The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient's case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant.

This icon represents the patient's case. Each paragraph that follows represents the discussant's thoughts.

An 89‐year‐old man presented to the emergency department with progressive fatigue, confusion, and generalized weakness over 2 months, worsening in the prior few days.

Four categories of disease account for most cases of confusion in the elderly: metabolic derangements; infection (both within and outside of the central nervous system); structural brain disorder (eg, bleed or tumor); and toxins (generally medications). It will be important early on to determine if weakness refers to true loss of motor function, reflecting a neuromuscular lesion.

At baseline, the patient had normal cognition, ambulated without assistance, and was independent in activities of daily living. Over the preceding 2 months, general functional decline, unsteady gait, balance problems, and word‐finding difficulty developed. He also needed a front‐wheel walker to avoid falling. One month prior to presentation, the patient's children noticed he was markedly fatigued and was requiring a nightly sedative‐hypnotic in order to fall asleep.

He denied any recent travel, sick contacts, or recent illness. He denied vertigo, dizziness, or syncope. He reported occasional urinary incontinence which he attributed to being too weak to get to the bathroom promptly.

This rapid progression over 2 months is not consistent with the time course of the more common neurodegenerative causes of dementia, such as Alzheimer's or Parkinson's disease. In Parkinson's, cognitive impairment is a late feature, occurring years after gait and motor disturbances develop. Normal pressure hydrocephalus, which causes the classic triad of incontinence, ataxia, and confusion, would also be unlikely to develop so abruptly. Although we do not think of vascular (multi‐infarct) dementia as having such a short time course, on occasion a seemingly rapid presentation is the postscript to a more insidious progression that has been underway for years. A subdural hematoma, which may have occurred with any of his falls, must also be considered, as should neoplastic and paraneoplastic processes.

His past medical history included paroxysmal atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease complicated by prior myocardial infarction for which he underwent coronary artery bypass grafting 7 years prior, mild aortic sclerosis and insufficiency, mild mitral regurgitation, anemia, recurrent low‐grade bladder cancer treated with serial local resections over the last 8 years, low‐grade prostate cancer which had not required treatment, hypothyroidism, chronic kidney disease, and lumbar spinal stenosis.

His atrial fibrillation and valvular disease put him at risk for thrombotic and infective embolic phenomena causing multiple cerebral infarcts. He has all the requisite underlying conditions for vascular dementia. Untreated hypothyroidism could explain his decline and sedation. Prostate and bladder cancers would be unusual causes of subacute central nervous system (CNS) disease. Finally, his chronic kidney disease may have progressed to uremia.

One year prior to admission, the patient developed bilateral shoulder pain, right‐sided headache with loss of vision in his right eye, fevers, and an elevated erythrocyte sedimentation rate (ESR). Although temporal artery biopsy specimens did not reveal arterial inflammation, he was started on high‐dose prednisone for polymyalgia rheumatica and giant cell arteritis (GCA); he experienced improvement in his ESR and in all symptoms, with the exception of permanent right eye blindness. Maintenance prednisone was continued for disease suppression.

Even without confirmatory biopsy results, the clinical case for GCA was compelling and the rationale for starting steroids strong; his sustained response over 1 year further supports the diagnosis. GCA is almost always confined to extracranial vessels, and altered sensorium would be an unusual manifestation. His extended treatment with prednisone expands the list of CNS and systemic infections, particularly opportunistic ones, for which he is now at risk.

Outpatient medications were prednisone at doses fluctuating between 10 and 20 mg daily, furosemide 20 mg daily, amiodarone 200 mg daily, levothyroxine 50 mcg daily, alendronate 70 mg weekly, eszopiclone 1 mg nightly, losartan 50 mg daily, and warfarin. The patient was an accomplished professor and had published a book 1 year prior to admission. He quit smoking over 30 years ago, and he occasionally drank wine. He denied any drug use.

Three months prior to the current presentation, the patient was hospitalized for right upper‐lobe pneumonia for which he received a course of doxycycline, and his symptoms improved. Follow‐up chest x‐ray, 4 weeks later (2 months prior to admission), showed only slight improvement of the right upper‐lobe opacity.

Leading possibilities for the persistent lung opacity are cancer and untreated infection. After 3 decades of being tobacco‐free, his smoking‐related risk of cancer is low, but remains above baseline population risk. There are at least 4 ways untreated lung cancer may render patients confused: direct metastases to the brain, carcinomatous or lymphomatous meningitis, paraneoplastic phenomenon (eg, limbic encephalitis), and metabolic derangements (eg, syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia).

The upper‐lobe infiltrate that failed to improve with doxycycline could also reflect an aspiration pneumonia that evolved into an abscess, or an infection with mycobacteria or endemic fungi.

In the emergency department, the patient's temperature was 38.5C, blood pressure 139/56 mmHg, heart rate 92 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation while breathing ambient room air was 98%.

He was alert and well‐appearing. Jugular venous pressure was normal. The thyroid was normal. He had rhonchi in his right anterior upper chest and right lower lung base. Cardiac exam demonstrated a regular rhythm, with a 3/6 systolic murmur at the second right intercostal space that radiated to the carotids, and a 2/6 nonradiating holosystolic murmur at the apex. Abdomen was soft with no organomegaly or masses. There was no lymphadenopathy, and his extremities showed no clubbing or edema. There were multiple contusions in various stages of healing on his legs.

He was confused, had word‐finding difficulty, and frequently would lose his train of thought, stopping in mid‐sentence. He had no dysarthria. Cranial nerves were normal, except for reduced visual acuity and diminished pupillary response to light in his right pupil, which had been previously documented. Finger‐to‐nose testing was slow bilaterally, but was more sluggish on the right. Rapid alternating hand movements were intact. He was unable to perform heel‐to‐shin testing. Sensation was intact. Plantar reflexes were flexor bilaterally. Strength in his limbs was preserved both distally and proximally, and deep tendon reflexes were normal. However, he was unable to sit up or stand on his own due to weakness.

The fever on prednisone is a red flag for infection. The infection may be the primary diagnosis (eg, meningoencephalitis) or may reflect an additional superimposed insult (eg, urinary tract infection) on the underlying encephalopathy. Two murmurs in a febrile patient with the multifocal CNS findings suggest endocarditis. The abnormalities on chest examination could indicate a lung infection complicated by hematogenous spread to the brain, such as a lung abscess (secondary to the aspiration event), tuberculosis (TB), or endemic fungal infection.

Serum chemistries were normal, and the serum creatinine was 1.1 mg/dL. White blood cell count was 20,100 per mm³ with 90% neutrophils, 9% lymphocytes, and 1% monocytes. Hemoglobin was 13.7 g/dL, platelet count was 464,000 per mm³. Thyroid stimulating hormone (TSH) was 6.0 IU/mL (normal, 5.5). International normalized ratio (INR) was 2.2. Urinalysis was normal. Transaminases, bilirubin, and alkaline phosphatase were normal. Lactate was 1.9 mmol/L.

Electrocardiogram (EKG) was unchanged from his baseline. ESR was >120 mm/hr (the maximum reportable value); his ESR measurements had been gradually rising during the previous 4 months. Chest x‐ray demonstrated a right upper‐lobe opacity, slightly more pronounced in comparison with chest x‐ray 2 months earlier.

His fever, leukocytosis, elevated ESR, and thrombocytosis all reflect severe inflammation. While infection and then malignancy remain the primary considerations, a third category of inflammatory diseaseautoimmunitywarrants mention. For instance, Wegener's granulomatosis can cause pulmonary and CNS disease in the elderly.

Intravenous ceftriaxone and oral doxycycline were administered. Chest computed tomography (CT) (Figure 1) demonstrated dense right upper‐lobe mass‐like consolidation with associated adenopathy and pleural effusion; in addition, several nodules were present in the left and right lower lobes, the largest of which was 10 mm. CT of the chest 10 months prior to current admission had been normal. CT of the brain, performed without contrast, demonstrated multiple areas of abnormal vasogenic edema with suggestion of underlying masses.

Figure 1

The imaging provides evidence of a combined pulmonaryCNS syndrome. It is far more common for disease to originate in the lungs (a common portal of entry and environmental exposure) and spread to the brain than vice versa. The list of diseases and pathogens that affect the lungs and spread to the brain includes: primary lung cancer, lymphoma, bacteria, mycobacteria, fungi, molds (eg, Aspergillus), Wegener's granulomatosis, and lymphomatoid granulomatosis. Bacterial lung abscess, such as that caused by Streptococcus milleri group, may spread to the brain. Nocardia, a ubiquitous soil organism, infects immunocompromised patients and causes a similar pattern. Actinomycosis is an atypical infection that may mimic cancer, particularly in the lungs; while head and neck disease is characteristic, CNS involvement is less so. Overall, the imaging does not specifically pinpoint 1 entity, but infection remains heavily favored over malignancy, with autoimmunity a distant third.

Respiratory cultures showed normal respiratory flora. Blood cultures grew no organisms. Two samples of induced sputum were negative for acid‐fast bacilli (AFB) on smear examination. Forty‐eight hours after a purified protein derivative (PPD) skin test was placed, there was 0 mm of induration. Magnetic resonance imaging (MRI) of the brain (Figure 2) demonstrated 8 ring‐enhancing supratentorial lesions at the graywhite junction.

Figure 2

Negative blood cultures substantially lower the probability of bacterial endocarditis; there are no epidemiologic risk factors for the rare causes of culture‐negative endocarditis (eg, farm exposure, homelessness). Two negative smears for AFB with dense pulmonary or cavitary disease signify a low probability of tuberculosis.

In the setting of depressed cell‐mediated immunity (eg, human immunodeficiency virus [HIV] infection or chronic prednisone use), multiple ring‐enhancing CNS lesions are a classic appearance of toxoplasmosis, but they also are typical of bacterial brain abscesses and Nocardia. Brain metastases are usually solid, but as central necrosis develops, peripheral enhancement may appear. The diffuse distribution and the localization at the graywhite junction further support a hematogenously disseminated process, but do not differentiate infection from metastases.

Transthoracic echocardiogram demonstrated normal left ventricular ejection fraction, clinically insignificant aortic sclerosis and mitral regurgitation, and no evidence of vegetations. Results of a CT‐guided fine‐needle aspiration of the lung were nondiagnostic, showing necropurulent material and benign lung parenchyma with fibrosis. A core biopsy of the lung showed alveolar tissue with patchy mild deposition of fibrinous material and rare scattered acute and chronic inflammatory cells without granulomas. Pleural fluid cytology showed reactive mesothelial cells with mixed inflammatory cells. There were no fungal elements or malignant cells.

The failure to detect malignancy after 2 biopsies and 1 thoracentesis lowers the suspicion of cancer, and thereby bolsters the probability of atypical infections which may elude diagnosis on routine cultures and biopsy. A detailed history, with attention to geographic exposures, is warranted to see which endemic mycosis would put him most at risk. Based on his California residency, disseminated coccidiomycosis or the ubiquitous Cryptococcus are conceivable. Nocardia remains a strong consideration because of his chronic immunosuppression and the lung‐CNS pattern.

Fungal stains and cultures from the biopsies and pleural fluid were negative. Serum antibodies to coccidiomycosis and serum cryptococcal antigen tests were negative. On the eighth hospital day, the microbiology lab reported a few acid‐fast bacilli from a third induced sputum sample. RNA amplification testing for Mycobacterium tuberculosis was negative.

Due to his continued decline, the patient met with the palliative care team and expressed his desire to go home with hospice. While arrangements were being made, he died later that day in the hospital.

There is reasonable evidence that tuberculosis is not the culprit pathogen here: negative PPD, 2 negative sputa in the setting of a massive necrotic lesion, and a negative RNA amplification test. Nontuberculous mycobacteria such as Mycobacterium avium complex (MAC) and M. kansasii may cause disease similar to TB, but they are usually not this difficult to identify. Nocardia is classically a weakly acid‐fast positive bacteria and fits this patient's clinical picture best.

Four colonies of Nocardia (not further speciated) were identified postmortem from the patient's sputum.

DISCUSSION

Nocardia species are ubiquitous soil‐dwelling, Gram‐positive, branching rods which are weakly positive with acid‐fast staining.1 Almost all Nocardia infections occur in patients with immune systems compromised by chronic disease (HIV, malignancy, alcoholism, chronic lung or kidney disease) or by medications. Corticosteroid treatment is the most frequent risk factor. In cases of nocardiosis in patients taking steroids, the median daily prednisone dose was 25 mg (range, 1080 mg) for a median duration of 3 months.2, 3

Nocardia should be considered in any patient with unexplained pulmonary, CNS, or cutaneous disease and appropriate risk factors. Pulmonary disease is most common, seen in approximately two‐thirds of patients, and is typically bilateral. Chest radiographic findings include infiltrates (59%), nodules (35%), effusions, and cavities.2 Up to half of all cases of pulmonary nocardiosis are associated with hematogenous dissemination, most commonly to the CNS, where manifestations include incidentally discovered asymptomatic lesions, headache, confusion, and focal neurologic deficits; meningitis is rare.1 CNS involvement and severe predisposing illness are adverse prognostic markers.

Diagnosis of nocardiosis is typically delayed by 6 weeks to 1 year.4, 5 This has been attributed to its rarity, its nonspecific and indolent presentation, its slow growth, and the difficulty isolating Nocardia from clinical specimens. Although Nocardia may disseminate widely to almost any site, isolation of Nocardia from blood cultures is rare. Clinicians must rely on sputum or tissue samples to demonstrate the characteristic Gram‐positive rods which stain weakly on acid‐fast preparations. Polymerase chain reaction (PCR)‐based tests improve the yield but are not routinely available.

The standard antibiotic for the treatment of Nocardia infections is trimethoprim‐sulfamethoxazole (TMP‐SMX) which has excellent CNS penetration. In patients with pulmonary disease or CNS dissemination, a second parenteral antimicrobial (usually amikacin or imipenem) is typically added to TMP‐SMX, and treatment is extended to 12 months or longer.6, 7 Prophylaxis with TMP‐SMX, which is usually prescribed to prevent Pneumocystis jirovecii in susceptible hosts, also reduces the incidence of Nocardia.2, 3, 6 Nocardia's restricted susceptibility pattern presents a challenge for hospitalists, as TMP‐SMX and aminoglycosides are rarely administered empirically for cases of suspected pneumonia or atypical pulmonary infections (other than P. jirovecii).

When confronted with the pattern of simultaneous pulmonary and CNS lesions, hospitalists must consider infections (lung abscess, mycobacteria, fungi, Nocardia), malignancies, and autoimmune conditions (sarcoidosis, Wegener's granulomatosis). This patient's weakness was a direct result of his weakened immune system, which allowed this weakly acid‐fast organism to flourish. Only by recognizing the possibility of nocardiosis (eg, a patient receiving steroids who develops pulmonary and CNS lesions) is there hope for early diagnosis and treatment.

TEACHING POINTS

• 1

  Suspect disseminated nocardiosis in immunocompromised patients with unexplained pulmonary disease and CNS disease characterized by multiple ring‐enhancing abscesses.

• 2

  Corticosteroid treatment is the most common risk factor for Nocardia infections. Patients taking prednisone at doses in excess of 10 mg daily for greater than 3 months should receive P. jirovecii prophylaxis with TMP‐SMX, which also reduces the incidence of Nocardia.

• 3

  Prolonged courses of TMP‐SMX combined with at least 1 other agent for at least 612 months are typically required to treat disseminated Nocardia.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient's case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant.

This icon represents the patient's case. Each paragraph that follows represents the discussant's thoughts.

An 89‐year‐old man presented to the emergency department with progressive fatigue, confusion, and generalized weakness over 2 months, worsening in the prior few days.

Four categories of disease account for most cases of confusion in the elderly: metabolic derangements; infection (both within and outside of the central nervous system); structural brain disorder (eg, bleed or tumor); and toxins (generally medications). It will be important early on to determine if weakness refers to true loss of motor function, reflecting a neuromuscular lesion.

At baseline, the patient had normal cognition, ambulated without assistance, and was independent in activities of daily living. Over the preceding 2 months, general functional decline, unsteady gait, balance problems, and word‐finding difficulty developed. He also needed a front‐wheel walker to avoid falling. One month prior to presentation, the patient's children noticed he was markedly fatigued and was requiring a nightly sedative‐hypnotic in order to fall asleep.

He denied any recent travel, sick contacts, or recent illness. He denied vertigo, dizziness, or syncope. He reported occasional urinary incontinence which he attributed to being too weak to get to the bathroom promptly.

This rapid progression over 2 months is not consistent with the time course of the more common neurodegenerative causes of dementia, such as Alzheimer's or Parkinson's disease. In Parkinson's, cognitive impairment is a late feature, occurring years after gait and motor disturbances develop. Normal pressure hydrocephalus, which causes the classic triad of incontinence, ataxia, and confusion, would also be unlikely to develop so abruptly. Although we do not think of vascular (multi‐infarct) dementia as having such a short time course, on occasion a seemingly rapid presentation is the postscript to a more insidious progression that has been underway for years. A subdural hematoma, which may have occurred with any of his falls, must also be considered, as should neoplastic and paraneoplastic processes.

His past medical history included paroxysmal atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease complicated by prior myocardial infarction for which he underwent coronary artery bypass grafting 7 years prior, mild aortic sclerosis and insufficiency, mild mitral regurgitation, anemia, recurrent low‐grade bladder cancer treated with serial local resections over the last 8 years, low‐grade prostate cancer which had not required treatment, hypothyroidism, chronic kidney disease, and lumbar spinal stenosis.

His atrial fibrillation and valvular disease put him at risk for thrombotic and infective embolic phenomena causing multiple cerebral infarcts. He has all the requisite underlying conditions for vascular dementia. Untreated hypothyroidism could explain his decline and sedation. Prostate and bladder cancers would be unusual causes of subacute central nervous system (CNS) disease. Finally, his chronic kidney disease may have progressed to uremia.

One year prior to admission, the patient developed bilateral shoulder pain, right‐sided headache with loss of vision in his right eye, fevers, and an elevated erythrocyte sedimentation rate (ESR). Although temporal artery biopsy specimens did not reveal arterial inflammation, he was started on high‐dose prednisone for polymyalgia rheumatica and giant cell arteritis (GCA); he experienced improvement in his ESR and in all symptoms, with the exception of permanent right eye blindness. Maintenance prednisone was continued for disease suppression.

Even without confirmatory biopsy results, the clinical case for GCA was compelling and the rationale for starting steroids strong; his sustained response over 1 year further supports the diagnosis. GCA is almost always confined to extracranial vessels, and altered sensorium would be an unusual manifestation. His extended treatment with prednisone expands the list of CNS and systemic infections, particularly opportunistic ones, for which he is now at risk.

Outpatient medications were prednisone at doses fluctuating between 10 and 20 mg daily, furosemide 20 mg daily, amiodarone 200 mg daily, levothyroxine 50 mcg daily, alendronate 70 mg weekly, eszopiclone 1 mg nightly, losartan 50 mg daily, and warfarin. The patient was an accomplished professor and had published a book 1 year prior to admission. He quit smoking over 30 years ago, and he occasionally drank wine. He denied any drug use.

Three months prior to the current presentation, the patient was hospitalized for right upper‐lobe pneumonia for which he received a course of doxycycline, and his symptoms improved. Follow‐up chest x‐ray, 4 weeks later (2 months prior to admission), showed only slight improvement of the right upper‐lobe opacity.

Leading possibilities for the persistent lung opacity are cancer and untreated infection. After 3 decades of being tobacco‐free, his smoking‐related risk of cancer is low, but remains above baseline population risk. There are at least 4 ways untreated lung cancer may render patients confused: direct metastases to the brain, carcinomatous or lymphomatous meningitis, paraneoplastic phenomenon (eg, limbic encephalitis), and metabolic derangements (eg, syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia).

The upper‐lobe infiltrate that failed to improve with doxycycline could also reflect an aspiration pneumonia that evolved into an abscess, or an infection with mycobacteria or endemic fungi.

In the emergency department, the patient's temperature was 38.5C, blood pressure 139/56 mmHg, heart rate 92 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation while breathing ambient room air was 98%.

He was alert and well‐appearing. Jugular venous pressure was normal. The thyroid was normal. He had rhonchi in his right anterior upper chest and right lower lung base. Cardiac exam demonstrated a regular rhythm, with a 3/6 systolic murmur at the second right intercostal space that radiated to the carotids, and a 2/6 nonradiating holosystolic murmur at the apex. Abdomen was soft with no organomegaly or masses. There was no lymphadenopathy, and his extremities showed no clubbing or edema. There were multiple contusions in various stages of healing on his legs.

He was confused, had word‐finding difficulty, and frequently would lose his train of thought, stopping in mid‐sentence. He had no dysarthria. Cranial nerves were normal, except for reduced visual acuity and diminished pupillary response to light in his right pupil, which had been previously documented. Finger‐to‐nose testing was slow bilaterally, but was more sluggish on the right. Rapid alternating hand movements were intact. He was unable to perform heel‐to‐shin testing. Sensation was intact. Plantar reflexes were flexor bilaterally. Strength in his limbs was preserved both distally and proximally, and deep tendon reflexes were normal. However, he was unable to sit up or stand on his own due to weakness.

The fever on prednisone is a red flag for infection. The infection may be the primary diagnosis (eg, meningoencephalitis) or may reflect an additional superimposed insult (eg, urinary tract infection) on the underlying encephalopathy. Two murmurs in a febrile patient with the multifocal CNS findings suggest endocarditis. The abnormalities on chest examination could indicate a lung infection complicated by hematogenous spread to the brain, such as a lung abscess (secondary to the aspiration event), tuberculosis (TB), or endemic fungal infection.

Serum chemistries were normal, and the serum creatinine was 1.1 mg/dL. White blood cell count was 20,100 per mm³ with 90% neutrophils, 9% lymphocytes, and 1% monocytes. Hemoglobin was 13.7 g/dL, platelet count was 464,000 per mm³. Thyroid stimulating hormone (TSH) was 6.0 IU/mL (normal, 5.5). International normalized ratio (INR) was 2.2. Urinalysis was normal. Transaminases, bilirubin, and alkaline phosphatase were normal. Lactate was 1.9 mmol/L.

Electrocardiogram (EKG) was unchanged from his baseline. ESR was >120 mm/hr (the maximum reportable value); his ESR measurements had been gradually rising during the previous 4 months. Chest x‐ray demonstrated a right upper‐lobe opacity, slightly more pronounced in comparison with chest x‐ray 2 months earlier.

His fever, leukocytosis, elevated ESR, and thrombocytosis all reflect severe inflammation. While infection and then malignancy remain the primary considerations, a third category of inflammatory diseaseautoimmunitywarrants mention. For instance, Wegener's granulomatosis can cause pulmonary and CNS disease in the elderly.

Intravenous ceftriaxone and oral doxycycline were administered. Chest computed tomography (CT) (Figure 1) demonstrated dense right upper‐lobe mass‐like consolidation with associated adenopathy and pleural effusion; in addition, several nodules were present in the left and right lower lobes, the largest of which was 10 mm. CT of the chest 10 months prior to current admission had been normal. CT of the brain, performed without contrast, demonstrated multiple areas of abnormal vasogenic edema with suggestion of underlying masses.

Figure 1

The imaging provides evidence of a combined pulmonaryCNS syndrome. It is far more common for disease to originate in the lungs (a common portal of entry and environmental exposure) and spread to the brain than vice versa. The list of diseases and pathogens that affect the lungs and spread to the brain includes: primary lung cancer, lymphoma, bacteria, mycobacteria, fungi, molds (eg, Aspergillus), Wegener's granulomatosis, and lymphomatoid granulomatosis. Bacterial lung abscess, such as that caused by Streptococcus milleri group, may spread to the brain. Nocardia, a ubiquitous soil organism, infects immunocompromised patients and causes a similar pattern. Actinomycosis is an atypical infection that may mimic cancer, particularly in the lungs; while head and neck disease is characteristic, CNS involvement is less so. Overall, the imaging does not specifically pinpoint 1 entity, but infection remains heavily favored over malignancy, with autoimmunity a distant third.

Respiratory cultures showed normal respiratory flora. Blood cultures grew no organisms. Two samples of induced sputum were negative for acid‐fast bacilli (AFB) on smear examination. Forty‐eight hours after a purified protein derivative (PPD) skin test was placed, there was 0 mm of induration. Magnetic resonance imaging (MRI) of the brain (Figure 2) demonstrated 8 ring‐enhancing supratentorial lesions at the graywhite junction.

Figure 2

Negative blood cultures substantially lower the probability of bacterial endocarditis; there are no epidemiologic risk factors for the rare causes of culture‐negative endocarditis (eg, farm exposure, homelessness). Two negative smears for AFB with dense pulmonary or cavitary disease signify a low probability of tuberculosis.

In the setting of depressed cell‐mediated immunity (eg, human immunodeficiency virus [HIV] infection or chronic prednisone use), multiple ring‐enhancing CNS lesions are a classic appearance of toxoplasmosis, but they also are typical of bacterial brain abscesses and Nocardia. Brain metastases are usually solid, but as central necrosis develops, peripheral enhancement may appear. The diffuse distribution and the localization at the graywhite junction further support a hematogenously disseminated process, but do not differentiate infection from metastases.

Transthoracic echocardiogram demonstrated normal left ventricular ejection fraction, clinically insignificant aortic sclerosis and mitral regurgitation, and no evidence of vegetations. Results of a CT‐guided fine‐needle aspiration of the lung were nondiagnostic, showing necropurulent material and benign lung parenchyma with fibrosis. A core biopsy of the lung showed alveolar tissue with patchy mild deposition of fibrinous material and rare scattered acute and chronic inflammatory cells without granulomas. Pleural fluid cytology showed reactive mesothelial cells with mixed inflammatory cells. There were no fungal elements or malignant cells.

The failure to detect malignancy after 2 biopsies and 1 thoracentesis lowers the suspicion of cancer, and thereby bolsters the probability of atypical infections which may elude diagnosis on routine cultures and biopsy. A detailed history, with attention to geographic exposures, is warranted to see which endemic mycosis would put him most at risk. Based on his California residency, disseminated coccidiomycosis or the ubiquitous Cryptococcus are conceivable. Nocardia remains a strong consideration because of his chronic immunosuppression and the lung‐CNS pattern.

Fungal stains and cultures from the biopsies and pleural fluid were negative. Serum antibodies to coccidiomycosis and serum cryptococcal antigen tests were negative. On the eighth hospital day, the microbiology lab reported a few acid‐fast bacilli from a third induced sputum sample. RNA amplification testing for Mycobacterium tuberculosis was negative.

Due to his continued decline, the patient met with the palliative care team and expressed his desire to go home with hospice. While arrangements were being made, he died later that day in the hospital.

There is reasonable evidence that tuberculosis is not the culprit pathogen here: negative PPD, 2 negative sputa in the setting of a massive necrotic lesion, and a negative RNA amplification test. Nontuberculous mycobacteria such as Mycobacterium avium complex (MAC) and M. kansasii may cause disease similar to TB, but they are usually not this difficult to identify. Nocardia is classically a weakly acid‐fast positive bacteria and fits this patient's clinical picture best.

Four colonies of Nocardia (not further speciated) were identified postmortem from the patient's sputum.

DISCUSSION

Nocardia species are ubiquitous soil‐dwelling, Gram‐positive, branching rods which are weakly positive with acid‐fast staining.1 Almost all Nocardia infections occur in patients with immune systems compromised by chronic disease (HIV, malignancy, alcoholism, chronic lung or kidney disease) or by medications. Corticosteroid treatment is the most frequent risk factor. In cases of nocardiosis in patients taking steroids, the median daily prednisone dose was 25 mg (range, 1080 mg) for a median duration of 3 months.2, 3

Nocardia should be considered in any patient with unexplained pulmonary, CNS, or cutaneous disease and appropriate risk factors. Pulmonary disease is most common, seen in approximately two‐thirds of patients, and is typically bilateral. Chest radiographic findings include infiltrates (59%), nodules (35%), effusions, and cavities.2 Up to half of all cases of pulmonary nocardiosis are associated with hematogenous dissemination, most commonly to the CNS, where manifestations include incidentally discovered asymptomatic lesions, headache, confusion, and focal neurologic deficits; meningitis is rare.1 CNS involvement and severe predisposing illness are adverse prognostic markers.

Diagnosis of nocardiosis is typically delayed by 6 weeks to 1 year.4, 5 This has been attributed to its rarity, its nonspecific and indolent presentation, its slow growth, and the difficulty isolating Nocardia from clinical specimens. Although Nocardia may disseminate widely to almost any site, isolation of Nocardia from blood cultures is rare. Clinicians must rely on sputum or tissue samples to demonstrate the characteristic Gram‐positive rods which stain weakly on acid‐fast preparations. Polymerase chain reaction (PCR)‐based tests improve the yield but are not routinely available.

The standard antibiotic for the treatment of Nocardia infections is trimethoprim‐sulfamethoxazole (TMP‐SMX) which has excellent CNS penetration. In patients with pulmonary disease or CNS dissemination, a second parenteral antimicrobial (usually amikacin or imipenem) is typically added to TMP‐SMX, and treatment is extended to 12 months or longer.6, 7 Prophylaxis with TMP‐SMX, which is usually prescribed to prevent Pneumocystis jirovecii in susceptible hosts, also reduces the incidence of Nocardia.2, 3, 6 Nocardia's restricted susceptibility pattern presents a challenge for hospitalists, as TMP‐SMX and aminoglycosides are rarely administered empirically for cases of suspected pneumonia or atypical pulmonary infections (other than P. jirovecii).

When confronted with the pattern of simultaneous pulmonary and CNS lesions, hospitalists must consider infections (lung abscess, mycobacteria, fungi, Nocardia), malignancies, and autoimmune conditions (sarcoidosis, Wegener's granulomatosis). This patient's weakness was a direct result of his weakened immune system, which allowed this weakly acid‐fast organism to flourish. Only by recognizing the possibility of nocardiosis (eg, a patient receiving steroids who develops pulmonary and CNS lesions) is there hope for early diagnosis and treatment.

TEACHING POINTS

• 1

  Suspect disseminated nocardiosis in immunocompromised patients with unexplained pulmonary disease and CNS disease characterized by multiple ring‐enhancing abscesses.

• 2

  Corticosteroid treatment is the most common risk factor for Nocardia infections. Patients taking prednisone at doses in excess of 10 mg daily for greater than 3 months should receive P. jirovecii prophylaxis with TMP‐SMX, which also reduces the incidence of Nocardia.

• 3

  Prolonged courses of TMP‐SMX combined with at least 1 other agent for at least 612 months are typically required to treat disseminated Nocardia.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient's case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant.

This icon represents the patient's case. Each paragraph that follows represents the discussant's thoughts.

An 89‐year‐old man presented to the emergency department with progressive fatigue, confusion, and generalized weakness over 2 months, worsening in the prior few days.

Four categories of disease account for most cases of confusion in the elderly: metabolic derangements; infection (both within and outside of the central nervous system); structural brain disorder (eg, bleed or tumor); and toxins (generally medications). It will be important early on to determine if weakness refers to true loss of motor function, reflecting a neuromuscular lesion.

At baseline, the patient had normal cognition, ambulated without assistance, and was independent in activities of daily living. Over the preceding 2 months, general functional decline, unsteady gait, balance problems, and word‐finding difficulty developed. He also needed a front‐wheel walker to avoid falling. One month prior to presentation, the patient's children noticed he was markedly fatigued and was requiring a nightly sedative‐hypnotic in order to fall asleep.

He denied any recent travel, sick contacts, or recent illness. He denied vertigo, dizziness, or syncope. He reported occasional urinary incontinence which he attributed to being too weak to get to the bathroom promptly.

This rapid progression over 2 months is not consistent with the time course of the more common neurodegenerative causes of dementia, such as Alzheimer's or Parkinson's disease. In Parkinson's, cognitive impairment is a late feature, occurring years after gait and motor disturbances develop. Normal pressure hydrocephalus, which causes the classic triad of incontinence, ataxia, and confusion, would also be unlikely to develop so abruptly. Although we do not think of vascular (multi‐infarct) dementia as having such a short time course, on occasion a seemingly rapid presentation is the postscript to a more insidious progression that has been underway for years. A subdural hematoma, which may have occurred with any of his falls, must also be considered, as should neoplastic and paraneoplastic processes.

His past medical history included paroxysmal atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease complicated by prior myocardial infarction for which he underwent coronary artery bypass grafting 7 years prior, mild aortic sclerosis and insufficiency, mild mitral regurgitation, anemia, recurrent low‐grade bladder cancer treated with serial local resections over the last 8 years, low‐grade prostate cancer which had not required treatment, hypothyroidism, chronic kidney disease, and lumbar spinal stenosis.

His atrial fibrillation and valvular disease put him at risk for thrombotic and infective embolic phenomena causing multiple cerebral infarcts. He has all the requisite underlying conditions for vascular dementia. Untreated hypothyroidism could explain his decline and sedation. Prostate and bladder cancers would be unusual causes of subacute central nervous system (CNS) disease. Finally, his chronic kidney disease may have progressed to uremia.

One year prior to admission, the patient developed bilateral shoulder pain, right‐sided headache with loss of vision in his right eye, fevers, and an elevated erythrocyte sedimentation rate (ESR). Although temporal artery biopsy specimens did not reveal arterial inflammation, he was started on high‐dose prednisone for polymyalgia rheumatica and giant cell arteritis (GCA); he experienced improvement in his ESR and in all symptoms, with the exception of permanent right eye blindness. Maintenance prednisone was continued for disease suppression.

Even without confirmatory biopsy results, the clinical case for GCA was compelling and the rationale for starting steroids strong; his sustained response over 1 year further supports the diagnosis. GCA is almost always confined to extracranial vessels, and altered sensorium would be an unusual manifestation. His extended treatment with prednisone expands the list of CNS and systemic infections, particularly opportunistic ones, for which he is now at risk.

Outpatient medications were prednisone at doses fluctuating between 10 and 20 mg daily, furosemide 20 mg daily, amiodarone 200 mg daily, levothyroxine 50 mcg daily, alendronate 70 mg weekly, eszopiclone 1 mg nightly, losartan 50 mg daily, and warfarin. The patient was an accomplished professor and had published a book 1 year prior to admission. He quit smoking over 30 years ago, and he occasionally drank wine. He denied any drug use.

Three months prior to the current presentation, the patient was hospitalized for right upper‐lobe pneumonia for which he received a course of doxycycline, and his symptoms improved. Follow‐up chest x‐ray, 4 weeks later (2 months prior to admission), showed only slight improvement of the right upper‐lobe opacity.

Leading possibilities for the persistent lung opacity are cancer and untreated infection. After 3 decades of being tobacco‐free, his smoking‐related risk of cancer is low, but remains above baseline population risk. There are at least 4 ways untreated lung cancer may render patients confused: direct metastases to the brain, carcinomatous or lymphomatous meningitis, paraneoplastic phenomenon (eg, limbic encephalitis), and metabolic derangements (eg, syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia).

The upper‐lobe infiltrate that failed to improve with doxycycline could also reflect an aspiration pneumonia that evolved into an abscess, or an infection with mycobacteria or endemic fungi.

In the emergency department, the patient's temperature was 38.5C, blood pressure 139/56 mmHg, heart rate 92 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation while breathing ambient room air was 98%.

He was alert and well‐appearing. Jugular venous pressure was normal. The thyroid was normal. He had rhonchi in his right anterior upper chest and right lower lung base. Cardiac exam demonstrated a regular rhythm, with a 3/6 systolic murmur at the second right intercostal space that radiated to the carotids, and a 2/6 nonradiating holosystolic murmur at the apex. Abdomen was soft with no organomegaly or masses. There was no lymphadenopathy, and his extremities showed no clubbing or edema. There were multiple contusions in various stages of healing on his legs.

He was confused, had word‐finding difficulty, and frequently would lose his train of thought, stopping in mid‐sentence. He had no dysarthria. Cranial nerves were normal, except for reduced visual acuity and diminished pupillary response to light in his right pupil, which had been previously documented. Finger‐to‐nose testing was slow bilaterally, but was more sluggish on the right. Rapid alternating hand movements were intact. He was unable to perform heel‐to‐shin testing. Sensation was intact. Plantar reflexes were flexor bilaterally. Strength in his limbs was preserved both distally and proximally, and deep tendon reflexes were normal. However, he was unable to sit up or stand on his own due to weakness.

The fever on prednisone is a red flag for infection. The infection may be the primary diagnosis (eg, meningoencephalitis) or may reflect an additional superimposed insult (eg, urinary tract infection) on the underlying encephalopathy. Two murmurs in a febrile patient with the multifocal CNS findings suggest endocarditis. The abnormalities on chest examination could indicate a lung infection complicated by hematogenous spread to the brain, such as a lung abscess (secondary to the aspiration event), tuberculosis (TB), or endemic fungal infection.

Serum chemistries were normal, and the serum creatinine was 1.1 mg/dL. White blood cell count was 20,100 per mm³ with 90% neutrophils, 9% lymphocytes, and 1% monocytes. Hemoglobin was 13.7 g/dL, platelet count was 464,000 per mm³. Thyroid stimulating hormone (TSH) was 6.0 IU/mL (normal, 5.5). International normalized ratio (INR) was 2.2. Urinalysis was normal. Transaminases, bilirubin, and alkaline phosphatase were normal. Lactate was 1.9 mmol/L.

Electrocardiogram (EKG) was unchanged from his baseline. ESR was >120 mm/hr (the maximum reportable value); his ESR measurements had been gradually rising during the previous 4 months. Chest x‐ray demonstrated a right upper‐lobe opacity, slightly more pronounced in comparison with chest x‐ray 2 months earlier.

His fever, leukocytosis, elevated ESR, and thrombocytosis all reflect severe inflammation. While infection and then malignancy remain the primary considerations, a third category of inflammatory diseaseautoimmunitywarrants mention. For instance, Wegener's granulomatosis can cause pulmonary and CNS disease in the elderly.

Intravenous ceftriaxone and oral doxycycline were administered. Chest computed tomography (CT) (Figure 1) demonstrated dense right upper‐lobe mass‐like consolidation with associated adenopathy and pleural effusion; in addition, several nodules were present in the left and right lower lobes, the largest of which was 10 mm. CT of the chest 10 months prior to current admission had been normal. CT of the brain, performed without contrast, demonstrated multiple areas of abnormal vasogenic edema with suggestion of underlying masses.

Figure 1

The imaging provides evidence of a combined pulmonaryCNS syndrome. It is far more common for disease to originate in the lungs (a common portal of entry and environmental exposure) and spread to the brain than vice versa. The list of diseases and pathogens that affect the lungs and spread to the brain includes: primary lung cancer, lymphoma, bacteria, mycobacteria, fungi, molds (eg, Aspergillus), Wegener's granulomatosis, and lymphomatoid granulomatosis. Bacterial lung abscess, such as that caused by Streptococcus milleri group, may spread to the brain. Nocardia, a ubiquitous soil organism, infects immunocompromised patients and causes a similar pattern. Actinomycosis is an atypical infection that may mimic cancer, particularly in the lungs; while head and neck disease is characteristic, CNS involvement is less so. Overall, the imaging does not specifically pinpoint 1 entity, but infection remains heavily favored over malignancy, with autoimmunity a distant third.

Respiratory cultures showed normal respiratory flora. Blood cultures grew no organisms. Two samples of induced sputum were negative for acid‐fast bacilli (AFB) on smear examination. Forty‐eight hours after a purified protein derivative (PPD) skin test was placed, there was 0 mm of induration. Magnetic resonance imaging (MRI) of the brain (Figure 2) demonstrated 8 ring‐enhancing supratentorial lesions at the graywhite junction.

Figure 2

Negative blood cultures substantially lower the probability of bacterial endocarditis; there are no epidemiologic risk factors for the rare causes of culture‐negative endocarditis (eg, farm exposure, homelessness). Two negative smears for AFB with dense pulmonary or cavitary disease signify a low probability of tuberculosis.

In the setting of depressed cell‐mediated immunity (eg, human immunodeficiency virus [HIV] infection or chronic prednisone use), multiple ring‐enhancing CNS lesions are a classic appearance of toxoplasmosis, but they also are typical of bacterial brain abscesses and Nocardia. Brain metastases are usually solid, but as central necrosis develops, peripheral enhancement may appear. The diffuse distribution and the localization at the graywhite junction further support a hematogenously disseminated process, but do not differentiate infection from metastases.

Transthoracic echocardiogram demonstrated normal left ventricular ejection fraction, clinically insignificant aortic sclerosis and mitral regurgitation, and no evidence of vegetations. Results of a CT‐guided fine‐needle aspiration of the lung were nondiagnostic, showing necropurulent material and benign lung parenchyma with fibrosis. A core biopsy of the lung showed alveolar tissue with patchy mild deposition of fibrinous material and rare scattered acute and chronic inflammatory cells without granulomas. Pleural fluid cytology showed reactive mesothelial cells with mixed inflammatory cells. There were no fungal elements or malignant cells.

The failure to detect malignancy after 2 biopsies and 1 thoracentesis lowers the suspicion of cancer, and thereby bolsters the probability of atypical infections which may elude diagnosis on routine cultures and biopsy. A detailed history, with attention to geographic exposures, is warranted to see which endemic mycosis would put him most at risk. Based on his California residency, disseminated coccidiomycosis or the ubiquitous Cryptococcus are conceivable. Nocardia remains a strong consideration because of his chronic immunosuppression and the lung‐CNS pattern.

Fungal stains and cultures from the biopsies and pleural fluid were negative. Serum antibodies to coccidiomycosis and serum cryptococcal antigen tests were negative. On the eighth hospital day, the microbiology lab reported a few acid‐fast bacilli from a third induced sputum sample. RNA amplification testing for Mycobacterium tuberculosis was negative.

Due to his continued decline, the patient met with the palliative care team and expressed his desire to go home with hospice. While arrangements were being made, he died later that day in the hospital.

There is reasonable evidence that tuberculosis is not the culprit pathogen here: negative PPD, 2 negative sputa in the setting of a massive necrotic lesion, and a negative RNA amplification test. Nontuberculous mycobacteria such as Mycobacterium avium complex (MAC) and M. kansasii may cause disease similar to TB, but they are usually not this difficult to identify. Nocardia is classically a weakly acid‐fast positive bacteria and fits this patient's clinical picture best.

Four colonies of Nocardia (not further speciated) were identified postmortem from the patient's sputum.

DISCUSSION

Nocardia species are ubiquitous soil‐dwelling, Gram‐positive, branching rods which are weakly positive with acid‐fast staining.1 Almost all Nocardia infections occur in patients with immune systems compromised by chronic disease (HIV, malignancy, alcoholism, chronic lung or kidney disease) or by medications. Corticosteroid treatment is the most frequent risk factor. In cases of nocardiosis in patients taking steroids, the median daily prednisone dose was 25 mg (range, 1080 mg) for a median duration of 3 months.2, 3

Nocardia should be considered in any patient with unexplained pulmonary, CNS, or cutaneous disease and appropriate risk factors. Pulmonary disease is most common, seen in approximately two‐thirds of patients, and is typically bilateral. Chest radiographic findings include infiltrates (59%), nodules (35%), effusions, and cavities.2 Up to half of all cases of pulmonary nocardiosis are associated with hematogenous dissemination, most commonly to the CNS, where manifestations include incidentally discovered asymptomatic lesions, headache, confusion, and focal neurologic deficits; meningitis is rare.1 CNS involvement and severe predisposing illness are adverse prognostic markers.

Diagnosis of nocardiosis is typically delayed by 6 weeks to 1 year.4, 5 This has been attributed to its rarity, its nonspecific and indolent presentation, its slow growth, and the difficulty isolating Nocardia from clinical specimens. Although Nocardia may disseminate widely to almost any site, isolation of Nocardia from blood cultures is rare. Clinicians must rely on sputum or tissue samples to demonstrate the characteristic Gram‐positive rods which stain weakly on acid‐fast preparations. Polymerase chain reaction (PCR)‐based tests improve the yield but are not routinely available.

The standard antibiotic for the treatment of Nocardia infections is trimethoprim‐sulfamethoxazole (TMP‐SMX) which has excellent CNS penetration. In patients with pulmonary disease or CNS dissemination, a second parenteral antimicrobial (usually amikacin or imipenem) is typically added to TMP‐SMX, and treatment is extended to 12 months or longer.6, 7 Prophylaxis with TMP‐SMX, which is usually prescribed to prevent Pneumocystis jirovecii in susceptible hosts, also reduces the incidence of Nocardia.2, 3, 6 Nocardia's restricted susceptibility pattern presents a challenge for hospitalists, as TMP‐SMX and aminoglycosides are rarely administered empirically for cases of suspected pneumonia or atypical pulmonary infections (other than P. jirovecii).

When confronted with the pattern of simultaneous pulmonary and CNS lesions, hospitalists must consider infections (lung abscess, mycobacteria, fungi, Nocardia), malignancies, and autoimmune conditions (sarcoidosis, Wegener's granulomatosis). This patient's weakness was a direct result of his weakened immune system, which allowed this weakly acid‐fast organism to flourish. Only by recognizing the possibility of nocardiosis (eg, a patient receiving steroids who develops pulmonary and CNS lesions) is there hope for early diagnosis and treatment.

TEACHING POINTS

• 1

  Suspect disseminated nocardiosis in immunocompromised patients with unexplained pulmonary disease and CNS disease characterized by multiple ring‐enhancing abscesses.

• 2

  Corticosteroid treatment is the most common risk factor for Nocardia infections. Patients taking prednisone at doses in excess of 10 mg daily for greater than 3 months should receive P. jirovecii prophylaxis with TMP‐SMX, which also reduces the incidence of Nocardia.

• 3

  Prolonged courses of TMP‐SMX combined with at least 1 other agent for at least 612 months are typically required to treat disseminated Nocardia.

A 76‐year‐old white male presented to his primary care physician with a 40‐pound weight loss and gradual decline in function over the prior 6 months. In addition, over the previous 2 months, he had begun to suffer a constant, non‐bloody, and non‐productive cough accompanied by night sweats. Associated complaints included a decline in physical activity, increased sleep needs, decreased appetite, irritability, and generalized body aches.

The patient, an elderly man, presents with a subacute, progressive systemic illness, which appears to have a pulmonary component. Broad disease categories meriting consideration include infections such as tuberculosis, endemic fungi, and infectious endocarditis; malignancies including bronchogenic carcinoma, as well as a variety of other neoplasms; and rheumatologic conditions including temporal arteritis/polymyalgia rheumatica and Wegener's granulomatosis. His complaints of anhedonia, somnolence, and irritability, while decidedly nonspecific, raise the possibility of central nervous system involvement.

His past medical history was notable for coronary artery disease, moderate aortic stenosis, hypertension, hyperlipidemia, and chronic sinusitis. Two years ago, he had unexplained kidney failure. Anti‐neutrophilic cytoplasmic antibodies (ANCA) were present, and indirect immunoflorescence revealed a peri‐nuclear (P‐ANCA) pattern on kidney biopsy. The patient had been empirically placed on azathioprine for presumed focal segmental glomerulosclerosis (FSGS), and his renal function remained stable at an estimated glomerular filtrate rate ranging from 15 to 30 mL/min/1.73 m². His other medications included nifedipine, metoprolol, aspirin, isosorbide mononitrate, atorvastatin, calcitriol, and docusate. His family and social histories were unremarkable, including no history of tobacco. He had no pets and denied illicit drug use. He admitted to spending a considerable amount of time gardening, including working in his yard in bare feet.

The associations of focal segmental glomerulosclerosis, if indeed this diagnosis is correct, include lupus, vasculitis, and human immunodeficiency virus (HIV) infection. The nephrotic syndrome is a frequent manifestation of this entity, although, based on limited information, this patient does not appear to be clinically nephrotic. If possible, the biopsy pathology should be reviewed by a pathologist with interest in the kidney. The report of a positive P‐ANCA may not be particularly helpful here, given the frequency of false‐positive results, and in any event, P‐ANCAs have been associated with a host of conditions other than vasculitis.

The patient's gardening exposure, in bare feet no less, is intriguing. This potentially places him at risk for fungal infections including blastomycosis, histoplasmosis, cryptococcosis, and sporotrichosis. Gardening without shoes is a somewhat different enterprise in northeast Ohio than, say, Mississippi, and it will be helpful to know where this took place. Exposure in Appalachia or the South should prompt consideration of disseminated strongyloidiasis, given his azathioprine use.

Vital signs were as follows: blood pressure 151/76 mmHg, pulse 67 beats per minute, respiratory rate 20 breaths per minute, temperature 35.6C, and oxygen saturation 98% on room air. On examination, he appeared very thin but not in distress. Examination of the skin did not reveal rashes or lesions, and there was no lymphadenopathy. His thyroid was symmetric and normal in size. Lungs were clear to auscultation, and cardiac exam revealed a regular rate with a previously documented III/VI holosystolic murmur over the aortic auscultatory area. Abdominal exam revealed no organomegaly or tenderness. Joints were noted to be non‐inflamed, and extremities non‐edematous. Radial, brachial, popliteal, and dorsalis pedis pulses were normal bilaterally. A neurological exam revealed no focal deficits.

The physical examination does not help to substantively narrow or redirect the differential diagnosis. Although he appears to be tachypneic, this may simply reflect charting artifact. At this point, I would like to proceed with a number of basic diagnostic studies. In addition to complete blood count with differential, chemistries, and liver function panel, I would also obtain a thyroid stimulating hormone (TSH) assay, urinalysis, blood cultures, erythrocyte sedimentation rate/C‐reactive protein, a HIV enzyme‐linked immunosorbent assay (ELISA), chest radiograph, and a repeat ANCA panel. A purified protein derivative (PPD) skin test should be placed.

Blood chemistries were as follows: glucose 88 mg/dL, blood urea nitrogen (BUN) 48 mg/dL, creatinine 2.71 mg/dL, sodium 139 mmol/L, potassium 5.5 mmol/L, chloride 103 mmol/L, CO₂ 28 mmol/L, and anion gap 8 mmol/L. TSH, urinalysis, and PPD tests were unremarkable. His white blood cell count (WBC) was 33.62 K/L with 94% eosinophils and an absolute eosinophil count of 31.6 K/L. His platelet count was 189 K/L, hemoglobin 12.1 g/dL, and hematocrit 36.9%. A chest x‐ray revealed reticular opacities in the mid‐to‐lower lungs, and subsequent computed tomography (CT) scan of the chest demonstrated multiple bilateral indeterminate nodules and right axillary adenopathy.

The patient's strikingly elevated absolute eosinophil count is a very important clue that helps to significantly focus the diagnostic possibilities. In general, an eosinophilia this pronounced signifies one of several possibilities, including primary hypereosinophilic syndrome, ChurgStrauss syndrome, parasitic infection with an active tissue migration phase, eosinophilic leukemia, and perhaps chronic eosinophilic pneumonia. In addition, Wegener's granulomatosis still merits consideration, although an eosinophil count this high would certainly be unusual.

Of the above possibilities, ChurgStrauss seems less likely given his apparent absence of a history of asthma. Parasitic infections, particularly ascariasis but also strongyloidiasis, hookworm, and even visceral larva migrans are possible, although we have not been told whether geographical exposure exists to support the first 3 of these. Hypereosinophilic syndrome remains a strong consideration, although the patient does not yet clearly meet criteria for this diagnosis.

At this juncture, I would send stool and sputum for ova and parasite exam, and order Strongyloides serology, have the peripheral smear reviewed by a pathologist, await the repeat ANCA studies, and consider obtaining hematology consultation.

Tests for anti‐Smith, anti‐ribonuclear (RNP), anti‐SSA, anti‐SSB, anti‐centromere, anti‐Scl 70, and anti‐Jo antibodies were negative. Repeat ANCA testing was positive with P‐ANCA pattern on indirect immunofluorescence. His erythrocyte sedimentation rate and C‐reactive Protein (CRP) were mildly elevated at 29 mm/hr and 1.1 mg/dL, respectively. An immunodeficiency panel work‐up consisting of CD3, CD4, CD8, CD19, T‐cell, B‐cell, and natural killer (NK) cell differential counts demonstrated CD8 T‐cell depletion. Blood cultures demonstrated no growth at 72 hours. No definite M protein was identified on serum and urine protein electrophoresis. Strongyloides IgG was negative. HIV ELISA was negative. A serologic fungal battery to measure antibodies against Aspergillus, Blastomyces, Histoplasma, and Coccidiodes was negative. A microscopic examination of stool and sputum for ova and parasites was also negative. A peripheral blood smear showed anisocytosis and confirmed the elevated eosinophil count.

The preceding wealth of information helps to further refine the picture. The positive P‐ANCA by ELISA as well as immunofluorescence suggests this is a real phenomenon, and makes ChurgStrauss syndrome more likely, despite the absence of preceding or concurrent asthma. I am not aware of an association between P‐ANCA and hypereosinophilic syndrome, nor of a similar link to either chronic eosinophilic pneumonia or hematological malignancies. Although I would like to see 2 additional stool studies for ova and parasites performed by an experienced laboratory technician before discarding the diagnosis of parasitic infection entirely, I am increasingly suspicious that this patient has a prednisone‐deficient state, most likely ChurgStrauss syndrome. I am uncertain of the relationship between his more recent symptoms and his pre‐existing kidney disease, but proceeding to lung biopsy appears to be appropriate.

Bronchoscopic examination with accompanying bronchoalveolar lavage (BAL) and transbronchial biopsy were performed. The BAL showed many Aspergillus fumigatus as well as hemosiderin‐laden macrophages, and the biopsy demonstrated an eosinophilic infiltrate throughout the interstitia, alveolar spaces, and bronchiolar walls. However, the airways did not show features of asthma, capillaritis, vasculitis, or granulomas. A bone marrow biopsy showed no evidence of clonal hematologic disease.

The Aspergillus recovered from BAL, although unexpected, probably does not adequately explain the picture. I am not convinced that the patient has invasive aspergillosis, and although components of the case are consistent with allergic bronchopulmonary aspergillosis, the absence of an asthma history and the extreme degree of peripheral eosinophilia seem to speak against this diagnosis. The biopsy does not corroborate a vasculitic process, but the yield of transbronchial biopsy is relatively low in this setting, and the pulmonary vasculitides remain in play unless a more substantial biopsy specimen is obtained. It is worth noting that high‐dose corticosteroids are a risk factor for the conversion of Aspergillus colonization to invasive aspergillosis, and treatment with voriconazole would certainly be appropriate if prednisone was to be initiated.

I believe ChurgStrauss syndrome, hypereosinophilic syndrome, and chronic eosinophilic pneumonia remain the leading diagnostic possibilities, with the P‐ANCA likely serving as a red herring if the diagnosis turns out to be one of the latter entities. An open lung biopsy would be an appropriate next step, after first obtaining those additional ova and parasite exams for completeness.

An infectious diseases specialist recommended that the patient be discharged on voriconazole 300 mg PO bid for Aspergillus colonization with an underlying lung disease and likely allergic bronchopulmonary aspergillosis or invasive aspergillosis. Steroid therapy was contemplated but not initiated.

Three weeks later, the patient re‐presented with worsening of fatigue and cognitive deterioration marked by episodes of confusion and word‐finding difficulties. His WBC had increased to 45.67 K/L (94% eosinophils). He had now lost a total of 70 pounds, and an increase in generalized weakness was apparent. His blood pressure on presentation was 120/63 mmHg, pulse rate 75 beats per minute, respiratory rate 18 breaths per minute, temperature 35.8C, and oxygen saturation 97% on room air. He appeared cachectic, but not in overt distress. His skin, head, neck, chest, cardiac, abdominal, peripheral vascular, and neurological exam demonstrated no change from the last admission. A follow‐up chest x‐ray showed mild pulmonary edema and new poorly defined pulmonary nodules in the right upper lobe. A repeat CT scan of the thorax demonstrated interval progression of ground‐glass attenuation nodules, which were now more solid‐appearing and increased in number, and present in all lobes of the lung. A CT of the brain did not reveal acute processes such as intracranial hemorrhage, infarction, or mass lesions. Lumbar puncture was performed, with a normal opening pressure. Analysis of the clear and colorless cerebrospinal fluid (CSF) showed 1 red blood cell count (RBC)/L, 2 WBC/L with 92% lymphocytes, glucose 68 mg/dL, and protein 39 mg/dL. CSF fungal cultures, routine cultures, venereal disease reaction level (VDRL), and cryptococcal antigen were negative. CSF cytology did not demonstrate malignant cells. Multiple ova and parasite exams obtained from the previous admission were confirmed to be negative.

The patient's continued deterioration points to either ChurgStrauss syndrome or hypereosinophilic syndrome, I believe. His renal function and P‐ANCA (if related) support the former possibility, while the development of what now appear to be clear encephalopathic symptoms are more in favor of the latter. I would initiate steroid therapy while proceeding to an open lung biopsy in an effort to secure a definitive diagnosis, again under the cover of voriconazole, and would ask for hematology input if this had not already been obtained.

A video‐assisted right thoracoscopy with wedge resection of 2 visible nodules in the right lower lobe was performed. The biopsy conclusively diagnosed a peripheral T‐cell lymphoma. The patient's condition deteriorated, and ultimately he and his family chose a palliative approach.

COMMENTARY

Eosinophils are cells of myeloid lineage that contain cationic‐rich protein granules that mediate allergic response, reaction to parasitic infections, tissue inflammation, and immune modulation.1, 2 Eosinophilia (absolute eosinophil count 600 cells/L) suggests the possibility of a wide array of disorders. The degree of eosinophilia can be categorized as mild (6001500 cells/L), moderate (15005000 cells/L), or severe (>5000 cells/L).3 It may signify a reactive phenomenon (secondary) or, less commonly, either an underlying hematological neoplasm (primary) or an idiopathic process.2 Clinicians faced with an unexplained eosinophilia should seek the most frequent causes first.

Initial investigation should include a careful travel history; consideration of both prescription and over‐the‐counter medications, especially non‐steroidal anti‐inflammatory drugs (NSAIDs), with withdrawal of non‐essential agents; serology for Strongyloides stercoralis antibodies (and possibly other helminths, depending on potential exposure) should be assessed; and stool examinations for ova and parasites should be obtained. The possibility of a wide variety of other potential causes of eosinophilia (Table 1) should be entertained,413 and a careful search for end‐organ damage related to eosinophilic infiltration should be performed if eosinophilia is moderate or severe.1

Hypereosinophilia is defined as an eosinophil level greater than 1500 cells/L. These levels may be associated with end‐organ damage regardless of the underlying etiology, although the degree of eosinophilia frequently does not correlate closely with eosinophilic tissue infiltration. As a result, relatively modest degrees of peripheral eosinophilia may be seen in association with end‐organ damage, while severe eosinophilia may be tolerated well for prolonged periods in other cases.1 The most serious complications of hypereosinophilia are myocardial damage with ultimate development of cardiac fibrosis and refractory heart failure; pulmonary involvement with hypoxia; and involvement of both the central and peripheral nervous systems including stroke, encephalopathy, and mononeuritis multiplex. A number of studies should be considered to help evaluate for the possibility of end‐organ damage as well as to assess for the presence of primary and idiopathic causes of hypereosinophilia. These include peripheral blood smear looking particularly for dysplastic eosinophils or blasts, serum tryptase, serum vitamin B₁₂, serum IgE, cardiac troponin levels, anti‐neutrophil cytoplasmic antibody, electrocardiography, echocardiography, pulmonary function tests, and thoracoabdominal CT scanning. Endoscopic studies with esophageal, duodenal, and colonic biopsy should be performed if eosinophilic gastroenteritis is suspected.1, 7, 10

While more modest degrees of eosinophilia are associated with a plethora of conditions, severe eosinophilia, especially that approaching the levels displayed by this patient, suggests a much more circumscribed differential diagnosis. This should prompt consideration of ChurgStrauss syndrome, parasitic infection with an active tissue migration phase, and hypereosinophilic syndrome (HES).4 HES has classically been characterized by hypereosinophilia for at least 6 months, exclusion of both secondary and clonal eosinophilia, and evidence of end‐organ involvement. More recently, however, a revised definition consisting of marked eosinophilia with reasonable exclusion of other causes has gained favor.1, 7, 10, 1416 While perhaps as many as 75% of cases of HES continue to be considered idiopathic at present, 2 subtypes have now been recognized, with important prognostic and therapeutic implications. Myeloproliferative HES has a strong male predominance, is frequently associated with elevated serum tryptase and B₁₂ levels, often manifests with hepatosplenomegaly, and displays a characteristic gene mutation, FIP1L1/PDGFRA. Lymphocytic HES is typified by polyclonal eosinophilic expansion in response to elevated IL‐5 levels, is associated with less cardiac involvement and a somewhat more favorable prognosis in the absence of therapy, and has been associated with transformation into T‐cell lymphoma.1, 1417 We suspect, though we are unable to prove, that our patient was finally diagnosed at the end of a journey that began as lymphocytic HES and ultimately progressed to T‐cell lymphoma. T‐cell lymphoma has rarely been associated with profound eosinophilia. This appears to reflect disordered production of IL‐5, as was true of this patient, and many of these cases may represent transformed lymphocytic HES.14

Specific therapy exists for the myeloproliferative subtype of HES, consisting of the tyrosine kinase inhibitor imatinib, with excellent response in typical cases. Initial treatment of most other extreme eosinophilic syndromes not caused by parasitic infection, including lymphocytic and idiopathic HES as well as ChurgStrauss syndrome, consists of high‐dose corticosteroids, with a variety of other agents used as second‐line and steroid‐sparing treatments. The urgency of therapy is dictated by the presence and severity of end‐organ damage, and in some instances corticosteroids may need to be given before the diagnosis is fully secure. When S. stercoralis infection has not been ruled out, concurrent therapy with ivermectin should be given to prevent triggering Strongyloides hyperinfection. Hematology input is critical when HES is under serious consideration, with bone marrow examination, cytogenetic studies, T‐cell phenotyping and T‐cell receptor rearrangement studies essential in helping to establish the correct diagnosis.10, 17

The differential diagnosis of peripheral eosinophilia is broad and requires a thorough, stepwise approach. Although profound eosinophilia is usually caused by a limited number of diseases, this patient reminds us that Captain Renault's advice in the film Casablanca to round up the usual suspects does not always suffice, as the diagnosis of T‐cell lymphoma was not considered by either the clinicians or the discussant until lung biopsy results became available. Most patients with hypereosinophilia not caused by parasitic infection will ultimately require an invasive procedure to establish a diagnosis, which is essential before embarking on an often‐toxic course of therapy, as well as for providing an accurate prognosis.

TEACHING POINTS

• 1

  The most common causes of eosinophilia include helminthic infections (the leading cause worldwide), asthma, allergic conditions (the leading cause in the United States), malignancies, and drugs.

• 2

  Hypereosinophilia may lead to end‐organ damage. The most important etiologies include ChurgStrauss Syndrome, HES, or a helminthic infection in the larval migration phase.

• 3

  The mainstay of therapy for most cases of HES is corticosteroids. The goal of therapy is to prevent, or ameliorate, end‐organ damage.

A 76‐year‐old white male presented to his primary care physician with a 40‐pound weight loss and gradual decline in function over the prior 6 months. In addition, over the previous 2 months, he had begun to suffer a constant, non‐bloody, and non‐productive cough accompanied by night sweats. Associated complaints included a decline in physical activity, increased sleep needs, decreased appetite, irritability, and generalized body aches.

The patient, an elderly man, presents with a subacute, progressive systemic illness, which appears to have a pulmonary component. Broad disease categories meriting consideration include infections such as tuberculosis, endemic fungi, and infectious endocarditis; malignancies including bronchogenic carcinoma, as well as a variety of other neoplasms; and rheumatologic conditions including temporal arteritis/polymyalgia rheumatica and Wegener's granulomatosis. His complaints of anhedonia, somnolence, and irritability, while decidedly nonspecific, raise the possibility of central nervous system involvement.

His past medical history was notable for coronary artery disease, moderate aortic stenosis, hypertension, hyperlipidemia, and chronic sinusitis. Two years ago, he had unexplained kidney failure. Anti‐neutrophilic cytoplasmic antibodies (ANCA) were present, and indirect immunoflorescence revealed a peri‐nuclear (P‐ANCA) pattern on kidney biopsy. The patient had been empirically placed on azathioprine for presumed focal segmental glomerulosclerosis (FSGS), and his renal function remained stable at an estimated glomerular filtrate rate ranging from 15 to 30 mL/min/1.73 m². His other medications included nifedipine, metoprolol, aspirin, isosorbide mononitrate, atorvastatin, calcitriol, and docusate. His family and social histories were unremarkable, including no history of tobacco. He had no pets and denied illicit drug use. He admitted to spending a considerable amount of time gardening, including working in his yard in bare feet.

The associations of focal segmental glomerulosclerosis, if indeed this diagnosis is correct, include lupus, vasculitis, and human immunodeficiency virus (HIV) infection. The nephrotic syndrome is a frequent manifestation of this entity, although, based on limited information, this patient does not appear to be clinically nephrotic. If possible, the biopsy pathology should be reviewed by a pathologist with interest in the kidney. The report of a positive P‐ANCA may not be particularly helpful here, given the frequency of false‐positive results, and in any event, P‐ANCAs have been associated with a host of conditions other than vasculitis.

The patient's gardening exposure, in bare feet no less, is intriguing. This potentially places him at risk for fungal infections including blastomycosis, histoplasmosis, cryptococcosis, and sporotrichosis. Gardening without shoes is a somewhat different enterprise in northeast Ohio than, say, Mississippi, and it will be helpful to know where this took place. Exposure in Appalachia or the South should prompt consideration of disseminated strongyloidiasis, given his azathioprine use.

Vital signs were as follows: blood pressure 151/76 mmHg, pulse 67 beats per minute, respiratory rate 20 breaths per minute, temperature 35.6C, and oxygen saturation 98% on room air. On examination, he appeared very thin but not in distress. Examination of the skin did not reveal rashes or lesions, and there was no lymphadenopathy. His thyroid was symmetric and normal in size. Lungs were clear to auscultation, and cardiac exam revealed a regular rate with a previously documented III/VI holosystolic murmur over the aortic auscultatory area. Abdominal exam revealed no organomegaly or tenderness. Joints were noted to be non‐inflamed, and extremities non‐edematous. Radial, brachial, popliteal, and dorsalis pedis pulses were normal bilaterally. A neurological exam revealed no focal deficits.

The physical examination does not help to substantively narrow or redirect the differential diagnosis. Although he appears to be tachypneic, this may simply reflect charting artifact. At this point, I would like to proceed with a number of basic diagnostic studies. In addition to complete blood count with differential, chemistries, and liver function panel, I would also obtain a thyroid stimulating hormone (TSH) assay, urinalysis, blood cultures, erythrocyte sedimentation rate/C‐reactive protein, a HIV enzyme‐linked immunosorbent assay (ELISA), chest radiograph, and a repeat ANCA panel. A purified protein derivative (PPD) skin test should be placed.

Blood chemistries were as follows: glucose 88 mg/dL, blood urea nitrogen (BUN) 48 mg/dL, creatinine 2.71 mg/dL, sodium 139 mmol/L, potassium 5.5 mmol/L, chloride 103 mmol/L, CO₂ 28 mmol/L, and anion gap 8 mmol/L. TSH, urinalysis, and PPD tests were unremarkable. His white blood cell count (WBC) was 33.62 K/L with 94% eosinophils and an absolute eosinophil count of 31.6 K/L. His platelet count was 189 K/L, hemoglobin 12.1 g/dL, and hematocrit 36.9%. A chest x‐ray revealed reticular opacities in the mid‐to‐lower lungs, and subsequent computed tomography (CT) scan of the chest demonstrated multiple bilateral indeterminate nodules and right axillary adenopathy.

The patient's strikingly elevated absolute eosinophil count is a very important clue that helps to significantly focus the diagnostic possibilities. In general, an eosinophilia this pronounced signifies one of several possibilities, including primary hypereosinophilic syndrome, ChurgStrauss syndrome, parasitic infection with an active tissue migration phase, eosinophilic leukemia, and perhaps chronic eosinophilic pneumonia. In addition, Wegener's granulomatosis still merits consideration, although an eosinophil count this high would certainly be unusual.

Of the above possibilities, ChurgStrauss seems less likely given his apparent absence of a history of asthma. Parasitic infections, particularly ascariasis but also strongyloidiasis, hookworm, and even visceral larva migrans are possible, although we have not been told whether geographical exposure exists to support the first 3 of these. Hypereosinophilic syndrome remains a strong consideration, although the patient does not yet clearly meet criteria for this diagnosis.

At this juncture, I would send stool and sputum for ova and parasite exam, and order Strongyloides serology, have the peripheral smear reviewed by a pathologist, await the repeat ANCA studies, and consider obtaining hematology consultation.

Tests for anti‐Smith, anti‐ribonuclear (RNP), anti‐SSA, anti‐SSB, anti‐centromere, anti‐Scl 70, and anti‐Jo antibodies were negative. Repeat ANCA testing was positive with P‐ANCA pattern on indirect immunofluorescence. His erythrocyte sedimentation rate and C‐reactive Protein (CRP) were mildly elevated at 29 mm/hr and 1.1 mg/dL, respectively. An immunodeficiency panel work‐up consisting of CD3, CD4, CD8, CD19, T‐cell, B‐cell, and natural killer (NK) cell differential counts demonstrated CD8 T‐cell depletion. Blood cultures demonstrated no growth at 72 hours. No definite M protein was identified on serum and urine protein electrophoresis. Strongyloides IgG was negative. HIV ELISA was negative. A serologic fungal battery to measure antibodies against Aspergillus, Blastomyces, Histoplasma, and Coccidiodes was negative. A microscopic examination of stool and sputum for ova and parasites was also negative. A peripheral blood smear showed anisocytosis and confirmed the elevated eosinophil count.

The preceding wealth of information helps to further refine the picture. The positive P‐ANCA by ELISA as well as immunofluorescence suggests this is a real phenomenon, and makes ChurgStrauss syndrome more likely, despite the absence of preceding or concurrent asthma. I am not aware of an association between P‐ANCA and hypereosinophilic syndrome, nor of a similar link to either chronic eosinophilic pneumonia or hematological malignancies. Although I would like to see 2 additional stool studies for ova and parasites performed by an experienced laboratory technician before discarding the diagnosis of parasitic infection entirely, I am increasingly suspicious that this patient has a prednisone‐deficient state, most likely ChurgStrauss syndrome. I am uncertain of the relationship between his more recent symptoms and his pre‐existing kidney disease, but proceeding to lung biopsy appears to be appropriate.

Bronchoscopic examination with accompanying bronchoalveolar lavage (BAL) and transbronchial biopsy were performed. The BAL showed many Aspergillus fumigatus as well as hemosiderin‐laden macrophages, and the biopsy demonstrated an eosinophilic infiltrate throughout the interstitia, alveolar spaces, and bronchiolar walls. However, the airways did not show features of asthma, capillaritis, vasculitis, or granulomas. A bone marrow biopsy showed no evidence of clonal hematologic disease.

The Aspergillus recovered from BAL, although unexpected, probably does not adequately explain the picture. I am not convinced that the patient has invasive aspergillosis, and although components of the case are consistent with allergic bronchopulmonary aspergillosis, the absence of an asthma history and the extreme degree of peripheral eosinophilia seem to speak against this diagnosis. The biopsy does not corroborate a vasculitic process, but the yield of transbronchial biopsy is relatively low in this setting, and the pulmonary vasculitides remain in play unless a more substantial biopsy specimen is obtained. It is worth noting that high‐dose corticosteroids are a risk factor for the conversion of Aspergillus colonization to invasive aspergillosis, and treatment with voriconazole would certainly be appropriate if prednisone was to be initiated.

I believe ChurgStrauss syndrome, hypereosinophilic syndrome, and chronic eosinophilic pneumonia remain the leading diagnostic possibilities, with the P‐ANCA likely serving as a red herring if the diagnosis turns out to be one of the latter entities. An open lung biopsy would be an appropriate next step, after first obtaining those additional ova and parasite exams for completeness.

An infectious diseases specialist recommended that the patient be discharged on voriconazole 300 mg PO bid for Aspergillus colonization with an underlying lung disease and likely allergic bronchopulmonary aspergillosis or invasive aspergillosis. Steroid therapy was contemplated but not initiated.

Three weeks later, the patient re‐presented with worsening of fatigue and cognitive deterioration marked by episodes of confusion and word‐finding difficulties. His WBC had increased to 45.67 K/L (94% eosinophils). He had now lost a total of 70 pounds, and an increase in generalized weakness was apparent. His blood pressure on presentation was 120/63 mmHg, pulse rate 75 beats per minute, respiratory rate 18 breaths per minute, temperature 35.8C, and oxygen saturation 97% on room air. He appeared cachectic, but not in overt distress. His skin, head, neck, chest, cardiac, abdominal, peripheral vascular, and neurological exam demonstrated no change from the last admission. A follow‐up chest x‐ray showed mild pulmonary edema and new poorly defined pulmonary nodules in the right upper lobe. A repeat CT scan of the thorax demonstrated interval progression of ground‐glass attenuation nodules, which were now more solid‐appearing and increased in number, and present in all lobes of the lung. A CT of the brain did not reveal acute processes such as intracranial hemorrhage, infarction, or mass lesions. Lumbar puncture was performed, with a normal opening pressure. Analysis of the clear and colorless cerebrospinal fluid (CSF) showed 1 red blood cell count (RBC)/L, 2 WBC/L with 92% lymphocytes, glucose 68 mg/dL, and protein 39 mg/dL. CSF fungal cultures, routine cultures, venereal disease reaction level (VDRL), and cryptococcal antigen were negative. CSF cytology did not demonstrate malignant cells. Multiple ova and parasite exams obtained from the previous admission were confirmed to be negative.

The patient's continued deterioration points to either ChurgStrauss syndrome or hypereosinophilic syndrome, I believe. His renal function and P‐ANCA (if related) support the former possibility, while the development of what now appear to be clear encephalopathic symptoms are more in favor of the latter. I would initiate steroid therapy while proceeding to an open lung biopsy in an effort to secure a definitive diagnosis, again under the cover of voriconazole, and would ask for hematology input if this had not already been obtained.

A video‐assisted right thoracoscopy with wedge resection of 2 visible nodules in the right lower lobe was performed. The biopsy conclusively diagnosed a peripheral T‐cell lymphoma. The patient's condition deteriorated, and ultimately he and his family chose a palliative approach.

COMMENTARY

Eosinophils are cells of myeloid lineage that contain cationic‐rich protein granules that mediate allergic response, reaction to parasitic infections, tissue inflammation, and immune modulation.1, 2 Eosinophilia (absolute eosinophil count 600 cells/L) suggests the possibility of a wide array of disorders. The degree of eosinophilia can be categorized as mild (6001500 cells/L), moderate (15005000 cells/L), or severe (>5000 cells/L).3 It may signify a reactive phenomenon (secondary) or, less commonly, either an underlying hematological neoplasm (primary) or an idiopathic process.2 Clinicians faced with an unexplained eosinophilia should seek the most frequent causes first.

Initial investigation should include a careful travel history; consideration of both prescription and over‐the‐counter medications, especially non‐steroidal anti‐inflammatory drugs (NSAIDs), with withdrawal of non‐essential agents; serology for Strongyloides stercoralis antibodies (and possibly other helminths, depending on potential exposure) should be assessed; and stool examinations for ova and parasites should be obtained. The possibility of a wide variety of other potential causes of eosinophilia (Table 1) should be entertained,413 and a careful search for end‐organ damage related to eosinophilic infiltration should be performed if eosinophilia is moderate or severe.1

Hypereosinophilia is defined as an eosinophil level greater than 1500 cells/L. These levels may be associated with end‐organ damage regardless of the underlying etiology, although the degree of eosinophilia frequently does not correlate closely with eosinophilic tissue infiltration. As a result, relatively modest degrees of peripheral eosinophilia may be seen in association with end‐organ damage, while severe eosinophilia may be tolerated well for prolonged periods in other cases.1 The most serious complications of hypereosinophilia are myocardial damage with ultimate development of cardiac fibrosis and refractory heart failure; pulmonary involvement with hypoxia; and involvement of both the central and peripheral nervous systems including stroke, encephalopathy, and mononeuritis multiplex. A number of studies should be considered to help evaluate for the possibility of end‐organ damage as well as to assess for the presence of primary and idiopathic causes of hypereosinophilia. These include peripheral blood smear looking particularly for dysplastic eosinophils or blasts, serum tryptase, serum vitamin B₁₂, serum IgE, cardiac troponin levels, anti‐neutrophil cytoplasmic antibody, electrocardiography, echocardiography, pulmonary function tests, and thoracoabdominal CT scanning. Endoscopic studies with esophageal, duodenal, and colonic biopsy should be performed if eosinophilic gastroenteritis is suspected.1, 7, 10

While more modest degrees of eosinophilia are associated with a plethora of conditions, severe eosinophilia, especially that approaching the levels displayed by this patient, suggests a much more circumscribed differential diagnosis. This should prompt consideration of ChurgStrauss syndrome, parasitic infection with an active tissue migration phase, and hypereosinophilic syndrome (HES).4 HES has classically been characterized by hypereosinophilia for at least 6 months, exclusion of both secondary and clonal eosinophilia, and evidence of end‐organ involvement. More recently, however, a revised definition consisting of marked eosinophilia with reasonable exclusion of other causes has gained favor.1, 7, 10, 1416 While perhaps as many as 75% of cases of HES continue to be considered idiopathic at present, 2 subtypes have now been recognized, with important prognostic and therapeutic implications. Myeloproliferative HES has a strong male predominance, is frequently associated with elevated serum tryptase and B₁₂ levels, often manifests with hepatosplenomegaly, and displays a characteristic gene mutation, FIP1L1/PDGFRA. Lymphocytic HES is typified by polyclonal eosinophilic expansion in response to elevated IL‐5 levels, is associated with less cardiac involvement and a somewhat more favorable prognosis in the absence of therapy, and has been associated with transformation into T‐cell lymphoma.1, 1417 We suspect, though we are unable to prove, that our patient was finally diagnosed at the end of a journey that began as lymphocytic HES and ultimately progressed to T‐cell lymphoma. T‐cell lymphoma has rarely been associated with profound eosinophilia. This appears to reflect disordered production of IL‐5, as was true of this patient, and many of these cases may represent transformed lymphocytic HES.14

Specific therapy exists for the myeloproliferative subtype of HES, consisting of the tyrosine kinase inhibitor imatinib, with excellent response in typical cases. Initial treatment of most other extreme eosinophilic syndromes not caused by parasitic infection, including lymphocytic and idiopathic HES as well as ChurgStrauss syndrome, consists of high‐dose corticosteroids, with a variety of other agents used as second‐line and steroid‐sparing treatments. The urgency of therapy is dictated by the presence and severity of end‐organ damage, and in some instances corticosteroids may need to be given before the diagnosis is fully secure. When S. stercoralis infection has not been ruled out, concurrent therapy with ivermectin should be given to prevent triggering Strongyloides hyperinfection. Hematology input is critical when HES is under serious consideration, with bone marrow examination, cytogenetic studies, T‐cell phenotyping and T‐cell receptor rearrangement studies essential in helping to establish the correct diagnosis.10, 17

The differential diagnosis of peripheral eosinophilia is broad and requires a thorough, stepwise approach. Although profound eosinophilia is usually caused by a limited number of diseases, this patient reminds us that Captain Renault's advice in the film Casablanca to round up the usual suspects does not always suffice, as the diagnosis of T‐cell lymphoma was not considered by either the clinicians or the discussant until lung biopsy results became available. Most patients with hypereosinophilia not caused by parasitic infection will ultimately require an invasive procedure to establish a diagnosis, which is essential before embarking on an often‐toxic course of therapy, as well as for providing an accurate prognosis.

TEACHING POINTS

• 1

  The most common causes of eosinophilia include helminthic infections (the leading cause worldwide), asthma, allergic conditions (the leading cause in the United States), malignancies, and drugs.

• 2

  Hypereosinophilia may lead to end‐organ damage. The most important etiologies include ChurgStrauss Syndrome, HES, or a helminthic infection in the larval migration phase.

• 3

  The mainstay of therapy for most cases of HES is corticosteroids. The goal of therapy is to prevent, or ameliorate, end‐organ damage.

A 76‐year‐old white male presented to his primary care physician with a 40‐pound weight loss and gradual decline in function over the prior 6 months. In addition, over the previous 2 months, he had begun to suffer a constant, non‐bloody, and non‐productive cough accompanied by night sweats. Associated complaints included a decline in physical activity, increased sleep needs, decreased appetite, irritability, and generalized body aches.

The patient, an elderly man, presents with a subacute, progressive systemic illness, which appears to have a pulmonary component. Broad disease categories meriting consideration include infections such as tuberculosis, endemic fungi, and infectious endocarditis; malignancies including bronchogenic carcinoma, as well as a variety of other neoplasms; and rheumatologic conditions including temporal arteritis/polymyalgia rheumatica and Wegener's granulomatosis. His complaints of anhedonia, somnolence, and irritability, while decidedly nonspecific, raise the possibility of central nervous system involvement.

His past medical history was notable for coronary artery disease, moderate aortic stenosis, hypertension, hyperlipidemia, and chronic sinusitis. Two years ago, he had unexplained kidney failure. Anti‐neutrophilic cytoplasmic antibodies (ANCA) were present, and indirect immunoflorescence revealed a peri‐nuclear (P‐ANCA) pattern on kidney biopsy. The patient had been empirically placed on azathioprine for presumed focal segmental glomerulosclerosis (FSGS), and his renal function remained stable at an estimated glomerular filtrate rate ranging from 15 to 30 mL/min/1.73 m². His other medications included nifedipine, metoprolol, aspirin, isosorbide mononitrate, atorvastatin, calcitriol, and docusate. His family and social histories were unremarkable, including no history of tobacco. He had no pets and denied illicit drug use. He admitted to spending a considerable amount of time gardening, including working in his yard in bare feet.

The associations of focal segmental glomerulosclerosis, if indeed this diagnosis is correct, include lupus, vasculitis, and human immunodeficiency virus (HIV) infection. The nephrotic syndrome is a frequent manifestation of this entity, although, based on limited information, this patient does not appear to be clinically nephrotic. If possible, the biopsy pathology should be reviewed by a pathologist with interest in the kidney. The report of a positive P‐ANCA may not be particularly helpful here, given the frequency of false‐positive results, and in any event, P‐ANCAs have been associated with a host of conditions other than vasculitis.

The patient's gardening exposure, in bare feet no less, is intriguing. This potentially places him at risk for fungal infections including blastomycosis, histoplasmosis, cryptococcosis, and sporotrichosis. Gardening without shoes is a somewhat different enterprise in northeast Ohio than, say, Mississippi, and it will be helpful to know where this took place. Exposure in Appalachia or the South should prompt consideration of disseminated strongyloidiasis, given his azathioprine use.

Vital signs were as follows: blood pressure 151/76 mmHg, pulse 67 beats per minute, respiratory rate 20 breaths per minute, temperature 35.6C, and oxygen saturation 98% on room air. On examination, he appeared very thin but not in distress. Examination of the skin did not reveal rashes or lesions, and there was no lymphadenopathy. His thyroid was symmetric and normal in size. Lungs were clear to auscultation, and cardiac exam revealed a regular rate with a previously documented III/VI holosystolic murmur over the aortic auscultatory area. Abdominal exam revealed no organomegaly or tenderness. Joints were noted to be non‐inflamed, and extremities non‐edematous. Radial, brachial, popliteal, and dorsalis pedis pulses were normal bilaterally. A neurological exam revealed no focal deficits.

The physical examination does not help to substantively narrow or redirect the differential diagnosis. Although he appears to be tachypneic, this may simply reflect charting artifact. At this point, I would like to proceed with a number of basic diagnostic studies. In addition to complete blood count with differential, chemistries, and liver function panel, I would also obtain a thyroid stimulating hormone (TSH) assay, urinalysis, blood cultures, erythrocyte sedimentation rate/C‐reactive protein, a HIV enzyme‐linked immunosorbent assay (ELISA), chest radiograph, and a repeat ANCA panel. A purified protein derivative (PPD) skin test should be placed.

Blood chemistries were as follows: glucose 88 mg/dL, blood urea nitrogen (BUN) 48 mg/dL, creatinine 2.71 mg/dL, sodium 139 mmol/L, potassium 5.5 mmol/L, chloride 103 mmol/L, CO₂ 28 mmol/L, and anion gap 8 mmol/L. TSH, urinalysis, and PPD tests were unremarkable. His white blood cell count (WBC) was 33.62 K/L with 94% eosinophils and an absolute eosinophil count of 31.6 K/L. His platelet count was 189 K/L, hemoglobin 12.1 g/dL, and hematocrit 36.9%. A chest x‐ray revealed reticular opacities in the mid‐to‐lower lungs, and subsequent computed tomography (CT) scan of the chest demonstrated multiple bilateral indeterminate nodules and right axillary adenopathy.

The patient's strikingly elevated absolute eosinophil count is a very important clue that helps to significantly focus the diagnostic possibilities. In general, an eosinophilia this pronounced signifies one of several possibilities, including primary hypereosinophilic syndrome, ChurgStrauss syndrome, parasitic infection with an active tissue migration phase, eosinophilic leukemia, and perhaps chronic eosinophilic pneumonia. In addition, Wegener's granulomatosis still merits consideration, although an eosinophil count this high would certainly be unusual.

Of the above possibilities, ChurgStrauss seems less likely given his apparent absence of a history of asthma. Parasitic infections, particularly ascariasis but also strongyloidiasis, hookworm, and even visceral larva migrans are possible, although we have not been told whether geographical exposure exists to support the first 3 of these. Hypereosinophilic syndrome remains a strong consideration, although the patient does not yet clearly meet criteria for this diagnosis.

At this juncture, I would send stool and sputum for ova and parasite exam, and order Strongyloides serology, have the peripheral smear reviewed by a pathologist, await the repeat ANCA studies, and consider obtaining hematology consultation.

Tests for anti‐Smith, anti‐ribonuclear (RNP), anti‐SSA, anti‐SSB, anti‐centromere, anti‐Scl 70, and anti‐Jo antibodies were negative. Repeat ANCA testing was positive with P‐ANCA pattern on indirect immunofluorescence. His erythrocyte sedimentation rate and C‐reactive Protein (CRP) were mildly elevated at 29 mm/hr and 1.1 mg/dL, respectively. An immunodeficiency panel work‐up consisting of CD3, CD4, CD8, CD19, T‐cell, B‐cell, and natural killer (NK) cell differential counts demonstrated CD8 T‐cell depletion. Blood cultures demonstrated no growth at 72 hours. No definite M protein was identified on serum and urine protein electrophoresis. Strongyloides IgG was negative. HIV ELISA was negative. A serologic fungal battery to measure antibodies against Aspergillus, Blastomyces, Histoplasma, and Coccidiodes was negative. A microscopic examination of stool and sputum for ova and parasites was also negative. A peripheral blood smear showed anisocytosis and confirmed the elevated eosinophil count.

The preceding wealth of information helps to further refine the picture. The positive P‐ANCA by ELISA as well as immunofluorescence suggests this is a real phenomenon, and makes ChurgStrauss syndrome more likely, despite the absence of preceding or concurrent asthma. I am not aware of an association between P‐ANCA and hypereosinophilic syndrome, nor of a similar link to either chronic eosinophilic pneumonia or hematological malignancies. Although I would like to see 2 additional stool studies for ova and parasites performed by an experienced laboratory technician before discarding the diagnosis of parasitic infection entirely, I am increasingly suspicious that this patient has a prednisone‐deficient state, most likely ChurgStrauss syndrome. I am uncertain of the relationship between his more recent symptoms and his pre‐existing kidney disease, but proceeding to lung biopsy appears to be appropriate.

Bronchoscopic examination with accompanying bronchoalveolar lavage (BAL) and transbronchial biopsy were performed. The BAL showed many Aspergillus fumigatus as well as hemosiderin‐laden macrophages, and the biopsy demonstrated an eosinophilic infiltrate throughout the interstitia, alveolar spaces, and bronchiolar walls. However, the airways did not show features of asthma, capillaritis, vasculitis, or granulomas. A bone marrow biopsy showed no evidence of clonal hematologic disease.

The Aspergillus recovered from BAL, although unexpected, probably does not adequately explain the picture. I am not convinced that the patient has invasive aspergillosis, and although components of the case are consistent with allergic bronchopulmonary aspergillosis, the absence of an asthma history and the extreme degree of peripheral eosinophilia seem to speak against this diagnosis. The biopsy does not corroborate a vasculitic process, but the yield of transbronchial biopsy is relatively low in this setting, and the pulmonary vasculitides remain in play unless a more substantial biopsy specimen is obtained. It is worth noting that high‐dose corticosteroids are a risk factor for the conversion of Aspergillus colonization to invasive aspergillosis, and treatment with voriconazole would certainly be appropriate if prednisone was to be initiated.

I believe ChurgStrauss syndrome, hypereosinophilic syndrome, and chronic eosinophilic pneumonia remain the leading diagnostic possibilities, with the P‐ANCA likely serving as a red herring if the diagnosis turns out to be one of the latter entities. An open lung biopsy would be an appropriate next step, after first obtaining those additional ova and parasite exams for completeness.

An infectious diseases specialist recommended that the patient be discharged on voriconazole 300 mg PO bid for Aspergillus colonization with an underlying lung disease and likely allergic bronchopulmonary aspergillosis or invasive aspergillosis. Steroid therapy was contemplated but not initiated.

Three weeks later, the patient re‐presented with worsening of fatigue and cognitive deterioration marked by episodes of confusion and word‐finding difficulties. His WBC had increased to 45.67 K/L (94% eosinophils). He had now lost a total of 70 pounds, and an increase in generalized weakness was apparent. His blood pressure on presentation was 120/63 mmHg, pulse rate 75 beats per minute, respiratory rate 18 breaths per minute, temperature 35.8C, and oxygen saturation 97% on room air. He appeared cachectic, but not in overt distress. His skin, head, neck, chest, cardiac, abdominal, peripheral vascular, and neurological exam demonstrated no change from the last admission. A follow‐up chest x‐ray showed mild pulmonary edema and new poorly defined pulmonary nodules in the right upper lobe. A repeat CT scan of the thorax demonstrated interval progression of ground‐glass attenuation nodules, which were now more solid‐appearing and increased in number, and present in all lobes of the lung. A CT of the brain did not reveal acute processes such as intracranial hemorrhage, infarction, or mass lesions. Lumbar puncture was performed, with a normal opening pressure. Analysis of the clear and colorless cerebrospinal fluid (CSF) showed 1 red blood cell count (RBC)/L, 2 WBC/L with 92% lymphocytes, glucose 68 mg/dL, and protein 39 mg/dL. CSF fungal cultures, routine cultures, venereal disease reaction level (VDRL), and cryptococcal antigen were negative. CSF cytology did not demonstrate malignant cells. Multiple ova and parasite exams obtained from the previous admission were confirmed to be negative.

The patient's continued deterioration points to either ChurgStrauss syndrome or hypereosinophilic syndrome, I believe. His renal function and P‐ANCA (if related) support the former possibility, while the development of what now appear to be clear encephalopathic symptoms are more in favor of the latter. I would initiate steroid therapy while proceeding to an open lung biopsy in an effort to secure a definitive diagnosis, again under the cover of voriconazole, and would ask for hematology input if this had not already been obtained.

A video‐assisted right thoracoscopy with wedge resection of 2 visible nodules in the right lower lobe was performed. The biopsy conclusively diagnosed a peripheral T‐cell lymphoma. The patient's condition deteriorated, and ultimately he and his family chose a palliative approach.

COMMENTARY

Eosinophils are cells of myeloid lineage that contain cationic‐rich protein granules that mediate allergic response, reaction to parasitic infections, tissue inflammation, and immune modulation.1, 2 Eosinophilia (absolute eosinophil count 600 cells/L) suggests the possibility of a wide array of disorders. The degree of eosinophilia can be categorized as mild (6001500 cells/L), moderate (15005000 cells/L), or severe (>5000 cells/L).3 It may signify a reactive phenomenon (secondary) or, less commonly, either an underlying hematological neoplasm (primary) or an idiopathic process.2 Clinicians faced with an unexplained eosinophilia should seek the most frequent causes first.

Initial investigation should include a careful travel history; consideration of both prescription and over‐the‐counter medications, especially non‐steroidal anti‐inflammatory drugs (NSAIDs), with withdrawal of non‐essential agents; serology for Strongyloides stercoralis antibodies (and possibly other helminths, depending on potential exposure) should be assessed; and stool examinations for ova and parasites should be obtained. The possibility of a wide variety of other potential causes of eosinophilia (Table 1) should be entertained,413 and a careful search for end‐organ damage related to eosinophilic infiltration should be performed if eosinophilia is moderate or severe.1

Hypereosinophilia is defined as an eosinophil level greater than 1500 cells/L. These levels may be associated with end‐organ damage regardless of the underlying etiology, although the degree of eosinophilia frequently does not correlate closely with eosinophilic tissue infiltration. As a result, relatively modest degrees of peripheral eosinophilia may be seen in association with end‐organ damage, while severe eosinophilia may be tolerated well for prolonged periods in other cases.1 The most serious complications of hypereosinophilia are myocardial damage with ultimate development of cardiac fibrosis and refractory heart failure; pulmonary involvement with hypoxia; and involvement of both the central and peripheral nervous systems including stroke, encephalopathy, and mononeuritis multiplex. A number of studies should be considered to help evaluate for the possibility of end‐organ damage as well as to assess for the presence of primary and idiopathic causes of hypereosinophilia. These include peripheral blood smear looking particularly for dysplastic eosinophils or blasts, serum tryptase, serum vitamin B₁₂, serum IgE, cardiac troponin levels, anti‐neutrophil cytoplasmic antibody, electrocardiography, echocardiography, pulmonary function tests, and thoracoabdominal CT scanning. Endoscopic studies with esophageal, duodenal, and colonic biopsy should be performed if eosinophilic gastroenteritis is suspected.1, 7, 10

While more modest degrees of eosinophilia are associated with a plethora of conditions, severe eosinophilia, especially that approaching the levels displayed by this patient, suggests a much more circumscribed differential diagnosis. This should prompt consideration of ChurgStrauss syndrome, parasitic infection with an active tissue migration phase, and hypereosinophilic syndrome (HES).4 HES has classically been characterized by hypereosinophilia for at least 6 months, exclusion of both secondary and clonal eosinophilia, and evidence of end‐organ involvement. More recently, however, a revised definition consisting of marked eosinophilia with reasonable exclusion of other causes has gained favor.1, 7, 10, 1416 While perhaps as many as 75% of cases of HES continue to be considered idiopathic at present, 2 subtypes have now been recognized, with important prognostic and therapeutic implications. Myeloproliferative HES has a strong male predominance, is frequently associated with elevated serum tryptase and B₁₂ levels, often manifests with hepatosplenomegaly, and displays a characteristic gene mutation, FIP1L1/PDGFRA. Lymphocytic HES is typified by polyclonal eosinophilic expansion in response to elevated IL‐5 levels, is associated with less cardiac involvement and a somewhat more favorable prognosis in the absence of therapy, and has been associated with transformation into T‐cell lymphoma.1, 1417 We suspect, though we are unable to prove, that our patient was finally diagnosed at the end of a journey that began as lymphocytic HES and ultimately progressed to T‐cell lymphoma. T‐cell lymphoma has rarely been associated with profound eosinophilia. This appears to reflect disordered production of IL‐5, as was true of this patient, and many of these cases may represent transformed lymphocytic HES.14

Specific therapy exists for the myeloproliferative subtype of HES, consisting of the tyrosine kinase inhibitor imatinib, with excellent response in typical cases. Initial treatment of most other extreme eosinophilic syndromes not caused by parasitic infection, including lymphocytic and idiopathic HES as well as ChurgStrauss syndrome, consists of high‐dose corticosteroids, with a variety of other agents used as second‐line and steroid‐sparing treatments. The urgency of therapy is dictated by the presence and severity of end‐organ damage, and in some instances corticosteroids may need to be given before the diagnosis is fully secure. When S. stercoralis infection has not been ruled out, concurrent therapy with ivermectin should be given to prevent triggering Strongyloides hyperinfection. Hematology input is critical when HES is under serious consideration, with bone marrow examination, cytogenetic studies, T‐cell phenotyping and T‐cell receptor rearrangement studies essential in helping to establish the correct diagnosis.10, 17

The differential diagnosis of peripheral eosinophilia is broad and requires a thorough, stepwise approach. Although profound eosinophilia is usually caused by a limited number of diseases, this patient reminds us that Captain Renault's advice in the film Casablanca to round up the usual suspects does not always suffice, as the diagnosis of T‐cell lymphoma was not considered by either the clinicians or the discussant until lung biopsy results became available. Most patients with hypereosinophilia not caused by parasitic infection will ultimately require an invasive procedure to establish a diagnosis, which is essential before embarking on an often‐toxic course of therapy, as well as for providing an accurate prognosis.

TEACHING POINTS

• 1

  The most common causes of eosinophilia include helminthic infections (the leading cause worldwide), asthma, allergic conditions (the leading cause in the United States), malignancies, and drugs.

• 2

  Hypereosinophilia may lead to end‐organ damage. The most important etiologies include ChurgStrauss Syndrome, HES, or a helminthic infection in the larval migration phase.

• 3

  The mainstay of therapy for most cases of HES is corticosteroids. The goal of therapy is to prevent, or ameliorate, end‐organ damage.

A 35‐year‐old woman presented to her primary care physician complaining of left post‐auricular pain, swelling, and redness. She described the pain as 8 out of 10, constant, sharp, and nonradiating. She denied fever or chills. A presumptive diagnosis of cellulitis led to a prescription for oral trimethoprim‐sulfamethoxazole. Left facial swelling worsened despite 4 days of antibiotics, so she came to the emergency department.

Noninfectious causes of this woman's symptoms include trauma, or an inflammatory condition such as polychondritis. Key infectious considerations are mastoiditis or a mastoid abscess. Herpes zoster with involvement of the pinna and auditory canal may also present with pain and redness. In the absence of findings suggestive of an infection arising from the auditory canal, cellulitis is a reasonable consideration. With the growing incidence of community‐acquired methicillin‐resistant Staphylococcus aureus infections, an agent effective against this pathogen such as trimethoprim‐sulfamethoxazole may be used, usually in combination with an antibiotic that provides more reliable coverage for group A streptococcus.

Her past medical history included poorly controlled type II diabetes mellitus and asthma. She reported no previous surgical history. Her current medications were insulin, albuterol inhaler, and trimethoprim‐sulfamethoxazole, although she had a history of noncompliance with her insulin. She was married with 1 child and was unemployed. She smoked 1 pack of cigarettes daily, drank up to 6 beers daily, and denied use of illicit drugs.

Her history of diabetes increases her risk of malignant otitis externa. Both diabetes and excess alcohol consumption are risk factors for herpes zoster. Smoking has been shown to increase the risk of otitis media and carriage by S. pneumoniae, a common pathogen in ear infections.

She was ill‐appearing and in moderate respiratory distress. Her temperature was 39C, blood pressure 149/93 mmHg, pulse 95 beats per minute, respiratory rate of 26 times per minute, with an oxygen saturation of 96% while breathing ambient air. She had swelling of the left side of the face extending to the left forehead and lateral neck. Examination of the external ear and auditory canal were unremarkable. The swelling had no associated erythema, tenderness, or lymphadenopathy. She had no oropharyngeal or nasal ulcers present. Her pupils were equal, round, and reactive to light and accommodation with normal sclera. Her trachea was midline; thyroid exam was normal. The heart sounds included normal S1 and S2 without murmurs, rubs, or gallops. Her lung exam was remarkable for inspiratory stridor. The abdominal examination revealed no distention, tenderness, organomegaly, or masses. Cranial nerve testing revealed a left‐sided central seventh nerve palsy along with decreased visual acuity of the left eye. Strength, sensation, and deep tendon reflexes were normal.

While there are many causes of facial nerve palsy, distinguishing between a peripheral palsy (which causes paralysis of the entire ipsilateral side of the face) and a central palsy (which spares the musculature of the forehead) is important. The most common type of peripheral facial nerve palsy is Bell's palsy. Infections such as meningitis or tumors of the central nervous system can cause central facial nerve or other cranial nerve palsy. Important infections to consider in this case would be viral such as herpes zoster or simplex, or atypical bacteria such as Mycoplasma and Rickettsia, which may explain the neurologic but not all of the other clinical findings in this case. It is also critical to determine whether she has an isolated seventh cranial nerve palsy or if other cranial nerves are involved such as may occur with basilar meningitis, which has a myriad of infectious and noninfectious causes. The decreased visual acuity may be a result of corneal dryness and abrasions from inability to close the eye but may also represent optic nerve problems, so detailed ophthalmologic exam is essential. Her ill appearance coupled with facial and neck swelling leads me to at least consider Lemierre's syndrome with central nervous system involvement. Finally, facial swelling and the inspiratory stridor may represent angioedema, although one‐sided involvement of the face would be unusual.

The results of initial laboratory testing were as follows: sodium, 138 mmol/L; potassium, 3.4 mmol/L; chloride, 109 mmol/L; bicarbonate, 14 mmol/L; blood urea nitrogen level, 19 mg/dL; creatinine, 1.1 mg/dL; white cell count, 23,510/mm³; differential, 90% neutrophils, 1% bands, 7% lymphocytes, 2% monocytes; hemoglobin level, 12.5 g/dL; platelet count, 566,000/mm³; hemoglobin A1c, 11%; albumin, 1.6 g/dL; total protein, 6.2 g/dL; total bilirubin, 0.8 mg/dL; alkaline phosphatase, 103 U/L; alanine aminotransferase level, 14 U/L; international normalized ratio of 1.2; partial thromboplastin time, 29 seconds (normal value, 2434 seconds); erythrocyte sedimentation rate, 121 mm/hr; creatine kinase, 561 U/L (normal value 25190). Arterial blood gas measurements with the patient breathing 50% oxygen revealed a pH of 7.34, a partial pressure of carbon dioxide of 28 mmHg, and a partial pressure of oxygen of 228 mmHg.

I am concerned that this patient has sepsis, likely due to an infectious trigger. With her clinical presentation localized to the head and neck, her history of diabetes, and the accelerated sedimentation rate, malignant otitis externa would explain many of her findings. Empiric anti‐infective therapy directed toward Pseudomonas aeruginosa should be initiated, and imaging of the head and ear should be undertaken.

The patient required intubation due to increased respiratory distress and stridor. Her physicians used intravenous vancomycin, clindamycin, and piperacillin/tazobactam to treat presumed cellulitis. Her abnormal neurologic exam led to magnetic resonance (MR) imaging and MR angiography of her neck and brain, which showed evidence of multiple regions of ischemia in the left occipital and inferior parietal distributions, as well as bilateral cerebellar distributions and enhancement of the parotid gland and mastoid air cells (Figure 1). A cerebral angiogram revealed irregularity and caliber reduction in multiple cervical and intracranial arteries, associated with intraluminal thrombi within the left intracranial vertebral artery, consistent with either vasculitis or infectious angioinvasion (Figure 2).

Figure 1

Figure 2

The angioinvasive nature of the findings on imaging leads me to suspect fungal infection. The patient's history of diabetes mellitus and acidosis are risk factors for mucormycosis. Aspergillus and Fusarium may also be angioinvasive but would be much more likely in neutropenic or severely immunocompromised patients. S. aureus may cause septic emboli mimicking angioinvasion but should be readily detected in conventional blood cultures. At this point, I would empirically begin amphotericin B; tissue, however, is needed for definitive diagnosis and a surgical consult should be requested.

After reviewing her imaging studies, an investigation for vasculitis and hypercoagulable states including antinuclear antibody, anti‐deoxyribonucleic acid, anti‐Smith antibody, anti‐SSA antibody level, anti‐SSB level, antineutrophil cytoplasmic antibody, activated protein C resistance level, factor VIII level, human immunodeficiency virus antibody, homocysteine level, cardiolipin antibody testing, lupus anticoagulant, prothrombin 20210 mutation, and protein C level was done, and all tests were normal. Protein S level was slightly low at 64% (normal value 65%140%). Given the enlarged parotid gland and the enhancement of the left parotid bed on magnetic resonance imaging, she underwent a parotid biopsy that revealed sialadenitis.

Systemic vasculitides can result in tissue damage, mediated by the release of endogenous cellular contents from dying cells, known as damage‐associated molecular patterns, sufficient to cause systemic inflammatory response syndrome (SIRS). This patient presented with acute symptoms but has negative laboratory studies for autoantibodies. The parotid biopsy also did not reveal evidence of vasculitis. All these findings make the diagnosis of vasculitis much less likely.

She remained in the medical intensive care unit on mechanical ventilation, with minimal symptomatic improvement. On hospital day 10, the patient developed necrosis of the left external ear. A punch biopsy of the necrotic area of her left pinna was performed; the pathology report read: Sections of punch biopsy of skin show an unremarkable epidermis. There is dermal necrosis involving the stroma and adnexal structures. Intravascular thrombi within the deep dermis are seen. Within superficial dermis there are broad, elongated, nonseptated hyaline structures reminiscent of Mucor. Special stains (periodic acid‐Schiff stain and Grocott Gomori methenamine silver stain [GMS]) performed with appropriately reactive controls fail to highlight these structures (Figure 3). The infectious disease team reviewed the pathology slides with the pathologist. As there was inconclusive evidence for zygomycosis, ie, only a few hyaline structures which failed to stain with GMS stain, the consultants recommended no change in the patient's management.

Figure 3

The gross and microscopic evidence of necrosis and areas of intravascular thrombi are nonspecific but compatible with a fungal infection in a patient with risk factors for zygomycosis. The GMS stain is a very sensitive stain for fungal structures, so a negative stain in this case is surprising, but additional testing such as immunohistochemistry should be pursued to confirm or refute this diagnosis. While Rhizopus species can be contaminants, the laboratory finding of these organisms in specimens from patients with risk factors for zygomycosis should not be ignored.

On hospital day 12, the patient was noted to have increased facial swelling. A computed tomographic (CT) angiogram of the neck revealed necrosis of the anterior and posterior paraspinal muscles from the skull base to C34, marked swelling of the left parotid gland, and left inferior parieto‐occipital enhancing lesion. An incisional parotid biopsy was performed. Special stains were positive for broad‐based fungal hyphae consistent with mucormycosis (Figure 4).

Figure 4

Given these findings, the patient should be started on amphotericin B immediately. Medical therapy alone generally does not suffice, and aggressive surgical debridement combined with intravenous antifungal therapy results in better outcomes. The longer the duration of symptoms and the greater the progression of disease, the less favorable the prognosis.

The patient was started on amphotericin B lipid complex and micafungin. However, after 16 days of therapy, repeat imaging of the neck showed worsening necrosis of the neck muscles. At this time, she underwent extensive debridement of face and neck, and posaconazole was added. After prolonged hospitalization, she was discharged to a rehabilitation facility on posaconazole. She resided in a nursing facility for 6 months. One year after her hospitalization, she is living at home and is able to ambulate independently, but requires feeding through a percutaneous endoscopic gastrostomy (PEG) tube because she remains dysphagic.

COMMENTARY

Infections caused by the ubiquitous fungi of the class Zygomycetes typically take 1 of 5 forms: rhinocerebral, pulmonary, gastrointestinal, disseminated, and cutaneous. The presentation varies widely, ranging from plaques, skin swelling, pustules, cellulitis, blisters, nodules, ulcerations, and ecthyma gangrenosum‐like lesions to deeper infections such as necrotizing fasciitis, osteomyelitis, and disseminated infection.1 Infections typically occur in immunocompromised hosts, including transplant recipients and patients with hematologic malignancy, but also occur in patients with diabetes mellitus, intravenous drug users, and patients on deferoxamine therapy.2 Deferoxamine and other iron‐binding therapy is thought to predispose to zygomycetes infections because of improved iron uptake of the fungal species and, thus, stimulation of growth.3 Pulmonary and rhinocerebral infections are the most common clinically encountered forms, and 44% of cutaneous infections are complicated by deep extension or dissemination.4

The articles cited above describe the more typical presentations of this rare disease. However, this patient had an unusual presentation, as parotid involvement due to zygomycosis has only been described once previously.5 Her inflammatory vasculitis and ensuing strokes from involvement of the carotid artery are recognized complications of zygomycosis, and in 1 case series of 41 patients with rhinocerebral mucormycosis, carotid involvement was seen in 31% of patients.6 After the punch biopsy of the patient's pinna showing nonseptated hyphae reminiscent of Mucor, why did her physicians delay administering amphotericin?

There are 2 likely possibilities: anchoring bias or error in medical decision‐making due to inaccurate probability estimates. Anchoring bias describes a heuristic where the initial diagnosis or gestalt biases the physician's process for assigning a final diagnosis.7, 8 This bias creates cognitive errors by limiting creativity in diagnosis. In this case, the infectious disease team carefully weighed the information obtained from the first biopsy. Given their low pretest estimate of this virtually unreported presentation of a rare disease, they decided to evaluate further without beginning antifungal therapy. Of note, there were few hyaline structures, and those structures lacked uptake of GMS. Since they considered the diagnosis yet rejected the diagnosis due to insufficient evidence, it is unlikely that anchoring bias played a role.

Was there an error in medical decision‐making? The physicians in this case faced a very common medical dilemma: whether or not to start a toxic medication empirically or wait for diagnostic confirmation prior to treatment.9 To solve this dilemma, one can apply decision analysis. Moskowitz et al described 5 phases of medical decision analysis by which a probabilistic right answer to clinical scenarios can be deduced mathematically.10 To solve this problem, probabilities must be assigned to the risk of giving a drug to a patient without the disease versus the risk of not giving a drug to a patient with the disease. For example, amphotericin deoxycholate causes acute renal failure in 30% to 47% of patients. Newer formulations of amphotericin, such as liposomal amphotericin and lipid complex, result in lower rates of nephrotoxicity (27% vs 47%). The risk of not giving amphotericin to a patient with zygomycosis is death. Even in patients treated with amphotericin, the mortality rate has been shown to be 66%, and up to 100% in those with strokes related to zygomycosis.2, 6, 11 Simply looking at these probabilities, decision analysis would favor empiric treatment.

The physicians caring for this patient did not have the luxury of retrospective speculation. After looking at all of the data, the equivocal skin biopsy and rare clinical presentation, the question to ask would change: What is the risk of giving amphotericin empirically to someone who, based on available information, has a very low probability of having zygomycosis? When phrased in this manner, there is a 47% chance of nephrotoxicity with amphotericin versus the very small probability that you have diagnosed a case of zygomycosis that has only been described once in the literature. Mathematically andmore importantlyclinically, this question becomes more difficult to answer. However, no value can be placed on the possibility of death in suspected zygomycosis, and the risk of short‐term amphotericin use is much less than that of a course of treatment. As such, empiric therapy should always be given.

Physicians are not mathematicians, and dynamic clinical scenarios are not so easily made into static math problems. Disease presentations evolve over time towards a diagnosable clinical pattern, as was the case with this patient. Two days after the aforementioned biopsy, she worsened and in less time than it would have taken to isolate zygomycosis from the first biopsy, a second biopsy revealed the typical nonseptated hyphae demarcated with the GMS stain. Even appropriate diagnostic testing, thoughtful interpretation, and avoidance of certain cognitive errors can result in incorrect diagnoses and delayed treatment. It is monitoring the progression of disease and collecting additional data that allows physicians to mold a diagnosis and create a treatment plan.

The primary treatment of zygomycosis should include amphotericin. However, there are limited data to support combination therapy with an echinocandin in severe cases, as in this patient.12 Posaconazole is not recommended for monotherapy as an initial therapy, but there is data for its use as salvage therapy in zygomycosis.13 This case highlights the difficulties that physicians face in the diagnosis and treatment of rare diseases. Cerebral infarction in a hematologic malignancy, uncontrolled diabetes, or iron chelation therapy could be the initial presentation of rhinocerebral zygomycosis. There truly are different strokes for different folks. Recognizing this and similar presentations may lead to a more rapid diagnosis and treatment of zygomycosis.

TEACHING POINTS

• 1

  Zygomycosis has a wide range of clinical presentations ranging from skin lesions to deep tissue infections. As it is an angioinvasive organism, it can also present as cerebral infarcts and brain abscesses.

• 2

  Zygomycosis infections should be suspected in patients with uncontrolled diabetes, hematologic or oncologic malignancies, and patients on iron chelation therapy with a potentially compatible clinical picture.

• 3

  If zygomycosis infection is suspected, rapid histologic diagnosis should be attempted. However, as histologic diagnosis can take time, empiric therapy with amphotericin should always be administered.

• 4

  Amphotericin remains the primary medical therapy for this disease; however, there is limited emerging evidence to suggest that echinocandins can be used in combination with amphotericin for improved treatment of severe rhinocerebral zygomyocosis. Posaconazole has a role as salvage therapy in zygomycosis, but should not be used as the sole primary treatment.

A 35‐year‐old woman presented to her primary care physician complaining of left post‐auricular pain, swelling, and redness. She described the pain as 8 out of 10, constant, sharp, and nonradiating. She denied fever or chills. A presumptive diagnosis of cellulitis led to a prescription for oral trimethoprim‐sulfamethoxazole. Left facial swelling worsened despite 4 days of antibiotics, so she came to the emergency department.

Noninfectious causes of this woman's symptoms include trauma, or an inflammatory condition such as polychondritis. Key infectious considerations are mastoiditis or a mastoid abscess. Herpes zoster with involvement of the pinna and auditory canal may also present with pain and redness. In the absence of findings suggestive of an infection arising from the auditory canal, cellulitis is a reasonable consideration. With the growing incidence of community‐acquired methicillin‐resistant Staphylococcus aureus infections, an agent effective against this pathogen such as trimethoprim‐sulfamethoxazole may be used, usually in combination with an antibiotic that provides more reliable coverage for group A streptococcus.

Her past medical history included poorly controlled type II diabetes mellitus and asthma. She reported no previous surgical history. Her current medications were insulin, albuterol inhaler, and trimethoprim‐sulfamethoxazole, although she had a history of noncompliance with her insulin. She was married with 1 child and was unemployed. She smoked 1 pack of cigarettes daily, drank up to 6 beers daily, and denied use of illicit drugs.

Her history of diabetes increases her risk of malignant otitis externa. Both diabetes and excess alcohol consumption are risk factors for herpes zoster. Smoking has been shown to increase the risk of otitis media and carriage by S. pneumoniae, a common pathogen in ear infections.

She was ill‐appearing and in moderate respiratory distress. Her temperature was 39C, blood pressure 149/93 mmHg, pulse 95 beats per minute, respiratory rate of 26 times per minute, with an oxygen saturation of 96% while breathing ambient air. She had swelling of the left side of the face extending to the left forehead and lateral neck. Examination of the external ear and auditory canal were unremarkable. The swelling had no associated erythema, tenderness, or lymphadenopathy. She had no oropharyngeal or nasal ulcers present. Her pupils were equal, round, and reactive to light and accommodation with normal sclera. Her trachea was midline; thyroid exam was normal. The heart sounds included normal S1 and S2 without murmurs, rubs, or gallops. Her lung exam was remarkable for inspiratory stridor. The abdominal examination revealed no distention, tenderness, organomegaly, or masses. Cranial nerve testing revealed a left‐sided central seventh nerve palsy along with decreased visual acuity of the left eye. Strength, sensation, and deep tendon reflexes were normal.

While there are many causes of facial nerve palsy, distinguishing between a peripheral palsy (which causes paralysis of the entire ipsilateral side of the face) and a central palsy (which spares the musculature of the forehead) is important. The most common type of peripheral facial nerve palsy is Bell's palsy. Infections such as meningitis or tumors of the central nervous system can cause central facial nerve or other cranial nerve palsy. Important infections to consider in this case would be viral such as herpes zoster or simplex, or atypical bacteria such as Mycoplasma and Rickettsia, which may explain the neurologic but not all of the other clinical findings in this case. It is also critical to determine whether she has an isolated seventh cranial nerve palsy or if other cranial nerves are involved such as may occur with basilar meningitis, which has a myriad of infectious and noninfectious causes. The decreased visual acuity may be a result of corneal dryness and abrasions from inability to close the eye but may also represent optic nerve problems, so detailed ophthalmologic exam is essential. Her ill appearance coupled with facial and neck swelling leads me to at least consider Lemierre's syndrome with central nervous system involvement. Finally, facial swelling and the inspiratory stridor may represent angioedema, although one‐sided involvement of the face would be unusual.

The results of initial laboratory testing were as follows: sodium, 138 mmol/L; potassium, 3.4 mmol/L; chloride, 109 mmol/L; bicarbonate, 14 mmol/L; blood urea nitrogen level, 19 mg/dL; creatinine, 1.1 mg/dL; white cell count, 23,510/mm³; differential, 90% neutrophils, 1% bands, 7% lymphocytes, 2% monocytes; hemoglobin level, 12.5 g/dL; platelet count, 566,000/mm³; hemoglobin A1c, 11%; albumin, 1.6 g/dL; total protein, 6.2 g/dL; total bilirubin, 0.8 mg/dL; alkaline phosphatase, 103 U/L; alanine aminotransferase level, 14 U/L; international normalized ratio of 1.2; partial thromboplastin time, 29 seconds (normal value, 2434 seconds); erythrocyte sedimentation rate, 121 mm/hr; creatine kinase, 561 U/L (normal value 25190). Arterial blood gas measurements with the patient breathing 50% oxygen revealed a pH of 7.34, a partial pressure of carbon dioxide of 28 mmHg, and a partial pressure of oxygen of 228 mmHg.

I am concerned that this patient has sepsis, likely due to an infectious trigger. With her clinical presentation localized to the head and neck, her history of diabetes, and the accelerated sedimentation rate, malignant otitis externa would explain many of her findings. Empiric anti‐infective therapy directed toward Pseudomonas aeruginosa should be initiated, and imaging of the head and ear should be undertaken.

The patient required intubation due to increased respiratory distress and stridor. Her physicians used intravenous vancomycin, clindamycin, and piperacillin/tazobactam to treat presumed cellulitis. Her abnormal neurologic exam led to magnetic resonance (MR) imaging and MR angiography of her neck and brain, which showed evidence of multiple regions of ischemia in the left occipital and inferior parietal distributions, as well as bilateral cerebellar distributions and enhancement of the parotid gland and mastoid air cells (Figure 1). A cerebral angiogram revealed irregularity and caliber reduction in multiple cervical and intracranial arteries, associated with intraluminal thrombi within the left intracranial vertebral artery, consistent with either vasculitis or infectious angioinvasion (Figure 2).

Figure 1

Figure 2

The angioinvasive nature of the findings on imaging leads me to suspect fungal infection. The patient's history of diabetes mellitus and acidosis are risk factors for mucormycosis. Aspergillus and Fusarium may also be angioinvasive but would be much more likely in neutropenic or severely immunocompromised patients. S. aureus may cause septic emboli mimicking angioinvasion but should be readily detected in conventional blood cultures. At this point, I would empirically begin amphotericin B; tissue, however, is needed for definitive diagnosis and a surgical consult should be requested.

After reviewing her imaging studies, an investigation for vasculitis and hypercoagulable states including antinuclear antibody, anti‐deoxyribonucleic acid, anti‐Smith antibody, anti‐SSA antibody level, anti‐SSB level, antineutrophil cytoplasmic antibody, activated protein C resistance level, factor VIII level, human immunodeficiency virus antibody, homocysteine level, cardiolipin antibody testing, lupus anticoagulant, prothrombin 20210 mutation, and protein C level was done, and all tests were normal. Protein S level was slightly low at 64% (normal value 65%140%). Given the enlarged parotid gland and the enhancement of the left parotid bed on magnetic resonance imaging, she underwent a parotid biopsy that revealed sialadenitis.

Systemic vasculitides can result in tissue damage, mediated by the release of endogenous cellular contents from dying cells, known as damage‐associated molecular patterns, sufficient to cause systemic inflammatory response syndrome (SIRS). This patient presented with acute symptoms but has negative laboratory studies for autoantibodies. The parotid biopsy also did not reveal evidence of vasculitis. All these findings make the diagnosis of vasculitis much less likely.

She remained in the medical intensive care unit on mechanical ventilation, with minimal symptomatic improvement. On hospital day 10, the patient developed necrosis of the left external ear. A punch biopsy of the necrotic area of her left pinna was performed; the pathology report read: Sections of punch biopsy of skin show an unremarkable epidermis. There is dermal necrosis involving the stroma and adnexal structures. Intravascular thrombi within the deep dermis are seen. Within superficial dermis there are broad, elongated, nonseptated hyaline structures reminiscent of Mucor. Special stains (periodic acid‐Schiff stain and Grocott Gomori methenamine silver stain [GMS]) performed with appropriately reactive controls fail to highlight these structures (Figure 3). The infectious disease team reviewed the pathology slides with the pathologist. As there was inconclusive evidence for zygomycosis, ie, only a few hyaline structures which failed to stain with GMS stain, the consultants recommended no change in the patient's management.

Figure 3

The gross and microscopic evidence of necrosis and areas of intravascular thrombi are nonspecific but compatible with a fungal infection in a patient with risk factors for zygomycosis. The GMS stain is a very sensitive stain for fungal structures, so a negative stain in this case is surprising, but additional testing such as immunohistochemistry should be pursued to confirm or refute this diagnosis. While Rhizopus species can be contaminants, the laboratory finding of these organisms in specimens from patients with risk factors for zygomycosis should not be ignored.

On hospital day 12, the patient was noted to have increased facial swelling. A computed tomographic (CT) angiogram of the neck revealed necrosis of the anterior and posterior paraspinal muscles from the skull base to C34, marked swelling of the left parotid gland, and left inferior parieto‐occipital enhancing lesion. An incisional parotid biopsy was performed. Special stains were positive for broad‐based fungal hyphae consistent with mucormycosis (Figure 4).

Figure 4

Given these findings, the patient should be started on amphotericin B immediately. Medical therapy alone generally does not suffice, and aggressive surgical debridement combined with intravenous antifungal therapy results in better outcomes. The longer the duration of symptoms and the greater the progression of disease, the less favorable the prognosis.

The patient was started on amphotericin B lipid complex and micafungin. However, after 16 days of therapy, repeat imaging of the neck showed worsening necrosis of the neck muscles. At this time, she underwent extensive debridement of face and neck, and posaconazole was added. After prolonged hospitalization, she was discharged to a rehabilitation facility on posaconazole. She resided in a nursing facility for 6 months. One year after her hospitalization, she is living at home and is able to ambulate independently, but requires feeding through a percutaneous endoscopic gastrostomy (PEG) tube because she remains dysphagic.

COMMENTARY

Infections caused by the ubiquitous fungi of the class Zygomycetes typically take 1 of 5 forms: rhinocerebral, pulmonary, gastrointestinal, disseminated, and cutaneous. The presentation varies widely, ranging from plaques, skin swelling, pustules, cellulitis, blisters, nodules, ulcerations, and ecthyma gangrenosum‐like lesions to deeper infections such as necrotizing fasciitis, osteomyelitis, and disseminated infection.1 Infections typically occur in immunocompromised hosts, including transplant recipients and patients with hematologic malignancy, but also occur in patients with diabetes mellitus, intravenous drug users, and patients on deferoxamine therapy.2 Deferoxamine and other iron‐binding therapy is thought to predispose to zygomycetes infections because of improved iron uptake of the fungal species and, thus, stimulation of growth.3 Pulmonary and rhinocerebral infections are the most common clinically encountered forms, and 44% of cutaneous infections are complicated by deep extension or dissemination.4

The articles cited above describe the more typical presentations of this rare disease. However, this patient had an unusual presentation, as parotid involvement due to zygomycosis has only been described once previously.5 Her inflammatory vasculitis and ensuing strokes from involvement of the carotid artery are recognized complications of zygomycosis, and in 1 case series of 41 patients with rhinocerebral mucormycosis, carotid involvement was seen in 31% of patients.6 After the punch biopsy of the patient's pinna showing nonseptated hyphae reminiscent of Mucor, why did her physicians delay administering amphotericin?

There are 2 likely possibilities: anchoring bias or error in medical decision‐making due to inaccurate probability estimates. Anchoring bias describes a heuristic where the initial diagnosis or gestalt biases the physician's process for assigning a final diagnosis.7, 8 This bias creates cognitive errors by limiting creativity in diagnosis. In this case, the infectious disease team carefully weighed the information obtained from the first biopsy. Given their low pretest estimate of this virtually unreported presentation of a rare disease, they decided to evaluate further without beginning antifungal therapy. Of note, there were few hyaline structures, and those structures lacked uptake of GMS. Since they considered the diagnosis yet rejected the diagnosis due to insufficient evidence, it is unlikely that anchoring bias played a role.

Was there an error in medical decision‐making? The physicians in this case faced a very common medical dilemma: whether or not to start a toxic medication empirically or wait for diagnostic confirmation prior to treatment.9 To solve this dilemma, one can apply decision analysis. Moskowitz et al described 5 phases of medical decision analysis by which a probabilistic right answer to clinical scenarios can be deduced mathematically.10 To solve this problem, probabilities must be assigned to the risk of giving a drug to a patient without the disease versus the risk of not giving a drug to a patient with the disease. For example, amphotericin deoxycholate causes acute renal failure in 30% to 47% of patients. Newer formulations of amphotericin, such as liposomal amphotericin and lipid complex, result in lower rates of nephrotoxicity (27% vs 47%). The risk of not giving amphotericin to a patient with zygomycosis is death. Even in patients treated with amphotericin, the mortality rate has been shown to be 66%, and up to 100% in those with strokes related to zygomycosis.2, 6, 11 Simply looking at these probabilities, decision analysis would favor empiric treatment.

The physicians caring for this patient did not have the luxury of retrospective speculation. After looking at all of the data, the equivocal skin biopsy and rare clinical presentation, the question to ask would change: What is the risk of giving amphotericin empirically to someone who, based on available information, has a very low probability of having zygomycosis? When phrased in this manner, there is a 47% chance of nephrotoxicity with amphotericin versus the very small probability that you have diagnosed a case of zygomycosis that has only been described once in the literature. Mathematically andmore importantlyclinically, this question becomes more difficult to answer. However, no value can be placed on the possibility of death in suspected zygomycosis, and the risk of short‐term amphotericin use is much less than that of a course of treatment. As such, empiric therapy should always be given.

Physicians are not mathematicians, and dynamic clinical scenarios are not so easily made into static math problems. Disease presentations evolve over time towards a diagnosable clinical pattern, as was the case with this patient. Two days after the aforementioned biopsy, she worsened and in less time than it would have taken to isolate zygomycosis from the first biopsy, a second biopsy revealed the typical nonseptated hyphae demarcated with the GMS stain. Even appropriate diagnostic testing, thoughtful interpretation, and avoidance of certain cognitive errors can result in incorrect diagnoses and delayed treatment. It is monitoring the progression of disease and collecting additional data that allows physicians to mold a diagnosis and create a treatment plan.

The primary treatment of zygomycosis should include amphotericin. However, there are limited data to support combination therapy with an echinocandin in severe cases, as in this patient.12 Posaconazole is not recommended for monotherapy as an initial therapy, but there is data for its use as salvage therapy in zygomycosis.13 This case highlights the difficulties that physicians face in the diagnosis and treatment of rare diseases. Cerebral infarction in a hematologic malignancy, uncontrolled diabetes, or iron chelation therapy could be the initial presentation of rhinocerebral zygomycosis. There truly are different strokes for different folks. Recognizing this and similar presentations may lead to a more rapid diagnosis and treatment of zygomycosis.

TEACHING POINTS

• 1

  Zygomycosis has a wide range of clinical presentations ranging from skin lesions to deep tissue infections. As it is an angioinvasive organism, it can also present as cerebral infarcts and brain abscesses.

• 2

  Zygomycosis infections should be suspected in patients with uncontrolled diabetes, hematologic or oncologic malignancies, and patients on iron chelation therapy with a potentially compatible clinical picture.

• 3

  If zygomycosis infection is suspected, rapid histologic diagnosis should be attempted. However, as histologic diagnosis can take time, empiric therapy with amphotericin should always be administered.

• 4

  Amphotericin remains the primary medical therapy for this disease; however, there is limited emerging evidence to suggest that echinocandins can be used in combination with amphotericin for improved treatment of severe rhinocerebral zygomyocosis. Posaconazole has a role as salvage therapy in zygomycosis, but should not be used as the sole primary treatment.

A 35‐year‐old woman presented to her primary care physician complaining of left post‐auricular pain, swelling, and redness. She described the pain as 8 out of 10, constant, sharp, and nonradiating. She denied fever or chills. A presumptive diagnosis of cellulitis led to a prescription for oral trimethoprim‐sulfamethoxazole. Left facial swelling worsened despite 4 days of antibiotics, so she came to the emergency department.

Noninfectious causes of this woman's symptoms include trauma, or an inflammatory condition such as polychondritis. Key infectious considerations are mastoiditis or a mastoid abscess. Herpes zoster with involvement of the pinna and auditory canal may also present with pain and redness. In the absence of findings suggestive of an infection arising from the auditory canal, cellulitis is a reasonable consideration. With the growing incidence of community‐acquired methicillin‐resistant Staphylococcus aureus infections, an agent effective against this pathogen such as trimethoprim‐sulfamethoxazole may be used, usually in combination with an antibiotic that provides more reliable coverage for group A streptococcus.

Her past medical history included poorly controlled type II diabetes mellitus and asthma. She reported no previous surgical history. Her current medications were insulin, albuterol inhaler, and trimethoprim‐sulfamethoxazole, although she had a history of noncompliance with her insulin. She was married with 1 child and was unemployed. She smoked 1 pack of cigarettes daily, drank up to 6 beers daily, and denied use of illicit drugs.

Her history of diabetes increases her risk of malignant otitis externa. Both diabetes and excess alcohol consumption are risk factors for herpes zoster. Smoking has been shown to increase the risk of otitis media and carriage by S. pneumoniae, a common pathogen in ear infections.

She was ill‐appearing and in moderate respiratory distress. Her temperature was 39C, blood pressure 149/93 mmHg, pulse 95 beats per minute, respiratory rate of 26 times per minute, with an oxygen saturation of 96% while breathing ambient air. She had swelling of the left side of the face extending to the left forehead and lateral neck. Examination of the external ear and auditory canal were unremarkable. The swelling had no associated erythema, tenderness, or lymphadenopathy. She had no oropharyngeal or nasal ulcers present. Her pupils were equal, round, and reactive to light and accommodation with normal sclera. Her trachea was midline; thyroid exam was normal. The heart sounds included normal S1 and S2 without murmurs, rubs, or gallops. Her lung exam was remarkable for inspiratory stridor. The abdominal examination revealed no distention, tenderness, organomegaly, or masses. Cranial nerve testing revealed a left‐sided central seventh nerve palsy along with decreased visual acuity of the left eye. Strength, sensation, and deep tendon reflexes were normal.

While there are many causes of facial nerve palsy, distinguishing between a peripheral palsy (which causes paralysis of the entire ipsilateral side of the face) and a central palsy (which spares the musculature of the forehead) is important. The most common type of peripheral facial nerve palsy is Bell's palsy. Infections such as meningitis or tumors of the central nervous system can cause central facial nerve or other cranial nerve palsy. Important infections to consider in this case would be viral such as herpes zoster or simplex, or atypical bacteria such as Mycoplasma and Rickettsia, which may explain the neurologic but not all of the other clinical findings in this case. It is also critical to determine whether she has an isolated seventh cranial nerve palsy or if other cranial nerves are involved such as may occur with basilar meningitis, which has a myriad of infectious and noninfectious causes. The decreased visual acuity may be a result of corneal dryness and abrasions from inability to close the eye but may also represent optic nerve problems, so detailed ophthalmologic exam is essential. Her ill appearance coupled with facial and neck swelling leads me to at least consider Lemierre's syndrome with central nervous system involvement. Finally, facial swelling and the inspiratory stridor may represent angioedema, although one‐sided involvement of the face would be unusual.

The results of initial laboratory testing were as follows: sodium, 138 mmol/L; potassium, 3.4 mmol/L; chloride, 109 mmol/L; bicarbonate, 14 mmol/L; blood urea nitrogen level, 19 mg/dL; creatinine, 1.1 mg/dL; white cell count, 23,510/mm³; differential, 90% neutrophils, 1% bands, 7% lymphocytes, 2% monocytes; hemoglobin level, 12.5 g/dL; platelet count, 566,000/mm³; hemoglobin A1c, 11%; albumin, 1.6 g/dL; total protein, 6.2 g/dL; total bilirubin, 0.8 mg/dL; alkaline phosphatase, 103 U/L; alanine aminotransferase level, 14 U/L; international normalized ratio of 1.2; partial thromboplastin time, 29 seconds (normal value, 2434 seconds); erythrocyte sedimentation rate, 121 mm/hr; creatine kinase, 561 U/L (normal value 25190). Arterial blood gas measurements with the patient breathing 50% oxygen revealed a pH of 7.34, a partial pressure of carbon dioxide of 28 mmHg, and a partial pressure of oxygen of 228 mmHg.

I am concerned that this patient has sepsis, likely due to an infectious trigger. With her clinical presentation localized to the head and neck, her history of diabetes, and the accelerated sedimentation rate, malignant otitis externa would explain many of her findings. Empiric anti‐infective therapy directed toward Pseudomonas aeruginosa should be initiated, and imaging of the head and ear should be undertaken.

The patient required intubation due to increased respiratory distress and stridor. Her physicians used intravenous vancomycin, clindamycin, and piperacillin/tazobactam to treat presumed cellulitis. Her abnormal neurologic exam led to magnetic resonance (MR) imaging and MR angiography of her neck and brain, which showed evidence of multiple regions of ischemia in the left occipital and inferior parietal distributions, as well as bilateral cerebellar distributions and enhancement of the parotid gland and mastoid air cells (Figure 1). A cerebral angiogram revealed irregularity and caliber reduction in multiple cervical and intracranial arteries, associated with intraluminal thrombi within the left intracranial vertebral artery, consistent with either vasculitis or infectious angioinvasion (Figure 2).

Figure 1

Figure 2

The angioinvasive nature of the findings on imaging leads me to suspect fungal infection. The patient's history of diabetes mellitus and acidosis are risk factors for mucormycosis. Aspergillus and Fusarium may also be angioinvasive but would be much more likely in neutropenic or severely immunocompromised patients. S. aureus may cause septic emboli mimicking angioinvasion but should be readily detected in conventional blood cultures. At this point, I would empirically begin amphotericin B; tissue, however, is needed for definitive diagnosis and a surgical consult should be requested.

After reviewing her imaging studies, an investigation for vasculitis and hypercoagulable states including antinuclear antibody, anti‐deoxyribonucleic acid, anti‐Smith antibody, anti‐SSA antibody level, anti‐SSB level, antineutrophil cytoplasmic antibody, activated protein C resistance level, factor VIII level, human immunodeficiency virus antibody, homocysteine level, cardiolipin antibody testing, lupus anticoagulant, prothrombin 20210 mutation, and protein C level was done, and all tests were normal. Protein S level was slightly low at 64% (normal value 65%140%). Given the enlarged parotid gland and the enhancement of the left parotid bed on magnetic resonance imaging, she underwent a parotid biopsy that revealed sialadenitis.

Systemic vasculitides can result in tissue damage, mediated by the release of endogenous cellular contents from dying cells, known as damage‐associated molecular patterns, sufficient to cause systemic inflammatory response syndrome (SIRS). This patient presented with acute symptoms but has negative laboratory studies for autoantibodies. The parotid biopsy also did not reveal evidence of vasculitis. All these findings make the diagnosis of vasculitis much less likely.

She remained in the medical intensive care unit on mechanical ventilation, with minimal symptomatic improvement. On hospital day 10, the patient developed necrosis of the left external ear. A punch biopsy of the necrotic area of her left pinna was performed; the pathology report read: Sections of punch biopsy of skin show an unremarkable epidermis. There is dermal necrosis involving the stroma and adnexal structures. Intravascular thrombi within the deep dermis are seen. Within superficial dermis there are broad, elongated, nonseptated hyaline structures reminiscent of Mucor. Special stains (periodic acid‐Schiff stain and Grocott Gomori methenamine silver stain [GMS]) performed with appropriately reactive controls fail to highlight these structures (Figure 3). The infectious disease team reviewed the pathology slides with the pathologist. As there was inconclusive evidence for zygomycosis, ie, only a few hyaline structures which failed to stain with GMS stain, the consultants recommended no change in the patient's management.

Figure 3

The gross and microscopic evidence of necrosis and areas of intravascular thrombi are nonspecific but compatible with a fungal infection in a patient with risk factors for zygomycosis. The GMS stain is a very sensitive stain for fungal structures, so a negative stain in this case is surprising, but additional testing such as immunohistochemistry should be pursued to confirm or refute this diagnosis. While Rhizopus species can be contaminants, the laboratory finding of these organisms in specimens from patients with risk factors for zygomycosis should not be ignored.

On hospital day 12, the patient was noted to have increased facial swelling. A computed tomographic (CT) angiogram of the neck revealed necrosis of the anterior and posterior paraspinal muscles from the skull base to C34, marked swelling of the left parotid gland, and left inferior parieto‐occipital enhancing lesion. An incisional parotid biopsy was performed. Special stains were positive for broad‐based fungal hyphae consistent with mucormycosis (Figure 4).

Figure 4

Given these findings, the patient should be started on amphotericin B immediately. Medical therapy alone generally does not suffice, and aggressive surgical debridement combined with intravenous antifungal therapy results in better outcomes. The longer the duration of symptoms and the greater the progression of disease, the less favorable the prognosis.

The patient was started on amphotericin B lipid complex and micafungin. However, after 16 days of therapy, repeat imaging of the neck showed worsening necrosis of the neck muscles. At this time, she underwent extensive debridement of face and neck, and posaconazole was added. After prolonged hospitalization, she was discharged to a rehabilitation facility on posaconazole. She resided in a nursing facility for 6 months. One year after her hospitalization, she is living at home and is able to ambulate independently, but requires feeding through a percutaneous endoscopic gastrostomy (PEG) tube because she remains dysphagic.

COMMENTARY

Infections caused by the ubiquitous fungi of the class Zygomycetes typically take 1 of 5 forms: rhinocerebral, pulmonary, gastrointestinal, disseminated, and cutaneous. The presentation varies widely, ranging from plaques, skin swelling, pustules, cellulitis, blisters, nodules, ulcerations, and ecthyma gangrenosum‐like lesions to deeper infections such as necrotizing fasciitis, osteomyelitis, and disseminated infection.1 Infections typically occur in immunocompromised hosts, including transplant recipients and patients with hematologic malignancy, but also occur in patients with diabetes mellitus, intravenous drug users, and patients on deferoxamine therapy.2 Deferoxamine and other iron‐binding therapy is thought to predispose to zygomycetes infections because of improved iron uptake of the fungal species and, thus, stimulation of growth.3 Pulmonary and rhinocerebral infections are the most common clinically encountered forms, and 44% of cutaneous infections are complicated by deep extension or dissemination.4

The articles cited above describe the more typical presentations of this rare disease. However, this patient had an unusual presentation, as parotid involvement due to zygomycosis has only been described once previously.5 Her inflammatory vasculitis and ensuing strokes from involvement of the carotid artery are recognized complications of zygomycosis, and in 1 case series of 41 patients with rhinocerebral mucormycosis, carotid involvement was seen in 31% of patients.6 After the punch biopsy of the patient's pinna showing nonseptated hyphae reminiscent of Mucor, why did her physicians delay administering amphotericin?

There are 2 likely possibilities: anchoring bias or error in medical decision‐making due to inaccurate probability estimates. Anchoring bias describes a heuristic where the initial diagnosis or gestalt biases the physician's process for assigning a final diagnosis.7, 8 This bias creates cognitive errors by limiting creativity in diagnosis. In this case, the infectious disease team carefully weighed the information obtained from the first biopsy. Given their low pretest estimate of this virtually unreported presentation of a rare disease, they decided to evaluate further without beginning antifungal therapy. Of note, there were few hyaline structures, and those structures lacked uptake of GMS. Since they considered the diagnosis yet rejected the diagnosis due to insufficient evidence, it is unlikely that anchoring bias played a role.

Was there an error in medical decision‐making? The physicians in this case faced a very common medical dilemma: whether or not to start a toxic medication empirically or wait for diagnostic confirmation prior to treatment.9 To solve this dilemma, one can apply decision analysis. Moskowitz et al described 5 phases of medical decision analysis by which a probabilistic right answer to clinical scenarios can be deduced mathematically.10 To solve this problem, probabilities must be assigned to the risk of giving a drug to a patient without the disease versus the risk of not giving a drug to a patient with the disease. For example, amphotericin deoxycholate causes acute renal failure in 30% to 47% of patients. Newer formulations of amphotericin, such as liposomal amphotericin and lipid complex, result in lower rates of nephrotoxicity (27% vs 47%). The risk of not giving amphotericin to a patient with zygomycosis is death. Even in patients treated with amphotericin, the mortality rate has been shown to be 66%, and up to 100% in those with strokes related to zygomycosis.2, 6, 11 Simply looking at these probabilities, decision analysis would favor empiric treatment.

The physicians caring for this patient did not have the luxury of retrospective speculation. After looking at all of the data, the equivocal skin biopsy and rare clinical presentation, the question to ask would change: What is the risk of giving amphotericin empirically to someone who, based on available information, has a very low probability of having zygomycosis? When phrased in this manner, there is a 47% chance of nephrotoxicity with amphotericin versus the very small probability that you have diagnosed a case of zygomycosis that has only been described once in the literature. Mathematically andmore importantlyclinically, this question becomes more difficult to answer. However, no value can be placed on the possibility of death in suspected zygomycosis, and the risk of short‐term amphotericin use is much less than that of a course of treatment. As such, empiric therapy should always be given.

Physicians are not mathematicians, and dynamic clinical scenarios are not so easily made into static math problems. Disease presentations evolve over time towards a diagnosable clinical pattern, as was the case with this patient. Two days after the aforementioned biopsy, she worsened and in less time than it would have taken to isolate zygomycosis from the first biopsy, a second biopsy revealed the typical nonseptated hyphae demarcated with the GMS stain. Even appropriate diagnostic testing, thoughtful interpretation, and avoidance of certain cognitive errors can result in incorrect diagnoses and delayed treatment. It is monitoring the progression of disease and collecting additional data that allows physicians to mold a diagnosis and create a treatment plan.

The primary treatment of zygomycosis should include amphotericin. However, there are limited data to support combination therapy with an echinocandin in severe cases, as in this patient.12 Posaconazole is not recommended for monotherapy as an initial therapy, but there is data for its use as salvage therapy in zygomycosis.13 This case highlights the difficulties that physicians face in the diagnosis and treatment of rare diseases. Cerebral infarction in a hematologic malignancy, uncontrolled diabetes, or iron chelation therapy could be the initial presentation of rhinocerebral zygomycosis. There truly are different strokes for different folks. Recognizing this and similar presentations may lead to a more rapid diagnosis and treatment of zygomycosis.

TEACHING POINTS

• 1

  Zygomycosis has a wide range of clinical presentations ranging from skin lesions to deep tissue infections. As it is an angioinvasive organism, it can also present as cerebral infarcts and brain abscesses.

• 2

  Zygomycosis infections should be suspected in patients with uncontrolled diabetes, hematologic or oncologic malignancies, and patients on iron chelation therapy with a potentially compatible clinical picture.

• 3

  If zygomycosis infection is suspected, rapid histologic diagnosis should be attempted. However, as histologic diagnosis can take time, empiric therapy with amphotericin should always be administered.

• 4

  Amphotericin remains the primary medical therapy for this disease; however, there is limited emerging evidence to suggest that echinocandins can be used in combination with amphotericin for improved treatment of severe rhinocerebral zygomyocosis. Posaconazole has a role as salvage therapy in zygomycosis, but should not be used as the sole primary treatment.