and present a wide differential diagnosis. One must determine whether the pain is from the neck or shoulder region.¹ The Table and Figures 1 to 6 describe the physical examination maneuvers used to differentiate the etiology.

The decision to pursue imaging should be based on injury severity and patient treatment goals. Although plain radiographic imaging may reveal spondylotic changes, such as degenerative joint changes at the vertebral facets and uncovertebral joints as well as decreased disc space, MRI is the imaging modality of choice for viewing disc herniations.⁶Nonoperative management of cervical radiculopathy focuses on restoration of full pain-free neck ROM, cervical muscle strengthening, and consideration for cervical traction. The use of either topical or oral medications can be considered if needed to aid in sleep and/or participation in active rehabilitation. Complimentary methods, such as acupuncture, yoga, or therapeutic massage also should be considered. Additionally, corticosteroid epidural injections can be considered, but these have increased risk compared with lumbar epidural injections.⁷ Surgical indications include persistent symptoms after 6 to 12 weeks of conservative therapy with no improvement of symptoms or progressively worsening motor/neurologic deficits.⁸

Conclusion

This case illustrates how 2 different conditions can present similarly and lead to diagnostic uncertainty. In this case, both the shoulder impingement and cervical radiculopathy manifested as shoulder and upper arm pain and could be separated only once the impingement had been treated. In addition the left-sided disc herniation causing right-sided symptoms was very unusual. To the best of the authors’ knowledge, this is only the second report of cervical disc herniation causing contralateral symptoms. In the only other available case report on cervical disc herniation with contralateral symptoms, the symptoms occurred in both the contralateral arm and leg.⁹

Background

Pericardial effusions are usually an incidental finding on bedside echocardiogram—unless a patient shows clinical signs of tamponade physiology and obstructive shock. Echocardiogram is both sensitive and specific to detecting pericardial effusions.¹ Although there are many causes of pericardial effusions, the most common causes of symptomatic effusions in the Western World are due to neoplasm, pericarditis, traumatic pathology, or idiopathic etiology. In developing countries, however, pericardial effusions are predominantly due to tuberculosis in an area where it is endemic.^2,3 The size of the effusion is classified based on measurements of a fluid pocket during diastole. Mild effusion is defined as less than 10 mm; moderate effusion, 10 to 20 mm; and large effusion, greater than 20 mm.³

It is important to note that the pericardial space contains up to 50 mL of physiological fluid which may be seen on echocardiography during systole. Small effusions usually contain less than 100 mL of fluid; moderate effusions contain 100 to 500 mL of fluid; and large effusions, over 500 mL of fluid. Fluid of smaller effusions typically layer posteriorly, while the fluid of some moderate and most large effusions may be seen circumferentially.

Clinical Signs and Symptoms

Patients with large chronic effusions are often asymptomatic, and clinical symptoms usually correlate to the acuity of pericardial accumulation. Patients with symptomatic effusions present with dyspnea on exertion that is followed by orthopnea, chest pain, and sometimes dysphagia, hoarseness, or hiccups due to irritation of surrounding structures until they exhibit tamponade physiology leading to hypotension secondary to obstructive shock. The most recognized signs of tamponade physiology on bedside echocardiography are early diastolic collapse of the right atrium and right ventricle, as well as ventricular interdependence.⁴

Imaging Technique

Pericardial effusion and cardiac tamponade can be detected in any of the standard echocardiographic views, with fluid usually appearing as an anechoic stripe. The fluid will first appear in the dependent portion of the pericardial space, but may become circumferential as it grows (Figure 1).

In the event of obstructive shock or pulseless electric activity with visualized or suspected tamponade, pericardiocentesis is considered standard of care. There are many approaches to performing a pericardiocentesis, including the classically taught blind subxiphoid approach, which is associated with high rates of morbidity and mortality.⁵ More recent image-guided approaches employ echocardiography-guided techniques that identify the location and distribution of fluid, and perform pericardiocentesis closest to the area largest fluid accumulation.

Most of these guided techniques involve in-plane visualization of the needle in either a subxiphoid, apical, or parasternal approach. Studies have shown that the subxiphoid approach has a higher risk of injury to the liver, heart, and IVC, with complication rates up to 20% depending on the study.⁶

The apical approach involves locating the cardiac apex and inserting the needle 1 cm lateral to the apex, with the point directed toward the effusion and in-line with the ultrasound probe, taking care to avoid the lingula. Studies have shown that complication rates with this approach are around 3%.⁷

Recent studies also suggest that in-line medial-to-lateral parasternal approaches may have minimal complications. However, when employing this approach, care must be taken to avoid the internal mammary artery, which can be identified using color-flow Doppler echocardiology.⁶

Conclusion

In general, bedside ultrasound is a quick and useful tool to evaluate for pericardial effusion and signs of tamponade physiology. When present, tamponade, a clinical diagnosis, is the likely cause of shock in the hemodynamically unstable patient with circumferential pericardial effusion.

While most cases of pericardial effusion are found incidentally, a stepwise approach to evaluate for tamponade is to quickly look for signs of early right-sided diastolic collapse or ventricular interdependence, as well as a plethoric IVC. For patients who have tamponade requiring pericardiocentesis, the ultrasound-guided apical or parasternal approaches have been shown to have fewer complications compared to the subxiphoid approach.

Background

Pericardial effusions are usually an incidental finding on bedside echocardiogram—unless a patient shows clinical signs of tamponade physiology and obstructive shock. Echocardiogram is both sensitive and specific to detecting pericardial effusions.¹ Although there are many causes of pericardial effusions, the most common causes of symptomatic effusions in the Western World are due to neoplasm, pericarditis, traumatic pathology, or idiopathic etiology. In developing countries, however, pericardial effusions are predominantly due to tuberculosis in an area where it is endemic.^2,3 The size of the effusion is classified based on measurements of a fluid pocket during diastole. Mild effusion is defined as less than 10 mm; moderate effusion, 10 to 20 mm; and large effusion, greater than 20 mm.³

It is important to note that the pericardial space contains up to 50 mL of physiological fluid which may be seen on echocardiography during systole. Small effusions usually contain less than 100 mL of fluid; moderate effusions contain 100 to 500 mL of fluid; and large effusions, over 500 mL of fluid. Fluid of smaller effusions typically layer posteriorly, while the fluid of some moderate and most large effusions may be seen circumferentially.

Clinical Signs and Symptoms

Patients with large chronic effusions are often asymptomatic, and clinical symptoms usually correlate to the acuity of pericardial accumulation. Patients with symptomatic effusions present with dyspnea on exertion that is followed by orthopnea, chest pain, and sometimes dysphagia, hoarseness, or hiccups due to irritation of surrounding structures until they exhibit tamponade physiology leading to hypotension secondary to obstructive shock. The most recognized signs of tamponade physiology on bedside echocardiography are early diastolic collapse of the right atrium and right ventricle, as well as ventricular interdependence.⁴

Imaging Technique

Pericardial effusion and cardiac tamponade can be detected in any of the standard echocardiographic views, with fluid usually appearing as an anechoic stripe. The fluid will first appear in the dependent portion of the pericardial space, but may become circumferential as it grows (Figure 1).

In the event of obstructive shock or pulseless electric activity with visualized or suspected tamponade, pericardiocentesis is considered standard of care. There are many approaches to performing a pericardiocentesis, including the classically taught blind subxiphoid approach, which is associated with high rates of morbidity and mortality.⁵ More recent image-guided approaches employ echocardiography-guided techniques that identify the location and distribution of fluid, and perform pericardiocentesis closest to the area largest fluid accumulation.

Most of these guided techniques involve in-plane visualization of the needle in either a subxiphoid, apical, or parasternal approach. Studies have shown that the subxiphoid approach has a higher risk of injury to the liver, heart, and IVC, with complication rates up to 20% depending on the study.⁶

The apical approach involves locating the cardiac apex and inserting the needle 1 cm lateral to the apex, with the point directed toward the effusion and in-line with the ultrasound probe, taking care to avoid the lingula. Studies have shown that complication rates with this approach are around 3%.⁷

Recent studies also suggest that in-line medial-to-lateral parasternal approaches may have minimal complications. However, when employing this approach, care must be taken to avoid the internal mammary artery, which can be identified using color-flow Doppler echocardiology.⁶

Conclusion

In general, bedside ultrasound is a quick and useful tool to evaluate for pericardial effusion and signs of tamponade physiology. When present, tamponade, a clinical diagnosis, is the likely cause of shock in the hemodynamically unstable patient with circumferential pericardial effusion.

While most cases of pericardial effusion are found incidentally, a stepwise approach to evaluate for tamponade is to quickly look for signs of early right-sided diastolic collapse or ventricular interdependence, as well as a plethoric IVC. For patients who have tamponade requiring pericardiocentesis, the ultrasound-guided apical or parasternal approaches have been shown to have fewer complications compared to the subxiphoid approach.

Background

Pericardial effusions are usually an incidental finding on bedside echocardiogram—unless a patient shows clinical signs of tamponade physiology and obstructive shock. Echocardiogram is both sensitive and specific to detecting pericardial effusions.¹ Although there are many causes of pericardial effusions, the most common causes of symptomatic effusions in the Western World are due to neoplasm, pericarditis, traumatic pathology, or idiopathic etiology. In developing countries, however, pericardial effusions are predominantly due to tuberculosis in an area where it is endemic.^2,3 The size of the effusion is classified based on measurements of a fluid pocket during diastole. Mild effusion is defined as less than 10 mm; moderate effusion, 10 to 20 mm; and large effusion, greater than 20 mm.³

It is important to note that the pericardial space contains up to 50 mL of physiological fluid which may be seen on echocardiography during systole. Small effusions usually contain less than 100 mL of fluid; moderate effusions contain 100 to 500 mL of fluid; and large effusions, over 500 mL of fluid. Fluid of smaller effusions typically layer posteriorly, while the fluid of some moderate and most large effusions may be seen circumferentially.

Clinical Signs and Symptoms

Patients with large chronic effusions are often asymptomatic, and clinical symptoms usually correlate to the acuity of pericardial accumulation. Patients with symptomatic effusions present with dyspnea on exertion that is followed by orthopnea, chest pain, and sometimes dysphagia, hoarseness, or hiccups due to irritation of surrounding structures until they exhibit tamponade physiology leading to hypotension secondary to obstructive shock. The most recognized signs of tamponade physiology on bedside echocardiography are early diastolic collapse of the right atrium and right ventricle, as well as ventricular interdependence.⁴

Imaging Technique

Pericardial effusion and cardiac tamponade can be detected in any of the standard echocardiographic views, with fluid usually appearing as an anechoic stripe. The fluid will first appear in the dependent portion of the pericardial space, but may become circumferential as it grows (Figure 1).

In the event of obstructive shock or pulseless electric activity with visualized or suspected tamponade, pericardiocentesis is considered standard of care. There are many approaches to performing a pericardiocentesis, including the classically taught blind subxiphoid approach, which is associated with high rates of morbidity and mortality.⁵ More recent image-guided approaches employ echocardiography-guided techniques that identify the location and distribution of fluid, and perform pericardiocentesis closest to the area largest fluid accumulation.

Most of these guided techniques involve in-plane visualization of the needle in either a subxiphoid, apical, or parasternal approach. Studies have shown that the subxiphoid approach has a higher risk of injury to the liver, heart, and IVC, with complication rates up to 20% depending on the study.⁶

The apical approach involves locating the cardiac apex and inserting the needle 1 cm lateral to the apex, with the point directed toward the effusion and in-line with the ultrasound probe, taking care to avoid the lingula. Studies have shown that complication rates with this approach are around 3%.⁷

Recent studies also suggest that in-line medial-to-lateral parasternal approaches may have minimal complications. However, when employing this approach, care must be taken to avoid the internal mammary artery, which can be identified using color-flow Doppler echocardiology.⁶

Conclusion

In general, bedside ultrasound is a quick and useful tool to evaluate for pericardial effusion and signs of tamponade physiology. When present, tamponade, a clinical diagnosis, is the likely cause of shock in the hemodynamically unstable patient with circumferential pericardial effusion.

While most cases of pericardial effusion are found incidentally, a stepwise approach to evaluate for tamponade is to quickly look for signs of early right-sided diastolic collapse or ventricular interdependence, as well as a plethoric IVC. For patients who have tamponade requiring pericardiocentesis, the ultrasound-guided apical or parasternal approaches have been shown to have fewer complications compared to the subxiphoid approach.

Sepsis can be the result of single or multiple factors and sources of infection. Oral sources of sepsis and systemic infection are not commonly considered as the first potential source of infection when evaluating a septic patient. Oral infections of odontogenic or periodontal origin are frequently associated with localized or diffuse cellulitis of the head and neck region. ¹ The patient’s health status and complicating problems, such as an immunocompromising condition, can further reduce the immune response for controlling chronic sources of infection. This in turn can lead to acute manifestations such as cellulitis, sepsis, or necrotizing fasciitis. Necrotizing fasciitis is caused by a polymicrobial or mixed aerobic-anaerobic infection from a variety of sources, including Streptococcus pyogenes .

Case

A 57-year-old woman with a history of major depressive disorder, paroxysmal atrial fibrillation, and opioid dependence that was in remission for more than 3 years was brought to the ED by a family member after the patient developed confusion and lethargy. She was primarily experiencing right breast pain and swelling. The breast pain was associated with high fevers, nausea, vomiting, and chills.

On examination, the patient’s vital signs were: blood pressure (BP), 109/58 mm Hg; heart rate, 160 beats/min; respiratory rate, 22 breaths/min; and temperature, 104°F. Laboratory evaluation was significant for a white blood cell count (WBC) of 8.7 x 10³. There was a noted skin abrasion on the patient’s right hand. She was lethargic and confused. Blood cultures were positive for S pyogenes, and a swab of the right breast was negative for bacterial growth.

The patient was admitted to the medical intensive care unit (MICU) and placed on two vasopressors for control of low BP and assistance with low urine output. After a 6-L fluid resuscitation, the patient was started on vancomycin and piperacillin/tazobactam for possible cellulitis causing sepsis. An echocardiogram was negative for endocarditis. The patient continued to decline the following day with continuing tachycardia and tachypnea with hypotension and was intubated. Pulmonology services was consulted for possible acute respiratory distress syndrome secondary to sepsis; general surgery services was consulted for possible necrotizing fasciitis of the chest wall; and cardiology services was consulted for low-cardiac output.

Discussion

Oral infections most often present with acute onset and noted oral-facial cellulitis or abscess. Oral source of septicemia often are considered after ruling out most other potential sources. Although it is not certain that this case is directly related to the advanced chronic periodontal disease, S pyogenes has been noted to be a pathogen in periodontal disease progression.

According to the American Dental Association in 2012, dental visits to the ED cost the US health care system $1.6 billion and an average cost of $749 per visit. There are more than 2 million ED visits each year for dental pain and infection, and 39% return due to nonresolution of the dental problem. Patients return to the ED due to lack of access and resources to routine and emergent dental care. ² The average daily cost of an MICU stay with mechanical ventilation was $2,193 in 2002. This particular case consisted of 11 days of mechanical ventilation, 20 MICU days, and an additional 20 days of inpatient rehabilitation which resulted in costs that exceeded $50,000. ³

Sepsis can be the result of single or multiple factors and sources of infection. Oral sources of sepsis and systemic infection are not commonly considered as the first potential source of infection when evaluating a septic patient. Oral infections of odontogenic or periodontal origin are frequently associated with localized or diffuse cellulitis of the head and neck region. ¹ The patient’s health status and complicating problems, such as an immunocompromising condition, can further reduce the immune response for controlling chronic sources of infection. This in turn can lead to acute manifestations such as cellulitis, sepsis, or necrotizing fasciitis. Necrotizing fasciitis is caused by a polymicrobial or mixed aerobic-anaerobic infection from a variety of sources, including Streptococcus pyogenes .

Case

A 57-year-old woman with a history of major depressive disorder, paroxysmal atrial fibrillation, and opioid dependence that was in remission for more than 3 years was brought to the ED by a family member after the patient developed confusion and lethargy. She was primarily experiencing right breast pain and swelling. The breast pain was associated with high fevers, nausea, vomiting, and chills.

On examination, the patient’s vital signs were: blood pressure (BP), 109/58 mm Hg; heart rate, 160 beats/min; respiratory rate, 22 breaths/min; and temperature, 104°F. Laboratory evaluation was significant for a white blood cell count (WBC) of 8.7 x 10³. There was a noted skin abrasion on the patient’s right hand. She was lethargic and confused. Blood cultures were positive for S pyogenes, and a swab of the right breast was negative for bacterial growth.

The patient was admitted to the medical intensive care unit (MICU) and placed on two vasopressors for control of low BP and assistance with low urine output. After a 6-L fluid resuscitation, the patient was started on vancomycin and piperacillin/tazobactam for possible cellulitis causing sepsis. An echocardiogram was negative for endocarditis. The patient continued to decline the following day with continuing tachycardia and tachypnea with hypotension and was intubated. Pulmonology services was consulted for possible acute respiratory distress syndrome secondary to sepsis; general surgery services was consulted for possible necrotizing fasciitis of the chest wall; and cardiology services was consulted for low-cardiac output.

Discussion

Oral infections most often present with acute onset and noted oral-facial cellulitis or abscess. Oral source of septicemia often are considered after ruling out most other potential sources. Although it is not certain that this case is directly related to the advanced chronic periodontal disease, S pyogenes has been noted to be a pathogen in periodontal disease progression.

According to the American Dental Association in 2012, dental visits to the ED cost the US health care system $1.6 billion and an average cost of $749 per visit. There are more than 2 million ED visits each year for dental pain and infection, and 39% return due to nonresolution of the dental problem. Patients return to the ED due to lack of access and resources to routine and emergent dental care. ² The average daily cost of an MICU stay with mechanical ventilation was $2,193 in 2002. This particular case consisted of 11 days of mechanical ventilation, 20 MICU days, and an additional 20 days of inpatient rehabilitation which resulted in costs that exceeded $50,000. ³

Sepsis can be the result of single or multiple factors and sources of infection. Oral sources of sepsis and systemic infection are not commonly considered as the first potential source of infection when evaluating a septic patient. Oral infections of odontogenic or periodontal origin are frequently associated with localized or diffuse cellulitis of the head and neck region. ¹ The patient’s health status and complicating problems, such as an immunocompromising condition, can further reduce the immune response for controlling chronic sources of infection. This in turn can lead to acute manifestations such as cellulitis, sepsis, or necrotizing fasciitis. Necrotizing fasciitis is caused by a polymicrobial or mixed aerobic-anaerobic infection from a variety of sources, including Streptococcus pyogenes .

Case

A 57-year-old woman with a history of major depressive disorder, paroxysmal atrial fibrillation, and opioid dependence that was in remission for more than 3 years was brought to the ED by a family member after the patient developed confusion and lethargy. She was primarily experiencing right breast pain and swelling. The breast pain was associated with high fevers, nausea, vomiting, and chills.

On examination, the patient’s vital signs were: blood pressure (BP), 109/58 mm Hg; heart rate, 160 beats/min; respiratory rate, 22 breaths/min; and temperature, 104°F. Laboratory evaluation was significant for a white blood cell count (WBC) of 8.7 x 10³. There was a noted skin abrasion on the patient’s right hand. She was lethargic and confused. Blood cultures were positive for S pyogenes, and a swab of the right breast was negative for bacterial growth.

The patient was admitted to the medical intensive care unit (MICU) and placed on two vasopressors for control of low BP and assistance with low urine output. After a 6-L fluid resuscitation, the patient was started on vancomycin and piperacillin/tazobactam for possible cellulitis causing sepsis. An echocardiogram was negative for endocarditis. The patient continued to decline the following day with continuing tachycardia and tachypnea with hypotension and was intubated. Pulmonology services was consulted for possible acute respiratory distress syndrome secondary to sepsis; general surgery services was consulted for possible necrotizing fasciitis of the chest wall; and cardiology services was consulted for low-cardiac output.

Discussion

Oral infections most often present with acute onset and noted oral-facial cellulitis or abscess. Oral source of septicemia often are considered after ruling out most other potential sources. Although it is not certain that this case is directly related to the advanced chronic periodontal disease, S pyogenes has been noted to be a pathogen in periodontal disease progression.

According to the American Dental Association in 2012, dental visits to the ED cost the US health care system $1.6 billion and an average cost of $749 per visit. There are more than 2 million ED visits each year for dental pain and infection, and 39% return due to nonresolution of the dental problem. Patients return to the ED due to lack of access and resources to routine and emergent dental care. ² The average daily cost of an MICU stay with mechanical ventilation was $2,193 in 2002. This particular case consisted of 11 days of mechanical ventilation, 20 MICU days, and an additional 20 days of inpatient rehabilitation which resulted in costs that exceeded $50,000. ³

Case

A 50-year-old Hispanic woman with a history of rheumatoid arthritis (RA), for which she was not currently taking medication, was referred to the ED by her primary care physician (PCP) for evaluation of generalized pruritus and jaundice, and an abnormal hepatic function panel.

The patient’s recent history was significant for a positive tuberculosis test (purified protein derivative [PPD], 13 mm), for which she had been on prophylactic medication. Laboratory evaluation taken during the patient’s recent follow-up visit with her PCP revealed the following significant hepatic abnormalities: total bilirubin, 20.0 mg/dL; direct bilirubin, 16.4 mg/dL; international normalized ratio, 2.9; aspartate aminotransferase, greater than 2,000 IU/L; and alanine aminotransferase, greater than 2,000 IU/L. The patient had no history of hepatic disease, and a hepatitis panel obtained in the ED was unremarkable.

Can this be drug-induced liver injury?

Drug-induced liver injury (DILI) accounts for nearly 50% of cases of acute liver failure in the United States.¹ According to the National Institutes of Health database of drugs, supplements, and herbal medications acetaminophen is the most common drug associated with hepatotoxicity in the United States, whereas amoxicillin-clavulanate is the most common implicated drug worldwide.^1,2 The histological pattern of DILI varies by drug (Table).³

Who is susceptible to drug-induced liver injury?

The factors that help predict DILI include drug pharmacokinetics and metabolism, as well as patient age, sex, and comorbidities. Although some patients are at an increased risk of DILI, it is extraordinarily difficult to accurately predict which patients will develop it. In general, there is a positive correlation between age and risk of developing DILI. For example, in a large US-based tuberculosis study, the incidence of isoniazid (INH)-induced hepatotoxicity was 4.4 per 1,000 patients aged 25 to 34 years. Patients older than age 50 years had a 20.83 per 1,000 incidence of DILI, and women also appear to be at increased risk.⁴

Pharmacogenetic factors affecting drug metabolism such as the specific cytochrome profile and acetylator status of an individual also influence a patient’s risk of developing DILI. Although our understanding of these issues is growing rapidly, our ability to apply this knowledge to the clinical venue is limited by the available technology, regulatory requirements, and cost.

Case Continuation

A detailed, careful history-taking in the ED revealed that, 2 months prior, the patient had been started on INH, rifampin, and pyridoxine for latent tuberculosis. She had been taking methotrexate for the RA but discontinued it 3 months ago because of the positive PPD. When routine outpatient laboratory testing results demonstrated significant hepatic dysfunction, the patient’s PCP advised her to immediately discontinue her medications and referred her to the ED for further evaluation and management.

By what mechanism does INH cause DILI?

Acute INH-associated hepatitis primarily results from the direct hepatotoxic effects of INH metabolites. Isoniazid is metabolized in the liver via N-acetylation to acetylisoniazid (Figure). Oxidation of this compound in the liver leads to an accumulation of the hepatotoxic metabolites acetylhydrazine and hydrazine.^5,6

Is there a role for N-acetylcysteine in INH hepatotoxicity?

No antidote is specifically designed to treat INH-induced hepatotoxicity, and management is largely supportive. Observation for progressive liver failure is indicated and evaluation for liver transplant may become necessary.

N-acetylcysteine (NAC) has a clear role in preventing hepatotoxicity from acetaminophen overdose through its ability to act as a precursor for the synthesis of glutathione—a compound that protects hepatocytes from oxidative damage. In advanced acetaminophen-toxic patients and those with non-acetaminophen toxicity, NAC has nonspecific effects that promote healing through several mechanisms, including anti-inflammatory effect and enhanced hepatic perfusion. Though there are no studies that specifically evaluate the role of NAC in patients with INH-induced hepatotoxicity, it is commonly and appropriately administered for its aforementioned nonspecific effects.⁸ Common side effects from NAC administration include nausea, vomiting, and diarrhea, which are generally treatable with symptomatic and supportive care.

Case Conclusion

The patient was admitted to the hepatology service for continued clinical care. Although she received NAC, hepatic function testing showed only mild improvement. Additional etiologies of liver failure were investigated, including a computed tomography scan of the abdomen/pelvis and an abdominal ultrasound with Doppler. Both studies were negative for any pathology, and autoimmune laboratory studies were likewise unremarkable.

The patient underwent a liver biopsy, which revealed inflammation and scattered eosinophils suggestive of drug-induced hepatic injury. Her clinical condition continued to deteriorate, and she was transferred to another hospital for transplant evaluation.

Case

A 50-year-old Hispanic woman with a history of rheumatoid arthritis (RA), for which she was not currently taking medication, was referred to the ED by her primary care physician (PCP) for evaluation of generalized pruritus and jaundice, and an abnormal hepatic function panel.

The patient’s recent history was significant for a positive tuberculosis test (purified protein derivative [PPD], 13 mm), for which she had been on prophylactic medication. Laboratory evaluation taken during the patient’s recent follow-up visit with her PCP revealed the following significant hepatic abnormalities: total bilirubin, 20.0 mg/dL; direct bilirubin, 16.4 mg/dL; international normalized ratio, 2.9; aspartate aminotransferase, greater than 2,000 IU/L; and alanine aminotransferase, greater than 2,000 IU/L. The patient had no history of hepatic disease, and a hepatitis panel obtained in the ED was unremarkable.

Can this be drug-induced liver injury?

Drug-induced liver injury (DILI) accounts for nearly 50% of cases of acute liver failure in the United States.¹ According to the National Institutes of Health database of drugs, supplements, and herbal medications acetaminophen is the most common drug associated with hepatotoxicity in the United States, whereas amoxicillin-clavulanate is the most common implicated drug worldwide.^1,2 The histological pattern of DILI varies by drug (Table).³

Who is susceptible to drug-induced liver injury?

The factors that help predict DILI include drug pharmacokinetics and metabolism, as well as patient age, sex, and comorbidities. Although some patients are at an increased risk of DILI, it is extraordinarily difficult to accurately predict which patients will develop it. In general, there is a positive correlation between age and risk of developing DILI. For example, in a large US-based tuberculosis study, the incidence of isoniazid (INH)-induced hepatotoxicity was 4.4 per 1,000 patients aged 25 to 34 years. Patients older than age 50 years had a 20.83 per 1,000 incidence of DILI, and women also appear to be at increased risk.⁴

Pharmacogenetic factors affecting drug metabolism such as the specific cytochrome profile and acetylator status of an individual also influence a patient’s risk of developing DILI. Although our understanding of these issues is growing rapidly, our ability to apply this knowledge to the clinical venue is limited by the available technology, regulatory requirements, and cost.

Case Continuation

A detailed, careful history-taking in the ED revealed that, 2 months prior, the patient had been started on INH, rifampin, and pyridoxine for latent tuberculosis. She had been taking methotrexate for the RA but discontinued it 3 months ago because of the positive PPD. When routine outpatient laboratory testing results demonstrated significant hepatic dysfunction, the patient’s PCP advised her to immediately discontinue her medications and referred her to the ED for further evaluation and management.

By what mechanism does INH cause DILI?

Acute INH-associated hepatitis primarily results from the direct hepatotoxic effects of INH metabolites. Isoniazid is metabolized in the liver via N-acetylation to acetylisoniazid (Figure). Oxidation of this compound in the liver leads to an accumulation of the hepatotoxic metabolites acetylhydrazine and hydrazine.^5,6

Is there a role for N-acetylcysteine in INH hepatotoxicity?

No antidote is specifically designed to treat INH-induced hepatotoxicity, and management is largely supportive. Observation for progressive liver failure is indicated and evaluation for liver transplant may become necessary.

N-acetylcysteine (NAC) has a clear role in preventing hepatotoxicity from acetaminophen overdose through its ability to act as a precursor for the synthesis of glutathione—a compound that protects hepatocytes from oxidative damage. In advanced acetaminophen-toxic patients and those with non-acetaminophen toxicity, NAC has nonspecific effects that promote healing through several mechanisms, including anti-inflammatory effect and enhanced hepatic perfusion. Though there are no studies that specifically evaluate the role of NAC in patients with INH-induced hepatotoxicity, it is commonly and appropriately administered for its aforementioned nonspecific effects.⁸ Common side effects from NAC administration include nausea, vomiting, and diarrhea, which are generally treatable with symptomatic and supportive care.

Case Conclusion

The patient was admitted to the hepatology service for continued clinical care. Although she received NAC, hepatic function testing showed only mild improvement. Additional etiologies of liver failure were investigated, including a computed tomography scan of the abdomen/pelvis and an abdominal ultrasound with Doppler. Both studies were negative for any pathology, and autoimmune laboratory studies were likewise unremarkable.

The patient underwent a liver biopsy, which revealed inflammation and scattered eosinophils suggestive of drug-induced hepatic injury. Her clinical condition continued to deteriorate, and she was transferred to another hospital for transplant evaluation.

Case

A 50-year-old Hispanic woman with a history of rheumatoid arthritis (RA), for which she was not currently taking medication, was referred to the ED by her primary care physician (PCP) for evaluation of generalized pruritus and jaundice, and an abnormal hepatic function panel.

The patient’s recent history was significant for a positive tuberculosis test (purified protein derivative [PPD], 13 mm), for which she had been on prophylactic medication. Laboratory evaluation taken during the patient’s recent follow-up visit with her PCP revealed the following significant hepatic abnormalities: total bilirubin, 20.0 mg/dL; direct bilirubin, 16.4 mg/dL; international normalized ratio, 2.9; aspartate aminotransferase, greater than 2,000 IU/L; and alanine aminotransferase, greater than 2,000 IU/L. The patient had no history of hepatic disease, and a hepatitis panel obtained in the ED was unremarkable.

Can this be drug-induced liver injury?

Drug-induced liver injury (DILI) accounts for nearly 50% of cases of acute liver failure in the United States.¹ According to the National Institutes of Health database of drugs, supplements, and herbal medications acetaminophen is the most common drug associated with hepatotoxicity in the United States, whereas amoxicillin-clavulanate is the most common implicated drug worldwide.^1,2 The histological pattern of DILI varies by drug (Table).³

Who is susceptible to drug-induced liver injury?

The factors that help predict DILI include drug pharmacokinetics and metabolism, as well as patient age, sex, and comorbidities. Although some patients are at an increased risk of DILI, it is extraordinarily difficult to accurately predict which patients will develop it. In general, there is a positive correlation between age and risk of developing DILI. For example, in a large US-based tuberculosis study, the incidence of isoniazid (INH)-induced hepatotoxicity was 4.4 per 1,000 patients aged 25 to 34 years. Patients older than age 50 years had a 20.83 per 1,000 incidence of DILI, and women also appear to be at increased risk.⁴

Pharmacogenetic factors affecting drug metabolism such as the specific cytochrome profile and acetylator status of an individual also influence a patient’s risk of developing DILI. Although our understanding of these issues is growing rapidly, our ability to apply this knowledge to the clinical venue is limited by the available technology, regulatory requirements, and cost.

Case Continuation

A detailed, careful history-taking in the ED revealed that, 2 months prior, the patient had been started on INH, rifampin, and pyridoxine for latent tuberculosis. She had been taking methotrexate for the RA but discontinued it 3 months ago because of the positive PPD. When routine outpatient laboratory testing results demonstrated significant hepatic dysfunction, the patient’s PCP advised her to immediately discontinue her medications and referred her to the ED for further evaluation and management.

By what mechanism does INH cause DILI?

Acute INH-associated hepatitis primarily results from the direct hepatotoxic effects of INH metabolites. Isoniazid is metabolized in the liver via N-acetylation to acetylisoniazid (Figure). Oxidation of this compound in the liver leads to an accumulation of the hepatotoxic metabolites acetylhydrazine and hydrazine.^5,6

Is there a role for N-acetylcysteine in INH hepatotoxicity?

No antidote is specifically designed to treat INH-induced hepatotoxicity, and management is largely supportive. Observation for progressive liver failure is indicated and evaluation for liver transplant may become necessary.

N-acetylcysteine (NAC) has a clear role in preventing hepatotoxicity from acetaminophen overdose through its ability to act as a precursor for the synthesis of glutathione—a compound that protects hepatocytes from oxidative damage. In advanced acetaminophen-toxic patients and those with non-acetaminophen toxicity, NAC has nonspecific effects that promote healing through several mechanisms, including anti-inflammatory effect and enhanced hepatic perfusion. Though there are no studies that specifically evaluate the role of NAC in patients with INH-induced hepatotoxicity, it is commonly and appropriately administered for its aforementioned nonspecific effects.⁸ Common side effects from NAC administration include nausea, vomiting, and diarrhea, which are generally treatable with symptomatic and supportive care.

Case Conclusion

The patient was admitted to the hepatology service for continued clinical care. Although she received NAC, hepatic function testing showed only mild improvement. Additional etiologies of liver failure were investigated, including a computed tomography scan of the abdomen/pelvis and an abdominal ultrasound with Doppler. Both studies were negative for any pathology, and autoimmune laboratory studies were likewise unremarkable.

The patient underwent a liver biopsy, which revealed inflammation and scattered eosinophils suggestive of drug-induced hepatic injury. Her clinical condition continued to deteriorate, and she was transferred to another hospital for transplant evaluation.

The early initial ulcerative lesion (chancre) caused by Treponema pallidum infection, has a median incubation period of 21 days (primary syphilis). When untreated, secondary syphilis will develop within weeks to months and is characterized by generalized symptoms such as malaise, fevers, headaches, sore throat, and myalgia. However, the most characteristic finding in secondary syphilis remains a rash that is classically identified as symmetric, macular, or papular, and involving the entire trunk and extremities, including the palms and soles.

When secondary syphilis is left untreated, late syphilis or tertiary syphilis can develop, which is characterized by cardiovascular involvement, including aortitis, gummatous syphilis (granulomatous nodules in a variety of organs but typically the skin and bones), or central nervous system involvement.^1-3 The following case describes a patient with nondescript symptoms, including malaise and cough, who had a characteristic rash of secondary syphilis that was diagnosed and treated in our Houston-area community hospital.

Case

In late autumn, a 30-year-old man presented to our community ED for evaluation of a cough productive of green sputum along with mild chest discomfort, malaise, and generalized myalgia, which were intermittent over the course of the past month. The patient denied rhinorrhea, fevers, chills, dyspnea, or any other systemic complaints. He also denied any sick contacts, but noted that his influenza vaccine was not up to date. 

The patient denied any remote or recent medical or surgical history. He further denied taking any medications, and noted that his only medical allergy was to penicillin. His family history was noncontributory. Regarding his social history, the patient admitted to smoking one pack of cigarettes per day and to a daily alcohol intake of approximately one 6-pack of beer. He also admitted to frequently smoking crystal methamphetamine, which he stated he had last used 2 days prior to presentation. The patient said his current chest pain was similar to prior episodes, noting that when the pain occurred, he would temporarily stop smoking crystal methamphetamine. 

On further questioning, the patient admitted to having multiple female sexual partners with whom he used barrier protection sporadically. A more detailed physical examination revealed multiple painless ulcerations/chancres over the penile shaft and scrotum, without urethral drainage or inguinal lymphadenopathy. The patient denied dysuria or hematuria.

Since the patient was allergic to penicillin, he was given a single oral dose of azithromycin 2 g, and started on a 2-week course of oral doxycycline 100 mg. Further laboratory studies included gonorrhea and chlamydia cultures, both of which were negative. He was instructed to follow-up with his primary care physician for extended sexually transmitted infection (STI) panel-testing, including HIV, hepatitis, and confirmatory syphilis testing. Unfortunately, it is not known whether the patient complied with discharge instructions as he was lost to follow-up.

Discussion

Diagnostic algorithms for syphilis, one of the best studied STIs, have changed with technological advancement, but diagnosis and treatment for the most part has remained mostly the same. The uniqueness of this case is really focused around the patient’s chief complaint. While it is classic to present with malaise, headache, and rash, our patient complained of cough productive of sputum with chest pain—a rare presentation of secondary syphilis. The fortuitous key finding of the truncal rash directed the emergency physician toward the appropriate diagnosis.

Diagnosis

In the ED, where patients such as the one in our case are often lost to follow-up, and consistent infectious disease and primary care follow-up is unavailable, prompt treatment based on history and physical examination alone is recommended. Patients should be tested for syphilis, as well as other STIs including chlamydia, gonorrhea, hepatitis, and HIV as an outpatient. In addition, any partners with whom the patient has had sexual contact within the last 90 days should also undergo STI testing; sexual partners from over 90 days should be notified of the patient’s status and evaluated with testing as indicated.⁴ All positive test results should be reported to the Centers for Disease Control and Prevention (CDC).⁵

Nontreponemal and Treponemal Testing

For patients with clinical signs and symptoms of syphilis, recommended laboratory evaluation includes both nontreponemal and treponemal testing. Nontreponemal tests include RPR, venereal disease research laboratory test, and toluidine red unheated serum test. Treponemal tests include fluorescent treponemal antibody absorption, microhemagglutination test for antibodies to T pallidum, T pallidum particle agglutination assay, T pallidum enzyme immunoassay, and chemiluminescence immunoassay. Patients who test positive for treponemal antibody will typically remain reactive for life.^5,6

In the setting of discordant test results, patients with a nonreactive treponemal result are generally considered to be negative for syphilis. Discordant results with a negative nontreponemal test are more complicated, and recommendations are based on symptomatology and repeat testing.⁵

Treatment

When a patient has a positive nontreponemal and treponemal test, treatment is usually indicated. As with the patient in this case, treatment is always indicated for patients who have no prior history of syphilis. For patients who have a history of treated syphilis, attention must be given to titer levels on previous testing and to patient symptomatology.

The treatment for early (primary and secondary) syphilis in patients with no penicillin allergy is a single dose of penicillin G benzathine intramuscularly, at a dose of 2.4 million U. Alternative regimens include doxycycline 100 mg orally twice daily for 14 days, and azithromycin 2 g orally as a single dose; however, there is an association of treatment failure with azithromycin due to macrolide resistance.⁵ The patient in this case received empiric treatment targeting syphilis, gonorrhea, and chlamydia.

Conclusion

Ten years ago, the rates of primary and secondary syphilis were low, leading the infectious disease community to believe that preventive efforts had been effective. According to the CDC, however, “[current] rates…are the highest they have been in more than 20 years.”⁵Figure 2 demonstrates the geographic distribution of syphilis cases in the United States in 2016.⁷

Heightened concern has prompted the CDC to promote the theme “Syphilis Strikes Back” in April 2017, which was STI Awareness Month.⁸ Identification of disease is critical in the ED, especially when a previously common disease has become uncommon, like the resurgence of syphilis we are now seeing.

The early initial ulcerative lesion (chancre) caused by Treponema pallidum infection, has a median incubation period of 21 days (primary syphilis). When untreated, secondary syphilis will develop within weeks to months and is characterized by generalized symptoms such as malaise, fevers, headaches, sore throat, and myalgia. However, the most characteristic finding in secondary syphilis remains a rash that is classically identified as symmetric, macular, or papular, and involving the entire trunk and extremities, including the palms and soles.

When secondary syphilis is left untreated, late syphilis or tertiary syphilis can develop, which is characterized by cardiovascular involvement, including aortitis, gummatous syphilis (granulomatous nodules in a variety of organs but typically the skin and bones), or central nervous system involvement.^1-3 The following case describes a patient with nondescript symptoms, including malaise and cough, who had a characteristic rash of secondary syphilis that was diagnosed and treated in our Houston-area community hospital.

Case

In late autumn, a 30-year-old man presented to our community ED for evaluation of a cough productive of green sputum along with mild chest discomfort, malaise, and generalized myalgia, which were intermittent over the course of the past month. The patient denied rhinorrhea, fevers, chills, dyspnea, or any other systemic complaints. He also denied any sick contacts, but noted that his influenza vaccine was not up to date. 

The patient denied any remote or recent medical or surgical history. He further denied taking any medications, and noted that his only medical allergy was to penicillin. His family history was noncontributory. Regarding his social history, the patient admitted to smoking one pack of cigarettes per day and to a daily alcohol intake of approximately one 6-pack of beer. He also admitted to frequently smoking crystal methamphetamine, which he stated he had last used 2 days prior to presentation. The patient said his current chest pain was similar to prior episodes, noting that when the pain occurred, he would temporarily stop smoking crystal methamphetamine. 

On further questioning, the patient admitted to having multiple female sexual partners with whom he used barrier protection sporadically. A more detailed physical examination revealed multiple painless ulcerations/chancres over the penile shaft and scrotum, without urethral drainage or inguinal lymphadenopathy. The patient denied dysuria or hematuria.

Since the patient was allergic to penicillin, he was given a single oral dose of azithromycin 2 g, and started on a 2-week course of oral doxycycline 100 mg. Further laboratory studies included gonorrhea and chlamydia cultures, both of which were negative. He was instructed to follow-up with his primary care physician for extended sexually transmitted infection (STI) panel-testing, including HIV, hepatitis, and confirmatory syphilis testing. Unfortunately, it is not known whether the patient complied with discharge instructions as he was lost to follow-up.

Discussion

Diagnostic algorithms for syphilis, one of the best studied STIs, have changed with technological advancement, but diagnosis and treatment for the most part has remained mostly the same. The uniqueness of this case is really focused around the patient’s chief complaint. While it is classic to present with malaise, headache, and rash, our patient complained of cough productive of sputum with chest pain—a rare presentation of secondary syphilis. The fortuitous key finding of the truncal rash directed the emergency physician toward the appropriate diagnosis.

Diagnosis

In the ED, where patients such as the one in our case are often lost to follow-up, and consistent infectious disease and primary care follow-up is unavailable, prompt treatment based on history and physical examination alone is recommended. Patients should be tested for syphilis, as well as other STIs including chlamydia, gonorrhea, hepatitis, and HIV as an outpatient. In addition, any partners with whom the patient has had sexual contact within the last 90 days should also undergo STI testing; sexual partners from over 90 days should be notified of the patient’s status and evaluated with testing as indicated.⁴ All positive test results should be reported to the Centers for Disease Control and Prevention (CDC).⁵

Nontreponemal and Treponemal Testing

For patients with clinical signs and symptoms of syphilis, recommended laboratory evaluation includes both nontreponemal and treponemal testing. Nontreponemal tests include RPR, venereal disease research laboratory test, and toluidine red unheated serum test. Treponemal tests include fluorescent treponemal antibody absorption, microhemagglutination test for antibodies to T pallidum, T pallidum particle agglutination assay, T pallidum enzyme immunoassay, and chemiluminescence immunoassay. Patients who test positive for treponemal antibody will typically remain reactive for life.^5,6

In the setting of discordant test results, patients with a nonreactive treponemal result are generally considered to be negative for syphilis. Discordant results with a negative nontreponemal test are more complicated, and recommendations are based on symptomatology and repeat testing.⁵

Treatment

When a patient has a positive nontreponemal and treponemal test, treatment is usually indicated. As with the patient in this case, treatment is always indicated for patients who have no prior history of syphilis. For patients who have a history of treated syphilis, attention must be given to titer levels on previous testing and to patient symptomatology.

The treatment for early (primary and secondary) syphilis in patients with no penicillin allergy is a single dose of penicillin G benzathine intramuscularly, at a dose of 2.4 million U. Alternative regimens include doxycycline 100 mg orally twice daily for 14 days, and azithromycin 2 g orally as a single dose; however, there is an association of treatment failure with azithromycin due to macrolide resistance.⁵ The patient in this case received empiric treatment targeting syphilis, gonorrhea, and chlamydia.

Conclusion

Ten years ago, the rates of primary and secondary syphilis were low, leading the infectious disease community to believe that preventive efforts had been effective. According to the CDC, however, “[current] rates…are the highest they have been in more than 20 years.”⁵Figure 2 demonstrates the geographic distribution of syphilis cases in the United States in 2016.⁷

Heightened concern has prompted the CDC to promote the theme “Syphilis Strikes Back” in April 2017, which was STI Awareness Month.⁸ Identification of disease is critical in the ED, especially when a previously common disease has become uncommon, like the resurgence of syphilis we are now seeing.

The early initial ulcerative lesion (chancre) caused by Treponema pallidum infection, has a median incubation period of 21 days (primary syphilis). When untreated, secondary syphilis will develop within weeks to months and is characterized by generalized symptoms such as malaise, fevers, headaches, sore throat, and myalgia. However, the most characteristic finding in secondary syphilis remains a rash that is classically identified as symmetric, macular, or papular, and involving the entire trunk and extremities, including the palms and soles.

When secondary syphilis is left untreated, late syphilis or tertiary syphilis can develop, which is characterized by cardiovascular involvement, including aortitis, gummatous syphilis (granulomatous nodules in a variety of organs but typically the skin and bones), or central nervous system involvement.^1-3 The following case describes a patient with nondescript symptoms, including malaise and cough, who had a characteristic rash of secondary syphilis that was diagnosed and treated in our Houston-area community hospital.

Case

In late autumn, a 30-year-old man presented to our community ED for evaluation of a cough productive of green sputum along with mild chest discomfort, malaise, and generalized myalgia, which were intermittent over the course of the past month. The patient denied rhinorrhea, fevers, chills, dyspnea, or any other systemic complaints. He also denied any sick contacts, but noted that his influenza vaccine was not up to date. 

The patient denied any remote or recent medical or surgical history. He further denied taking any medications, and noted that his only medical allergy was to penicillin. His family history was noncontributory. Regarding his social history, the patient admitted to smoking one pack of cigarettes per day and to a daily alcohol intake of approximately one 6-pack of beer. He also admitted to frequently smoking crystal methamphetamine, which he stated he had last used 2 days prior to presentation. The patient said his current chest pain was similar to prior episodes, noting that when the pain occurred, he would temporarily stop smoking crystal methamphetamine. 

On further questioning, the patient admitted to having multiple female sexual partners with whom he used barrier protection sporadically. A more detailed physical examination revealed multiple painless ulcerations/chancres over the penile shaft and scrotum, without urethral drainage or inguinal lymphadenopathy. The patient denied dysuria or hematuria.

Since the patient was allergic to penicillin, he was given a single oral dose of azithromycin 2 g, and started on a 2-week course of oral doxycycline 100 mg. Further laboratory studies included gonorrhea and chlamydia cultures, both of which were negative. He was instructed to follow-up with his primary care physician for extended sexually transmitted infection (STI) panel-testing, including HIV, hepatitis, and confirmatory syphilis testing. Unfortunately, it is not known whether the patient complied with discharge instructions as he was lost to follow-up.

Discussion

Diagnostic algorithms for syphilis, one of the best studied STIs, have changed with technological advancement, but diagnosis and treatment for the most part has remained mostly the same. The uniqueness of this case is really focused around the patient’s chief complaint. While it is classic to present with malaise, headache, and rash, our patient complained of cough productive of sputum with chest pain—a rare presentation of secondary syphilis. The fortuitous key finding of the truncal rash directed the emergency physician toward the appropriate diagnosis.

Diagnosis

In the ED, where patients such as the one in our case are often lost to follow-up, and consistent infectious disease and primary care follow-up is unavailable, prompt treatment based on history and physical examination alone is recommended. Patients should be tested for syphilis, as well as other STIs including chlamydia, gonorrhea, hepatitis, and HIV as an outpatient. In addition, any partners with whom the patient has had sexual contact within the last 90 days should also undergo STI testing; sexual partners from over 90 days should be notified of the patient’s status and evaluated with testing as indicated.⁴ All positive test results should be reported to the Centers for Disease Control and Prevention (CDC).⁵

Nontreponemal and Treponemal Testing

For patients with clinical signs and symptoms of syphilis, recommended laboratory evaluation includes both nontreponemal and treponemal testing. Nontreponemal tests include RPR, venereal disease research laboratory test, and toluidine red unheated serum test. Treponemal tests include fluorescent treponemal antibody absorption, microhemagglutination test for antibodies to T pallidum, T pallidum particle agglutination assay, T pallidum enzyme immunoassay, and chemiluminescence immunoassay. Patients who test positive for treponemal antibody will typically remain reactive for life.^5,6

In the setting of discordant test results, patients with a nonreactive treponemal result are generally considered to be negative for syphilis. Discordant results with a negative nontreponemal test are more complicated, and recommendations are based on symptomatology and repeat testing.⁵

Treatment

When a patient has a positive nontreponemal and treponemal test, treatment is usually indicated. As with the patient in this case, treatment is always indicated for patients who have no prior history of syphilis. For patients who have a history of treated syphilis, attention must be given to titer levels on previous testing and to patient symptomatology.

The treatment for early (primary and secondary) syphilis in patients with no penicillin allergy is a single dose of penicillin G benzathine intramuscularly, at a dose of 2.4 million U. Alternative regimens include doxycycline 100 mg orally twice daily for 14 days, and azithromycin 2 g orally as a single dose; however, there is an association of treatment failure with azithromycin due to macrolide resistance.⁵ The patient in this case received empiric treatment targeting syphilis, gonorrhea, and chlamydia.

Conclusion

Ten years ago, the rates of primary and secondary syphilis were low, leading the infectious disease community to believe that preventive efforts had been effective. According to the CDC, however, “[current] rates…are the highest they have been in more than 20 years.”⁵Figure 2 demonstrates the geographic distribution of syphilis cases in the United States in 2016.⁷

Heightened concern has prompted the CDC to promote the theme “Syphilis Strikes Back” in April 2017, which was STI Awareness Month.⁸ Identification of disease is critical in the ED, especially when a previously common disease has become uncommon, like the resurgence of syphilis we are now seeing.

Tension pneumoperitoneum (TPP), also known as hyperacute abdominal compartment syndrome or abdominal tamponade, is a rare condition most commonly associated with gastrointestinal (GI) perforation during endoscopy and iatrogenic insufflation of gas into the peritoneal cavity.¹ Other reported causes of TPP include gastric rupture after cardiopulmonary resuscitation, barotrauma during scuba diving, positive pressure ventilation through pleural-peritoneal channels, and spontaneous TPP of uncertain mechanism.^1-4

Case Presentation

A 76-year-old male with a history of ischemic cardiomyopathy, hypertension, and diabetes mellitus presented to the VA Puget Sound Health Care System in Seattle, Washington emergency department with painless jaundice, hematemesis, melena, and acute renal failure. On esophagogastroduodenoscopy (EGD), he was found to have an ulcer on the posterior wall of the duodenal bulb. The ulcer was coagulated and injected with epinephrine. The patient’s subsequent hospital course was complicated by worsening liver function, the need for renal replacement therapy, and recurrence of upper GI bleeding that required a transcatheter embolization of 2 separate superior pancreaticoduodenal arteries (SPDA) and the inferior pancreaticoduodenal artery (IPDA).

Once clinically stable, an endoscopic retrograde cholangiopancreatography (ERCP) was performed to evaluate for cholangiocarcinoma. A stricture was discovered in the common hepatic duct, brushings were taken, and a 15 cm, 7 Fr stent was placed in the common hepatic duct. The procedure was performed with an Olympus TJF Type Q180V duodenovideoscope (Tokyo, Japan) with an external diameter of 13.7 mm. The patient became hypotensive during the procedure and was treated with phenylephrine and ephedrine boluses. There was no endoscopic evidence of bleeding or bowel trauma.

After completion of the procedure, in the recovery area the patient became severely hypotensive and unresponsive. The physical examination was noteworthy for gross abdominal distention. Arterial blood gas analysis revealed severe metabolic and respiratory acidosis. Chest radiography demonstrated massive pneumoperitoneum, low lung volumes, and diaphragmatic compression (Figure).

Discussion

In relation to upper GI endoscopic procedures, TPP has been reported after diagnostic EGD, endoscopic sphincterotomy, and submucosal tumor dissection.^5-7 During these interventions, clinically apparent or overt iatrogenic perforations can occur either in the stomach or duodenum. These perforations may function as one-way valves that cause massive air accumulation and marked elevation of the diaphragm, which severely decreases lung volumes, pulmonary compliance, and limits gas exchange. Hemodynamically, compression of the inferior vena cava restricts venous return to the heart, resulting in decreased cardiac output.⁸

Patients with TPP present in acute distress with dyspnea, abdominal pain, and shock. On physical examination the abdomen is markedly distended, tympanic, and rigid. Rectal prolapse and subcutaneous emphysema also may be present.⁹ Roentographic features of TPP include findings of intraperitoneal air with elevation of the diaphragm, medial displacement of the liver (saddlebag sign), and juxtaposition of air in visceral interfaces, making intra-abdominal structures (spleen and gallbladder) appear more discrete.¹⁰ Abdominal computer tomography may show massive pneumoperitoneum with bowel loop compression and centralization of abdominal organs.⁴

Treatment strategies include emergent decompression either with percutaneous catheter insertion or abdominal drain placement followed by a definitive surgical repair. As with management of tension pneumothorax, treatment should not be delayed while awaiting confirmatory radiologic studies.⁹ When percutaneous needle decompression is undertaken, it is preferable to use a large bore (14-gauge venous catheter) and to advance a catheter over a needle to minimize the risk of visceral injury with egress of air and return of abdominal organs to their normal anatomical positions. The needle should be inserted directly above or below the umbilicus or in the left or right lower quadrants to avoid solid organ (ie, liver or spleen) injury.

Etiologic possibilities for the duodenal perforation in this case include mechanical trauma from the endoscope and duodenal tissue infarction after embolization of a bleeding duodenal ulcer. The duodenum and pancreatic head have a dual blood supply from the SPDA, a branch of the gastroduodenal artery, and the IPDA, a branch of the superior mesenteric artery.¹¹ After failed endoscopic management of persistent duodenal hemorrhage, the patient underwent synchronous embolization of 2 separate SPDAs and the IPDA. This might have put the first 2 segments of the duodenum at risk for ischemic damage and caused it to perforate at some point during the patient’s hospitalization (as evidenced by the bilious ascitis) or rendered them vulnerable to perforation from intraluminal insufflation during endoscopy.¹²

During the laparotomy, a pinhole-sized perforation was noted in the anterior wall of the second part of the duodenum, distinct form the duodenal ulcer present on the posterior wall. This perforation likely provided a pathway for the intraluminal gas to escape into the peritoneal cavity, culminating in abdominal tamponade, cardiopulmonary deterioration, and arrest. Needle decompression of the abdominal cavity provided an effective, though temporizing relief of this pressure, enabling return of spontaneous circulation.

This case highlights the need for a high index of suspicion for TPP in a patient with cardiopulmonary compromise and abdominal distension after upper GI endoscopic procedures even in the absence of identifiable perforations. Close coordination among gastroenterologists, anesthesiologists, and surgeons is key in prevention, recognition, and management of this rare but catastrophic complication.

Tension pneumoperitoneum (TPP), also known as hyperacute abdominal compartment syndrome or abdominal tamponade, is a rare condition most commonly associated with gastrointestinal (GI) perforation during endoscopy and iatrogenic insufflation of gas into the peritoneal cavity.¹ Other reported causes of TPP include gastric rupture after cardiopulmonary resuscitation, barotrauma during scuba diving, positive pressure ventilation through pleural-peritoneal channels, and spontaneous TPP of uncertain mechanism.^1-4

Case Presentation

A 76-year-old male with a history of ischemic cardiomyopathy, hypertension, and diabetes mellitus presented to the VA Puget Sound Health Care System in Seattle, Washington emergency department with painless jaundice, hematemesis, melena, and acute renal failure. On esophagogastroduodenoscopy (EGD), he was found to have an ulcer on the posterior wall of the duodenal bulb. The ulcer was coagulated and injected with epinephrine. The patient’s subsequent hospital course was complicated by worsening liver function, the need for renal replacement therapy, and recurrence of upper GI bleeding that required a transcatheter embolization of 2 separate superior pancreaticoduodenal arteries (SPDA) and the inferior pancreaticoduodenal artery (IPDA).

Once clinically stable, an endoscopic retrograde cholangiopancreatography (ERCP) was performed to evaluate for cholangiocarcinoma. A stricture was discovered in the common hepatic duct, brushings were taken, and a 15 cm, 7 Fr stent was placed in the common hepatic duct. The procedure was performed with an Olympus TJF Type Q180V duodenovideoscope (Tokyo, Japan) with an external diameter of 13.7 mm. The patient became hypotensive during the procedure and was treated with phenylephrine and ephedrine boluses. There was no endoscopic evidence of bleeding or bowel trauma.

After completion of the procedure, in the recovery area the patient became severely hypotensive and unresponsive. The physical examination was noteworthy for gross abdominal distention. Arterial blood gas analysis revealed severe metabolic and respiratory acidosis. Chest radiography demonstrated massive pneumoperitoneum, low lung volumes, and diaphragmatic compression (Figure).

Discussion

In relation to upper GI endoscopic procedures, TPP has been reported after diagnostic EGD, endoscopic sphincterotomy, and submucosal tumor dissection.^5-7 During these interventions, clinically apparent or overt iatrogenic perforations can occur either in the stomach or duodenum. These perforations may function as one-way valves that cause massive air accumulation and marked elevation of the diaphragm, which severely decreases lung volumes, pulmonary compliance, and limits gas exchange. Hemodynamically, compression of the inferior vena cava restricts venous return to the heart, resulting in decreased cardiac output.⁸

Patients with TPP present in acute distress with dyspnea, abdominal pain, and shock. On physical examination the abdomen is markedly distended, tympanic, and rigid. Rectal prolapse and subcutaneous emphysema also may be present.⁹ Roentographic features of TPP include findings of intraperitoneal air with elevation of the diaphragm, medial displacement of the liver (saddlebag sign), and juxtaposition of air in visceral interfaces, making intra-abdominal structures (spleen and gallbladder) appear more discrete.¹⁰ Abdominal computer tomography may show massive pneumoperitoneum with bowel loop compression and centralization of abdominal organs.⁴

Treatment strategies include emergent decompression either with percutaneous catheter insertion or abdominal drain placement followed by a definitive surgical repair. As with management of tension pneumothorax, treatment should not be delayed while awaiting confirmatory radiologic studies.⁹ When percutaneous needle decompression is undertaken, it is preferable to use a large bore (14-gauge venous catheter) and to advance a catheter over a needle to minimize the risk of visceral injury with egress of air and return of abdominal organs to their normal anatomical positions. The needle should be inserted directly above or below the umbilicus or in the left or right lower quadrants to avoid solid organ (ie, liver or spleen) injury.

Etiologic possibilities for the duodenal perforation in this case include mechanical trauma from the endoscope and duodenal tissue infarction after embolization of a bleeding duodenal ulcer. The duodenum and pancreatic head have a dual blood supply from the SPDA, a branch of the gastroduodenal artery, and the IPDA, a branch of the superior mesenteric artery.¹¹ After failed endoscopic management of persistent duodenal hemorrhage, the patient underwent synchronous embolization of 2 separate SPDAs and the IPDA. This might have put the first 2 segments of the duodenum at risk for ischemic damage and caused it to perforate at some point during the patient’s hospitalization (as evidenced by the bilious ascitis) or rendered them vulnerable to perforation from intraluminal insufflation during endoscopy.¹²

During the laparotomy, a pinhole-sized perforation was noted in the anterior wall of the second part of the duodenum, distinct form the duodenal ulcer present on the posterior wall. This perforation likely provided a pathway for the intraluminal gas to escape into the peritoneal cavity, culminating in abdominal tamponade, cardiopulmonary deterioration, and arrest. Needle decompression of the abdominal cavity provided an effective, though temporizing relief of this pressure, enabling return of spontaneous circulation.

This case highlights the need for a high index of suspicion for TPP in a patient with cardiopulmonary compromise and abdominal distension after upper GI endoscopic procedures even in the absence of identifiable perforations. Close coordination among gastroenterologists, anesthesiologists, and surgeons is key in prevention, recognition, and management of this rare but catastrophic complication.

Tension pneumoperitoneum (TPP), also known as hyperacute abdominal compartment syndrome or abdominal tamponade, is a rare condition most commonly associated with gastrointestinal (GI) perforation during endoscopy and iatrogenic insufflation of gas into the peritoneal cavity.¹ Other reported causes of TPP include gastric rupture after cardiopulmonary resuscitation, barotrauma during scuba diving, positive pressure ventilation through pleural-peritoneal channels, and spontaneous TPP of uncertain mechanism.^1-4

Case Presentation

A 76-year-old male with a history of ischemic cardiomyopathy, hypertension, and diabetes mellitus presented to the VA Puget Sound Health Care System in Seattle, Washington emergency department with painless jaundice, hematemesis, melena, and acute renal failure. On esophagogastroduodenoscopy (EGD), he was found to have an ulcer on the posterior wall of the duodenal bulb. The ulcer was coagulated and injected with epinephrine. The patient’s subsequent hospital course was complicated by worsening liver function, the need for renal replacement therapy, and recurrence of upper GI bleeding that required a transcatheter embolization of 2 separate superior pancreaticoduodenal arteries (SPDA) and the inferior pancreaticoduodenal artery (IPDA).

Once clinically stable, an endoscopic retrograde cholangiopancreatography (ERCP) was performed to evaluate for cholangiocarcinoma. A stricture was discovered in the common hepatic duct, brushings were taken, and a 15 cm, 7 Fr stent was placed in the common hepatic duct. The procedure was performed with an Olympus TJF Type Q180V duodenovideoscope (Tokyo, Japan) with an external diameter of 13.7 mm. The patient became hypotensive during the procedure and was treated with phenylephrine and ephedrine boluses. There was no endoscopic evidence of bleeding or bowel trauma.

After completion of the procedure, in the recovery area the patient became severely hypotensive and unresponsive. The physical examination was noteworthy for gross abdominal distention. Arterial blood gas analysis revealed severe metabolic and respiratory acidosis. Chest radiography demonstrated massive pneumoperitoneum, low lung volumes, and diaphragmatic compression (Figure).

Discussion

In relation to upper GI endoscopic procedures, TPP has been reported after diagnostic EGD, endoscopic sphincterotomy, and submucosal tumor dissection.^5-7 During these interventions, clinically apparent or overt iatrogenic perforations can occur either in the stomach or duodenum. These perforations may function as one-way valves that cause massive air accumulation and marked elevation of the diaphragm, which severely decreases lung volumes, pulmonary compliance, and limits gas exchange. Hemodynamically, compression of the inferior vena cava restricts venous return to the heart, resulting in decreased cardiac output.⁸

Patients with TPP present in acute distress with dyspnea, abdominal pain, and shock. On physical examination the abdomen is markedly distended, tympanic, and rigid. Rectal prolapse and subcutaneous emphysema also may be present.⁹ Roentographic features of TPP include findings of intraperitoneal air with elevation of the diaphragm, medial displacement of the liver (saddlebag sign), and juxtaposition of air in visceral interfaces, making intra-abdominal structures (spleen and gallbladder) appear more discrete.¹⁰ Abdominal computer tomography may show massive pneumoperitoneum with bowel loop compression and centralization of abdominal organs.⁴

Treatment strategies include emergent decompression either with percutaneous catheter insertion or abdominal drain placement followed by a definitive surgical repair. As with management of tension pneumothorax, treatment should not be delayed while awaiting confirmatory radiologic studies.⁹ When percutaneous needle decompression is undertaken, it is preferable to use a large bore (14-gauge venous catheter) and to advance a catheter over a needle to minimize the risk of visceral injury with egress of air and return of abdominal organs to their normal anatomical positions. The needle should be inserted directly above or below the umbilicus or in the left or right lower quadrants to avoid solid organ (ie, liver or spleen) injury.

Etiologic possibilities for the duodenal perforation in this case include mechanical trauma from the endoscope and duodenal tissue infarction after embolization of a bleeding duodenal ulcer. The duodenum and pancreatic head have a dual blood supply from the SPDA, a branch of the gastroduodenal artery, and the IPDA, a branch of the superior mesenteric artery.¹¹ After failed endoscopic management of persistent duodenal hemorrhage, the patient underwent synchronous embolization of 2 separate SPDAs and the IPDA. This might have put the first 2 segments of the duodenum at risk for ischemic damage and caused it to perforate at some point during the patient’s hospitalization (as evidenced by the bilious ascitis) or rendered them vulnerable to perforation from intraluminal insufflation during endoscopy.¹²

During the laparotomy, a pinhole-sized perforation was noted in the anterior wall of the second part of the duodenum, distinct form the duodenal ulcer present on the posterior wall. This perforation likely provided a pathway for the intraluminal gas to escape into the peritoneal cavity, culminating in abdominal tamponade, cardiopulmonary deterioration, and arrest. Needle decompression of the abdominal cavity provided an effective, though temporizing relief of this pressure, enabling return of spontaneous circulation.

This case highlights the need for a high index of suspicion for TPP in a patient with cardiopulmonary compromise and abdominal distension after upper GI endoscopic procedures even in the absence of identifiable perforations. Close coordination among gastroenterologists, anesthesiologists, and surgeons is key in prevention, recognition, and management of this rare but catastrophic complication.

Case Report

A 65-year-old man presented with multiple anesthetic, annular, erythematous, scaly plaques with a raised border of 6 weeks’ duration that were unresponsive to topical steroid therapy. Four plaques were noted on the lower back ranging from 2 to 4 cm in diameter as well as a fifth plaque on the anterior portion of the right ankle that was approximately 6×6 cm. He denied fever, malaise, muscle weakness, changes in vision, or sensory deficits outside of the lesions themselves. The patient also denied any recent travel to endemic areas or exposure to armadillos.

Biopsies were taken from lesions on the lumbar back and anterior aspect of the right ankle (Figure 1A). Hematoxylin and eosin staining revealed a granulomatous infiltrate spreading along neurovascular structures (Figure 2). Granulomas also were identified in the dermal interstitium exhibiting partial necrosis (Figure 2 inset). Conspicuous distension of lymphovascular and perineural areas also was noted. Immunohistochemical studies with S-100 and neurofilament stains allowed insight into the pathomechanism of the clinically observed anesthesia, as nerve fibers were identified showing different stages of damage elicited by the granulomatous inflammatory infiltrate (Figure 3). Fite staining was positive for occasional bacilli within histiocytes (Figure 3A inset). Despite the clinical, histologic, and immunohistochemical evidence, the patient had no known exposure to leprosy; consequently, a polymerase chain reaction (PCR) assay was ordered for confirmation of the diagnosis. Surprisingly, the PCR was positive for Mycobacterium leprae DNA. These findings were consistent with borderline tuberculoid leprosy.

The case was reported to the National Hansen’s Disease Program (Baton Rouge, Louisiana). The patient was started on rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months. The lesions exhibited marked improvement after completion of therapy (Figure 1B).

Comment

Disease Transmission
Hansen disease, also known as leprosy, is a chronic granulomatous infectious disease that is caused by M leprae, an obligate intracellular bacillus aerobe.¹ The mechanism of spread of M leprae is not clear. It is thought to be transmitted via respiratory droplets, though it may occur through injured skin.² Studies have suggested that in addition to humans, nine-banded armadillos are a source of infection.^2,3 Exposure to infected individuals, particularly multibacillary patients, increases the likelihood of contracting leprosy.²

According to the Centers for Disease Control and Prevention, 81 cases of Hansen disease were diagnosed in the United States in 2013,⁴ compared to 178 cases registered in 2015.⁵ Cases from Hawaii, Texas, California, Louisiana, New York, and Florida made up 72% (129/178) of the reported cases. There was an increase from 34 cases to 49 cases in Florida from 2014 to 2015.⁵ The spread of leprosy throughout Florida may be from the merge of 2 armadillo populations, an M leprae–infected population migrating east from Texas and one from south central Florida that historically had not been infected with M leprae until recently.^3,6 Our patient did not have any known exposures to armadillos.

Classification and Presentation
The clinical presentation of Hansen disease is widely variable, as it can present at any point along a spectrum ranging from tuberculoid leprosy to lepromatous leprosy with borderline conditions in between, according to the Ridley-Jopling critera.⁷ The World Health Organization also classifies leprosy based on the number of acid-fast bacilli seen in a skin smear as either paucibacillary or multibacillary.² The paucibacillary classification correlates with tuberculoid, borderline tuberculoid, and indeterminate leprosy, and multibacillary correlates with borderline lepromatous and lepromatous leprosy. Paucibacillary leprosy usually presents with a less dramatic clinical picture than multibacillary leprosy. The clinical presentation is dependent on the magnitude of immune response to M leprae.²

Paucibacillary infection occurs when the body generates a strong cell-mediated immune response against the bacteria,⁸ which causes the activation and proliferation of CD4 and CD8 T cells, limiting the spread of the mycobacterium. Subsequently, the patient typically presents with a mild clinical picture with few skin lesions and limited nerve involvement.⁸ The skin lesions are papules or plaques with raised borders that are usually hypopigmented on dark skin and erythematous on light skin. Nerve involvement in paucibacillary forms of leprosy include sensory impairment and anhidrosis within the lesions. Nerve enlargement usually affects superficial nerves, with the posterior tibial nerve being most commonly affected.

Multibacillary leprosy presents with systemic involvement due to a weak cell-mediated immune response. Patients generally present with diffuse, poorly defined nodules; greater nerve impairment; and other systemic symptoms such as blindness, swelling of the fingers and toes, and testicular atrophy (in men). Additionally, enlargement of the earlobes and widening of the nasal bridge may contribute to the appearance of leonine facies. Nerve impairment in multibacillary forms of leprosy may be more severe, including more diffuse sensory involvement (eg, stocking glove–pattern neuropathy, nerve-trunk palsies), which ultimately may lead to foot drop, claw toe, and lagophthalmos.⁸

In addition to the clinical presentation, the histology of the paucibacillary and multibacillary types differ. Multibacillary leprosy shows diffuse histiocytes without granulomas and multiple bacilli seen on Fite staining.⁸ In the paucibacillary form, there are well-formed granulomas with Langerhans giant cells and a perineural lymphocytic infiltrate seen on hematoxylin and eosin staining with rare acid-fast bacilli seen on Fite staining.

To diagnose leprosy, at least one of the following 3 clinical signs must be present: (1) a hypopigmented or erythematous lesion with loss of sensation, (2) thickened peripheral nerve, or (3) acid-fast bacilli on slit-skin smear.²

Management
The World Health Organization guidelines involve multidrug therapy over an extended period of time.² For adults, the paucibacillary regimen includes rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months. The adult regimen for multibacillary leprosy includes clofazimine 300 mg once monthly and 50 mg once daily, in addition to rifampicin 600 mg once monthly and dapsone 100 mg once daily for 12 months. If classification cannot be determined, it is recommended the patient be treated for multibacillary disease.²

Reversal Reactions
During the course of the disease, patients may upgrade (to a less severe form) or downgrade (to a more severe form) between the tuberculoid, borderline, and lepromatous forms.⁸ The patient’s clinical picture also may change with complications of leprosy, which include type 1 and type 2 reactions. Type 1 reaction is a reversal reaction seen in 15% to 30% of patients at risk, usually those with borderline forms of leprosy.⁹ Reversal reactions usually manifest as erythema and edema of current skin lesions, formation of new tumid lesions, and tenderness of peripheral nerves with loss of nerve function.⁸ Treatment of reversal reactions involves systemic corticosteroids.¹⁰ Type 2 reaction is classified as erythema nodosum leprosum. It presents within the first 2 years of treatment in approximately 20% of lepromatous patients and approximately 10% of borderline lepromatous patients but is rare in paucibacillary infections.¹¹ It presents with fever and crops of pink nodules and may include iritis, neuritis, lymphadenitis, orchitis, dactylitis, arthritis, and proteinuria.⁸ Treatment options for erythema nodosum leprosum include corticosteroids, clofazimine, and thalidomide.^12,13

Conclusion

Hansen disease is a rare condition in the United States. This case is unique because, to our knowledge, it is the first known PCR-confirmed case of Hansen disease in Okeechobee County, Florida. Additionally, the patient had no known exposure to M leprae. Exposure is increasing due to the increased geographical range of infected armadillos. Infection rates also may rise due to travel to endemic countries. Initially lesions may appear as innocuous erythematous plaques. When they do not respond to standard therapy, infectious agents such as M leprae should be part of the differential diagnosis. Because hematoxylin and eosin staining does not always yield results, if clinical suspicion is present, PCR should be performed. If a patient meets the clinical and histological diagnosis, the case should be reported to the National Hansen’s Disease Program.

After completion of treatment, our patient has shown excellent results. He has not yet demonstrated a reversal reaction; however, he may still be at risk, as it most commonly presents 2 months after starting treatment but can present years after treatment has been initiated.⁸ Cutaneous leprosy must be considered in the differential diagnosis for steroid-nonresponsive skin lesions, particularly in states such as Florida with a documented increase in incidence.

Acknowledgment
We thank Sharon Barrineau, ARNP (Okeechobee, Florida), for her acumen, contributions, and support on this case.

Case Report

A 65-year-old man presented with multiple anesthetic, annular, erythematous, scaly plaques with a raised border of 6 weeks’ duration that were unresponsive to topical steroid therapy. Four plaques were noted on the lower back ranging from 2 to 4 cm in diameter as well as a fifth plaque on the anterior portion of the right ankle that was approximately 6×6 cm. He denied fever, malaise, muscle weakness, changes in vision, or sensory deficits outside of the lesions themselves. The patient also denied any recent travel to endemic areas or exposure to armadillos.

Biopsies were taken from lesions on the lumbar back and anterior aspect of the right ankle (Figure 1A). Hematoxylin and eosin staining revealed a granulomatous infiltrate spreading along neurovascular structures (Figure 2). Granulomas also were identified in the dermal interstitium exhibiting partial necrosis (Figure 2 inset). Conspicuous distension of lymphovascular and perineural areas also was noted. Immunohistochemical studies with S-100 and neurofilament stains allowed insight into the pathomechanism of the clinically observed anesthesia, as nerve fibers were identified showing different stages of damage elicited by the granulomatous inflammatory infiltrate (Figure 3). Fite staining was positive for occasional bacilli within histiocytes (Figure 3A inset). Despite the clinical, histologic, and immunohistochemical evidence, the patient had no known exposure to leprosy; consequently, a polymerase chain reaction (PCR) assay was ordered for confirmation of the diagnosis. Surprisingly, the PCR was positive for Mycobacterium leprae DNA. These findings were consistent with borderline tuberculoid leprosy.

The case was reported to the National Hansen’s Disease Program (Baton Rouge, Louisiana). The patient was started on rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months. The lesions exhibited marked improvement after completion of therapy (Figure 1B).

Comment

Disease Transmission
Hansen disease, also known as leprosy, is a chronic granulomatous infectious disease that is caused by M leprae, an obligate intracellular bacillus aerobe.¹ The mechanism of spread of M leprae is not clear. It is thought to be transmitted via respiratory droplets, though it may occur through injured skin.² Studies have suggested that in addition to humans, nine-banded armadillos are a source of infection.^2,3 Exposure to infected individuals, particularly multibacillary patients, increases the likelihood of contracting leprosy.²

According to the Centers for Disease Control and Prevention, 81 cases of Hansen disease were diagnosed in the United States in 2013,⁴ compared to 178 cases registered in 2015.⁵ Cases from Hawaii, Texas, California, Louisiana, New York, and Florida made up 72% (129/178) of the reported cases. There was an increase from 34 cases to 49 cases in Florida from 2014 to 2015.⁵ The spread of leprosy throughout Florida may be from the merge of 2 armadillo populations, an M leprae–infected population migrating east from Texas and one from south central Florida that historically had not been infected with M leprae until recently.^3,6 Our patient did not have any known exposures to armadillos.

Classification and Presentation
The clinical presentation of Hansen disease is widely variable, as it can present at any point along a spectrum ranging from tuberculoid leprosy to lepromatous leprosy with borderline conditions in between, according to the Ridley-Jopling critera.⁷ The World Health Organization also classifies leprosy based on the number of acid-fast bacilli seen in a skin smear as either paucibacillary or multibacillary.² The paucibacillary classification correlates with tuberculoid, borderline tuberculoid, and indeterminate leprosy, and multibacillary correlates with borderline lepromatous and lepromatous leprosy. Paucibacillary leprosy usually presents with a less dramatic clinical picture than multibacillary leprosy. The clinical presentation is dependent on the magnitude of immune response to M leprae.²

Paucibacillary infection occurs when the body generates a strong cell-mediated immune response against the bacteria,⁸ which causes the activation and proliferation of CD4 and CD8 T cells, limiting the spread of the mycobacterium. Subsequently, the patient typically presents with a mild clinical picture with few skin lesions and limited nerve involvement.⁸ The skin lesions are papules or plaques with raised borders that are usually hypopigmented on dark skin and erythematous on light skin. Nerve involvement in paucibacillary forms of leprosy include sensory impairment and anhidrosis within the lesions. Nerve enlargement usually affects superficial nerves, with the posterior tibial nerve being most commonly affected.

Multibacillary leprosy presents with systemic involvement due to a weak cell-mediated immune response. Patients generally present with diffuse, poorly defined nodules; greater nerve impairment; and other systemic symptoms such as blindness, swelling of the fingers and toes, and testicular atrophy (in men). Additionally, enlargement of the earlobes and widening of the nasal bridge may contribute to the appearance of leonine facies. Nerve impairment in multibacillary forms of leprosy may be more severe, including more diffuse sensory involvement (eg, stocking glove–pattern neuropathy, nerve-trunk palsies), which ultimately may lead to foot drop, claw toe, and lagophthalmos.⁸

In addition to the clinical presentation, the histology of the paucibacillary and multibacillary types differ. Multibacillary leprosy shows diffuse histiocytes without granulomas and multiple bacilli seen on Fite staining.⁸ In the paucibacillary form, there are well-formed granulomas with Langerhans giant cells and a perineural lymphocytic infiltrate seen on hematoxylin and eosin staining with rare acid-fast bacilli seen on Fite staining.

To diagnose leprosy, at least one of the following 3 clinical signs must be present: (1) a hypopigmented or erythematous lesion with loss of sensation, (2) thickened peripheral nerve, or (3) acid-fast bacilli on slit-skin smear.²

Management
The World Health Organization guidelines involve multidrug therapy over an extended period of time.² For adults, the paucibacillary regimen includes rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months. The adult regimen for multibacillary leprosy includes clofazimine 300 mg once monthly and 50 mg once daily, in addition to rifampicin 600 mg once monthly and dapsone 100 mg once daily for 12 months. If classification cannot be determined, it is recommended the patient be treated for multibacillary disease.²

Reversal Reactions
During the course of the disease, patients may upgrade (to a less severe form) or downgrade (to a more severe form) between the tuberculoid, borderline, and lepromatous forms.⁸ The patient’s clinical picture also may change with complications of leprosy, which include type 1 and type 2 reactions. Type 1 reaction is a reversal reaction seen in 15% to 30% of patients at risk, usually those with borderline forms of leprosy.⁹ Reversal reactions usually manifest as erythema and edema of current skin lesions, formation of new tumid lesions, and tenderness of peripheral nerves with loss of nerve function.⁸ Treatment of reversal reactions involves systemic corticosteroids.¹⁰ Type 2 reaction is classified as erythema nodosum leprosum. It presents within the first 2 years of treatment in approximately 20% of lepromatous patients and approximately 10% of borderline lepromatous patients but is rare in paucibacillary infections.¹¹ It presents with fever and crops of pink nodules and may include iritis, neuritis, lymphadenitis, orchitis, dactylitis, arthritis, and proteinuria.⁸ Treatment options for erythema nodosum leprosum include corticosteroids, clofazimine, and thalidomide.^12,13

Conclusion

Hansen disease is a rare condition in the United States. This case is unique because, to our knowledge, it is the first known PCR-confirmed case of Hansen disease in Okeechobee County, Florida. Additionally, the patient had no known exposure to M leprae. Exposure is increasing due to the increased geographical range of infected armadillos. Infection rates also may rise due to travel to endemic countries. Initially lesions may appear as innocuous erythematous plaques. When they do not respond to standard therapy, infectious agents such as M leprae should be part of the differential diagnosis. Because hematoxylin and eosin staining does not always yield results, if clinical suspicion is present, PCR should be performed. If a patient meets the clinical and histological diagnosis, the case should be reported to the National Hansen’s Disease Program.

After completion of treatment, our patient has shown excellent results. He has not yet demonstrated a reversal reaction; however, he may still be at risk, as it most commonly presents 2 months after starting treatment but can present years after treatment has been initiated.⁸ Cutaneous leprosy must be considered in the differential diagnosis for steroid-nonresponsive skin lesions, particularly in states such as Florida with a documented increase in incidence.

Acknowledgment
We thank Sharon Barrineau, ARNP (Okeechobee, Florida), for her acumen, contributions, and support on this case.

Case Report

A 65-year-old man presented with multiple anesthetic, annular, erythematous, scaly plaques with a raised border of 6 weeks’ duration that were unresponsive to topical steroid therapy. Four plaques were noted on the lower back ranging from 2 to 4 cm in diameter as well as a fifth plaque on the anterior portion of the right ankle that was approximately 6×6 cm. He denied fever, malaise, muscle weakness, changes in vision, or sensory deficits outside of the lesions themselves. The patient also denied any recent travel to endemic areas or exposure to armadillos.

Biopsies were taken from lesions on the lumbar back and anterior aspect of the right ankle (Figure 1A). Hematoxylin and eosin staining revealed a granulomatous infiltrate spreading along neurovascular structures (Figure 2). Granulomas also were identified in the dermal interstitium exhibiting partial necrosis (Figure 2 inset). Conspicuous distension of lymphovascular and perineural areas also was noted. Immunohistochemical studies with S-100 and neurofilament stains allowed insight into the pathomechanism of the clinically observed anesthesia, as nerve fibers were identified showing different stages of damage elicited by the granulomatous inflammatory infiltrate (Figure 3). Fite staining was positive for occasional bacilli within histiocytes (Figure 3A inset). Despite the clinical, histologic, and immunohistochemical evidence, the patient had no known exposure to leprosy; consequently, a polymerase chain reaction (PCR) assay was ordered for confirmation of the diagnosis. Surprisingly, the PCR was positive for Mycobacterium leprae DNA. These findings were consistent with borderline tuberculoid leprosy.

The case was reported to the National Hansen’s Disease Program (Baton Rouge, Louisiana). The patient was started on rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months. The lesions exhibited marked improvement after completion of therapy (Figure 1B).

Comment

Disease Transmission
Hansen disease, also known as leprosy, is a chronic granulomatous infectious disease that is caused by M leprae, an obligate intracellular bacillus aerobe.¹ The mechanism of spread of M leprae is not clear. It is thought to be transmitted via respiratory droplets, though it may occur through injured skin.² Studies have suggested that in addition to humans, nine-banded armadillos are a source of infection.^2,3 Exposure to infected individuals, particularly multibacillary patients, increases the likelihood of contracting leprosy.²

According to the Centers for Disease Control and Prevention, 81 cases of Hansen disease were diagnosed in the United States in 2013,⁴ compared to 178 cases registered in 2015.⁵ Cases from Hawaii, Texas, California, Louisiana, New York, and Florida made up 72% (129/178) of the reported cases. There was an increase from 34 cases to 49 cases in Florida from 2014 to 2015.⁵ The spread of leprosy throughout Florida may be from the merge of 2 armadillo populations, an M leprae–infected population migrating east from Texas and one from south central Florida that historically had not been infected with M leprae until recently.^3,6 Our patient did not have any known exposures to armadillos.

Classification and Presentation
The clinical presentation of Hansen disease is widely variable, as it can present at any point along a spectrum ranging from tuberculoid leprosy to lepromatous leprosy with borderline conditions in between, according to the Ridley-Jopling critera.⁷ The World Health Organization also classifies leprosy based on the number of acid-fast bacilli seen in a skin smear as either paucibacillary or multibacillary.² The paucibacillary classification correlates with tuberculoid, borderline tuberculoid, and indeterminate leprosy, and multibacillary correlates with borderline lepromatous and lepromatous leprosy. Paucibacillary leprosy usually presents with a less dramatic clinical picture than multibacillary leprosy. The clinical presentation is dependent on the magnitude of immune response to M leprae.²

Paucibacillary infection occurs when the body generates a strong cell-mediated immune response against the bacteria,⁸ which causes the activation and proliferation of CD4 and CD8 T cells, limiting the spread of the mycobacterium. Subsequently, the patient typically presents with a mild clinical picture with few skin lesions and limited nerve involvement.⁸ The skin lesions are papules or plaques with raised borders that are usually hypopigmented on dark skin and erythematous on light skin. Nerve involvement in paucibacillary forms of leprosy include sensory impairment and anhidrosis within the lesions. Nerve enlargement usually affects superficial nerves, with the posterior tibial nerve being most commonly affected.

Multibacillary leprosy presents with systemic involvement due to a weak cell-mediated immune response. Patients generally present with diffuse, poorly defined nodules; greater nerve impairment; and other systemic symptoms such as blindness, swelling of the fingers and toes, and testicular atrophy (in men). Additionally, enlargement of the earlobes and widening of the nasal bridge may contribute to the appearance of leonine facies. Nerve impairment in multibacillary forms of leprosy may be more severe, including more diffuse sensory involvement (eg, stocking glove–pattern neuropathy, nerve-trunk palsies), which ultimately may lead to foot drop, claw toe, and lagophthalmos.⁸

In addition to the clinical presentation, the histology of the paucibacillary and multibacillary types differ. Multibacillary leprosy shows diffuse histiocytes without granulomas and multiple bacilli seen on Fite staining.⁸ In the paucibacillary form, there are well-formed granulomas with Langerhans giant cells and a perineural lymphocytic infiltrate seen on hematoxylin and eosin staining with rare acid-fast bacilli seen on Fite staining.

To diagnose leprosy, at least one of the following 3 clinical signs must be present: (1) a hypopigmented or erythematous lesion with loss of sensation, (2) thickened peripheral nerve, or (3) acid-fast bacilli on slit-skin smear.²

Management
The World Health Organization guidelines involve multidrug therapy over an extended period of time.² For adults, the paucibacillary regimen includes rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months. The adult regimen for multibacillary leprosy includes clofazimine 300 mg once monthly and 50 mg once daily, in addition to rifampicin 600 mg once monthly and dapsone 100 mg once daily for 12 months. If classification cannot be determined, it is recommended the patient be treated for multibacillary disease.²

Reversal Reactions
During the course of the disease, patients may upgrade (to a less severe form) or downgrade (to a more severe form) between the tuberculoid, borderline, and lepromatous forms.⁸ The patient’s clinical picture also may change with complications of leprosy, which include type 1 and type 2 reactions. Type 1 reaction is a reversal reaction seen in 15% to 30% of patients at risk, usually those with borderline forms of leprosy.⁹ Reversal reactions usually manifest as erythema and edema of current skin lesions, formation of new tumid lesions, and tenderness of peripheral nerves with loss of nerve function.⁸ Treatment of reversal reactions involves systemic corticosteroids.¹⁰ Type 2 reaction is classified as erythema nodosum leprosum. It presents within the first 2 years of treatment in approximately 20% of lepromatous patients and approximately 10% of borderline lepromatous patients but is rare in paucibacillary infections.¹¹ It presents with fever and crops of pink nodules and may include iritis, neuritis, lymphadenitis, orchitis, dactylitis, arthritis, and proteinuria.⁸ Treatment options for erythema nodosum leprosum include corticosteroids, clofazimine, and thalidomide.^12,13

Conclusion

Hansen disease is a rare condition in the United States. This case is unique because, to our knowledge, it is the first known PCR-confirmed case of Hansen disease in Okeechobee County, Florida. Additionally, the patient had no known exposure to M leprae. Exposure is increasing due to the increased geographical range of infected armadillos. Infection rates also may rise due to travel to endemic countries. Initially lesions may appear as innocuous erythematous plaques. When they do not respond to standard therapy, infectious agents such as M leprae should be part of the differential diagnosis. Because hematoxylin and eosin staining does not always yield results, if clinical suspicion is present, PCR should be performed. If a patient meets the clinical and histological diagnosis, the case should be reported to the National Hansen’s Disease Program.

After completion of treatment, our patient has shown excellent results. He has not yet demonstrated a reversal reaction; however, he may still be at risk, as it most commonly presents 2 months after starting treatment but can present years after treatment has been initiated.⁸ Cutaneous leprosy must be considered in the differential diagnosis for steroid-nonresponsive skin lesions, particularly in states such as Florida with a documented increase in incidence.

Acknowledgment
We thank Sharon Barrineau, ARNP (Okeechobee, Florida), for her acumen, contributions, and support on this case.

Well-known for its typical presentation, classic herpes zoster (HZ) presents as a dermatomal eruption of painful erythematous papules that evolve into grouped vesicles or bullae.^1,2 Thereafter, the lesions can become pustular or hemorrhagic.¹ Although the diagnosis most often is made clinically, confirmatory techniques for diagnosis include viral culture, direct fluorescent antibody testing, or polymerase chain reaction (PCR) assay.^1,3

The main risk factor for HZ is advanced age, most commonly affecting elderly patients.⁴ It is hypothesized that a physiological decline in varicella-zoster virus (VZV)–specific cell-mediated immunity among elderly individuals helps trigger reactivation of the virus within the dorsal root ganglion.^1,5 Similarly affected are immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection, due to suppression of T cells immune to VZV,^1,5 as well as immunosuppressed transplant recipients who have diminished VZV-specific cellular responses and VZV IgG antibody avidity.⁶

Secondary complications of VZV infection (eg, postherpetic neuralgia, bacterial superinfection progressing to cellulitis) lead to increased morbidity.^7,8 Disseminated cutaneous HZ is another grave complication of VZV infection and almost exclusively occurs with immunosuppression.^1,8 It manifests as an eruption of at least 20 widespread vesiculobullous lesions outside the primary and adjacent dermatomes.⁶ Immunocompromised patients also are at increased risk for visceral involvement of VZV infection, which may affect vital organs such as the brain, liver, or lungs.^7,8 Given the atypical presentation of VZV infection among some immunocompromised individuals, these patients are at increased risk for diagnostic delay and morbidity in the absence of high clinical suspicion for disseminated HZ.

Case Reports

Patient 1
A 52-year-old man developed a painless nonpruritic rash on the left leg of 4 days’ duration. It initially appeared as an erythematous maculopapular rash on the medial aspect of the left knee without any prodromal symptoms. Over the next 4 days, erythematous vesicles developed that progressed to pustules, and the rash spread both proximally and distally along the left leg. Shortly following hospital admission, he developed a fever (temperature, 38.4°C). His medical history included alcoholic liver cirrhosis and AIDS, with a CD4 count of 174 cells/µL (reference range, 500–1500 cells/µL). He had been taking antiretroviral therapy (abacavir-lamivudine and dolutegravir) and prophylaxis against opportunistic infections (dapsone and itraconazole).

Physical examination was remarkable for an extensive rash consisting of multiple 1-cm clusters of approximately 40 pustules each scattered in a nondermatomal distribution along the left leg (Figure 1). Many of the vesicles were confluent with an erythematous base and were in different stages of evolution with some crusted and others emanating a thin liquid exudate. The lesions were nontender and without notable induration. The leg was warm and edematous.

Clinically, the differential diagnosis included disseminated HZ with bacterial superinfection, Vibrio vulnificus infection, and herpes simplex virus (HSV) infection. The patient was treated with intravenous vancomycin, levofloxacin, and acyclovir, and no new lesions developed throughout the course of treatment. On this regimen, his fever resolved after 1 day, the active lesions began to crust, and the edema and erythema diminished. Results of bacterial cultures and plasma PCR and IgM for HSV types 1 and 2 were negative. Viral culture results were negative, but a PCR assay for VZV was positive, reflective of acute reactivation of VZV.

Patient 2
A 63-year-old man developed a pruritic burning rash involving the face, trunk, arms, and legs of 6 days’ duration. His medical history included a heart transplant 6 months prior to presentation, type 2 diabetes mellitus, and chronic kidney disease. He was taking antirejection therapy with mycophenolate mofetil (MMF), prednisone, and tacrolimus.

Physical examination was remarkable for an extensive rash consisting of clusters of 1- to 2-mm vesicles scattered in a nondermatomal pattern. Isolated vesicles involved the forehead, nose, and left ear, and diffuse vesicles with a relatively symmetric distribution were scattered across the back, chest, and proximal and distal arms and legs (Figure 2). Many of the vesicles had an associated overlying crust with hemorrhage. Some of the vesicles coalesced with central necrotic plaques.

Given a clinical suspicion for disseminated HZ, therapy with oral valacyclovir was initiated. Two punch biopsies were consistent with herpesvirus cytopathic changes. Multiple sections demonstrated ulceration as well as acantholysis and necrosis of keratinocytes with multinucleation and margination of chromatin. There was an intense lichenoid and perivascular lymphocytic infiltrate in the dermis. Immunohistochemistry staining was positive for VZV and negative for HSV, indicating acute reactivation of VZV (Figure 3). Upon completion of an antiviral regimen, the patient returned to clinic with healed crusted lesions.

Comment

Frequently, the clinical features of HZ in immunocompromised patients mirror those in immunocompetent hosts.⁸ However, each of our 2 patients developed an unusual presentation of atypical generalized HZ.⁷ In this clinical variant, lesions develop along a single dermatome, then a diffuse vesicular eruption subsequently develops without dermatomal localization. These lesions can be chronic, persisting for months or years.⁷

The classic clinical presentation of HZ is distinct and often is readily diagnosed by visual inspection.⁷ However, atypical presentations and their associated complications can pose diagnostic and therapeutic challenges.⁷ Painless HZ lesions in a nondermatomal pattern were described in a patient who also had AIDS.⁹ Interestingly, multiple reports have found that patients with a severe but painless rash are less likely to have experienced a viral prodrome consisting of hyperesthesia, paresthesia, or pruritus.^2,10 This observation suggests that lack of a prodrome, as in the case of patient 1 in our report, may aid in the recognition of painless HZ. Because of these atypical presentations, laboratory testing is even more important than in immunocompetent hosts, as diagnosis may be more difficult to establish on clinical presentation alone.

Several studies^11-32 have evaluated modalities for treatment and prophylaxis for disseminated HZ in immunocompromised hosts, given its increased risk and potentially fatal complications in this population. The current guidelines in patients with HIV/AIDS, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT) are summarized in the eTable.

HIV/AIDS Patients
Given their efficacy and low rate of toxicity, oral acyclovir, valacyclovir, and famciclovir are recommended treatment options for HIV patients with localized, mild, dermatomal HZ.¹¹ Two exceptions include HZ ophthalmicus and Ramsay Hunt syndrome for which some experts recommend intravenous acyclovir given the risk for vision loss and facial palsy, respectively. Intravenous acyclovir often is the drug of choice for treating complicated, disseminated, or severe HZ in HIV-infected patients, though prospective efficacy data remain limited.¹¹

With regard to prevention of infection, a large randomized trial in 2016 found that acyclovir prophylaxis resulted in a 68% reduction in HZ over 2 years among HIV patients.¹² Despite data that acyclovir may be effective for this purpose, long-term antiviral prophylaxis is not routinely recommended for HZ,^11,13 as it has been linked to rare cases of acyclovir-resistant HZ in HIV patients.^14,15 However, antiviral prophylaxis against HSV type 2 reactivation in HIV patients also confers protection against VZV reactivation.^11,12

Solid Organ Transplantation
Localized, mild to moderately severe dermatomal HZ can be treated with oral acyclovir, valacyclovir, or famciclovir. As in HIV patients, SOT patients with severe, disseminated, or complicated HZ should receive IV acyclovir.¹¹ In the first 3 to 6 months following the procedure, SOT patients receive cytomegalovirus prophylaxis with ganciclovir or valgan-ciclovir, which also provides protection against HZ.^13-18 For patients not receiving cytomegalovirus prophylaxis, HSV prophylaxis with oral acyclovir or valacyclovir is given for at least the first month after transplantation, which also confers protection against HZ.^16,19 Antiviral therapy is critical during the early posttransplantation period when patients are most severely immunosuppressed and thus have the highest risk for VZV-associated complications.²⁰ Although immunosuppression is lifelong in most SOT recipients, there is insufficient evidence for extending prophylaxis beyond 6 months.^16,21

As a possible risk factor for HZ,²² MMF use is another consideration among SOT patients, similar to patient 2 in our report. A 2003 observational study supported withdrawal of MMF therapy during active VZV infection due to clinical observation of an association with HZ.²³ However, a multicenter, randomized, controlled trial reported no cases of HZ in renal transplant recipients on MMF.²⁴ Additionally, MMF has been observed to enhance the antiviral activity of acyclovir, at least in vitro.²⁵ Given the lack of evidence of MMF as a risk factor for HZ, there is insufficient evidence for cessation of use during VZVreactivation in SOT patients.

Hematopoietic Stem Cell Transplantation
The preferred agents for treatment of localized mild dermatomal HZ are oral acyclovir or valacyclovir, as data on the safety and efficacy of famciclovir among HSCT recipients are limited.^13,26 Patients should receive antiviral prophylaxis with one of these agents during the first year following allogeneic or autologous HSCT. This 1-year course has proven highly effective in reducing HZ in the first year following transplantation when most severe cases occur,^21,26-29 and it has been associated with a persistently decreased risk for HZ even after discontinuation.²¹ Prophylaxis may be continued beyond 1 year in allogeneic HSCT recipients experiencing graft-versus-host disease who should receive acyclovir until 6 months after the end of immunosuppressive therapy.^21,26

Vaccination remains a potential strategy to reduce the incidence of HZ in this patient population. A heat-inactivated vaccine administered within the first 3 months after the procedure has been shown to be safe among autologous and allogeneic HSCT patients.^30,31 The vaccine notably reduced the incidence of HZ in patients who underwent autologous HSCT,³² but no known data are available on its clinical efficacy in allogeneic HSCT patients. Accordingly, there are no known official recommendations to date regarding vaccine use in these patient populations.²⁶

Conclusion

It is incumbent upon clinicians to recognize the spectrum of atypical presentations of HZ and maintain a low threshold for performing appropriate diagnostic or confirmatory studies among at-risk patients with impaired immune function. Disseminated HZ can have potentially life-threatening visceral complications such as encephalitis, hepatitis, or pneumonitis.^7,8 As such, an understanding of prevention and treatment modalities for VZV infection among immunocompromised patients is critical. Because the morbidity associated with complications of VZV infection is substantial and the risks associated with antiviral agents are minimal, antiviral prophylaxis is recommended for 6 months following SOT or 1 year following HSCT, and prompt treatment is warranted in cases of reasonable clinical suspicion for HZ.

Acknowledgment
The authors gratefully acknowledge the generosity of our patients in permitting photography of their skin findings for the furthering of medical education.

Well-known for its typical presentation, classic herpes zoster (HZ) presents as a dermatomal eruption of painful erythematous papules that evolve into grouped vesicles or bullae.^1,2 Thereafter, the lesions can become pustular or hemorrhagic.¹ Although the diagnosis most often is made clinically, confirmatory techniques for diagnosis include viral culture, direct fluorescent antibody testing, or polymerase chain reaction (PCR) assay.^1,3

The main risk factor for HZ is advanced age, most commonly affecting elderly patients.⁴ It is hypothesized that a physiological decline in varicella-zoster virus (VZV)–specific cell-mediated immunity among elderly individuals helps trigger reactivation of the virus within the dorsal root ganglion.^1,5 Similarly affected are immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection, due to suppression of T cells immune to VZV,^1,5 as well as immunosuppressed transplant recipients who have diminished VZV-specific cellular responses and VZV IgG antibody avidity.⁶

Secondary complications of VZV infection (eg, postherpetic neuralgia, bacterial superinfection progressing to cellulitis) lead to increased morbidity.^7,8 Disseminated cutaneous HZ is another grave complication of VZV infection and almost exclusively occurs with immunosuppression.^1,8 It manifests as an eruption of at least 20 widespread vesiculobullous lesions outside the primary and adjacent dermatomes.⁶ Immunocompromised patients also are at increased risk for visceral involvement of VZV infection, which may affect vital organs such as the brain, liver, or lungs.^7,8 Given the atypical presentation of VZV infection among some immunocompromised individuals, these patients are at increased risk for diagnostic delay and morbidity in the absence of high clinical suspicion for disseminated HZ.

Case Reports

Patient 1
A 52-year-old man developed a painless nonpruritic rash on the left leg of 4 days’ duration. It initially appeared as an erythematous maculopapular rash on the medial aspect of the left knee without any prodromal symptoms. Over the next 4 days, erythematous vesicles developed that progressed to pustules, and the rash spread both proximally and distally along the left leg. Shortly following hospital admission, he developed a fever (temperature, 38.4°C). His medical history included alcoholic liver cirrhosis and AIDS, with a CD4 count of 174 cells/µL (reference range, 500–1500 cells/µL). He had been taking antiretroviral therapy (abacavir-lamivudine and dolutegravir) and prophylaxis against opportunistic infections (dapsone and itraconazole).

Physical examination was remarkable for an extensive rash consisting of multiple 1-cm clusters of approximately 40 pustules each scattered in a nondermatomal distribution along the left leg (Figure 1). Many of the vesicles were confluent with an erythematous base and were in different stages of evolution with some crusted and others emanating a thin liquid exudate. The lesions were nontender and without notable induration. The leg was warm and edematous.

Clinically, the differential diagnosis included disseminated HZ with bacterial superinfection, Vibrio vulnificus infection, and herpes simplex virus (HSV) infection. The patient was treated with intravenous vancomycin, levofloxacin, and acyclovir, and no new lesions developed throughout the course of treatment. On this regimen, his fever resolved after 1 day, the active lesions began to crust, and the edema and erythema diminished. Results of bacterial cultures and plasma PCR and IgM for HSV types 1 and 2 were negative. Viral culture results were negative, but a PCR assay for VZV was positive, reflective of acute reactivation of VZV.

Patient 2
A 63-year-old man developed a pruritic burning rash involving the face, trunk, arms, and legs of 6 days’ duration. His medical history included a heart transplant 6 months prior to presentation, type 2 diabetes mellitus, and chronic kidney disease. He was taking antirejection therapy with mycophenolate mofetil (MMF), prednisone, and tacrolimus.

Physical examination was remarkable for an extensive rash consisting of clusters of 1- to 2-mm vesicles scattered in a nondermatomal pattern. Isolated vesicles involved the forehead, nose, and left ear, and diffuse vesicles with a relatively symmetric distribution were scattered across the back, chest, and proximal and distal arms and legs (Figure 2). Many of the vesicles had an associated overlying crust with hemorrhage. Some of the vesicles coalesced with central necrotic plaques.

Given a clinical suspicion for disseminated HZ, therapy with oral valacyclovir was initiated. Two punch biopsies were consistent with herpesvirus cytopathic changes. Multiple sections demonstrated ulceration as well as acantholysis and necrosis of keratinocytes with multinucleation and margination of chromatin. There was an intense lichenoid and perivascular lymphocytic infiltrate in the dermis. Immunohistochemistry staining was positive for VZV and negative for HSV, indicating acute reactivation of VZV (Figure 3). Upon completion of an antiviral regimen, the patient returned to clinic with healed crusted lesions.

Comment

Frequently, the clinical features of HZ in immunocompromised patients mirror those in immunocompetent hosts.⁸ However, each of our 2 patients developed an unusual presentation of atypical generalized HZ.⁷ In this clinical variant, lesions develop along a single dermatome, then a diffuse vesicular eruption subsequently develops without dermatomal localization. These lesions can be chronic, persisting for months or years.⁷

The classic clinical presentation of HZ is distinct and often is readily diagnosed by visual inspection.⁷ However, atypical presentations and their associated complications can pose diagnostic and therapeutic challenges.⁷ Painless HZ lesions in a nondermatomal pattern were described in a patient who also had AIDS.⁹ Interestingly, multiple reports have found that patients with a severe but painless rash are less likely to have experienced a viral prodrome consisting of hyperesthesia, paresthesia, or pruritus.^2,10 This observation suggests that lack of a prodrome, as in the case of patient 1 in our report, may aid in the recognition of painless HZ. Because of these atypical presentations, laboratory testing is even more important than in immunocompetent hosts, as diagnosis may be more difficult to establish on clinical presentation alone.

Several studies^11-32 have evaluated modalities for treatment and prophylaxis for disseminated HZ in immunocompromised hosts, given its increased risk and potentially fatal complications in this population. The current guidelines in patients with HIV/AIDS, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT) are summarized in the eTable.

HIV/AIDS Patients
Given their efficacy and low rate of toxicity, oral acyclovir, valacyclovir, and famciclovir are recommended treatment options for HIV patients with localized, mild, dermatomal HZ.¹¹ Two exceptions include HZ ophthalmicus and Ramsay Hunt syndrome for which some experts recommend intravenous acyclovir given the risk for vision loss and facial palsy, respectively. Intravenous acyclovir often is the drug of choice for treating complicated, disseminated, or severe HZ in HIV-infected patients, though prospective efficacy data remain limited.¹¹

With regard to prevention of infection, a large randomized trial in 2016 found that acyclovir prophylaxis resulted in a 68% reduction in HZ over 2 years among HIV patients.¹² Despite data that acyclovir may be effective for this purpose, long-term antiviral prophylaxis is not routinely recommended for HZ,^11,13 as it has been linked to rare cases of acyclovir-resistant HZ in HIV patients.^14,15 However, antiviral prophylaxis against HSV type 2 reactivation in HIV patients also confers protection against VZV reactivation.^11,12

Solid Organ Transplantation
Localized, mild to moderately severe dermatomal HZ can be treated with oral acyclovir, valacyclovir, or famciclovir. As in HIV patients, SOT patients with severe, disseminated, or complicated HZ should receive IV acyclovir.¹¹ In the first 3 to 6 months following the procedure, SOT patients receive cytomegalovirus prophylaxis with ganciclovir or valgan-ciclovir, which also provides protection against HZ.^13-18 For patients not receiving cytomegalovirus prophylaxis, HSV prophylaxis with oral acyclovir or valacyclovir is given for at least the first month after transplantation, which also confers protection against HZ.^16,19 Antiviral therapy is critical during the early posttransplantation period when patients are most severely immunosuppressed and thus have the highest risk for VZV-associated complications.²⁰ Although immunosuppression is lifelong in most SOT recipients, there is insufficient evidence for extending prophylaxis beyond 6 months.^16,21

As a possible risk factor for HZ,²² MMF use is another consideration among SOT patients, similar to patient 2 in our report. A 2003 observational study supported withdrawal of MMF therapy during active VZV infection due to clinical observation of an association with HZ.²³ However, a multicenter, randomized, controlled trial reported no cases of HZ in renal transplant recipients on MMF.²⁴ Additionally, MMF has been observed to enhance the antiviral activity of acyclovir, at least in vitro.²⁵ Given the lack of evidence of MMF as a risk factor for HZ, there is insufficient evidence for cessation of use during VZVreactivation in SOT patients.

Hematopoietic Stem Cell Transplantation
The preferred agents for treatment of localized mild dermatomal HZ are oral acyclovir or valacyclovir, as data on the safety and efficacy of famciclovir among HSCT recipients are limited.^13,26 Patients should receive antiviral prophylaxis with one of these agents during the first year following allogeneic or autologous HSCT. This 1-year course has proven highly effective in reducing HZ in the first year following transplantation when most severe cases occur,^21,26-29 and it has been associated with a persistently decreased risk for HZ even after discontinuation.²¹ Prophylaxis may be continued beyond 1 year in allogeneic HSCT recipients experiencing graft-versus-host disease who should receive acyclovir until 6 months after the end of immunosuppressive therapy.^21,26

Vaccination remains a potential strategy to reduce the incidence of HZ in this patient population. A heat-inactivated vaccine administered within the first 3 months after the procedure has been shown to be safe among autologous and allogeneic HSCT patients.^30,31 The vaccine notably reduced the incidence of HZ in patients who underwent autologous HSCT,³² but no known data are available on its clinical efficacy in allogeneic HSCT patients. Accordingly, there are no known official recommendations to date regarding vaccine use in these patient populations.²⁶

Conclusion

It is incumbent upon clinicians to recognize the spectrum of atypical presentations of HZ and maintain a low threshold for performing appropriate diagnostic or confirmatory studies among at-risk patients with impaired immune function. Disseminated HZ can have potentially life-threatening visceral complications such as encephalitis, hepatitis, or pneumonitis.^7,8 As such, an understanding of prevention and treatment modalities for VZV infection among immunocompromised patients is critical. Because the morbidity associated with complications of VZV infection is substantial and the risks associated with antiviral agents are minimal, antiviral prophylaxis is recommended for 6 months following SOT or 1 year following HSCT, and prompt treatment is warranted in cases of reasonable clinical suspicion for HZ.

Acknowledgment
The authors gratefully acknowledge the generosity of our patients in permitting photography of their skin findings for the furthering of medical education.

Well-known for its typical presentation, classic herpes zoster (HZ) presents as a dermatomal eruption of painful erythematous papules that evolve into grouped vesicles or bullae.^1,2 Thereafter, the lesions can become pustular or hemorrhagic.¹ Although the diagnosis most often is made clinically, confirmatory techniques for diagnosis include viral culture, direct fluorescent antibody testing, or polymerase chain reaction (PCR) assay.^1,3

The main risk factor for HZ is advanced age, most commonly affecting elderly patients.⁴ It is hypothesized that a physiological decline in varicella-zoster virus (VZV)–specific cell-mediated immunity among elderly individuals helps trigger reactivation of the virus within the dorsal root ganglion.^1,5 Similarly affected are immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection, due to suppression of T cells immune to VZV,^1,5 as well as immunosuppressed transplant recipients who have diminished VZV-specific cellular responses and VZV IgG antibody avidity.⁶

Secondary complications of VZV infection (eg, postherpetic neuralgia, bacterial superinfection progressing to cellulitis) lead to increased morbidity.^7,8 Disseminated cutaneous HZ is another grave complication of VZV infection and almost exclusively occurs with immunosuppression.^1,8 It manifests as an eruption of at least 20 widespread vesiculobullous lesions outside the primary and adjacent dermatomes.⁶ Immunocompromised patients also are at increased risk for visceral involvement of VZV infection, which may affect vital organs such as the brain, liver, or lungs.^7,8 Given the atypical presentation of VZV infection among some immunocompromised individuals, these patients are at increased risk for diagnostic delay and morbidity in the absence of high clinical suspicion for disseminated HZ.

Case Reports

Patient 1
A 52-year-old man developed a painless nonpruritic rash on the left leg of 4 days’ duration. It initially appeared as an erythematous maculopapular rash on the medial aspect of the left knee without any prodromal symptoms. Over the next 4 days, erythematous vesicles developed that progressed to pustules, and the rash spread both proximally and distally along the left leg. Shortly following hospital admission, he developed a fever (temperature, 38.4°C). His medical history included alcoholic liver cirrhosis and AIDS, with a CD4 count of 174 cells/µL (reference range, 500–1500 cells/µL). He had been taking antiretroviral therapy (abacavir-lamivudine and dolutegravir) and prophylaxis against opportunistic infections (dapsone and itraconazole).

Physical examination was remarkable for an extensive rash consisting of multiple 1-cm clusters of approximately 40 pustules each scattered in a nondermatomal distribution along the left leg (Figure 1). Many of the vesicles were confluent with an erythematous base and were in different stages of evolution with some crusted and others emanating a thin liquid exudate. The lesions were nontender and without notable induration. The leg was warm and edematous.

Clinically, the differential diagnosis included disseminated HZ with bacterial superinfection, Vibrio vulnificus infection, and herpes simplex virus (HSV) infection. The patient was treated with intravenous vancomycin, levofloxacin, and acyclovir, and no new lesions developed throughout the course of treatment. On this regimen, his fever resolved after 1 day, the active lesions began to crust, and the edema and erythema diminished. Results of bacterial cultures and plasma PCR and IgM for HSV types 1 and 2 were negative. Viral culture results were negative, but a PCR assay for VZV was positive, reflective of acute reactivation of VZV.

Patient 2
A 63-year-old man developed a pruritic burning rash involving the face, trunk, arms, and legs of 6 days’ duration. His medical history included a heart transplant 6 months prior to presentation, type 2 diabetes mellitus, and chronic kidney disease. He was taking antirejection therapy with mycophenolate mofetil (MMF), prednisone, and tacrolimus.

Physical examination was remarkable for an extensive rash consisting of clusters of 1- to 2-mm vesicles scattered in a nondermatomal pattern. Isolated vesicles involved the forehead, nose, and left ear, and diffuse vesicles with a relatively symmetric distribution were scattered across the back, chest, and proximal and distal arms and legs (Figure 2). Many of the vesicles had an associated overlying crust with hemorrhage. Some of the vesicles coalesced with central necrotic plaques.

Given a clinical suspicion for disseminated HZ, therapy with oral valacyclovir was initiated. Two punch biopsies were consistent with herpesvirus cytopathic changes. Multiple sections demonstrated ulceration as well as acantholysis and necrosis of keratinocytes with multinucleation and margination of chromatin. There was an intense lichenoid and perivascular lymphocytic infiltrate in the dermis. Immunohistochemistry staining was positive for VZV and negative for HSV, indicating acute reactivation of VZV (Figure 3). Upon completion of an antiviral regimen, the patient returned to clinic with healed crusted lesions.

Comment

Frequently, the clinical features of HZ in immunocompromised patients mirror those in immunocompetent hosts.⁸ However, each of our 2 patients developed an unusual presentation of atypical generalized HZ.⁷ In this clinical variant, lesions develop along a single dermatome, then a diffuse vesicular eruption subsequently develops without dermatomal localization. These lesions can be chronic, persisting for months or years.⁷

The classic clinical presentation of HZ is distinct and often is readily diagnosed by visual inspection.⁷ However, atypical presentations and their associated complications can pose diagnostic and therapeutic challenges.⁷ Painless HZ lesions in a nondermatomal pattern were described in a patient who also had AIDS.⁹ Interestingly, multiple reports have found that patients with a severe but painless rash are less likely to have experienced a viral prodrome consisting of hyperesthesia, paresthesia, or pruritus.^2,10 This observation suggests that lack of a prodrome, as in the case of patient 1 in our report, may aid in the recognition of painless HZ. Because of these atypical presentations, laboratory testing is even more important than in immunocompetent hosts, as diagnosis may be more difficult to establish on clinical presentation alone.

Several studies^11-32 have evaluated modalities for treatment and prophylaxis for disseminated HZ in immunocompromised hosts, given its increased risk and potentially fatal complications in this population. The current guidelines in patients with HIV/AIDS, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT) are summarized in the eTable.

HIV/AIDS Patients
Given their efficacy and low rate of toxicity, oral acyclovir, valacyclovir, and famciclovir are recommended treatment options for HIV patients with localized, mild, dermatomal HZ.¹¹ Two exceptions include HZ ophthalmicus and Ramsay Hunt syndrome for which some experts recommend intravenous acyclovir given the risk for vision loss and facial palsy, respectively. Intravenous acyclovir often is the drug of choice for treating complicated, disseminated, or severe HZ in HIV-infected patients, though prospective efficacy data remain limited.¹¹

With regard to prevention of infection, a large randomized trial in 2016 found that acyclovir prophylaxis resulted in a 68% reduction in HZ over 2 years among HIV patients.¹² Despite data that acyclovir may be effective for this purpose, long-term antiviral prophylaxis is not routinely recommended for HZ,^11,13 as it has been linked to rare cases of acyclovir-resistant HZ in HIV patients.^14,15 However, antiviral prophylaxis against HSV type 2 reactivation in HIV patients also confers protection against VZV reactivation.^11,12

Solid Organ Transplantation
Localized, mild to moderately severe dermatomal HZ can be treated with oral acyclovir, valacyclovir, or famciclovir. As in HIV patients, SOT patients with severe, disseminated, or complicated HZ should receive IV acyclovir.¹¹ In the first 3 to 6 months following the procedure, SOT patients receive cytomegalovirus prophylaxis with ganciclovir or valgan-ciclovir, which also provides protection against HZ.^13-18 For patients not receiving cytomegalovirus prophylaxis, HSV prophylaxis with oral acyclovir or valacyclovir is given for at least the first month after transplantation, which also confers protection against HZ.^16,19 Antiviral therapy is critical during the early posttransplantation period when patients are most severely immunosuppressed and thus have the highest risk for VZV-associated complications.²⁰ Although immunosuppression is lifelong in most SOT recipients, there is insufficient evidence for extending prophylaxis beyond 6 months.^16,21

As a possible risk factor for HZ,²² MMF use is another consideration among SOT patients, similar to patient 2 in our report. A 2003 observational study supported withdrawal of MMF therapy during active VZV infection due to clinical observation of an association with HZ.²³ However, a multicenter, randomized, controlled trial reported no cases of HZ in renal transplant recipients on MMF.²⁴ Additionally, MMF has been observed to enhance the antiviral activity of acyclovir, at least in vitro.²⁵ Given the lack of evidence of MMF as a risk factor for HZ, there is insufficient evidence for cessation of use during VZVreactivation in SOT patients.

Hematopoietic Stem Cell Transplantation
The preferred agents for treatment of localized mild dermatomal HZ are oral acyclovir or valacyclovir, as data on the safety and efficacy of famciclovir among HSCT recipients are limited.^13,26 Patients should receive antiviral prophylaxis with one of these agents during the first year following allogeneic or autologous HSCT. This 1-year course has proven highly effective in reducing HZ in the first year following transplantation when most severe cases occur,^21,26-29 and it has been associated with a persistently decreased risk for HZ even after discontinuation.²¹ Prophylaxis may be continued beyond 1 year in allogeneic HSCT recipients experiencing graft-versus-host disease who should receive acyclovir until 6 months after the end of immunosuppressive therapy.^21,26

Vaccination remains a potential strategy to reduce the incidence of HZ in this patient population. A heat-inactivated vaccine administered within the first 3 months after the procedure has been shown to be safe among autologous and allogeneic HSCT patients.^30,31 The vaccine notably reduced the incidence of HZ in patients who underwent autologous HSCT,³² but no known data are available on its clinical efficacy in allogeneic HSCT patients. Accordingly, there are no known official recommendations to date regarding vaccine use in these patient populations.²⁶

Conclusion

It is incumbent upon clinicians to recognize the spectrum of atypical presentations of HZ and maintain a low threshold for performing appropriate diagnostic or confirmatory studies among at-risk patients with impaired immune function. Disseminated HZ can have potentially life-threatening visceral complications such as encephalitis, hepatitis, or pneumonitis.^7,8 As such, an understanding of prevention and treatment modalities for VZV infection among immunocompromised patients is critical. Because the morbidity associated with complications of VZV infection is substantial and the risks associated with antiviral agents are minimal, antiviral prophylaxis is recommended for 6 months following SOT or 1 year following HSCT, and prompt treatment is warranted in cases of reasonable clinical suspicion for HZ.

Acknowledgment
The authors gratefully acknowledge the generosity of our patients in permitting photography of their skin findings for the furthering of medical education.

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that primarily affects the lungs and lymphatic system but also may involve the skin, eyes, liver, spleen, muscles, bones, and nervous system.¹ Cutaneous symptoms of sarcoidosis occur in approximately 25% of patients and are classified as specific and nonspecific, with specific lesions demonstrating noncaseating granuloma formation, which is typical of sarcoidosis.² Nonspecific lesions primarily include erythema nodosum and calcinosis cutis. Specific lesions commonly present as reddish brown infiltrated plaques that may be annular, polycyclic, or serpiginous.^1,3 They also may appear as yellowish brown or violaceous maculopapular lesions. However, specific lesions may present in a wide variety of morphologies, most often papules, nodules, subcutaneous infiltrates, and lupus pernio.⁴ Additionally, atypical cutaneous manifestations of sarcoidosis include erythroderma; scarring alopecia; nail dystrophy; and verrucous, ichthyosiform, psoriasiform, hypopigmented, or ulcerative skin lesions.^3-5 Among these many potential clinical presentations, ulcerative sarcoidosis is quite uncommon.

We report a case of a patient who presented with classic clinical and histopathological findings of ulcerative sarcoidosis to highlight the prototypical presentation of a rare condition. We also review 34 additional cases of ulcerative sarcoidosis published in the English-language literature based on a PubMed search of articles indexed for MEDLINE using the term ulcerative sarcoid.^4-32 Analyzing this historical information, the scope of this unusual form of cutaneous sarcoidosis can be better understood, recognized, and treated. Although current standard-of-care treatments are most often successful, there is a paucity of definitive clinical trials to justify and verify comparative therapeutic efficacy.

Case Report

A 49-year-old black man with known pulmonary sarcoidosis, idiopathic (human immunodeficiency virus–negative) CD4 depletion syndrome, and chronic kidney disease presented with persistent bilateral ulcers of the legs of 1 month’s duration. The lesions first appeared as multiple “dark spots” on the legs. After the patient applied homemade aloe vera extract under occlusion for 1 to 2 days, the lesions became painful and began to ulcerate approximately 3 months prior to presentation. The patient applied a combination of a topical first aid antibiotic ointment, Epsom salts, and hydrogen peroxide without any improvement. A current review of systems was negative.

The patient’s medical history was notable for sarcoidosis diagnosed more than 10 years prior. During this time, he had intermittently been treated elsewhere with low-dose oral prednisone (5 mg once daily), hydroxychloroquine (200 mg twice daily), and an inhaled steroid as needed. He had a history of human immunodeficiency virus–negative, idiopathic CD4 depletion syndrome, which had been complicated by cryptococcal meningitis 7 years prior to presentation. He also had renal insufficiency, with baseline creatinine levels ranging from 1.4 to 1.7 mg/dL (reference range, 0.6–1.2 mg/dL). There was no personal or family history of known or suspected inflammatory bowel disease.

On physical examination, numerous discrete, coalescing, punched out–appearing ulcerations with foul-smelling, greenish yellow, purulent drainage were present bilaterally on the legs (Figure 1). The ulcers had a rolled border with a moderate amount of seemingly nonviable necrotic tissue. A number of hyperpigmented round papules, patches, and plaques also were present on the proximal legs. Laboratory evaluation revealed a CD4 count of 151 cc/mm³ (reference range, 500–1600 cc/mm³) and mildly elevated calcium of 10.7 mg/dL (reference range, 8.2–10.2 mg/dL).

Aerobic, anaerobic, mycobacterial, and fungal cultures of the purulent exudate were obtained. Given a high suspicion for secondary infection of the exogenous wound sites, doxycycline (100 mg twice daily) and topical mupir-ocin were initiated. Gram stain revealed few to moderate polymorphonuclear cells and many gram-positive cocci in pairs, chains, and clusters, along with many gram-negative rods. Bacterial culture grew Pseudomonas aeruginosa, Enterococcus species group G streptococci, and methicillin-resistant Staphylococcus aureus–positive staphylococci. Ciprofloxacin (500 mg twice daily) was then initiated, but the ulcers showed absolutely no clinical improvement and in fact worsened both in number and depth (Figure 2) over subsequent clinic visits during the next 3 months, even after amoxicillin (500 mg 3 times daily) was added. The patient was admitted for treatment with intravenous antibiotics after additional wound cultures revealed fluoroquinolone-resistant Pseudomonas.

Punch biopsies of the ulcers showed nonspecific acute inflammation and tissue necrosis in the active ulcers with nonnecrotizing granulomatous inflammation extending into the deep dermis, with many Langerhans-type giant cells present in the palpable ulcer borders (Figure 3). Neither birefringent particles nor asteroid bodies were observed. Tissue Gram stains did not reveal evidence of bacterial infection. Special stains for acid-fast and fungal organisms (ie, periodic acid–Schiff, Gomori methenamine-silver, Fite, acid-fast bacilli) were similarly negative. Tissue cultures obtained on deep biopsy revealed only rare colonies of P aeruginosa and no isolates on anaerobic, mycobacterial, or fungal cultures. Polymerase chain reaction for mycobacteria and common endemic fungi also was negative. In the absence of infection and considering his history of known sarcoidosis, these histologic features were consistent with ulcerative sarcoidosis. The patient was started on prednisone (60 mg once daily) and hydroxychloroquine (200 mg twice daily). The prednisone was tapered to 20 mg once daily over a 2-year period, at which point 90% of the ulcers had healed. He was continued on hydroxychloroquine at the initial dose, and at a 3-year follow-up his ulcers had healed completely without relapse.

Comment

Ulcerative sarcoidosis is rare, seen worldwide in only 5% of patients with cutaneous sarcoidosis.³³ However, cases have been encountered worldwide, with reports emanating from Japan, China, Germany, France, and Russia, among others.^6,34-55 We reviewed 34 cases from the English-language literature based on a PubMed search of articles indexed for MEDLINE using the term ulcerative sarcoid and examined patient demographics, clinical presentation, histological findings, treatment type, and outcome. Key references are presented in the Table. Disease prevalence previously has been estimated as being 3-times more common in women than men¹; in our literature review, we found a female to male ratio of 3.25 to 1. Additionally, ulcerative sarcoidosis is reported to be twice as common in black versus white individuals.³³ In our literature review, when race was reported, 66% (21/32) of patients were black. Disease prevalence has been reported to peak at 20 to 40 years of age.³ In this review, the average age of presentation was 45 years (age range, 24–79 years).

Ulceration may arise de novo but more commonly arises in preexisting scars or cutaneous lesions. There are 2 distinct patterns seen in ulcerative sarcoidosis.⁴ The first is characterized by ulceration within necrotic yellow plaques.² The second pattern is characterized by violaceous nodules arising in an annular confluent pattern that eventually ulcerate.⁴ This presentation commonly mimics or may be mimicked by multiple disease states, including sporotrichosis, tuberculosis, stasis dermatitis with venous ulceration, and even metastatic breast cancer.^7,46,55,56 Regardless of presentation, the legs are the most common location of ulcer formation.^1,33 In our review, 85% (29/34) of cases presented with involvement of the legs, including our own case. Other locations of ulcer formation have included the face, arms, trunk, and genital area.

On histologic examination of ulcerative sarcoidosis, epithelioid granulomas composed of multinucleated giant cells, histiocytes, and scant numbers of lymphocytes are present.^1,3 These formations are the noncaseating granulomas typical of sarcoidosis (Table). All of the cases in our review of the literature were described as either a collection of epithelioid granulomas with giant cell formation or noncaseating granulomas. There also have been reports of atypical features including necrotizing granulomas and granulomatous vasculitis.^4,8,9,50 The histologic differential diagnosis in this case also would primarily include an infectious granulomatous process and less so an id reaction, rosacea, a paraneoplastic phenomenon, foreign body granulomas, and metastatic Crohn disease. The presence of ulceration, the large number of lesions, and the anatomic distribution help rule out most of these alternate diagnostic considerations. Diligent extensive workup was done in our patient to insure it was not an infection.

The goals of treatment include symptomatic relief, improvement in objective parameters of disease activity, and prevention of disease progression and subsequent disability.^33,57 Fortunately, the majority of sarcoidosis patients with cutaneous symptoms achieve full recovery within months to years.³³ Our literature review indicated that 81% (22/27) of patients with ulcerative lesions experienced full resolution within 1 year of treatment. Of those that did not (19% [5/27]), the patients were either lost to follow-up or died from other complications of sarcoidosis.

The widely accepted standard therapy for cutaneous sarcoidosis includes topical, intralesional, and systemic corticosteroids; antimalarials; and methotrexate.^33,57 Steroids and methotrexate act by suppressing granuloma formation, while antimalarials prevent antigen presentation (presumably part of the pathogenesis).³³ For mild to moderate disease, topical and intralesional steroids may be all that is necessary.^33,57 Systemic steroids are used for disfiguring, destructive, and widespread lesions that have been refractory to local and other systemic therapies.^33,57 Steroids are tapered gradually depending on the patient’s response, as it is common for patients to relapse below a certain dose.^33,57 Antimalarials (chloroquine or hydroxychloroquine) and methotrexate are considered adjunct treatments for patients who are either steroid unresponsive or who are unable to tolerate corticosteroid treatment due to adverse events.^33,57

Standard therapy is complicated by the side effects of treatment. Use of corticosteroids may lead to gastrointestinal tract upset, increased appetite, mood disturbances, impaired wound healing, hyperglycemia, hypertension, cushingoid features, and acne.⁵⁷ Antimalarials can cause nausea, anorexia, and agranulocytosis, and chloroquine therapy in particular can lead to blurred vision, corneal deposits, and central retinopathy.^33,57 Methotrexate is associated with hematologic, gastrointestinal tract, pulmonary, and hepatic toxicities well known to most practitioners.

Because of the variable clinical response of patients to standard therapy and their associated toxicities, other treatment options have been used including pentoxifylline, tetracyclines, isotretinoin, leflunomide, thalidomide, infliximab, adalimumab, allopurinol, and the pulsed dye or CO₂ laser.^10,33,57 In nonhealing ulcers, split-thickness grafting and a bilayered bioengineered skin substitute have been used with good results in conjunction with ongoing systemic therapy.^11,47 Additionally, nanoparticle silver burn paste has been used successfully, with resolution of ulcers within 2 weeks in the Chinese literature.⁵³

All of these treatment recommendations are based on historically accepted modalities. Controlled trials with longitudinal follow-up are needed to provide justification for the current standard of care.³⁴

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that primarily affects the lungs and lymphatic system but also may involve the skin, eyes, liver, spleen, muscles, bones, and nervous system.¹ Cutaneous symptoms of sarcoidosis occur in approximately 25% of patients and are classified as specific and nonspecific, with specific lesions demonstrating noncaseating granuloma formation, which is typical of sarcoidosis.² Nonspecific lesions primarily include erythema nodosum and calcinosis cutis. Specific lesions commonly present as reddish brown infiltrated plaques that may be annular, polycyclic, or serpiginous.^1,3 They also may appear as yellowish brown or violaceous maculopapular lesions. However, specific lesions may present in a wide variety of morphologies, most often papules, nodules, subcutaneous infiltrates, and lupus pernio.⁴ Additionally, atypical cutaneous manifestations of sarcoidosis include erythroderma; scarring alopecia; nail dystrophy; and verrucous, ichthyosiform, psoriasiform, hypopigmented, or ulcerative skin lesions.^3-5 Among these many potential clinical presentations, ulcerative sarcoidosis is quite uncommon.

We report a case of a patient who presented with classic clinical and histopathological findings of ulcerative sarcoidosis to highlight the prototypical presentation of a rare condition. We also review 34 additional cases of ulcerative sarcoidosis published in the English-language literature based on a PubMed search of articles indexed for MEDLINE using the term ulcerative sarcoid.^4-32 Analyzing this historical information, the scope of this unusual form of cutaneous sarcoidosis can be better understood, recognized, and treated. Although current standard-of-care treatments are most often successful, there is a paucity of definitive clinical trials to justify and verify comparative therapeutic efficacy.

Case Report

A 49-year-old black man with known pulmonary sarcoidosis, idiopathic (human immunodeficiency virus–negative) CD4 depletion syndrome, and chronic kidney disease presented with persistent bilateral ulcers of the legs of 1 month’s duration. The lesions first appeared as multiple “dark spots” on the legs. After the patient applied homemade aloe vera extract under occlusion for 1 to 2 days, the lesions became painful and began to ulcerate approximately 3 months prior to presentation. The patient applied a combination of a topical first aid antibiotic ointment, Epsom salts, and hydrogen peroxide without any improvement. A current review of systems was negative.

The patient’s medical history was notable for sarcoidosis diagnosed more than 10 years prior. During this time, he had intermittently been treated elsewhere with low-dose oral prednisone (5 mg once daily), hydroxychloroquine (200 mg twice daily), and an inhaled steroid as needed. He had a history of human immunodeficiency virus–negative, idiopathic CD4 depletion syndrome, which had been complicated by cryptococcal meningitis 7 years prior to presentation. He also had renal insufficiency, with baseline creatinine levels ranging from 1.4 to 1.7 mg/dL (reference range, 0.6–1.2 mg/dL). There was no personal or family history of known or suspected inflammatory bowel disease.

On physical examination, numerous discrete, coalescing, punched out–appearing ulcerations with foul-smelling, greenish yellow, purulent drainage were present bilaterally on the legs (Figure 1). The ulcers had a rolled border with a moderate amount of seemingly nonviable necrotic tissue. A number of hyperpigmented round papules, patches, and plaques also were present on the proximal legs. Laboratory evaluation revealed a CD4 count of 151 cc/mm³ (reference range, 500–1600 cc/mm³) and mildly elevated calcium of 10.7 mg/dL (reference range, 8.2–10.2 mg/dL).

Aerobic, anaerobic, mycobacterial, and fungal cultures of the purulent exudate were obtained. Given a high suspicion for secondary infection of the exogenous wound sites, doxycycline (100 mg twice daily) and topical mupir-ocin were initiated. Gram stain revealed few to moderate polymorphonuclear cells and many gram-positive cocci in pairs, chains, and clusters, along with many gram-negative rods. Bacterial culture grew Pseudomonas aeruginosa, Enterococcus species group G streptococci, and methicillin-resistant Staphylococcus aureus–positive staphylococci. Ciprofloxacin (500 mg twice daily) was then initiated, but the ulcers showed absolutely no clinical improvement and in fact worsened both in number and depth (Figure 2) over subsequent clinic visits during the next 3 months, even after amoxicillin (500 mg 3 times daily) was added. The patient was admitted for treatment with intravenous antibiotics after additional wound cultures revealed fluoroquinolone-resistant Pseudomonas.

Punch biopsies of the ulcers showed nonspecific acute inflammation and tissue necrosis in the active ulcers with nonnecrotizing granulomatous inflammation extending into the deep dermis, with many Langerhans-type giant cells present in the palpable ulcer borders (Figure 3). Neither birefringent particles nor asteroid bodies were observed. Tissue Gram stains did not reveal evidence of bacterial infection. Special stains for acid-fast and fungal organisms (ie, periodic acid–Schiff, Gomori methenamine-silver, Fite, acid-fast bacilli) were similarly negative. Tissue cultures obtained on deep biopsy revealed only rare colonies of P aeruginosa and no isolates on anaerobic, mycobacterial, or fungal cultures. Polymerase chain reaction for mycobacteria and common endemic fungi also was negative. In the absence of infection and considering his history of known sarcoidosis, these histologic features were consistent with ulcerative sarcoidosis. The patient was started on prednisone (60 mg once daily) and hydroxychloroquine (200 mg twice daily). The prednisone was tapered to 20 mg once daily over a 2-year period, at which point 90% of the ulcers had healed. He was continued on hydroxychloroquine at the initial dose, and at a 3-year follow-up his ulcers had healed completely without relapse.

Comment

Ulcerative sarcoidosis is rare, seen worldwide in only 5% of patients with cutaneous sarcoidosis.³³ However, cases have been encountered worldwide, with reports emanating from Japan, China, Germany, France, and Russia, among others.^6,34-55 We reviewed 34 cases from the English-language literature based on a PubMed search of articles indexed for MEDLINE using the term ulcerative sarcoid and examined patient demographics, clinical presentation, histological findings, treatment type, and outcome. Key references are presented in the Table. Disease prevalence previously has been estimated as being 3-times more common in women than men¹; in our literature review, we found a female to male ratio of 3.25 to 1. Additionally, ulcerative sarcoidosis is reported to be twice as common in black versus white individuals.³³ In our literature review, when race was reported, 66% (21/32) of patients were black. Disease prevalence has been reported to peak at 20 to 40 years of age.³ In this review, the average age of presentation was 45 years (age range, 24–79 years).

Ulceration may arise de novo but more commonly arises in preexisting scars or cutaneous lesions. There are 2 distinct patterns seen in ulcerative sarcoidosis.⁴ The first is characterized by ulceration within necrotic yellow plaques.² The second pattern is characterized by violaceous nodules arising in an annular confluent pattern that eventually ulcerate.⁴ This presentation commonly mimics or may be mimicked by multiple disease states, including sporotrichosis, tuberculosis, stasis dermatitis with venous ulceration, and even metastatic breast cancer.^7,46,55,56 Regardless of presentation, the legs are the most common location of ulcer formation.^1,33 In our review, 85% (29/34) of cases presented with involvement of the legs, including our own case. Other locations of ulcer formation have included the face, arms, trunk, and genital area.

On histologic examination of ulcerative sarcoidosis, epithelioid granulomas composed of multinucleated giant cells, histiocytes, and scant numbers of lymphocytes are present.^1,3 These formations are the noncaseating granulomas typical of sarcoidosis (Table). All of the cases in our review of the literature were described as either a collection of epithelioid granulomas with giant cell formation or noncaseating granulomas. There also have been reports of atypical features including necrotizing granulomas and granulomatous vasculitis.^4,8,9,50 The histologic differential diagnosis in this case also would primarily include an infectious granulomatous process and less so an id reaction, rosacea, a paraneoplastic phenomenon, foreign body granulomas, and metastatic Crohn disease. The presence of ulceration, the large number of lesions, and the anatomic distribution help rule out most of these alternate diagnostic considerations. Diligent extensive workup was done in our patient to insure it was not an infection.

The goals of treatment include symptomatic relief, improvement in objective parameters of disease activity, and prevention of disease progression and subsequent disability.^33,57 Fortunately, the majority of sarcoidosis patients with cutaneous symptoms achieve full recovery within months to years.³³ Our literature review indicated that 81% (22/27) of patients with ulcerative lesions experienced full resolution within 1 year of treatment. Of those that did not (19% [5/27]), the patients were either lost to follow-up or died from other complications of sarcoidosis.

The widely accepted standard therapy for cutaneous sarcoidosis includes topical, intralesional, and systemic corticosteroids; antimalarials; and methotrexate.^33,57 Steroids and methotrexate act by suppressing granuloma formation, while antimalarials prevent antigen presentation (presumably part of the pathogenesis).³³ For mild to moderate disease, topical and intralesional steroids may be all that is necessary.^33,57 Systemic steroids are used for disfiguring, destructive, and widespread lesions that have been refractory to local and other systemic therapies.^33,57 Steroids are tapered gradually depending on the patient’s response, as it is common for patients to relapse below a certain dose.^33,57 Antimalarials (chloroquine or hydroxychloroquine) and methotrexate are considered adjunct treatments for patients who are either steroid unresponsive or who are unable to tolerate corticosteroid treatment due to adverse events.^33,57

Standard therapy is complicated by the side effects of treatment. Use of corticosteroids may lead to gastrointestinal tract upset, increased appetite, mood disturbances, impaired wound healing, hyperglycemia, hypertension, cushingoid features, and acne.⁵⁷ Antimalarials can cause nausea, anorexia, and agranulocytosis, and chloroquine therapy in particular can lead to blurred vision, corneal deposits, and central retinopathy.^33,57 Methotrexate is associated with hematologic, gastrointestinal tract, pulmonary, and hepatic toxicities well known to most practitioners.

Because of the variable clinical response of patients to standard therapy and their associated toxicities, other treatment options have been used including pentoxifylline, tetracyclines, isotretinoin, leflunomide, thalidomide, infliximab, adalimumab, allopurinol, and the pulsed dye or CO₂ laser.^10,33,57 In nonhealing ulcers, split-thickness grafting and a bilayered bioengineered skin substitute have been used with good results in conjunction with ongoing systemic therapy.^11,47 Additionally, nanoparticle silver burn paste has been used successfully, with resolution of ulcers within 2 weeks in the Chinese literature.⁵³

All of these treatment recommendations are based on historically accepted modalities. Controlled trials with longitudinal follow-up are needed to provide justification for the current standard of care.³⁴

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that primarily affects the lungs and lymphatic system but also may involve the skin, eyes, liver, spleen, muscles, bones, and nervous system.¹ Cutaneous symptoms of sarcoidosis occur in approximately 25% of patients and are classified as specific and nonspecific, with specific lesions demonstrating noncaseating granuloma formation, which is typical of sarcoidosis.² Nonspecific lesions primarily include erythema nodosum and calcinosis cutis. Specific lesions commonly present as reddish brown infiltrated plaques that may be annular, polycyclic, or serpiginous.^1,3 They also may appear as yellowish brown or violaceous maculopapular lesions. However, specific lesions may present in a wide variety of morphologies, most often papules, nodules, subcutaneous infiltrates, and lupus pernio.⁴ Additionally, atypical cutaneous manifestations of sarcoidosis include erythroderma; scarring alopecia; nail dystrophy; and verrucous, ichthyosiform, psoriasiform, hypopigmented, or ulcerative skin lesions.^3-5 Among these many potential clinical presentations, ulcerative sarcoidosis is quite uncommon.

We report a case of a patient who presented with classic clinical and histopathological findings of ulcerative sarcoidosis to highlight the prototypical presentation of a rare condition. We also review 34 additional cases of ulcerative sarcoidosis published in the English-language literature based on a PubMed search of articles indexed for MEDLINE using the term ulcerative sarcoid.^4-32 Analyzing this historical information, the scope of this unusual form of cutaneous sarcoidosis can be better understood, recognized, and treated. Although current standard-of-care treatments are most often successful, there is a paucity of definitive clinical trials to justify and verify comparative therapeutic efficacy.

Case Report

A 49-year-old black man with known pulmonary sarcoidosis, idiopathic (human immunodeficiency virus–negative) CD4 depletion syndrome, and chronic kidney disease presented with persistent bilateral ulcers of the legs of 1 month’s duration. The lesions first appeared as multiple “dark spots” on the legs. After the patient applied homemade aloe vera extract under occlusion for 1 to 2 days, the lesions became painful and began to ulcerate approximately 3 months prior to presentation. The patient applied a combination of a topical first aid antibiotic ointment, Epsom salts, and hydrogen peroxide without any improvement. A current review of systems was negative.

The patient’s medical history was notable for sarcoidosis diagnosed more than 10 years prior. During this time, he had intermittently been treated elsewhere with low-dose oral prednisone (5 mg once daily), hydroxychloroquine (200 mg twice daily), and an inhaled steroid as needed. He had a history of human immunodeficiency virus–negative, idiopathic CD4 depletion syndrome, which had been complicated by cryptococcal meningitis 7 years prior to presentation. He also had renal insufficiency, with baseline creatinine levels ranging from 1.4 to 1.7 mg/dL (reference range, 0.6–1.2 mg/dL). There was no personal or family history of known or suspected inflammatory bowel disease.

On physical examination, numerous discrete, coalescing, punched out–appearing ulcerations with foul-smelling, greenish yellow, purulent drainage were present bilaterally on the legs (Figure 1). The ulcers had a rolled border with a moderate amount of seemingly nonviable necrotic tissue. A number of hyperpigmented round papules, patches, and plaques also were present on the proximal legs. Laboratory evaluation revealed a CD4 count of 151 cc/mm³ (reference range, 500–1600 cc/mm³) and mildly elevated calcium of 10.7 mg/dL (reference range, 8.2–10.2 mg/dL).

Aerobic, anaerobic, mycobacterial, and fungal cultures of the purulent exudate were obtained. Given a high suspicion for secondary infection of the exogenous wound sites, doxycycline (100 mg twice daily) and topical mupir-ocin were initiated. Gram stain revealed few to moderate polymorphonuclear cells and many gram-positive cocci in pairs, chains, and clusters, along with many gram-negative rods. Bacterial culture grew Pseudomonas aeruginosa, Enterococcus species group G streptococci, and methicillin-resistant Staphylococcus aureus–positive staphylococci. Ciprofloxacin (500 mg twice daily) was then initiated, but the ulcers showed absolutely no clinical improvement and in fact worsened both in number and depth (Figure 2) over subsequent clinic visits during the next 3 months, even after amoxicillin (500 mg 3 times daily) was added. The patient was admitted for treatment with intravenous antibiotics after additional wound cultures revealed fluoroquinolone-resistant Pseudomonas.

Punch biopsies of the ulcers showed nonspecific acute inflammation and tissue necrosis in the active ulcers with nonnecrotizing granulomatous inflammation extending into the deep dermis, with many Langerhans-type giant cells present in the palpable ulcer borders (Figure 3). Neither birefringent particles nor asteroid bodies were observed. Tissue Gram stains did not reveal evidence of bacterial infection. Special stains for acid-fast and fungal organisms (ie, periodic acid–Schiff, Gomori methenamine-silver, Fite, acid-fast bacilli) were similarly negative. Tissue cultures obtained on deep biopsy revealed only rare colonies of P aeruginosa and no isolates on anaerobic, mycobacterial, or fungal cultures. Polymerase chain reaction for mycobacteria and common endemic fungi also was negative. In the absence of infection and considering his history of known sarcoidosis, these histologic features were consistent with ulcerative sarcoidosis. The patient was started on prednisone (60 mg once daily) and hydroxychloroquine (200 mg twice daily). The prednisone was tapered to 20 mg once daily over a 2-year period, at which point 90% of the ulcers had healed. He was continued on hydroxychloroquine at the initial dose, and at a 3-year follow-up his ulcers had healed completely without relapse.

Comment

Ulcerative sarcoidosis is rare, seen worldwide in only 5% of patients with cutaneous sarcoidosis.³³ However, cases have been encountered worldwide, with reports emanating from Japan, China, Germany, France, and Russia, among others.^6,34-55 We reviewed 34 cases from the English-language literature based on a PubMed search of articles indexed for MEDLINE using the term ulcerative sarcoid and examined patient demographics, clinical presentation, histological findings, treatment type, and outcome. Key references are presented in the Table. Disease prevalence previously has been estimated as being 3-times more common in women than men¹; in our literature review, we found a female to male ratio of 3.25 to 1. Additionally, ulcerative sarcoidosis is reported to be twice as common in black versus white individuals.³³ In our literature review, when race was reported, 66% (21/32) of patients were black. Disease prevalence has been reported to peak at 20 to 40 years of age.³ In this review, the average age of presentation was 45 years (age range, 24–79 years).

Ulceration may arise de novo but more commonly arises in preexisting scars or cutaneous lesions. There are 2 distinct patterns seen in ulcerative sarcoidosis.⁴ The first is characterized by ulceration within necrotic yellow plaques.² The second pattern is characterized by violaceous nodules arising in an annular confluent pattern that eventually ulcerate.⁴ This presentation commonly mimics or may be mimicked by multiple disease states, including sporotrichosis, tuberculosis, stasis dermatitis with venous ulceration, and even metastatic breast cancer.^7,46,55,56 Regardless of presentation, the legs are the most common location of ulcer formation.^1,33 In our review, 85% (29/34) of cases presented with involvement of the legs, including our own case. Other locations of ulcer formation have included the face, arms, trunk, and genital area.

On histologic examination of ulcerative sarcoidosis, epithelioid granulomas composed of multinucleated giant cells, histiocytes, and scant numbers of lymphocytes are present.^1,3 These formations are the noncaseating granulomas typical of sarcoidosis (Table). All of the cases in our review of the literature were described as either a collection of epithelioid granulomas with giant cell formation or noncaseating granulomas. There also have been reports of atypical features including necrotizing granulomas and granulomatous vasculitis.^4,8,9,50 The histologic differential diagnosis in this case also would primarily include an infectious granulomatous process and less so an id reaction, rosacea, a paraneoplastic phenomenon, foreign body granulomas, and metastatic Crohn disease. The presence of ulceration, the large number of lesions, and the anatomic distribution help rule out most of these alternate diagnostic considerations. Diligent extensive workup was done in our patient to insure it was not an infection.

The goals of treatment include symptomatic relief, improvement in objective parameters of disease activity, and prevention of disease progression and subsequent disability.^33,57 Fortunately, the majority of sarcoidosis patients with cutaneous symptoms achieve full recovery within months to years.³³ Our literature review indicated that 81% (22/27) of patients with ulcerative lesions experienced full resolution within 1 year of treatment. Of those that did not (19% [5/27]), the patients were either lost to follow-up or died from other complications of sarcoidosis.

The widely accepted standard therapy for cutaneous sarcoidosis includes topical, intralesional, and systemic corticosteroids; antimalarials; and methotrexate.^33,57 Steroids and methotrexate act by suppressing granuloma formation, while antimalarials prevent antigen presentation (presumably part of the pathogenesis).³³ For mild to moderate disease, topical and intralesional steroids may be all that is necessary.^33,57 Systemic steroids are used for disfiguring, destructive, and widespread lesions that have been refractory to local and other systemic therapies.^33,57 Steroids are tapered gradually depending on the patient’s response, as it is common for patients to relapse below a certain dose.^33,57 Antimalarials (chloroquine or hydroxychloroquine) and methotrexate are considered adjunct treatments for patients who are either steroid unresponsive or who are unable to tolerate corticosteroid treatment due to adverse events.^33,57

Standard therapy is complicated by the side effects of treatment. Use of corticosteroids may lead to gastrointestinal tract upset, increased appetite, mood disturbances, impaired wound healing, hyperglycemia, hypertension, cushingoid features, and acne.⁵⁷ Antimalarials can cause nausea, anorexia, and agranulocytosis, and chloroquine therapy in particular can lead to blurred vision, corneal deposits, and central retinopathy.^33,57 Methotrexate is associated with hematologic, gastrointestinal tract, pulmonary, and hepatic toxicities well known to most practitioners.

Because of the variable clinical response of patients to standard therapy and their associated toxicities, other treatment options have been used including pentoxifylline, tetracyclines, isotretinoin, leflunomide, thalidomide, infliximab, adalimumab, allopurinol, and the pulsed dye or CO₂ laser.^10,33,57 In nonhealing ulcers, split-thickness grafting and a bilayered bioengineered skin substitute have been used with good results in conjunction with ongoing systemic therapy.^11,47 Additionally, nanoparticle silver burn paste has been used successfully, with resolution of ulcers within 2 weeks in the Chinese literature.⁵³

All of these treatment recommendations are based on historically accepted modalities. Controlled trials with longitudinal follow-up are needed to provide justification for the current standard of care.³⁴

Varicella-zoster virus (VZV) is a neurotropic human herpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). During infection, the virus invades the dorsal root ganglia and establishes permanent latency. It can later reactivate and travel through sensory nerves to the skin where localized viral replication causes herpes zoster (HZ), which manifests with pain in a unilateral dermatomal distribution followed closely by an eruption of grouped macules and papules that evolve into vesicles on an erythematous base.¹ These lesions form pustules and crusts over 7 to 10 days and heal completely within 4 weeks. Although postherpetic neuralgia is rare in children, the pain associated with HZ can last months or years.^1,2

Universal childhood vaccination against VZV has existed in the United States since 1995, with a 2-dose vaccine regimen recommended by the CDC since 2007. Consequently, primary varicella infection in children is uncommon, and the majority of cases now occur in the vaccinated population.³ However, breakthrough varicella infection and postvaccination HZ are rare due to the long-lasting immunity and low virulence of the attenuated vaccine strain. We recount the case of a 6-year-old vaccinated girl with a unique presentation of HZ with no known primary varicella infection.

Case Report

A healthy 6-year-old girl presented with a stabbing burning pain in the left thigh extending down the calf of 4 days’ duration. The intense pain made walking difficult and responded minimally to ibuprofen and naproxen. Poor appetite, nausea, colicky abdominal pain, and fever (temperature, 38°C) accompanied the pain. Three days after the pain began she developed a pruritic rash on the same leg. Notably, she reported falling on a rosebush and sustaining a thorn prick in the left thigh 3 days prior to the onset of pain. Before presenting to our dermatology clinic, she was seen by a pediatrician, an emergency department physician, and an infectious disease specialist. The initial workup included a complete blood cell count, C-reactive protein test, erythrocyte sedimentation rate test, and hip and femur radiograph, which were all unremarkable. She was referred to dermatology with a differential diagnosis of sporotrichosis, contact dermatitis, reactive arthritis, viral myalgia, and Legg-Calvé-Perthes disease.

Physical examination revealed a well-appearing child with pink eczematous patches and plaques extending from the left side of the lower back to the mid shin in an L5 distribution (Figure). The left thigh was tender to palpation, and nontender left inguinal lymphadenopathy was present. A single isolated 2-mm vesicle was found on the anterior aspect of the left lower leg. Direct fluorescent antibody testing of vesicle fluid was positive for VZV antigen, confirming the diagnosis of HZ.

Comment

Herpes zoster is rare in young healthy children, and its incidence has decreased since the introduction of universal varicella vaccination.⁴ Reported incidence rates in vaccinated children vary from approximately 15 to 93 per 100,000 person-years,^5,6 and the reported relative risk is 0.08 to 0.36 in vaccinated compared to unvaccinated children.^6,7 No correlations with gender, race, or ethnicity and postvaccination HZ have been observed.^5,8 Reported intervals between vaccination and HZ presentation are as short as 3 months and as long as 11 years.⁹ Although HZ is uncommon in immunocompetent children, the diagnosis of HZ itself is not an indication for formal workup for an underlying immunodeficiency or malignancy.¹⁰

Both wild-type and vaccine-strain VZV establish latent infection and can cause HZ in vaccinated children. Direct fluorescent antibody testing or polymerase chain reaction of HZ lesions can be used to identify VZV. Genotyping can distinguish the wild-type versus the vaccine strain but is not required for clinical management.³ In previously vaccinated children with HZ, approximately half present with wild-type and half with vaccine-strain VZV. In approximately half of wild-type cases, prior clinical varicella infection also occurred.⁸

Regardless of virus strain, vaccinated children typically present with the characteristic painful, vesicular, dermatomal HZ rash.^8,9 This presentation can be milder with less pain and fewer vesicles than with unvaccinated cases.⁶ When vaccine-strain HZ occurs, the rash often presents at or near the site of initial vaccination, which typically is the arm or thigh.^3,4,6,9 The vaccine strain has lower virulence than the wild-type virus. Eight cases of vaccine-strain zoster severe enough to cause neurological complications such as meningitis or encephalitis have been reported in children, with 6 cases reported in healthy children.^9,11-17 Antiviral drugs hasten the healing of the HZ rash and shorten the duration of associated pain.¹

Although pediatric HZ is uncommon, all physicians should be aware of possible atypical presentations in healthy vaccinated children to appropriately and quickly manage treatment.

Varicella-zoster virus (VZV) is a neurotropic human herpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). During infection, the virus invades the dorsal root ganglia and establishes permanent latency. It can later reactivate and travel through sensory nerves to the skin where localized viral replication causes herpes zoster (HZ), which manifests with pain in a unilateral dermatomal distribution followed closely by an eruption of grouped macules and papules that evolve into vesicles on an erythematous base.¹ These lesions form pustules and crusts over 7 to 10 days and heal completely within 4 weeks. Although postherpetic neuralgia is rare in children, the pain associated with HZ can last months or years.^1,2

Universal childhood vaccination against VZV has existed in the United States since 1995, with a 2-dose vaccine regimen recommended by the CDC since 2007. Consequently, primary varicella infection in children is uncommon, and the majority of cases now occur in the vaccinated population.³ However, breakthrough varicella infection and postvaccination HZ are rare due to the long-lasting immunity and low virulence of the attenuated vaccine strain. We recount the case of a 6-year-old vaccinated girl with a unique presentation of HZ with no known primary varicella infection.

Case Report

A healthy 6-year-old girl presented with a stabbing burning pain in the left thigh extending down the calf of 4 days’ duration. The intense pain made walking difficult and responded minimally to ibuprofen and naproxen. Poor appetite, nausea, colicky abdominal pain, and fever (temperature, 38°C) accompanied the pain. Three days after the pain began she developed a pruritic rash on the same leg. Notably, she reported falling on a rosebush and sustaining a thorn prick in the left thigh 3 days prior to the onset of pain. Before presenting to our dermatology clinic, she was seen by a pediatrician, an emergency department physician, and an infectious disease specialist. The initial workup included a complete blood cell count, C-reactive protein test, erythrocyte sedimentation rate test, and hip and femur radiograph, which were all unremarkable. She was referred to dermatology with a differential diagnosis of sporotrichosis, contact dermatitis, reactive arthritis, viral myalgia, and Legg-Calvé-Perthes disease.

Physical examination revealed a well-appearing child with pink eczematous patches and plaques extending from the left side of the lower back to the mid shin in an L5 distribution (Figure). The left thigh was tender to palpation, and nontender left inguinal lymphadenopathy was present. A single isolated 2-mm vesicle was found on the anterior aspect of the left lower leg. Direct fluorescent antibody testing of vesicle fluid was positive for VZV antigen, confirming the diagnosis of HZ.

Comment

Herpes zoster is rare in young healthy children, and its incidence has decreased since the introduction of universal varicella vaccination.⁴ Reported incidence rates in vaccinated children vary from approximately 15 to 93 per 100,000 person-years,^5,6 and the reported relative risk is 0.08 to 0.36 in vaccinated compared to unvaccinated children.^6,7 No correlations with gender, race, or ethnicity and postvaccination HZ have been observed.^5,8 Reported intervals between vaccination and HZ presentation are as short as 3 months and as long as 11 years.⁹ Although HZ is uncommon in immunocompetent children, the diagnosis of HZ itself is not an indication for formal workup for an underlying immunodeficiency or malignancy.¹⁰

Both wild-type and vaccine-strain VZV establish latent infection and can cause HZ in vaccinated children. Direct fluorescent antibody testing or polymerase chain reaction of HZ lesions can be used to identify VZV. Genotyping can distinguish the wild-type versus the vaccine strain but is not required for clinical management.³ In previously vaccinated children with HZ, approximately half present with wild-type and half with vaccine-strain VZV. In approximately half of wild-type cases, prior clinical varicella infection also occurred.⁸

Regardless of virus strain, vaccinated children typically present with the characteristic painful, vesicular, dermatomal HZ rash.^8,9 This presentation can be milder with less pain and fewer vesicles than with unvaccinated cases.⁶ When vaccine-strain HZ occurs, the rash often presents at or near the site of initial vaccination, which typically is the arm or thigh.^3,4,6,9 The vaccine strain has lower virulence than the wild-type virus. Eight cases of vaccine-strain zoster severe enough to cause neurological complications such as meningitis or encephalitis have been reported in children, with 6 cases reported in healthy children.^9,11-17 Antiviral drugs hasten the healing of the HZ rash and shorten the duration of associated pain.¹

Although pediatric HZ is uncommon, all physicians should be aware of possible atypical presentations in healthy vaccinated children to appropriately and quickly manage treatment.

Varicella-zoster virus (VZV) is a neurotropic human herpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). During infection, the virus invades the dorsal root ganglia and establishes permanent latency. It can later reactivate and travel through sensory nerves to the skin where localized viral replication causes herpes zoster (HZ), which manifests with pain in a unilateral dermatomal distribution followed closely by an eruption of grouped macules and papules that evolve into vesicles on an erythematous base.¹ These lesions form pustules and crusts over 7 to 10 days and heal completely within 4 weeks. Although postherpetic neuralgia is rare in children, the pain associated with HZ can last months or years.^1,2

Universal childhood vaccination against VZV has existed in the United States since 1995, with a 2-dose vaccine regimen recommended by the CDC since 2007. Consequently, primary varicella infection in children is uncommon, and the majority of cases now occur in the vaccinated population.³ However, breakthrough varicella infection and postvaccination HZ are rare due to the long-lasting immunity and low virulence of the attenuated vaccine strain. We recount the case of a 6-year-old vaccinated girl with a unique presentation of HZ with no known primary varicella infection.

Case Report

A healthy 6-year-old girl presented with a stabbing burning pain in the left thigh extending down the calf of 4 days’ duration. The intense pain made walking difficult and responded minimally to ibuprofen and naproxen. Poor appetite, nausea, colicky abdominal pain, and fever (temperature, 38°C) accompanied the pain. Three days after the pain began she developed a pruritic rash on the same leg. Notably, she reported falling on a rosebush and sustaining a thorn prick in the left thigh 3 days prior to the onset of pain. Before presenting to our dermatology clinic, she was seen by a pediatrician, an emergency department physician, and an infectious disease specialist. The initial workup included a complete blood cell count, C-reactive protein test, erythrocyte sedimentation rate test, and hip and femur radiograph, which were all unremarkable. She was referred to dermatology with a differential diagnosis of sporotrichosis, contact dermatitis, reactive arthritis, viral myalgia, and Legg-Calvé-Perthes disease.

Physical examination revealed a well-appearing child with pink eczematous patches and plaques extending from the left side of the lower back to the mid shin in an L5 distribution (Figure). The left thigh was tender to palpation, and nontender left inguinal lymphadenopathy was present. A single isolated 2-mm vesicle was found on the anterior aspect of the left lower leg. Direct fluorescent antibody testing of vesicle fluid was positive for VZV antigen, confirming the diagnosis of HZ.

Comment

Herpes zoster is rare in young healthy children, and its incidence has decreased since the introduction of universal varicella vaccination.⁴ Reported incidence rates in vaccinated children vary from approximately 15 to 93 per 100,000 person-years,^5,6 and the reported relative risk is 0.08 to 0.36 in vaccinated compared to unvaccinated children.^6,7 No correlations with gender, race, or ethnicity and postvaccination HZ have been observed.^5,8 Reported intervals between vaccination and HZ presentation are as short as 3 months and as long as 11 years.⁹ Although HZ is uncommon in immunocompetent children, the diagnosis of HZ itself is not an indication for formal workup for an underlying immunodeficiency or malignancy.¹⁰

Both wild-type and vaccine-strain VZV establish latent infection and can cause HZ in vaccinated children. Direct fluorescent antibody testing or polymerase chain reaction of HZ lesions can be used to identify VZV. Genotyping can distinguish the wild-type versus the vaccine strain but is not required for clinical management.³ In previously vaccinated children with HZ, approximately half present with wild-type and half with vaccine-strain VZV. In approximately half of wild-type cases, prior clinical varicella infection also occurred.⁸

Regardless of virus strain, vaccinated children typically present with the characteristic painful, vesicular, dermatomal HZ rash.^8,9 This presentation can be milder with less pain and fewer vesicles than with unvaccinated cases.⁶ When vaccine-strain HZ occurs, the rash often presents at or near the site of initial vaccination, which typically is the arm or thigh.^3,4,6,9 The vaccine strain has lower virulence than the wild-type virus. Eight cases of vaccine-strain zoster severe enough to cause neurological complications such as meningitis or encephalitis have been reported in children, with 6 cases reported in healthy children.^9,11-17 Antiviral drugs hasten the healing of the HZ rash and shorten the duration of associated pain.¹

Although pediatric HZ is uncommon, all physicians should be aware of possible atypical presentations in healthy vaccinated children to appropriately and quickly manage treatment.