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19-Year-Old Man With Chest Pain, Fever, and Vomiting

      A previously healthy man aged 19 years was transferred to the emergency department with a 5-day history of fever, chills, and night sweats; 2 days of nausea and severe vomiting; and 1 day of acute substernal chest pain that was sharp, radiated to the left shoulder, and was exacerbated both by inspiration and movement. The patient also reported that during the past 2 days his urine had progressively darkened. His medical history was remarkable only for a heart murmur noted in childhood. He denied any past or present use of tobacco, alcohol, or illicit drugs. He also denied any recent contact with ill people or travel outside of Iowa.
      The vital signs of the young man, who appeared anxious, were as follows: pulse rate, 120 beats/min; respiratory rate, 24 breaths/min; blood pressure, 110/72 mm Hg; and temperature, 38.4γC. Cardiopulmonary examination revealed a grade II/VI harsh holosystolic murmur heard throughout the precordium with reproducible tenderness to palpation over the sternum. No pericardial friction rubs were audible, and no pathological heart sounds were noted. The patient's lungs were clear to auscultation with normal inspiratory effort. Findings on abdominal examination were within normal limits, and no peripheral stigmata of endocarditis were observed. Initial laboratory results were as follows (reference ranges provided parenthetically): hemoglobin, 11.9 g/dL (13.5-17.5 g/dL); leukocyte count, 21.0 × 109/L (3.5-10.5 × 109/L); neutrophils, 18.1 × 109/L (1.7-7.0 × 109/L), platelet count, 273 × 109/L (150-450 × 109/L); sodium, 134 mEq/L (135-145 mEq/L); potassium, 3.6 mEq/L (3.6-4.8 mEq/L); urea nitrogen, 11 mg/dL (8-24 mg/dL); and creatinine, 1.0 mg/dL (0.9-1.4 mg/dL). Urinalysis revealed 31 to 40 red blood cells per high-power field, 1 to 2 white blood cells per high-power field, and no white or red blood cell casts. Initial chest radiographs showed cardiomegaly, pulmonary vascular congestion, and bilateral lower-lobe consolidation.
      • 1.
        Which one of the following is the least likely in the differential diagnosis of this patient's constellation of symptoms?
        • a.
          Acute myocardial infarction
        • b.
          Community-acquired pneumonia
        • c.
          Pulmonary embolus
        • d.
          Myopericarditis
        • e.
          Infective endocarditis
      Acute myocardial infarction, with its potential for life-threatening consequences, should always be considered when a patient presents with chest pain. However, it is the least likely diagnosis in this patient because of his age (19 years), the lack of cardiovascular risk factors, and the symptoms of fever, night sweats, and vomiting that preceded the development of chest pain. Community-acquired pneumonia, which commonly presents with fever, shortness of breath, pleuritic chest pain, and shaking chills, should be considered in the initial differential diagnosis for this patient. Pulmonary embolus must be considered in the differential diagnosis of any patient who presents with tachycardia and tachypnea, particularly in the context of acute onset of pleuritic chest pain. Myopericarditis must always be considered in any young patient who presents with fever that is accompanied by tachycardia, tachypnea, and evidence of pulmonary venous congestion on chest radiography. Infective endocarditis should also be considered in this patient given his fevers and history of childhood murmur, particularly given the devastating consequences of delayed diagnosis and therapy.
      Subsequent computed tomography of the chest revealed a 5.4 × 2.5-cm air- and fluid-filled cavity consistent with an abscess impinging on the left main bronchus, hilar lymphadenopathy, and a small pericardial effusion. Electrocardiography revealed sinus tachycardia with diffuse ST-segment elevations consistent with a diagnosis of pericarditis. Blood cultures were negative for anaerobic bacteria.
      • 2.
        Which one of the following is the most appropriate next step in the evaluation of this patient?
        • a.
          Bronchoscopy
        • b.
          Mediastinoscopy
        • c.
          Esophagraphy
        • d.
          Esophagogastroduodenoscopy (EGD)
        • e.
          Transesophageal echocardiography (TEE)
      This patient has findings consistent with a possible mediastinal abscess, with associated impingement of his left main stem bronchus. Esophageal rupture should be ruled out emergently, given the disastrous consequences of a missed diagnosis. Although a bronchoscopy would be a reasonable diagnostic modality, it would not be appropriate in this patient given his symptoms of acute chest pain and vomiting. Mediastinoscopy, which is an invasive test that requires general anesthesia, would not be appropriate at this stage in the diagnostic process. The appropriate next step would be to perform Gastrografin esophagraphy to rule out acute esophageal tears or rupture. An EGD would not be indicated in the setting of suspected esophageal rupture because it could worsen the perforation and cause a pneumomediastinum. A TEE, which would be helpful in establishing the diagnosis of infective endocarditis or pericardial tamponade, is not the appropriate next step in this patient given the findings on chest computed tomography, especially in the setting of negative blood cultures.
      Findings on Gastrografin esophagraphy were normal, ruling out esophageal rupture. The patient was treated empirically with piperacillin-tazobactam. Subsequently, an EGD with endoscopic ultrasonography was performed, revealing a normal esophagus with no dilatation or perforation. However, endoscopic ultrasonography revealed a 4 × 3-cm subcarinal mass, and a needle aspiration yielded 2 to 3 mL of pus. Cytology was negative for malignancy and revealed acute and chronic inflammation with abundant histiocytes. Cultures of the fluid revealed anaerobic gram-negative bacilli resembling fusobacterium, anaerobic gram-positive cocci, anaerobic gram-positive bacilli, and Prevotella melaninogenica consistent with a polymicrobial mediastinitis. The patient continued to be febrile, tachycardic, and tachypneic, but remained hemodynamically stable.
      • 3.
        Which one of the following is the most appropriate next step in the management of this patient?
        • a.
          Fiberoptic bronchoscopy
        • b.
          Mediastinoscopy
        • c.
          Addition of an antifungal agent
        • d.
          Cardiac magnetic resonance imaging
        • e.
          Radionucleotide-tagged white blood cell scan
      This patient presented with diffuse bilateral interstitial infiltrates with evidence of polymicrobial abscess formation and impingement of the left main bronchus. A fiberoptic bronchoscopy, which would both provide additional specimens for culture and facilitate biopsy of the hilar lymph nodes for pathological diagnosis, would be the most appropriate next step in the management of this patient. Mediastinoscopy would again require an invasive procedure in the absence of a pathological diagnosis and could place the patient at increased risk. In the absence of objective evidence of fungal infection (ie, positive potassium hydroxide smears and/or cultures), the addition of an antifungal agent would not be justified. Cardiac magnetic resonance imaging with gadolinium could be helpful in diagnosing myocarditis if delayed enhancement of the affected myocardium were found; however, given the over-whelming evidence for an infectious etiology, this expensive test would not be worthwhile. Radionucleotide-tagged white blood cell scans can help in the localization of infection but would be redundant in this patient, whose fever already has a clear cause.
      A fiberoptic bronchoscopy was performed with bronchoalveolar lavage, revealing an irregular and necrotic left main bronchus as well as mucosal edema and hyperemia of the left upper and lower lobe bronchi. Biopsy specimens obtained from perihilar lymph nodes were negative for malignancy, acid-fast bacillus, and potassium hydroxide stains. Cultures once again yielded a polymicrobial flora. The patient was subsequently admitted to the hospital, where his fever, tachycardia, and hypoxia worsened; only minimal improvement was seen with oxygen supplementation. He remained hemodynamically stable, and his chest radiograph was unchanged from admission.
      • 4.
        Which one of the following is the most likely cause of this patient's acute decompensation?
        • a.
          Acute pericarditis
        • b.
          Pulmonary embolus
        • c.
          Cardiac tamponade
        • d.
          Acute pulmonary edema
        • e.
          Bronchomediastinal fistula
      Our patient developed acute-onset hypoxemia after bronchoalveolar lavage. Acute pericarditis, which commonly presents with fever and severe chest pain that is relieved when the patient sits forward, is an unlikely cause of acute decompensation in this patient. Pulmonary embolus, which usually causes ventilation-perfusion mismatch, right-to-left shunting, and dead space, must always be considered in the diagnosis of acute hypoxia. This patient remained hemodynamically stable, and his oxygen saturations failed to correct with increasing oxygen tension, making pulmonary embolus an unlikely diagnosis given his lack of risk factors. Cardiac tamponade causes hypoxemia, resulting in perfusion of poorly oxygenated lung fields. However, patients with tamponade typically present with hypotension, distant heart sounds, and elevated jugular venous pressure, none of which this patient exhibited, making tamponade less likely in this situation. Similarly, acute pulmonary edema causes hypoxemia but would be expected to have physical examination findings consistent with fluid overload; this patient lacked underlying cardiac pathology, making acute pulmonary edema less likely. Given the recent bronchoscopy, procedural complications such as bronchomediastinal fistula must be considered. This patient developed air leakage as well as polymicrobial mediastinitis; his alveolar Pao2 could therefore not be increased and his fraction of inspired oxygen was elevated because of poor oxygenation of his left lung zones distal to the fistula formation. An arterial blood gas analysis was performed, revealing a pH of 7.43, a Pco2 of 48 mm Hg, and a Po2 of 94 mm Hg.
      • 5.
        Which one of the following is the most appropriate next step in the management of this patient?
        • a.
          Emergent TEE
        • b.
          Thoracic surgery consult for emergent debridement and repair of left main bronchus
        • c.
          Emergent intubation
        • d.
          Broadened antibiotic coverage with vancomycin and metronidazole
        • e.
          Repeated bronchoscopy
      In an acute care setting, it is often difficult to prioritize the most appropriate next step in management, particularly when the patient becomes unstable. Our patient had an air leak into his mediastinum with associated abscess formation in conjunction with diffuse pulmonary infiltrates and evidence of polymicrobial infection. Emergent TEE would not be an appropriate next step given that the underlying pathophysiology is not cardiac related but rather an acute bronchial tear. The next step in the care of this patient would be a thoracic surgery consult for urgent debridement and repair of his left main bronchus. Because adequate Po2 levels were maintained in this patient with no evidence of metabolic derangements, emergent intubation would not be helpful in his care. Given his rapid decompensation, consideration of broadened antimicrobial coverage would be reasonable; however, piperacillin-tazobactam provides excellent anaerobic coverage that would not be broadened by the addition of an agent such as metronidazole. Vancomycin would not be indicated for this patient because he showed no signs of a staphylococcal infection. A second bronchoscopy would be unlikely to provide additional information at this point.
      This patient was taken emergently to surgery for mediastinal debridement and was found to have a marked inflammatory process throughout the mediastinum with associated air leakage from the left main bronchus. Unfortunately, the left main bronchus was extensively necrotic and could not be repaired. The patient underwent a left pneumonectomy with extensive mediastinal debridement. Surgical specimens were sent for analysis, and the resected lymph nodes showed necrotizing granulomatous inflammation, with yeast cells resembling Histoplasma capsulatum seen on silver stain. The patient was initiated on amphotericin B and ertapenem; after 2 weeks he was switched to a 6-week course of itraconazole, ceftriaxone, and metronidazole, which he completed. The patient was extubated; he tolerated antimicrobial therapy well and has fully recovered. Fungal cultures from the resected tissue were negative. On follow-up, the patient was found to have recurrent chest pain that was diagnosed as inflammatory pericarditis; after therapy, he recovered without further complications.

      DISCUSSION

      This patient developed polymicrobial mediastinitis as a complication of mediastinal histoplasmosis, presumably via erosion of granulomatous lymphadenitis into the contiguous airway. Analysis of tissue specimens revealed organisms consistent with H capsulatum; however, fungal cultures were negative, suggesting prior infection rather than acute histoplasmosis.
      Histoplasmosis, caused by the dimorphic fungus H capsulatum var capsulatum that grows as a mold in the soil and as yeast in human tissue, is an endemic pathogen in some areas of the United States, particularly in the Ohio, Missouri, and Mississippi river valleys. It prefers moist soil enriched by the droppings of birds and bats. In the endemic areas of the United States, up to 80% of the population may have been exposed to the organism. The infectious spores, which are typically carried by prevailing winds, can travel miles at a time; the degree of illness is often related to the intensity of exposure.
      • Wheat JL
      Histoplasmosis: experience during outbreaks in Indianapolis and review of the literature.
      The inhaled endospores are small enough to reach the alveoli. There, they can cause a granulomatous reaction and local pneumonitis, as well as granulomatous lymphadenitis.
      • Woods JP
      • Heinecke EL
      • Luecke JW
      • et al.
      Pathogenesis of Histoplasma capsulatum.
      Depending on the degree of exposure, there may be no dissemination, limited dissemination to organs such as the spleen, or fulminant systemic histoplasmosis. After low-level exposure, fewer than 5% of patients develop symptomatic disease.
      • Wheat LJ
      Diagnosis and management of histoplasmosis.
      When the organism infects the lung, a granuloma is formed, often with caseating necrosis that mimics that caused by Mycobacterium tuberculosis. A rounded mass of scar tissue, which is called a histoplasmoma, then forms with or without central calcification.
      The clinical manifestations of histoplasmosis are variable depending on the level of exposure and underlying immunologic integrity of the host. Patients who are immunocompromised, such as those who have AIDS or are receiving corticosteroid therapy, are at greater risk for developing disseminated histoplasmosis; conversely, immunocompetent patients with low-level exposure are often asymptomatic.
      • Brodsky AL
      • Gregg MB
      • Loewenstein MS
      • Kaufman L
      • Mallison GF
      Outbreak of histoplasmosis associated with the 1970 Earth Day activities.
      Disseminated histoplasmosis can be either a complication of acute infection or a reactivation of a previous exposure. Acute pulmonary histoplasmosis typically presents with a constellation of constitutional symptoms such as fever, malaise, cough, and chest pain; however, most patients remain asymptomatic. Chest radiography may reveal hilar adenopathy (in 20% of patients) or diffuse reticulonodular or miliary infiltrates (80% of patients).
      • Sathapatayavongs B
      • Batteiger BE
      • Wheat LJ
      • Slama TG
      • Wass JL
      Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks.
      Chronic pulmonary histoplasmosis, typically seen in patients with underlying chronic pulmonary disease, is often an indolent infection. Taking several weeks to months to fully develop, it presents most frequently with chronic cough, fever, and night sweats. Disseminated histoplasmosis, a progressive extrapulmonary infection in which hematogenous spread usually occurs within days of the acute infection,
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      is characterized by fever, emaciation, hepatosplenomegaly, adenopathy, pancytopenia, and diffuse pulmonary infiltration that can mimic Pneumocystis pneumonia.
      Several complications of histoplasmosis have been well documented in the literature. Mediastinal granuloma results from the fusion of caseous mediastinal lymph nodes, which commonly develop in clinically silent disease. These calcified, necrotic nodes erode into surrounding tissue including blood vessels, the esophagus, and, as was the case in our patient, the airways.
      • Gula LJ
      • Malthaner RA
      • Quantz MA
      Pyopneumopericardium caused by mediastinal granuloma.
      Interestingly, on pathological examination that includes special fungal staining and culture, biopsied tissue specimens are often negative. However, organisms can sometimes be identified, as in this patient, suggesting inactive disease. Broncholithiasis is another complication that stems from the same pathophysiology. Patients with this condition often present with hemoptysis or cough productive of white, chalky material from erosion of calcified granuloma. A more devastating and less common complication of histoplasmosis is fibrosing mediastinitis, which is characterized by progressive pulmonary fibrosis, elevation of right-sided heart pressures, and development of cor pulmonale. Chest radiography may reveal progressive fibrosis with encasement of mediastinal structures such as the pulmonary artery, superior vena cava, or esophagus. Like our patient, up to 10% of patients develop inflammatory pericarditis, a complication more common in acute disease and immunocompetent hosts secondary to immense cytokine activation.
      • Wang JJ
      • Reimold SC
      Chest pain resulting from histoplasmosis pericarditis: a brief report and review of the literature.
      The diagnosis of histoplasmosis, usually based on cultures, fungal stains, and antigen/antibody assays, is often difficult and requires a high degree of clinical suspicion on the part of physicians. A metabolic panel may reveal hyper-bilirubinemia or elevated levels of liver transaminase or lactate dehydrogenase. Cultures obtained from blood, sputum, bronchoalveolar lavage, bone marrow, or direct tissue biopsy remain the criterion standard for the definitive diagnosis of histoplasmosis. Because a week may be required for culture results, visualization of the organism in tissue offers the best opportunity for rapid diagnosis. Cultures are positive for histoplasmosis in 85% of disseminated cases. Fungal stains, which are prepared from directly biopsied tissue sections, often reveal the 2- to 4-μm yeast structure of H capsulatum. Methenamine silver or periodic acid-Schiff stains are best for visualization of fungal organisms. Serologic tests, such as complement-fixation and immunodiffusion studies, may also be helpful in the diagnosis of histoplasmosis. The urine antigen test may also be useful, especially in patients with disseminated histoplasmosis who are infected with the human immunodeficiency virus. If urine antigen levels are elevated, they can be followed serially to assess response to therapy.
      Treatment for histoplasmosis largely depends on level of exposure and, not surprisingly, severity of disease. Immunocompetent patients who present with only constitutional symptoms of acute pulmonary histoplasmosis do not require treatment and generally make a full recovery within 3 weeks. For patients who present with worsening fever, hypoxemia, or diffuse interstitial infiltrates on chest radiography after 1 month, 6 to 12 weeks of itraconazole therapy is recommended.
      • Hecht FM
      • Wheat J
      • Korzun AH
      • et al.
      Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial.
      Immunocompetent patients who are critically ill and require mechanical ventilation should receive amphotericin B and corticosteroid therapy to diminish the inflammatory response. Disseminated histoplasmosis requires prompt recognition and therapy; however, debate remains as to the optimal choice of agents. One study found most antifungal agents (eg, amphotericin B, itraconazole, fluconazole) to be equally efficacious, with the exception of ketoconazole, which was slightly superior to the rest.
      • National Institute of Allergy and Infectious Diseases Mycoses Study Group
      Treatment of blastomycosis and histoplasmosis with ketoconazole: results of a prospective randomized clinical trial.
      Despite maximal therapy, mortality from disseminated histoplasmosis approaches 25%, and therefore therapy should be initiated as soon as possible.

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        • et al.
        Pathogenesis of Histoplasma capsulatum.
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        Diagnosis and management of histoplasmosis.
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        Outbreak of histoplasmosis associated with the 1970 Earth Day activities.
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        Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks.
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        Disseminated histoplasmosis: clinical and pathologic correlations.
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        Pyopneumopericardium caused by mediastinal granuloma.
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        Chest pain resulting from histoplasmosis pericarditis: a brief report and review of the literature.
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        • Korzun AH
        • et al.
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