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Cases from The Ohio State University Medical Center
By Beth W. Liston, MD, PhD, FACP; Jayne Barr, MD, FACP; Allison Heacock, MD, ACP Member; Rashmi Ganith, MD; Chirag Patel, MD; Jennifer Allen, MD; Karen Catignani, MD; Rob Matthew, MD; Aaron Wenger, MD; and Kimberly Tartaglia, MD, FACP
Physician editor: Christopher Sankey, MD, ACP Member.
Case 1: Hypereosinophilia causing cardiac and pulmonary disease
A 41-year-old male with no past medical history presented for a second opinion with chest pain, cough, fever and an 80-pound weight loss over two months. Previous evaluation revealed peripheral eosinophilia, pericarditis and pneumonia. Upon presentation, his leukocyte count was 28,000 cells/µL with an absolute eosinophil count of 12,600 cells/µL. An evaluation was performed to rule out secondary causes of hypereosinophilia including antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, cortisol stimulation testing, stool cultures, comprehensive ova and parasite testing, strongyloides, histoplasmosis and toxocara serologies, human immunodeficiency virus, lactate dehydrogenase, immunoglobulin E level, and upper endoscopy. All were non- diagnostic. Pulmonary function tests showed moderate restriction with decreased diffusion capacity. Bronchioalveolar lavage showed increased eosinophils (18%) and negative cultures. Cardiac magnetic resonance imaging revealed an apical thrombus with subendocardial fibrosis suggesting Loeffler endocarditis and a mildly reduced ejection fraction of 45%. Vitamin B12 was elevated and serum tryptase was normal. Bone marrow biopsy was performed and revealed hypercellular marrow with 34% eosinophils and no blasts present. Testing for FIP1L1-PDGRA was negative.
Hypereosinophilic syndrome (HES) is a group of disorders characterized by the presence of marked unexplained eosinophilia of blood and tissues. HES usually presents in adults age 20 to 50. The clinical manifestations are varied and most commonly involve the dermatologic, pulmonary, gastrointestinal, rheumatologic and cardiac organ systems. The disease also may be asymptomatic. The criteria for diagnosis of HES include persistent eosinophilia greater than 1,500 cells/µL without discernible cause, along with signs or symptoms of target-organ damage. A systematic approach to a patient with eosinophilia is necessary when diagnosing hypereosinophilic syndrome. First, clinicians need to rule out causes of secondary eosinophilia such as allergic, infectious, endocrine or neoplastic processes. Next, the patient must be assessed for end-organ damage, using standard chemistries, liver function testing, troponin levels, electrocardiogram, echocardiogram, pulmonary function tests, chest radiograph, chest and abdominal computed tomography. If end-organ damage exists, it is crucial to determine the subtype of hypereosinophilic syndrome, as it guides therapy. A hematology consult is typically obtained; however, the hospitalist should initiate the evaluation by ordering serum vitamin B12 and tryptase levels, which, if elevated, may indicate the myeloproliferative variant of HES. This should be followed by a bone marrow biopsy to assess cellularity, cytogenetics and molecular genetics, especially for PDGFRA/B and FGFR1 mutations. This testing further helps delineate the subtype of hypereosinophilic syndrome.
- Eosinophilia is a common incidental finding among hospitalized patients, and although rare, HES should be considered as a potential diagnosis.
- Following a systematic approach to early diagnosis and treatment of the specific subtypes of HES is necessary to prevent permanent organ damage and, in some cases, death.
Case 2: Pulmonary embolism presenting as syncope in an elderly woman
An 80-year-old woman presented with an episode of syncope associated with a prodrome of exertional dizziness. She reported a three-day history of dry nonproductive cough and fatigue but denied hemoptysis, fever, chills, nausea, vomiting or abdominal pain. Upon presentation to the emergency department, she was alert and oriented with no obvious traumatic injuries. She was afebrile. Her pulse was 120, respirations were 35, and blood pressure was normal. Room air oxygen saturation was 90% and improved to 94% on two liters of supplemental oxygen. Lungs were noted to have crackles in the bases bilaterally. Her cardiac, abdominal and neurologic exams were normal, as were blood counts, basic chemistries, and computed tomography of the head. Chest radiography showed a possible right middle lobe infiltrate, and she was admitted for pneumonia, hypoxia, and syncope. After three days of antibiotic treatment, she continued to complain of shortness of breath and fatigue. Her oxygen requirement increased to 4 L/min by nasal cannula, and she was noted to be tachycardic with episodes of paroxysmal atrial fibrillation. An echocardiogram demonstrated right ventricular hypertrophy. Further review of the past medical history revealed remote treatment for breast cancer. Computed tomography (CT) angiogram of the chest showed a large saddle pulmonary embolus, and anticoagulation was initiated.
When syncope is the presenting symptom of pulmonary embolism (PE) in an elderly patient, it can be a difficult clinical correlation to make. There are case reports of PE in the elderly presenting as syncope and it is estimated that syncope occurs in approximately 10% of patients with acute PE. The frequency of PE may be underestimated in the elderly, as unwitnessed syncopal events are often misrepresented as falls. Compounding the diagnostic challenge in the elderly is the varied presentation of signs and symptoms associated with PE. Typical electrocardiogram (EKG) findings can include sinus tachycardia, right bundle-branch block, atrial fibrillation, and non-specific ST-T wave abnormalities. Tachycardia is a less common presenting sign in the elderly as compared to the general population, and other EKG abnormalities are more prevalent in this population at baseline. The D-dimer test can be misleading, as it may be elevated in the elderly due to other comorbid conditions. In addition, due to chronic renal failure, the elderly often undergo ventilation/perfusion (VQ) scan testing rather than CT angiography to diagnose PE. The positive predictive value of the VQ decreases in the elderly. The sensitivity, specificity and positive predictive value of the CT angiogram are not influenced by age. In-hospital mortality for elderly patients with pulmonary embolism is high, and up to 40% of PEs are found at autopsy.
- Pulmonary embolism should be considered in the differential diagnosis of the elderly patient presenting with syncope or an unwitnessed fall.
- The diagnosis of pulmonary embolism is more challenging in the elderly due to atypical presentations and the influence of age on common tests such as D-dimer and ventilation/perfusion scans.
Case 3: Methicillin-resistant Staphylococcus aureus myopericarditis
A 29-year-old male presented with sharp, stabbing mid-sternal chest pain radiating to his back, with shortness of breath, malaise and subjective fevers. His past medical history was significant for polysubstance abuse and a recent tooth extraction. He also complained of left wrist, right shoulder and neck pain. Upon presentation, physical exam revealed a low-grade fever and normal cardiopulmonary examination. His right neck and shoulder were tender without proximal joint involvement. His left wrist demonstrated pain, effusion, and warmth. Troponin on admission was 3.57 mg/mL and peaked to 9.26 mg/mL. Electrocardiogram showed ST-segment elevation and PR-segment depression in the inferior leads as well as in V5 and V6. White blood cell count was slightly elevated with a normal differential. C-reactive protein (3.6 mg/L) and erythrocyte sedimentation rate (112 mm/h) were elevated. Urine toxicology was positive for cocaine. Computed tomography (CT) of the chest showed bilateral cavitary lung lesions consistent with septic emboli and CT of the neck showed a small focal enhancing fluid collection within the sternocleidomastoid muscle suggestive of abscess. Magnetic resonance imaging (MRI) of the wrist suggested septic arthritis and tenosynovitis. Subsequent wrist aspiration revealed greater than 150,000 white blood cells and intracellular cocci although cultures were negative. Drainage of the sternocleidomastoid abscess revealed methicillin-resistant Staphylococcus aureus (MRSA). Blood cultures grew MRSA and the patient was started on vancomycin. Transthoracic echocardiography showed mild four-chamber dilation with an ejection fraction of 44% and no pericardial effusion. Transesophageal echocardiography did not reveal any signs of infectious endocarditis. Cardiac MRI showed signals consistent with myocardial inflammation and no valvular disease.
The patient presented with MRSA bacteremia and multiple sites of septic embolization. In this case, it was felt that the source of the MRSA was most likely to be his intravenous drug use or recent dental procedure leading to his septic joint and abscess development. This patient's cardiac symptoms and findings were consistent with myopericarditis, which occurs in approximately 15% of myocarditis cases. This condition is most common in males under age 40 who had a recent febrile illness. Signs and symptoms may mimic acute myocardial infarction, with chest pain and elevated troponins. Acute myocarditis most commonly has a viral etiology. Bacterial myocarditis is rare, especially independent of infective endocarditis, but it's most commonly caused by Staphylococcus aureus bacteremia. Other bacterial causes include Streptococcus species and Borrelia burgdorferi. Non-infectious causes of myocarditis include drugs, toxins, and autoimmune disorders such as sarcoidosis. Complications are rare and include arrhythmias, atrioventricular block, congestive heart failure, and ventricular rupture. Treatment includes non-steroidal anti-inflammatory agents and intravenous antibiotics. This patient was started on an angiotensin-converting enzyme inhibitor due to impaired ejection fraction and evidence of non-ischemic cardiomyopathy on MRI. Repeat echocardiography five months later showed normal chamber size and function.
- Acute myopericarditis can mimic signs and symptoms of acute coronary syndrome and should be considered in patients at low risk for coronary disease presenting with concurrent signs of infection.
- Although endocarditis is frequently considered in patients with MRSA bacteremia, additional cardiac complications of MRSA bacteremia include myocarditis and myopericarditis, which can occur in the absence of endocarditis.
Case 4: Histoplasmosis or sarcoidosis?
A 44-year-old man with no past medical history presented with bilateral parotid gland enlargement and xerostomia. Evaluation revealed cervical and mediastinal lymphadenopathy, and mediastinoscopy with lymph node biopsy showed non-necrotizing granulomas. The patient reported a 30-pound weight loss over three months, and he was noted to have hypercalcemia (11.5 mg/dL) and acute kidney injury (serum creatinine 2.8 mg/dL from normal baseline). At admission, fungal immunodiffusion showed an “H band” suggestive of active disseminated histoplasmosis. Renal biopsy revealed granulomatous interstitial nephritis consistent with a diagnosis of sarcoidosis. However, before starting systemic steroids for sarcoid with renal involvement, additional histoplasmosis testing was obtained. Fungal blood cultures, urine Histoplasma antigen, fungal complement fixation, and Histoplasma antigen on bronchoalveolar lavage were negative, but immunodiffusion for Histoplasma was repeatedly positive with an H band. Therefore, itraconazole was initiated in lieu of prednisone. Upon follow-up, the patient had self-discontinued the itraconazole due to high cost with no ill effects. Steroid therapy was initiated, and the creatinine initially improved; however, several attempts to taper his prednisone resulted in worsening renal function, requiring re-escalation of therapy.
Given the patient's clinical course, the diagnosis is sarcoidosis. Sarcoidosis and disseminated histoplasmosis are granulomatous diseases that can have similar clinical presentations. Laboratory tests including fungal cultures, antigen testing, immunoserologic tests, and special tissue stains can all be used to help distinguish histoplasmosis from sarcoidosis. In our patient, the diagnosis of sarcoidosis was called into question by positive serologic testing for Histoplasma. The immunodiffusion test for Histoplasma has a sensitivity of 90% and is more specific than complement fixation; however, there are reports of positive results in patients with other granulomatous diseases. A previously published case report from our institution discussed a patient with pulmonary histoplasmosis that evolved into sarcoidosis (Respiratory Medicine, April 2007). Additionally, there have been numerous other case reports of patients diagnosed with sarcoidosis who have developed disseminated Histoplasma infections. Whether sarcoidosis or treatment for sarcoidosis predisposes patients to Histoplasma infections is unknown. Immunosuppression is the greatest risk factor for disseminated histoplasmosis; however, approximately 20% of patients with disseminated histoplasmosis have no risk factors for the disease.
- Sarcoidosis has no defined etiologic agent but evidence is accumulating that there is a close relationship between histoplasmosis and sarcoidosis.
- Given concern that sarcoidosis may be a risk factor for disseminated histoplasmosis, we recommend antifungal treatment in patients with evidence of active Histoplasma infection prior to initiating immunosuppressant medications for sarcoidosis.
Case 5: The Chiari network
A 70-year-old woman with a history of embolic stroke, hypertension, diastolic heart failure and diabetes presented with an altered mental status. She was difficult to arouse and manifested new left hemineglect and hemiparesis, inappropriate affect and dysphagia. Her cardiovascular evaluation was unremarkable. Brain magnetic resonance imaging demonstrated two frontal lobe infarcts and a subacute hematoma of the right thalamus. Transthoracic echocardiography noted normal left ventricular function and a suspected mass in the right atrium. Transesophageal echocardiography demonstrated a thrombus in the right atrium that was connected to a Chiari network (CN) by six “finger-like” projections; the bubble study was positive for a patent foramen ovale (PFO). Lower-extremity Doppler ultrasonography showed extensive clots, computed tomography angiography of the chest showed multiple pulmonary emboli, and telemetry monitoring revealed atrial fibrillation. An inferior vena cava filter was placed, intravenous heparin therapy was initiated, and she was ultimately transitioned to warfarin. Her neurological status improved and her atrial thrombus resolved less than six weeks after initial presentation, verified with repeat echocardiography. Her PFO was successfully closed two months after discharge.
This patient was found to have a Chiari network (CN). CN is an embryological remnant of the sinus venosus and the eustachian valve located at the junction of the inferior vena cava and right atrium. In utero, the eustachian valve directs oxygenated blood from the right atrium to the left atrium via the foramen ovale. The CN is present in roughly 2% of the adult population; it may prolapse into the right atrium, entrap thrombus, and predispose to supraventricular tachycardias. This patient exhibits several interesting sequelae of a CN: thrombus, arrhythmia and stroke. Therapeutic options for the patient include placement of inferior vena cava filter, deployment of a septal occluding device, and surgical removal of the clot. Given her multitude of comorbidities and complications, this patient's PFO was closed and removal of the CN was considered; however, she was a poor surgical candidate.
In 1897, Hans Chiari described 11 cases showing that the CN can entrap clots, thereby preventing embolization. Case studies show that closure of the PFO after transient ischemic attacks, peripheral embolism, disabling migraines, and cryptogenic stroke decreases sequelae; however, closure of a PFO can also place the patient at risk for development of an accessory pathway that will accelerate arrhythmias. Case studies associate CN with supraventricular tachycardias. This patient's deep venous thrombosis, PFO and atrial fibrillation obscured the etiology of her embolic stroke and pulmonary embolism.
- Chiari networks are rare but can contribute to thromboembolic events and arrhythmias.
- Treatment options include placement of an inferior vena cava filter, removal of the clot from the Chiari network, or removal of the Chiari network to prevent future embolic events.
Worsening muscle weakness and rash
By Vishal Mundra, MD, ACP Member, and Steve Jenks, PA
Physician editor: Christopher Sankey, MD, ACP Member
The following case was submitted individually to The Brief Case. We welcome your submissions; e-mail us.
A 53-year-old female with a medical history of breast cancer on chemotherapy presented with eight weeks of worsening muscle weakness. The weakness was described as proximal and progressive in nature; she could not stand from a seated position or comb her hair and developed difficulty swallowing. She also noticed a rash around her neck, eyelids and upper chest. Relevant medications included a statin.
On initial physical examination, she had a rash over her eyelids, purple in color and associated with mild edema (heliotrope rash). She also had a rash around her neck (“shawl sign”) and on her knuckles (Gottron's papules). There was significant bilateral proximal muscle weakness noted in her upper and lower extremities, though her reflexes and cranial nerves were intact. Muscle biopsy showed patchy mild fibrosis with chronic inflammation and fiber atrophy, consistent with an inflammatory myopathy.
Her laboratory results are seen in the table.
This patient's diagnosis is dermatomyositis (DM), though complications relating to her malignancy, chemotherapy, and statin medication were all considered. DM is uncommon, but it is more prevalent in females between the ages of 40 and 50. The presence of skin findings is the characteristic feature of DM. Classic physical findings in DM are heliotrope rash (sensitivity 67.2%, specificity 99.6%), Gottron's papules (sensitivity 62.1%, specificity 98.7%) and “shawl sign” (erythematous rash over the upper chest, neck, and back in V-shaped pattern), in addition to proximal muscle weakness. These skin findings are pathognomonic of DM. DM may overlap with other connective tissue disorders such as lupus, scleroderma and mixed connective tissue disorder. The incidence of malignancy (ovarian, lung, stomach, and pancreas most frequently) is approximately five times higher in these patients than the general population and is associated with a worse prognosis.
Creatine kinase (CK) is the most sensitive laboratory test for DM, and levels vary from 1,000 to 10,000 units/L depending on the course of the disease. An exception is amyopathic DM, in which CK levels are normal (10% to 20% cases). Antinuclear antibodies testing is positive in approximately 80% of patients but is non-specific. Only 30% of patients have positive myositis-specific antibodies such anti-Jo-1, anti-Mi-2, anti-SRP (signal recognition particle), and anti-Ku. These antibodies, when present, are more useful in assessing prognosis than diagnosis. Electromyography can also aid in diagnosis, but the findings are also nonspecific. Muscle or skin biopsy can help to make a definitive diagnosis. Important entities to consider in the differential diagnosis include toxins, drugs, hypothyroidism, myasthenia, amyotrophic lateral sclerosis, lupus and scleroderma. Treatment options include high-dose glucocorticoids and other immunomodulators. Five-year survival of DM is greater than 90%.
Our patient was started on high-dose steroids. At the time of her discharge to a rehabilitation center, her CK had improved to 498 units/L with clinical and symptomatic improvement.
- Dermatomyositis can often be accurately diagnosed with a combination of history, physical examination and readily available laboratory testing.
- Adjunctive testing is confirmatory, and negative rheumatologic serologies do not rule out dermatomyositis.
Dr. Mundra and Mr. Jenks are hospitalists at St. John Medical Center in Tulsa, Okla.
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From the April 16, 2014 edition
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