Imaging

Periprocedural administration of intravenous sodium bicarbonate did not improve outcomes compared with standard sodium chloride in patients with impaired kidney function undergoing angiography, according to results of a randomized study of 5,177 patients.

In addition, there was no benefit for oral acetylcysteine administration over placebo for mitigating those same postangiography risks, Steven D. Weisbord, MD, said at the American Heart Association scientific sessions in Anaheim, Calif.

Hypothetically, both sodium bicarbonate and acetylcysteine could help prevent acute kidney injury associated with contrast material used during angiography, said Dr. Weisbord of the University of Pittsburgh.

However, multiple studies of the two agents have yielded “inconsistent results … consequently, equipoise exists regarding these interventions, despite their widespread use in clinical practice,” Dr. Weisbord said.

To provide more definitive evidence, Dr. Weisbord and his colleagues conducted PRESERVE, a multicenter, randomized, controlled trial comprising 5,177 patients scheduled for angiography who were at high risk of renal complications. Using a 2-by-2 factorial design, patients were randomized to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride, and to 5 days of oral acetylcysteine or oral placebo.

They found no significant differences between arms in the study’s composite primary endpoint of death, need for dialysis, or persistent increase in serum creatinine by 50% or more.

That composite endpoint occurred in 4.4% of patients receiving sodium bicarbonate, and similarly in 4.7% of patients receiving sodium chloride.

Likewise, the endpoint occurred in 4.6% of patients in the acetylcysteine group and 4.5% of the placebo group, Dr. Weisbord reported.

The investigators had planned to enroll 7,680 patients, but the sponsor of the trial stopped the study after enrollment of 5,177 based on the results showing no significant benefit of either treatment, he noted.

There are a few reasons why results of PRESERVE might show a lack of benefit for these agents, in contrast to some previous studies suggesting both the treatments might reduce risk of contrast-associated renal complications in high-risk patients.

Notably, “most of these interventions have been underpowered,” Dr. Weisbord noted.

Also, most previous trials used a primary endpoint of increase in blood creatinine level within days of the angiography. By contrast, the primary endpoint of the current study was a composite of serious adverse events “that are recognized sequelae of acute kidney injury,” he added.

Although subsequent investigations could shed new light on the controversy, the findings of PRESERVE support the “strong likelihood that these interventions are not clinically effective” in preventing acute kidney injury or longer-term adverse outcomes after angiography, he concluded.

The PRESERVE results were published simultaneously with Dr. Weisbord’s presentation (N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMoa1710933).

The study was supported by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia. Dr. Weisbord reported receiving personal fees from Durect outside the submitted work.

Periprocedural administration of intravenous sodium bicarbonate did not improve outcomes compared with standard sodium chloride in patients with impaired kidney function undergoing angiography, according to results of a randomized study of 5,177 patients.

In addition, there was no benefit for oral acetylcysteine administration over placebo for mitigating those same postangiography risks, Steven D. Weisbord, MD, said at the American Heart Association scientific sessions in Anaheim, Calif.

Hypothetically, both sodium bicarbonate and acetylcysteine could help prevent acute kidney injury associated with contrast material used during angiography, said Dr. Weisbord of the University of Pittsburgh.

However, multiple studies of the two agents have yielded “inconsistent results … consequently, equipoise exists regarding these interventions, despite their widespread use in clinical practice,” Dr. Weisbord said.

To provide more definitive evidence, Dr. Weisbord and his colleagues conducted PRESERVE, a multicenter, randomized, controlled trial comprising 5,177 patients scheduled for angiography who were at high risk of renal complications. Using a 2-by-2 factorial design, patients were randomized to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride, and to 5 days of oral acetylcysteine or oral placebo.

They found no significant differences between arms in the study’s composite primary endpoint of death, need for dialysis, or persistent increase in serum creatinine by 50% or more.

That composite endpoint occurred in 4.4% of patients receiving sodium bicarbonate, and similarly in 4.7% of patients receiving sodium chloride.

Likewise, the endpoint occurred in 4.6% of patients in the acetylcysteine group and 4.5% of the placebo group, Dr. Weisbord reported.

The investigators had planned to enroll 7,680 patients, but the sponsor of the trial stopped the study after enrollment of 5,177 based on the results showing no significant benefit of either treatment, he noted.

There are a few reasons why results of PRESERVE might show a lack of benefit for these agents, in contrast to some previous studies suggesting both the treatments might reduce risk of contrast-associated renal complications in high-risk patients.

Notably, “most of these interventions have been underpowered,” Dr. Weisbord noted.

Also, most previous trials used a primary endpoint of increase in blood creatinine level within days of the angiography. By contrast, the primary endpoint of the current study was a composite of serious adverse events “that are recognized sequelae of acute kidney injury,” he added.

Although subsequent investigations could shed new light on the controversy, the findings of PRESERVE support the “strong likelihood that these interventions are not clinically effective” in preventing acute kidney injury or longer-term adverse outcomes after angiography, he concluded.

The PRESERVE results were published simultaneously with Dr. Weisbord’s presentation (N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMoa1710933).

The study was supported by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia. Dr. Weisbord reported receiving personal fees from Durect outside the submitted work.

Periprocedural administration of intravenous sodium bicarbonate did not improve outcomes compared with standard sodium chloride in patients with impaired kidney function undergoing angiography, according to results of a randomized study of 5,177 patients.

In addition, there was no benefit for oral acetylcysteine administration over placebo for mitigating those same postangiography risks, Steven D. Weisbord, MD, said at the American Heart Association scientific sessions in Anaheim, Calif.

Hypothetically, both sodium bicarbonate and acetylcysteine could help prevent acute kidney injury associated with contrast material used during angiography, said Dr. Weisbord of the University of Pittsburgh.

However, multiple studies of the two agents have yielded “inconsistent results … consequently, equipoise exists regarding these interventions, despite their widespread use in clinical practice,” Dr. Weisbord said.

To provide more definitive evidence, Dr. Weisbord and his colleagues conducted PRESERVE, a multicenter, randomized, controlled trial comprising 5,177 patients scheduled for angiography who were at high risk of renal complications. Using a 2-by-2 factorial design, patients were randomized to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride, and to 5 days of oral acetylcysteine or oral placebo.

They found no significant differences between arms in the study’s composite primary endpoint of death, need for dialysis, or persistent increase in serum creatinine by 50% or more.

That composite endpoint occurred in 4.4% of patients receiving sodium bicarbonate, and similarly in 4.7% of patients receiving sodium chloride.

Likewise, the endpoint occurred in 4.6% of patients in the acetylcysteine group and 4.5% of the placebo group, Dr. Weisbord reported.

The investigators had planned to enroll 7,680 patients, but the sponsor of the trial stopped the study after enrollment of 5,177 based on the results showing no significant benefit of either treatment, he noted.

There are a few reasons why results of PRESERVE might show a lack of benefit for these agents, in contrast to some previous studies suggesting both the treatments might reduce risk of contrast-associated renal complications in high-risk patients.

Notably, “most of these interventions have been underpowered,” Dr. Weisbord noted.

Also, most previous trials used a primary endpoint of increase in blood creatinine level within days of the angiography. By contrast, the primary endpoint of the current study was a composite of serious adverse events “that are recognized sequelae of acute kidney injury,” he added.

Although subsequent investigations could shed new light on the controversy, the findings of PRESERVE support the “strong likelihood that these interventions are not clinically effective” in preventing acute kidney injury or longer-term adverse outcomes after angiography, he concluded.

The PRESERVE results were published simultaneously with Dr. Weisbord’s presentation (N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMoa1710933).

The study was supported by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia. Dr. Weisbord reported receiving personal fees from Durect outside the submitted work.

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.

Smells – of skin, breath, or bodily fluids – can, in some cases, reveal the presence of disease. This fact has led researchers to try to build an odor sensor that could make a fast, reliable diagnosis, and now the field may be on the verge of a breakthrough, according to a recent article in the New York Times.

In addition to various efforts in Austria, Switzerland, and Japan, an English manufacturer – Owlstone Medical – has been making headway with an odor analysis technology. It will be part of a National Health Service trial that will test the sensor for diagnosing lung cancer. The company also is conducting a trial using urine samples to detect colon cancer; its program allows changing the software to change what disease you detect.

Meanwhile, an Israeli chemical engineer, Hossam Haick, is using similar technology, with molecular receptors that have an affinity for certain biomarkers of disease found in the breath. Artificial intelligence allows the sensors to improve with each use, and a paper published last year showed that this system could distinguish among 17 different diseases with up to 86% accuracy.

And in the United States, researchers from the Monell Chemical Senses Center and the University of Pennsylvania are working on an odor sensor that detects ovarian cancer in samples of blood plasma. They chose plasma because it is less likely than breath or urine to be affected by other factors such as diet or environmental chemicals.

These technologies could be available to doctors in 3-5 years, experts say.

Reference

Murphy K. One Day, a Machine Will Smell Whether You’re Sick . New York Times. May 1, 2017. Accessed May 29, 2017.

Smells – of skin, breath, or bodily fluids – can, in some cases, reveal the presence of disease. This fact has led researchers to try to build an odor sensor that could make a fast, reliable diagnosis, and now the field may be on the verge of a breakthrough, according to a recent article in the New York Times.

In addition to various efforts in Austria, Switzerland, and Japan, an English manufacturer – Owlstone Medical – has been making headway with an odor analysis technology. It will be part of a National Health Service trial that will test the sensor for diagnosing lung cancer. The company also is conducting a trial using urine samples to detect colon cancer; its program allows changing the software to change what disease you detect.

Meanwhile, an Israeli chemical engineer, Hossam Haick, is using similar technology, with molecular receptors that have an affinity for certain biomarkers of disease found in the breath. Artificial intelligence allows the sensors to improve with each use, and a paper published last year showed that this system could distinguish among 17 different diseases with up to 86% accuracy.

And in the United States, researchers from the Monell Chemical Senses Center and the University of Pennsylvania are working on an odor sensor that detects ovarian cancer in samples of blood plasma. They chose plasma because it is less likely than breath or urine to be affected by other factors such as diet or environmental chemicals.

These technologies could be available to doctors in 3-5 years, experts say.

Reference

Murphy K. One Day, a Machine Will Smell Whether You’re Sick . New York Times. May 1, 2017. Accessed May 29, 2017.

Smells – of skin, breath, or bodily fluids – can, in some cases, reveal the presence of disease. This fact has led researchers to try to build an odor sensor that could make a fast, reliable diagnosis, and now the field may be on the verge of a breakthrough, according to a recent article in the New York Times.

In addition to various efforts in Austria, Switzerland, and Japan, an English manufacturer – Owlstone Medical – has been making headway with an odor analysis technology. It will be part of a National Health Service trial that will test the sensor for diagnosing lung cancer. The company also is conducting a trial using urine samples to detect colon cancer; its program allows changing the software to change what disease you detect.

Meanwhile, an Israeli chemical engineer, Hossam Haick, is using similar technology, with molecular receptors that have an affinity for certain biomarkers of disease found in the breath. Artificial intelligence allows the sensors to improve with each use, and a paper published last year showed that this system could distinguish among 17 different diseases with up to 86% accuracy.

And in the United States, researchers from the Monell Chemical Senses Center and the University of Pennsylvania are working on an odor sensor that detects ovarian cancer in samples of blood plasma. They chose plasma because it is less likely than breath or urine to be affected by other factors such as diet or environmental chemicals.

These technologies could be available to doctors in 3-5 years, experts say.

Reference

Murphy K. One Day, a Machine Will Smell Whether You’re Sick . New York Times. May 1, 2017. Accessed May 29, 2017.

Clinical question: Do rib fractures observed on chest CT carry the same morbidity and mortality risk as those observed in chest radiograph?

Background: Traditionally studies have shown that first and second rib fractures on chest radiograph after blunt trauma are associated with substantial morbidity and mortality. With growing frequency of CT imaging in the “panscan” era, it is unknown whether similar rib fractures found on CT carry the same meaning.

Dr. Xu is assistant professor and hospitalist, Icahn School of Medicine of the Mount Sinai Health System, New York.
 

Clinical question: Do rib fractures observed on chest CT carry the same morbidity and mortality risk as those observed in chest radiograph?

Background: Traditionally studies have shown that first and second rib fractures on chest radiograph after blunt trauma are associated with substantial morbidity and mortality. With growing frequency of CT imaging in the “panscan” era, it is unknown whether similar rib fractures found on CT carry the same meaning.

Dr. Xu is assistant professor and hospitalist, Icahn School of Medicine of the Mount Sinai Health System, New York.
 

Clinical question: Do rib fractures observed on chest CT carry the same morbidity and mortality risk as those observed in chest radiograph?

Background: Traditionally studies have shown that first and second rib fractures on chest radiograph after blunt trauma are associated with substantial morbidity and mortality. With growing frequency of CT imaging in the “panscan” era, it is unknown whether similar rib fractures found on CT carry the same meaning.

Dr. Xu is assistant professor and hospitalist, Icahn School of Medicine of the Mount Sinai Health System, New York.
 

A woman in her 30s presented with an itchy skin-colored rash over her left scapular region that had first appeared 8 years earlier. It had started as itchy skin-colored papules that coalesced to a patch and later became hyperpigmented because of repeated scratching.

She had undergone total thyroidectomy for medullary thyroid carcinoma 1 year ago, and the rash had been diagnosed at that time as lichen planus. She was referred to us by her physician for histopathologic confirmation of the lesions. She denied any history of episodic headache or palpitation.

Her urine normetanephrine excretion was elevated at 1,425 μg/day (reference range 148–560), and her metanephrine excretion was also high at 2,024 μg/day (reference range 44–261).

At a 3-month follow-up visit, the woman’s skin lesions had improved with twice-a-day application of mometasone 0.1% cream; she was lost to follow-up after that visit.

MULTIPLE ENDOCRINE NEOPLASIA

Our patient’s scapular lesions and first-degree family history of MEN type 2A confirmed the diagnosis of the newly recognized variant, MEN type 2A-related cutaneous lichen amyloidosis, in which the characteristic pigmented scapular rash typically predates the first diagnosis of neoplasia.¹ The dermal amyloidosis is caused by deposition of keratinlike peptides rather than calcitoninlike peptides.²

A recent systematic review on MEN type 2A with cutaneous lichen amyloidosis showed a female preponderance and a high penetrance of cutaneous lichen amyloidosis, which was the second most frequent manifestation of the syndrome, preceded only by medullary thyroid carcinoma.¹

As in our patient’s case, scapular rash and a history of medullary thyroid carcinoma should prompt an investigation for MEN type 2A. These patients should be closely followed for underlying MEN type 2A-related neoplasms.

The mucosal neuromas and skin lipomas seen in MEN type 1 and MEN type 2B are absent in MEN type 2A.³ Cutaneous lichen amyloidosis is the only dermatologic marker for MEN type 2A. Owing to a similar genetic background, cutaneous lichen amyloidosis is also associated with familial medullary thyroid carcinoma, another rare variant of MEN type 2A.⁴

DIFFERENTIAL DIAGNOSIS

Notalgia paresthetica is a unilateral chronic neuropathic pruritus on the back, mostly located between the shoulders and corresponding to the second and the sixth thoracic nerves. It is mostly attributed to compression of spinal nerves by an abnormality of the thoracic spine.⁵ In our patient, this was ruled out by the radiologic evaluation.

Before MEN type 2A with cutaneous lichen amyloidosis was recognized as a variant of MEN type 2A, lesions suggestive of notalgia paresthetica were reported with MEN type 2A.³ The classic infrascapular location, history of painful neck muscle spasms, touch hyperesthesia of the lesions, and absence of amyloid deposits on histopathologic study help to differentiate notalgia paresthetica from cutaneous lichen amyloidosis. However, later phases of notalgia paresthetica may show amyloid deposits on histopathologic study, while detection of a scant amount of amyloid is difficult in the early stages of cutaneous lichen amyloidosis.

TAKE-HOME POINT

Cutaneous lichen amyloidosis is usually seen on the extensor surfaces of the extremities. It is considered benign, caused by filamentous degeneration of keratinocytes from repeated scratching. But cutaneous lichen amyloidosis at an early age in the scapular area of women warrants a detailed family history for endocrine neoplasia, blood pressure monitoring, thyroid palpation, and blood testing for serum calcium, calcitonin, and parathyroid hormone.

A woman in her 30s presented with an itchy skin-colored rash over her left scapular region that had first appeared 8 years earlier. It had started as itchy skin-colored papules that coalesced to a patch and later became hyperpigmented because of repeated scratching.

She had undergone total thyroidectomy for medullary thyroid carcinoma 1 year ago, and the rash had been diagnosed at that time as lichen planus. She was referred to us by her physician for histopathologic confirmation of the lesions. She denied any history of episodic headache or palpitation.

Her urine normetanephrine excretion was elevated at 1,425 μg/day (reference range 148–560), and her metanephrine excretion was also high at 2,024 μg/day (reference range 44–261).

At a 3-month follow-up visit, the woman’s skin lesions had improved with twice-a-day application of mometasone 0.1% cream; she was lost to follow-up after that visit.

MULTIPLE ENDOCRINE NEOPLASIA

Our patient’s scapular lesions and first-degree family history of MEN type 2A confirmed the diagnosis of the newly recognized variant, MEN type 2A-related cutaneous lichen amyloidosis, in which the characteristic pigmented scapular rash typically predates the first diagnosis of neoplasia.¹ The dermal amyloidosis is caused by deposition of keratinlike peptides rather than calcitoninlike peptides.²

A recent systematic review on MEN type 2A with cutaneous lichen amyloidosis showed a female preponderance and a high penetrance of cutaneous lichen amyloidosis, which was the second most frequent manifestation of the syndrome, preceded only by medullary thyroid carcinoma.¹

As in our patient’s case, scapular rash and a history of medullary thyroid carcinoma should prompt an investigation for MEN type 2A. These patients should be closely followed for underlying MEN type 2A-related neoplasms.

The mucosal neuromas and skin lipomas seen in MEN type 1 and MEN type 2B are absent in MEN type 2A.³ Cutaneous lichen amyloidosis is the only dermatologic marker for MEN type 2A. Owing to a similar genetic background, cutaneous lichen amyloidosis is also associated with familial medullary thyroid carcinoma, another rare variant of MEN type 2A.⁴

DIFFERENTIAL DIAGNOSIS

Notalgia paresthetica is a unilateral chronic neuropathic pruritus on the back, mostly located between the shoulders and corresponding to the second and the sixth thoracic nerves. It is mostly attributed to compression of spinal nerves by an abnormality of the thoracic spine.⁵ In our patient, this was ruled out by the radiologic evaluation.

Before MEN type 2A with cutaneous lichen amyloidosis was recognized as a variant of MEN type 2A, lesions suggestive of notalgia paresthetica were reported with MEN type 2A.³ The classic infrascapular location, history of painful neck muscle spasms, touch hyperesthesia of the lesions, and absence of amyloid deposits on histopathologic study help to differentiate notalgia paresthetica from cutaneous lichen amyloidosis. However, later phases of notalgia paresthetica may show amyloid deposits on histopathologic study, while detection of a scant amount of amyloid is difficult in the early stages of cutaneous lichen amyloidosis.

TAKE-HOME POINT

Cutaneous lichen amyloidosis is usually seen on the extensor surfaces of the extremities. It is considered benign, caused by filamentous degeneration of keratinocytes from repeated scratching. But cutaneous lichen amyloidosis at an early age in the scapular area of women warrants a detailed family history for endocrine neoplasia, blood pressure monitoring, thyroid palpation, and blood testing for serum calcium, calcitonin, and parathyroid hormone.

A woman in her 30s presented with an itchy skin-colored rash over her left scapular region that had first appeared 8 years earlier. It had started as itchy skin-colored papules that coalesced to a patch and later became hyperpigmented because of repeated scratching.

She had undergone total thyroidectomy for medullary thyroid carcinoma 1 year ago, and the rash had been diagnosed at that time as lichen planus. She was referred to us by her physician for histopathologic confirmation of the lesions. She denied any history of episodic headache or palpitation.

Her urine normetanephrine excretion was elevated at 1,425 μg/day (reference range 148–560), and her metanephrine excretion was also high at 2,024 μg/day (reference range 44–261).

At a 3-month follow-up visit, the woman’s skin lesions had improved with twice-a-day application of mometasone 0.1% cream; she was lost to follow-up after that visit.

MULTIPLE ENDOCRINE NEOPLASIA

Our patient’s scapular lesions and first-degree family history of MEN type 2A confirmed the diagnosis of the newly recognized variant, MEN type 2A-related cutaneous lichen amyloidosis, in which the characteristic pigmented scapular rash typically predates the first diagnosis of neoplasia.¹ The dermal amyloidosis is caused by deposition of keratinlike peptides rather than calcitoninlike peptides.²

A recent systematic review on MEN type 2A with cutaneous lichen amyloidosis showed a female preponderance and a high penetrance of cutaneous lichen amyloidosis, which was the second most frequent manifestation of the syndrome, preceded only by medullary thyroid carcinoma.¹

As in our patient’s case, scapular rash and a history of medullary thyroid carcinoma should prompt an investigation for MEN type 2A. These patients should be closely followed for underlying MEN type 2A-related neoplasms.

The mucosal neuromas and skin lipomas seen in MEN type 1 and MEN type 2B are absent in MEN type 2A.³ Cutaneous lichen amyloidosis is the only dermatologic marker for MEN type 2A. Owing to a similar genetic background, cutaneous lichen amyloidosis is also associated with familial medullary thyroid carcinoma, another rare variant of MEN type 2A.⁴

DIFFERENTIAL DIAGNOSIS

Notalgia paresthetica is a unilateral chronic neuropathic pruritus on the back, mostly located between the shoulders and corresponding to the second and the sixth thoracic nerves. It is mostly attributed to compression of spinal nerves by an abnormality of the thoracic spine.⁵ In our patient, this was ruled out by the radiologic evaluation.

Before MEN type 2A with cutaneous lichen amyloidosis was recognized as a variant of MEN type 2A, lesions suggestive of notalgia paresthetica were reported with MEN type 2A.³ The classic infrascapular location, history of painful neck muscle spasms, touch hyperesthesia of the lesions, and absence of amyloid deposits on histopathologic study help to differentiate notalgia paresthetica from cutaneous lichen amyloidosis. However, later phases of notalgia paresthetica may show amyloid deposits on histopathologic study, while detection of a scant amount of amyloid is difficult in the early stages of cutaneous lichen amyloidosis.

TAKE-HOME POINT

Cutaneous lichen amyloidosis is usually seen on the extensor surfaces of the extremities. It is considered benign, caused by filamentous degeneration of keratinocytes from repeated scratching. But cutaneous lichen amyloidosis at an early age in the scapular area of women warrants a detailed family history for endocrine neoplasia, blood pressure monitoring, thyroid palpation, and blood testing for serum calcium, calcitonin, and parathyroid hormone.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A  52-year-old woman with diabetes mellitus presented with a 1-month history of pain in the right lower abdomen and right back. Although she had a fever when the pain started and her pain was aggravated by walking, her pain and fever had gotten better after taking antibiotics prescribed earlier.

The patient was admitted to the hospital for percutaneous drainage, which produced 26 mL of pus on the first day and 320 mL on the next day; culture was positive for Escherichia coli. Urine culture was also positive for E coli; blood culture was not. We concluded that these results were secondary to pyeloneph­ritis.

We started intravenous piperacillin-tazobactam 2.25 g every 8 hours for empiric therapy. We changed this to oral ampicillin-cloxacillin 2 g/day after E coli was cultured and pyelonephritis was suspected. The patient was discharged after a 2-week hospital stay, with no significant complications.

ILIOPSOAS ABSCESS: DIAGNOSTIC CLUES

Iliopsoas abscess can occur at any age.^1–3 Pain is the most common symptom, occurring in more than 90% of patients.¹ Fever with temperatures over 38°C is less common at first, found in less than half of patients.^1,2

Only 13% of patients with iliopsoas abscess may have a palpable mass on physical examination.¹ The psoas sign—a worsening of lower abdominal pain on the affected side with passive extension of the thigh while supine—has a sensitivity of only 24% for iliopsoas abscess; it can also indicate inflammation to the iliopsoas muscle in other conditions such as retrocecal appendicitis.³

Hip flexion deformity can be a helpful diagnostic feature, as 96% of patients with iliopsoas abscess hold the hip in flexion to relieve pain.⁴ But pain on hip flexion can also occur in conditions such as septic arthritis.⁴

Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein may be elevated in all patients with iliopsoas abscess, so if those markers are not elevated, we may have to consider other conditions such as cancer.¹ Computed tomography is nearly 100% sensitive for iliopsoas abscess and is the gold standard for diagnosis.³

TREATMENT

Inadequate treatment of iliopsoas abscess raises the risk of relapse and death.³ Drainage and appropriate antibiotic therapy have been shown to be effective.^1,3

Iliopsoas abscess can also be secondary to a number of conditions, eg, Crohn disease, appendicitis, intra-abdominal infection, and cancer,⁵ and the primary condition needs to be addressed. In addition, culture of a secondary abscess is more likely to grow mixed organisms.⁵

The average size of the abscess is 6 cm. Percutaneous drainage is required if the mass is larger than 3.5 cm.¹

TAKE-HOME MESSAGES

Iliopsoas abscess is difficult to diagnose because patients have few specific complaints. Checking for hip flexion deformity and inflammatory markers may help rule out the disease. When iliopsoas abscess is suspected, computed tomography is necessary to confirm the diagnosis. Drainage and appropriate antibiotics are effective treatment.

A  52-year-old woman with diabetes mellitus presented with a 1-month history of pain in the right lower abdomen and right back. Although she had a fever when the pain started and her pain was aggravated by walking, her pain and fever had gotten better after taking antibiotics prescribed earlier.

The patient was admitted to the hospital for percutaneous drainage, which produced 26 mL of pus on the first day and 320 mL on the next day; culture was positive for Escherichia coli. Urine culture was also positive for E coli; blood culture was not. We concluded that these results were secondary to pyeloneph­ritis.

We started intravenous piperacillin-tazobactam 2.25 g every 8 hours for empiric therapy. We changed this to oral ampicillin-cloxacillin 2 g/day after E coli was cultured and pyelonephritis was suspected. The patient was discharged after a 2-week hospital stay, with no significant complications.

ILIOPSOAS ABSCESS: DIAGNOSTIC CLUES

Iliopsoas abscess can occur at any age.^1–3 Pain is the most common symptom, occurring in more than 90% of patients.¹ Fever with temperatures over 38°C is less common at first, found in less than half of patients.^1,2

Only 13% of patients with iliopsoas abscess may have a palpable mass on physical examination.¹ The psoas sign—a worsening of lower abdominal pain on the affected side with passive extension of the thigh while supine—has a sensitivity of only 24% for iliopsoas abscess; it can also indicate inflammation to the iliopsoas muscle in other conditions such as retrocecal appendicitis.³

Hip flexion deformity can be a helpful diagnostic feature, as 96% of patients with iliopsoas abscess hold the hip in flexion to relieve pain.⁴ But pain on hip flexion can also occur in conditions such as septic arthritis.⁴

Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein may be elevated in all patients with iliopsoas abscess, so if those markers are not elevated, we may have to consider other conditions such as cancer.¹ Computed tomography is nearly 100% sensitive for iliopsoas abscess and is the gold standard for diagnosis.³

TREATMENT

Inadequate treatment of iliopsoas abscess raises the risk of relapse and death.³ Drainage and appropriate antibiotic therapy have been shown to be effective.^1,3

Iliopsoas abscess can also be secondary to a number of conditions, eg, Crohn disease, appendicitis, intra-abdominal infection, and cancer,⁵ and the primary condition needs to be addressed. In addition, culture of a secondary abscess is more likely to grow mixed organisms.⁵

The average size of the abscess is 6 cm. Percutaneous drainage is required if the mass is larger than 3.5 cm.¹

TAKE-HOME MESSAGES

Iliopsoas abscess is difficult to diagnose because patients have few specific complaints. Checking for hip flexion deformity and inflammatory markers may help rule out the disease. When iliopsoas abscess is suspected, computed tomography is necessary to confirm the diagnosis. Drainage and appropriate antibiotics are effective treatment.

A  52-year-old woman with diabetes mellitus presented with a 1-month history of pain in the right lower abdomen and right back. Although she had a fever when the pain started and her pain was aggravated by walking, her pain and fever had gotten better after taking antibiotics prescribed earlier.

The patient was admitted to the hospital for percutaneous drainage, which produced 26 mL of pus on the first day and 320 mL on the next day; culture was positive for Escherichia coli. Urine culture was also positive for E coli; blood culture was not. We concluded that these results were secondary to pyeloneph­ritis.

We started intravenous piperacillin-tazobactam 2.25 g every 8 hours for empiric therapy. We changed this to oral ampicillin-cloxacillin 2 g/day after E coli was cultured and pyelonephritis was suspected. The patient was discharged after a 2-week hospital stay, with no significant complications.

ILIOPSOAS ABSCESS: DIAGNOSTIC CLUES

Iliopsoas abscess can occur at any age.^1–3 Pain is the most common symptom, occurring in more than 90% of patients.¹ Fever with temperatures over 38°C is less common at first, found in less than half of patients.^1,2

Only 13% of patients with iliopsoas abscess may have a palpable mass on physical examination.¹ The psoas sign—a worsening of lower abdominal pain on the affected side with passive extension of the thigh while supine—has a sensitivity of only 24% for iliopsoas abscess; it can also indicate inflammation to the iliopsoas muscle in other conditions such as retrocecal appendicitis.³

Hip flexion deformity can be a helpful diagnostic feature, as 96% of patients with iliopsoas abscess hold the hip in flexion to relieve pain.⁴ But pain on hip flexion can also occur in conditions such as septic arthritis.⁴

Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein may be elevated in all patients with iliopsoas abscess, so if those markers are not elevated, we may have to consider other conditions such as cancer.¹ Computed tomography is nearly 100% sensitive for iliopsoas abscess and is the gold standard for diagnosis.³

TREATMENT

Inadequate treatment of iliopsoas abscess raises the risk of relapse and death.³ Drainage and appropriate antibiotic therapy have been shown to be effective.^1,3

Iliopsoas abscess can also be secondary to a number of conditions, eg, Crohn disease, appendicitis, intra-abdominal infection, and cancer,⁵ and the primary condition needs to be addressed. In addition, culture of a secondary abscess is more likely to grow mixed organisms.⁵

The average size of the abscess is 6 cm. Percutaneous drainage is required if the mass is larger than 3.5 cm.¹

TAKE-HOME MESSAGES

Iliopsoas abscess is difficult to diagnose because patients have few specific complaints. Checking for hip flexion deformity and inflammatory markers may help rule out the disease. When iliopsoas abscess is suspected, computed tomography is necessary to confirm the diagnosis. Drainage and appropriate antibiotics are effective treatment.

Case

A 3-year-old boy was brought to the ED by his parents for evaluation of left periorbital swelling. A few days prior to presentation, the child was seen at an outpatient center where he was diagnosed with preseptal cellulitis and given an oral antibiotic. However, even after receiving three doses of the antibiotic, the periorbital swelling and redness around the child’s eye worsened, prompting this visit to the ED.

Physical examination revealed edema and erythema both above and below the left eye, with associated tenderness to palpation. A contrast-enhanced maxillofacial computed tomography (CT) scan, with special attention to the orbits, was ordered; representative images are shown (Figure 1a-1c).

What is the diagnosis?

Answer

The CT images of the orbits demonstrated edema in the superficial left eyelid (white arrows, Figure 2a and 2b) and left deep orbital septum (red arrows, Figure 2a-2c). A peripherally enhancing fluid collection centered in the left nasolacrimal gland was present (red asterisks, Figure 2b and 2c) with mild mass effect on the left globe. Opacification was also noted within the paranasal sinuses (white asterisks, Figure 2a-2c). Together these findings indicated sinusitis with dacryocystitis and orbital cellulitis.

Dacryocystitis

Dacryocystitis is an infection or inflammation of the lacrimal sac, usually developing secondary to blockage of the nasolacrimal duct. Orbital cellulitis is an infection involving the contents of the orbit, including the fat and ocular muscles. Orbital cellulitis should not be confused with preseptal cellulitis, which is an infection involving the eyelid occurring posterior to the orbital septum. While both of these conditions are more common in children than in adults, preseptal cellulitis is much more common than orbital cellulitis.

Preseptal Cellulitis

Preseptal cellulitis is typically due to local trauma, local skin infection, or dacryocystitis.¹ Preseptal cellulitis rarely extends into the orbit, though a minority of cases have been reported in patients with concomitant dacryocystitis.² Orbital cellulitis most commonly results from paranasal sinus disease, particularly of the ethmoid sinus, which is only separated from the orbit by the thin lamina papyracea.³ While both preseptal cellulitis and orbital cellulitis can cause eyelid swelling and erythema, preseptal cellulitis is typically a mild condition. Orbital cellulitis, however, is a serious medical emergency that requires prompt diagnosis and treatment to avoid loss of vision and intracranial complications, such as venous thrombosis and empyema.³

Imaging Studies

Although the clinical features of orbital cellulitis (eg, proptosis, ophthalmoplegia, pain with ocular movement) can sometimes distinguish it from preseptal cellulitis, imaging studies are helpful to confirm the diagnosis.⁴ As previously noted, prompt recognition, diagnosis, and treatment of orbital cellulitis are essential to avoid serious complications.

Computed tomography has a high specificity and sensitivity in detecting the extension of infection into the orbit and associated complications such as subperiosteal or intracranial abscess. For patients in whom intravenous (IV) contrast is contraindicated or who wish to avoid ionizing radiation, magnetic resonance imaging is a useful alternate modality, and diffusion-weighted imaging is particularly sensitive in diagnosing abscess.⁵

Treatment

Since polymicrobial infection is common in periorbital cellulitis, broad-spectrum IV antibiotics (eg, ampicillin-sulbactam, cefuroxime, ceftriaxone, piperacillin/tazobactam) are usually indicated initially.⁶ The patient in this case was given IV ceftriaxone and clindamycin and oral amoxicillin/clavulanic acid for 3 days, after which he was discharged home in the care of his parents with instructions to complete a 14-day total course of oral amoxicillin/clavulanic acid as well as a 21-day course of fluticasone for nasal irrigation.

Case

A 3-year-old boy was brought to the ED by his parents for evaluation of left periorbital swelling. A few days prior to presentation, the child was seen at an outpatient center where he was diagnosed with preseptal cellulitis and given an oral antibiotic. However, even after receiving three doses of the antibiotic, the periorbital swelling and redness around the child’s eye worsened, prompting this visit to the ED.

Physical examination revealed edema and erythema both above and below the left eye, with associated tenderness to palpation. A contrast-enhanced maxillofacial computed tomography (CT) scan, with special attention to the orbits, was ordered; representative images are shown (Figure 1a-1c).

What is the diagnosis?

Answer

The CT images of the orbits demonstrated edema in the superficial left eyelid (white arrows, Figure 2a and 2b) and left deep orbital septum (red arrows, Figure 2a-2c). A peripherally enhancing fluid collection centered in the left nasolacrimal gland was present (red asterisks, Figure 2b and 2c) with mild mass effect on the left globe. Opacification was also noted within the paranasal sinuses (white asterisks, Figure 2a-2c). Together these findings indicated sinusitis with dacryocystitis and orbital cellulitis.

Dacryocystitis

Dacryocystitis is an infection or inflammation of the lacrimal sac, usually developing secondary to blockage of the nasolacrimal duct. Orbital cellulitis is an infection involving the contents of the orbit, including the fat and ocular muscles. Orbital cellulitis should not be confused with preseptal cellulitis, which is an infection involving the eyelid occurring posterior to the orbital septum. While both of these conditions are more common in children than in adults, preseptal cellulitis is much more common than orbital cellulitis.

Preseptal Cellulitis

Preseptal cellulitis is typically due to local trauma, local skin infection, or dacryocystitis.¹ Preseptal cellulitis rarely extends into the orbit, though a minority of cases have been reported in patients with concomitant dacryocystitis.² Orbital cellulitis most commonly results from paranasal sinus disease, particularly of the ethmoid sinus, which is only separated from the orbit by the thin lamina papyracea.³ While both preseptal cellulitis and orbital cellulitis can cause eyelid swelling and erythema, preseptal cellulitis is typically a mild condition. Orbital cellulitis, however, is a serious medical emergency that requires prompt diagnosis and treatment to avoid loss of vision and intracranial complications, such as venous thrombosis and empyema.³

Imaging Studies

Although the clinical features of orbital cellulitis (eg, proptosis, ophthalmoplegia, pain with ocular movement) can sometimes distinguish it from preseptal cellulitis, imaging studies are helpful to confirm the diagnosis.⁴ As previously noted, prompt recognition, diagnosis, and treatment of orbital cellulitis are essential to avoid serious complications.

Computed tomography has a high specificity and sensitivity in detecting the extension of infection into the orbit and associated complications such as subperiosteal or intracranial abscess. For patients in whom intravenous (IV) contrast is contraindicated or who wish to avoid ionizing radiation, magnetic resonance imaging is a useful alternate modality, and diffusion-weighted imaging is particularly sensitive in diagnosing abscess.⁵

Treatment

Since polymicrobial infection is common in periorbital cellulitis, broad-spectrum IV antibiotics (eg, ampicillin-sulbactam, cefuroxime, ceftriaxone, piperacillin/tazobactam) are usually indicated initially.⁶ The patient in this case was given IV ceftriaxone and clindamycin and oral amoxicillin/clavulanic acid for 3 days, after which he was discharged home in the care of his parents with instructions to complete a 14-day total course of oral amoxicillin/clavulanic acid as well as a 21-day course of fluticasone for nasal irrigation.

Case

A 3-year-old boy was brought to the ED by his parents for evaluation of left periorbital swelling. A few days prior to presentation, the child was seen at an outpatient center where he was diagnosed with preseptal cellulitis and given an oral antibiotic. However, even after receiving three doses of the antibiotic, the periorbital swelling and redness around the child’s eye worsened, prompting this visit to the ED.

Physical examination revealed edema and erythema both above and below the left eye, with associated tenderness to palpation. A contrast-enhanced maxillofacial computed tomography (CT) scan, with special attention to the orbits, was ordered; representative images are shown (Figure 1a-1c).

What is the diagnosis?

Answer

The CT images of the orbits demonstrated edema in the superficial left eyelid (white arrows, Figure 2a and 2b) and left deep orbital septum (red arrows, Figure 2a-2c). A peripherally enhancing fluid collection centered in the left nasolacrimal gland was present (red asterisks, Figure 2b and 2c) with mild mass effect on the left globe. Opacification was also noted within the paranasal sinuses (white asterisks, Figure 2a-2c). Together these findings indicated sinusitis with dacryocystitis and orbital cellulitis.

Dacryocystitis

Dacryocystitis is an infection or inflammation of the lacrimal sac, usually developing secondary to blockage of the nasolacrimal duct. Orbital cellulitis is an infection involving the contents of the orbit, including the fat and ocular muscles. Orbital cellulitis should not be confused with preseptal cellulitis, which is an infection involving the eyelid occurring posterior to the orbital septum. While both of these conditions are more common in children than in adults, preseptal cellulitis is much more common than orbital cellulitis.

Preseptal Cellulitis

Preseptal cellulitis is typically due to local trauma, local skin infection, or dacryocystitis.¹ Preseptal cellulitis rarely extends into the orbit, though a minority of cases have been reported in patients with concomitant dacryocystitis.² Orbital cellulitis most commonly results from paranasal sinus disease, particularly of the ethmoid sinus, which is only separated from the orbit by the thin lamina papyracea.³ While both preseptal cellulitis and orbital cellulitis can cause eyelid swelling and erythema, preseptal cellulitis is typically a mild condition. Orbital cellulitis, however, is a serious medical emergency that requires prompt diagnosis and treatment to avoid loss of vision and intracranial complications, such as venous thrombosis and empyema.³

Imaging Studies

Although the clinical features of orbital cellulitis (eg, proptosis, ophthalmoplegia, pain with ocular movement) can sometimes distinguish it from preseptal cellulitis, imaging studies are helpful to confirm the diagnosis.⁴ As previously noted, prompt recognition, diagnosis, and treatment of orbital cellulitis are essential to avoid serious complications.

Computed tomography has a high specificity and sensitivity in detecting the extension of infection into the orbit and associated complications such as subperiosteal or intracranial abscess. For patients in whom intravenous (IV) contrast is contraindicated or who wish to avoid ionizing radiation, magnetic resonance imaging is a useful alternate modality, and diffusion-weighted imaging is particularly sensitive in diagnosing abscess.⁵

Treatment

Since polymicrobial infection is common in periorbital cellulitis, broad-spectrum IV antibiotics (eg, ampicillin-sulbactam, cefuroxime, ceftriaxone, piperacillin/tazobactam) are usually indicated initially.⁶ The patient in this case was given IV ceftriaxone and clindamycin and oral amoxicillin/clavulanic acid for 3 days, after which he was discharged home in the care of his parents with instructions to complete a 14-day total course of oral amoxicillin/clavulanic acid as well as a 21-day course of fluticasone for nasal irrigation.

A 41-year-old woman presented with coughing, wheezing, and painful subcutaneous nodules on her legs. She had presented 6 years ago with similar nodules and enlarged retroauricular, occipital, and maxillary lymph nodes. At that time, biopsy study of submaxillary lymph nodes and skin showed nonnecrotizing granulomas, with negative microbiology studies. Chest radiography and spirometry were normal. A diagnosis of sarcoidosis was made. Treatment was offered but refused.

Based on this history, computed tomography of the thorax and abdomen was performed and showed mediastinal and hilar lymphadenopathy, small bilateral lung nodules, and osseous cystic areas in both iliac blades. Magnetic resonance imaging (MRI) showed numerous discrete lesions in both iliac bones (Figure 1). Biopsy study of iliac bone revealed preserved architecture with no evidence of malignancy or granulomas.

Radiography of the hands showed an osseous lytic lesion in the third proximal phalanx of the right hand. No other radiographic abnormalities were noted.

The clinical and radiographic features and the patient’s clinical course were consistent with osseous sarcoidosis. She was started on methotrexate and a low-dose corticosteroid and was symptom-free at 12-month follow-up. Follow-up MRI showed reduction in the lymphadenopathies and stabilization of the bone lesions.

SARCOIDOSIS AND BONE

Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases. Skeletal involvement has been reported in 1% to 14% of patients.^1,2 Typical osseous involvement is cystic osteitis of the phalangeal bones of the hands and feet, but any part of the skeleton may be involved.³

Bone sarcoidosis is usually asymptomatic and is discovered incidentally. The diagnosis of sarcoidosis has usually been established clinically before bone lesions are detected on MRI. However, sarcoidosis-related bone lesions resembling bone metastases on MRI may be the initial presentation. The presence of intralesional fat has been described as a feature that excludes malignancy. 

No treatment has been shown to be of benefit.⁴ Sarcoidosis is a diagnosis of exclusion and radiographic lytic bone features are not specific, so a neoplastic cause (such as primary osteoblastoma, metastasis, or multiple myeloma) must always be ruled out, as well as other bone conditions such as osteomyelitis or bone cyst.

A 41-year-old woman presented with coughing, wheezing, and painful subcutaneous nodules on her legs. She had presented 6 years ago with similar nodules and enlarged retroauricular, occipital, and maxillary lymph nodes. At that time, biopsy study of submaxillary lymph nodes and skin showed nonnecrotizing granulomas, with negative microbiology studies. Chest radiography and spirometry were normal. A diagnosis of sarcoidosis was made. Treatment was offered but refused.

Based on this history, computed tomography of the thorax and abdomen was performed and showed mediastinal and hilar lymphadenopathy, small bilateral lung nodules, and osseous cystic areas in both iliac blades. Magnetic resonance imaging (MRI) showed numerous discrete lesions in both iliac bones (Figure 1). Biopsy study of iliac bone revealed preserved architecture with no evidence of malignancy or granulomas.

Radiography of the hands showed an osseous lytic lesion in the third proximal phalanx of the right hand. No other radiographic abnormalities were noted.

The clinical and radiographic features and the patient’s clinical course were consistent with osseous sarcoidosis. She was started on methotrexate and a low-dose corticosteroid and was symptom-free at 12-month follow-up. Follow-up MRI showed reduction in the lymphadenopathies and stabilization of the bone lesions.

SARCOIDOSIS AND BONE

Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases. Skeletal involvement has been reported in 1% to 14% of patients.^1,2 Typical osseous involvement is cystic osteitis of the phalangeal bones of the hands and feet, but any part of the skeleton may be involved.³

Bone sarcoidosis is usually asymptomatic and is discovered incidentally. The diagnosis of sarcoidosis has usually been established clinically before bone lesions are detected on MRI. However, sarcoidosis-related bone lesions resembling bone metastases on MRI may be the initial presentation. The presence of intralesional fat has been described as a feature that excludes malignancy. 

No treatment has been shown to be of benefit.⁴ Sarcoidosis is a diagnosis of exclusion and radiographic lytic bone features are not specific, so a neoplastic cause (such as primary osteoblastoma, metastasis, or multiple myeloma) must always be ruled out, as well as other bone conditions such as osteomyelitis or bone cyst.

A 41-year-old woman presented with coughing, wheezing, and painful subcutaneous nodules on her legs. She had presented 6 years ago with similar nodules and enlarged retroauricular, occipital, and maxillary lymph nodes. At that time, biopsy study of submaxillary lymph nodes and skin showed nonnecrotizing granulomas, with negative microbiology studies. Chest radiography and spirometry were normal. A diagnosis of sarcoidosis was made. Treatment was offered but refused.

Based on this history, computed tomography of the thorax and abdomen was performed and showed mediastinal and hilar lymphadenopathy, small bilateral lung nodules, and osseous cystic areas in both iliac blades. Magnetic resonance imaging (MRI) showed numerous discrete lesions in both iliac bones (Figure 1). Biopsy study of iliac bone revealed preserved architecture with no evidence of malignancy or granulomas.

Radiography of the hands showed an osseous lytic lesion in the third proximal phalanx of the right hand. No other radiographic abnormalities were noted.

The clinical and radiographic features and the patient’s clinical course were consistent with osseous sarcoidosis. She was started on methotrexate and a low-dose corticosteroid and was symptom-free at 12-month follow-up. Follow-up MRI showed reduction in the lymphadenopathies and stabilization of the bone lesions.

SARCOIDOSIS AND BONE

Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases. Skeletal involvement has been reported in 1% to 14% of patients.^1,2 Typical osseous involvement is cystic osteitis of the phalangeal bones of the hands and feet, but any part of the skeleton may be involved.³

Bone sarcoidosis is usually asymptomatic and is discovered incidentally. The diagnosis of sarcoidosis has usually been established clinically before bone lesions are detected on MRI. However, sarcoidosis-related bone lesions resembling bone metastases on MRI may be the initial presentation. The presence of intralesional fat has been described as a feature that excludes malignancy. 

No treatment has been shown to be of benefit.⁴ Sarcoidosis is a diagnosis of exclusion and radiographic lytic bone features are not specific, so a neoplastic cause (such as primary osteoblastoma, metastasis, or multiple myeloma) must always be ruled out, as well as other bone conditions such as osteomyelitis or bone cyst.

Evaluating pediatric patients presenting to the ED with head trauma can be a challenging task for emergency physicians (EPs). Specifically, identifying a nondisplaced skull fracture is not always possible through physical examination alone.¹ However, point-of-care (POC) ultrasound permits rapid identification of skull fractures, which in turn assists the EP to determine if advanced imaging studies such as computed tomography (CT) are necessary.

Case

A previously healthy 10-month-old male infant presented to the ED with his mother for evaluation of rhinorrhea, cough, and fever, the onset of which began 24 hours prior to presentation. The patient’s mother reported that the infant continually tugged at his right ear throughout the previous evening and was increasingly irritable, but not inconsolable.

Initial vital signs at presentation were: blood pressure, 95/54 mm Hg; heart rate, 146 beats/min; respiratory rate, 36 beats/min, and temperature, 101.8°F. Oxygen saturation was 96% on room air. The physical examination was notable for an alert well-appearing infant who had a tender nonecchymotic scalp hematoma superior to the right pinna, clear tympanic membranes, crusted mucous bilaterally at the nares, nonlabored respirations, and wheezing throughout the lung fields.

Imaging Technique

To evaluate for skull fractures using POC ultrasound, the area of localized trauma must first be identified.^2,3 Evidence of trauma includes an area of focal tenderness, abrasion, soft-tissue swelling, and hematoma.^2,3 The presence of any depressed and open cranial injuries are contraindications to ultrasound. In which case, a physician should consult a neurosurgical specialist and obtain a CT scan of the head.

A high-frequency linear probe (5-10 MHz) is used to scan the area of localized trauma; this should be performed in two perpendicular planes using copious gel and light pressure (Figures 2a-2c).

Discussion

Closed head trauma is one of the most common pediatric injuries, accounting for roughly 1.4 million ED visits annually in the United States.⁵ Four to 12% percent of these minor traumas result in an intracranial injury,² and the presence of a skull fracture is associated with a 4- to 20-fold increase in risk of underlying intracranial hemorrhage.³

Clinical assessment alone is not always reliable in predicting skull fracture and intracranial injury, especially in children younger than 2 years of age.^2,3 Ultrasound is safe, noninvasive, expedient, cost-effective, and well tolerated in the pediatric population for identifying skull fractures,³ and can obviate the need for skull radiographs⁴ or procedural sedation. Moreover, POC ultrasound can serve as an adjunct to the Pediatric Emergency Care Applied Research Network head injury algorithm for head CT use decision rules if the fracture is not palpable on examination.

Several prospective studies and case reports have demonstrated the usefulness of POC ultrasound in diagnosing pediatric skull fractures in the ED.^1-4 Two of the four cases published represented cases in which the EP identified an undisclosed nonaccidental trauma through POC ultrasound. Rabiner et al,³ estimates a combined sensitivity and specificity of 94% and 96%, respectively. It is important to remember that intracranial injury can still occur without an associated skull fracture. As our case demonstrates, POC ultrasound is a useful tool in risk-stratifying minor head trauma in children.

Case Conclusion

The head CT study confirmed a nondisplaced, oblique, and acute-appearing linear fracture of the right parietal bone extending from the squamosal to the lambdoid suture. There was no associated intracranial hemorrhage. The patient was admitted to the hospital for a nonaccidental trauma evaluation. The Department of Children and Family Services was contacted and the patient was discharged in the temporary custody of his maternal grandmother.

Summary

Point-of-care ultrasound is a useful diagnostic tool to rapidly evaluate for, and diagnose skull fractures in pediatric patients. Given its high sensitivity and specificity, ultrasound can help EPs identify occult nondisplaced skull fractures in children.

Evaluating pediatric patients presenting to the ED with head trauma can be a challenging task for emergency physicians (EPs). Specifically, identifying a nondisplaced skull fracture is not always possible through physical examination alone.¹ However, point-of-care (POC) ultrasound permits rapid identification of skull fractures, which in turn assists the EP to determine if advanced imaging studies such as computed tomography (CT) are necessary.

Case

A previously healthy 10-month-old male infant presented to the ED with his mother for evaluation of rhinorrhea, cough, and fever, the onset of which began 24 hours prior to presentation. The patient’s mother reported that the infant continually tugged at his right ear throughout the previous evening and was increasingly irritable, but not inconsolable.

Initial vital signs at presentation were: blood pressure, 95/54 mm Hg; heart rate, 146 beats/min; respiratory rate, 36 beats/min, and temperature, 101.8°F. Oxygen saturation was 96% on room air. The physical examination was notable for an alert well-appearing infant who had a tender nonecchymotic scalp hematoma superior to the right pinna, clear tympanic membranes, crusted mucous bilaterally at the nares, nonlabored respirations, and wheezing throughout the lung fields.

Imaging Technique

To evaluate for skull fractures using POC ultrasound, the area of localized trauma must first be identified.^2,3 Evidence of trauma includes an area of focal tenderness, abrasion, soft-tissue swelling, and hematoma.^2,3 The presence of any depressed and open cranial injuries are contraindications to ultrasound. In which case, a physician should consult a neurosurgical specialist and obtain a CT scan of the head.

A high-frequency linear probe (5-10 MHz) is used to scan the area of localized trauma; this should be performed in two perpendicular planes using copious gel and light pressure (Figures 2a-2c).

Discussion

Closed head trauma is one of the most common pediatric injuries, accounting for roughly 1.4 million ED visits annually in the United States.⁵ Four to 12% percent of these minor traumas result in an intracranial injury,² and the presence of a skull fracture is associated with a 4- to 20-fold increase in risk of underlying intracranial hemorrhage.³

Clinical assessment alone is not always reliable in predicting skull fracture and intracranial injury, especially in children younger than 2 years of age.^2,3 Ultrasound is safe, noninvasive, expedient, cost-effective, and well tolerated in the pediatric population for identifying skull fractures,³ and can obviate the need for skull radiographs⁴ or procedural sedation. Moreover, POC ultrasound can serve as an adjunct to the Pediatric Emergency Care Applied Research Network head injury algorithm for head CT use decision rules if the fracture is not palpable on examination.

Several prospective studies and case reports have demonstrated the usefulness of POC ultrasound in diagnosing pediatric skull fractures in the ED.^1-4 Two of the four cases published represented cases in which the EP identified an undisclosed nonaccidental trauma through POC ultrasound. Rabiner et al,³ estimates a combined sensitivity and specificity of 94% and 96%, respectively. It is important to remember that intracranial injury can still occur without an associated skull fracture. As our case demonstrates, POC ultrasound is a useful tool in risk-stratifying minor head trauma in children.

Case Conclusion

The head CT study confirmed a nondisplaced, oblique, and acute-appearing linear fracture of the right parietal bone extending from the squamosal to the lambdoid suture. There was no associated intracranial hemorrhage. The patient was admitted to the hospital for a nonaccidental trauma evaluation. The Department of Children and Family Services was contacted and the patient was discharged in the temporary custody of his maternal grandmother.

Summary

Point-of-care ultrasound is a useful diagnostic tool to rapidly evaluate for, and diagnose skull fractures in pediatric patients. Given its high sensitivity and specificity, ultrasound can help EPs identify occult nondisplaced skull fractures in children.

Evaluating pediatric patients presenting to the ED with head trauma can be a challenging task for emergency physicians (EPs). Specifically, identifying a nondisplaced skull fracture is not always possible through physical examination alone.¹ However, point-of-care (POC) ultrasound permits rapid identification of skull fractures, which in turn assists the EP to determine if advanced imaging studies such as computed tomography (CT) are necessary.

Case

A previously healthy 10-month-old male infant presented to the ED with his mother for evaluation of rhinorrhea, cough, and fever, the onset of which began 24 hours prior to presentation. The patient’s mother reported that the infant continually tugged at his right ear throughout the previous evening and was increasingly irritable, but not inconsolable.

Initial vital signs at presentation were: blood pressure, 95/54 mm Hg; heart rate, 146 beats/min; respiratory rate, 36 beats/min, and temperature, 101.8°F. Oxygen saturation was 96% on room air. The physical examination was notable for an alert well-appearing infant who had a tender nonecchymotic scalp hematoma superior to the right pinna, clear tympanic membranes, crusted mucous bilaterally at the nares, nonlabored respirations, and wheezing throughout the lung fields.

Imaging Technique

To evaluate for skull fractures using POC ultrasound, the area of localized trauma must first be identified.^2,3 Evidence of trauma includes an area of focal tenderness, abrasion, soft-tissue swelling, and hematoma.^2,3 The presence of any depressed and open cranial injuries are contraindications to ultrasound. In which case, a physician should consult a neurosurgical specialist and obtain a CT scan of the head.

A high-frequency linear probe (5-10 MHz) is used to scan the area of localized trauma; this should be performed in two perpendicular planes using copious gel and light pressure (Figures 2a-2c).

Discussion

Closed head trauma is one of the most common pediatric injuries, accounting for roughly 1.4 million ED visits annually in the United States.⁵ Four to 12% percent of these minor traumas result in an intracranial injury,² and the presence of a skull fracture is associated with a 4- to 20-fold increase in risk of underlying intracranial hemorrhage.³

Clinical assessment alone is not always reliable in predicting skull fracture and intracranial injury, especially in children younger than 2 years of age.^2,3 Ultrasound is safe, noninvasive, expedient, cost-effective, and well tolerated in the pediatric population for identifying skull fractures,³ and can obviate the need for skull radiographs⁴ or procedural sedation. Moreover, POC ultrasound can serve as an adjunct to the Pediatric Emergency Care Applied Research Network head injury algorithm for head CT use decision rules if the fracture is not palpable on examination.

Several prospective studies and case reports have demonstrated the usefulness of POC ultrasound in diagnosing pediatric skull fractures in the ED.^1-4 Two of the four cases published represented cases in which the EP identified an undisclosed nonaccidental trauma through POC ultrasound. Rabiner et al,³ estimates a combined sensitivity and specificity of 94% and 96%, respectively. It is important to remember that intracranial injury can still occur without an associated skull fracture. As our case demonstrates, POC ultrasound is a useful tool in risk-stratifying minor head trauma in children.

Case Conclusion

The head CT study confirmed a nondisplaced, oblique, and acute-appearing linear fracture of the right parietal bone extending from the squamosal to the lambdoid suture. There was no associated intracranial hemorrhage. The patient was admitted to the hospital for a nonaccidental trauma evaluation. The Department of Children and Family Services was contacted and the patient was discharged in the temporary custody of his maternal grandmother.

Summary

Point-of-care ultrasound is a useful diagnostic tool to rapidly evaluate for, and diagnose skull fractures in pediatric patients. Given its high sensitivity and specificity, ultrasound can help EPs identify occult nondisplaced skull fractures in children.