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The n e w e ng l a n d j o u r na l of m e dic i n e Case Records of the Massachusetts General Hospital Founded by Richard C. Cabot Eric S. Rosenberg, M.D., Editor Jo‑Anne O. Shepard, M.D., Associate Editor Sally H. Ebeling, Assistant Editor Nancy Lee Harris, M.D., Editor Alice M. Cort, M.D., Associate Editor Emily K. McDonald, Assistant Editor Case 37-2015: A 76-Year-Old Man with Fevers, Leukopenia, and Pulmonary Infiltrates Josalyn L. Cho, M.D., Shaunagh McDermott, M.D., Athe M. Tsibris, M.D., and Eugene J. Mark, M.D. Pr e sen tat ion of C a se From the Departments of Medicine (J.L.C., A.M.T.), Radiology (S.M.), and Pa‑ thology (E.J.M.), Massachusetts General Hospital, and the Departments of Medi‑ cine (J.L.C., A.M.T.), Radiology (S.M.), and Pathology (E.J.M.), Harvard Medical School — both in Boston. N Engl J Med 2015;373:2162-72. DOI: 10.1056/NEJMcpc1504839 Copyright © 2015 Massachusetts Medical Society. 2162 Dr. Christopher J. Danford (Medicine): A 76-year-old man with multiple medical problems was admitted to this hospital because of persistent fever, leukopenia, and pulmonary infiltrates. The patient had been generally well until approximately 5 weeks before this admission, when fever (to a temperature of 38.9°C), chills, cough, night sweats, diarrhea, fatigue, weakness, and anorexia occurred. Four weeks before this admission, he was seen by his physician, who noted that he had had a weight loss of 5 kg in the previous 7 months. Urinalysis and cultures of urine and blood were reportedly negative. A chest radiograph and computed tomographic (CT) scan of the abdomen and pelvis, obtained without the administration of contrast material, were reportedly negative and were not available for review. The diarrhea resolved, but other symptoms persisted. Three weeks before this admission, CT of the chest reportedly revealed diffuse symmetric fine interstitial reticular lung nodularities, small pleural effusions, and mild splenomegaly. Two days later, the patient fell because of profound weakness and was admitted to another hospital. He had hypertension, hyperlipidemia, chronic obstructive pulmonary disease, coronary artery disease (with previous bypass grafting), congestive heart failure, peripheral vascular disease (with previous aortofemoral bypass surgery), non–insulin-dependent diabetes mellitus, gout, and benign prostatic hypertrophy. He also had transitional-cell carcinoma of the bladder that was in remission after treatment including bacille Calmette–Guérin (BCG) therapy, which had most recently been administered 7 months earlier. Medications taken at home were sitagliptin, metformin, lisinopril, atorvastatin, atenolol, clopidogrel, finasteride, dutasteride, terazosin, allopurinol, citalopram, folate, a multivitamin, and ipratropium–albuterol (by inhalation). On examination, the temperature was 39.9°C, the blood pressure 110/82 mm Hg, the pulse 86 beats per minute, the respiratory rate 20 breaths per minute, and the oxygen saturation 93% while the patient was breathing ambient air and 97% while he was breathing oxygen through a nasal cannula at a rate of 2 liters per minute. n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital There was abdominal distention, with tenderness in the right upper quadrant. Results of coagulation tests and blood levels of total and direct bilirubin were normal; other test results are shown in Table 1. Abdominal ultrasonography revealed a horseshoe kidney and a mildly heterogeneous liver. A chest radiograph showed a patchy opacity in the right midzone (Fig. 1A). Transthoracic echocardiography reportedly revealed no evidence of endocarditis. During the first week, testing was negative for influenza antigen, as well as for human immunodeficiency virus (HIV), Epstein–Barr virus, cytomegalovirus, Borrelia burgdorferi, ehrlichia, Anaplasma phagocytophilum, babesia, rickettsia (Rocky Mountain spotted fever), parvovirus, and hepatitis A, B, and C viruses. Cultures of the blood and urine were negative. Pathological examination of a bone marrow–biopsy specimen and aspirate, which was performed because of the pancytopenia, was normal. Diffuse bilateral interstitial pulmonary edema developed; fluid was restricted, and furosemide administered. Dr. Shaunagh McDermott: On the fifth day, a chest radiograph showed a persistent patchy opacity in the right midzone and diffuse reticular opacities in the lung bases (Fig. 1B). The next day, a CT scan of the chest showed diffuse ground-glass opacities throughout both lungs; the ground-glass opacities in the dependent lower lobes were more confluent. There were also small bilateral pleural effusions. Dr. Danford: Laboratory test results are shown in Table 1. On the 9th day, hemoptysis occurred, the temperature rose to 39.1°C, and the oxygen saturation decreased to 89% while the patient was breathing oxygen through a nasal cannula at a rate of 1 liter per minute. The rate of oxygen supplementation was increased to 3 liters per minute. Bronchoalveolar lavage reportedly revealed no evidence of diffuse alveolar hemorrhage or malignant cells; cultures of the lavage fluid were negative. After consultation with a rheumatologist, methylprednisolone (1 g daily) was administered for 3 days, followed by prednisone (60 mg daily). The fevers initially improved but then recurred. On the 15th day, video-assisted thoracic surgery was performed. Pathological examination of a lung-biopsy specimen reportedly revealed extensive noncaseating granulomatous inflammation and granulomas in both bronchiolocentric and lymphangitic distributions. On the 18th day, hemoptysis recurred, and the oxygen saturation decreased to 86% while the patient was at rest and breathing ambient air. Dr. McDermott: A second CT scan of the chest (Fig. 2) revealed persistent diffuse ground-glass opacities with subpleural reticulations in the lower lobes bilaterally; these findings were now visible because of the decrease in size of the bilateral pleural effusions. There was evidence of wedge resections of the right upper and lower lobes and subcutaneous emphysema. Dr. Danford: Vancomycin and piperacillin– tazobactam were administered. The day before this admission, confusion developed, with associated myoclonus during sleep and a temperature of 38.9°C. Lumbar puncture and CT and magnetic resonance imaging (MRI) of the head were performed; the studies revealed atrophy but no evidence of acute infarction, hemorrhage, or space-occupying masses. The dose of glucocorticoid therapy was decreased. On the 22nd day, a chest radiograph showed a persistent opacity in the right midzone and subcutaneous emphysema. Ethambutol, rifampin, and isoniazid were administered. Laboratory test results are shown in Table 1. The patient was transferred and admitted to this hospital. The patient was allergic to contrast dye. He lived alone and had retired from the construction industry, with past exposure to asbestos. He had a 46-pack-year history of smoking and had stopped 10 years earlier; he had stopped drinking alcohol 20 years earlier and did not use illicit drugs. He had traveled to Mexico in the remote past. His son, who lived nearby, owned chickens. He was a hunter and had had exposures to deer, rabbits, and pheasants in the previous 5 months. His father and brother may have had rheumatoid arthritis. On examination, the patient appeared to be mildly uncomfortable and was flushed. The respiratory rate was 18 breaths per minute, and the oxygen saturation 93% while he was breathing ambient air; the other vital signs were normal. He had shallow ulcerations on the right side of the hard palate, crackles in both lung bases, occasional expiratory wheezes, and trace ankle edema on the left side. The remainder of the examination was normal. Results of coagulation tests and blood levels of phosphorus and total and direct bilirubin were normal; testing for antibodies to the Goodpasture antigen was n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 2163 The n e w e ng l a n d j o u r na l of m e dic i n e Table 1. Laboratory Data.* Reference Range, Adults† Days 1–3, Other Hospital Hematocrit (%) 41.0–53.0 (men) 38.5 (ref 39.0–50.0) 30.0 34.5 24.6 30.2 Hemoglobin (g/dl) 13.5–17.5 (men) 12.3 (ref 13.0–17.0) 9.6 10.4 7.8 9.6 4500–11,000 3500 (day 1), 1900 (day 3) (ref 4000–11,000) 2100 4000 2600 2900 Neutrophils 40–70 76.0 84.2 84.0 84.8 Band forms 0–10 8.0 Lymphocytes 22–44 14.0 10.5 7.0 9.0 Monocytes 4–11 2.0 4.9 4.1 5.2 Eosinophils 0–8 0.4 0.3 Basophils 0–3 0.1 0 Variable White-cell count (per mm3) Days 7–9, Day 20, Day 22, On Admission, Other Hospital Other Hospital Other Hospital This Hospital Differential count (%) 3.0 Metamyelocytes Platelet count (per mm3) Mean corpuscular volume (μm3) Erythrocyte count (per mm3) 1 150,000– 400,000 138,000 121,000 80–100 86 91.0 (ref 86–99) 4,500,000– 5,900,000 3,500,000 Peripheral smear Erythrocyte sedimentation rate (mm/hr) 139,000 89.9 85.3 3,540,000 Normochromic, normocytic, minimal aniso‑ poikilocytosis, rare platelet clumps 0–13 3 15 Sodium (mmol/liter) 135–145 136 136 137 139 135 Potassium (mmol/liter) 3.4–4.8 4.1 3.5 4.4 3.3 3.5 Chloride (mmol/liter) 100–108 99 95 95 104 95 Carbon dioxide (mmol/liter) 23.0–31.9 26 35 35 30 30.6 8–25 23 14 27 (ref 7–26) 21 26 0.60–1.50 1.20 0.93 1.39 (ref 0.0–1.4) 1.21 1.48 ≥60 >60 51 60 46 70–110 148 140 (ref 70–109) 104 101 Urea nitrogen (mg/dl) Creatinine (mg/dl) Estimated glomerular filtration rate (ml/min/1.73 m2) Glucose (mg/dl) 25 Protein (g/dl) Total 6.0–8.3 4.4 5.3 3.9 5.3 Albumin 3.3–5.0 2.8 3.4 2.5 3.3 Globulin 1.9–4.1 2.0 Magnesium (mg/dl) 1.7–2.4 Calcium (mg/dl) 8.5–10.5 8.0 7.8 9.5 7.7 9.3 Alkaline phosphatase (U/liter) 45–115 364 258 116 80 103 2164 1.7 1.5 n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital Table 1. (Continued.) Reference Range, Adults† Days 1–3, Other Hospital Aspartate aminotransferase (U/liter) 10–40 72 Alanine aminotransferase (U/liter) 10–55 61 <8.0 77 (ref 0–5) Variable C-reactive protein (mg/liter) Lactate dehydrogenase (U/liter) 110–210 Lactate (mmol/liter) 0.5–2.2 Days 7–9, Day 20, Day 22, On Admission, Other Hospital Other Hospital Other Hospital This Hospital 36 23 24 43 24 23 94.4 45.3 27 25 86.5 235 (ref 121–225) 3.5 25-Hydroxyvitamin D (ng/ml) 11 (ref 30–100) Interferon-γ release assay (QuantiFERON-TB Gold) Negative Negative Antineutrophil cytoplasmic antibodies Negative Negative Antinuclear antibodies Negative Negative Rheumatoid factor Negative Negative Negative Immunoglobulins (mg/dl) IgG 614–1295 447 IgA 69–309 86 IgM 53–334 41 Normal pattern Normal pat‑ tern, no M component Serum protein electrophoresis and immunofixation *The term ref denotes the reference range at the other hospital. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for magnesium to millimoles per liter, multiply by 0.4114. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for lactate to milligrams per deciliter, divide by 0.1110. †Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. negative, as were the results of a lung panel for hypersensitivity pneumonitis. Other test results are shown in Table 1. Antibiotic agents and glucocorticoids were not administered. On the third day, a diagnostic test was performed. specific, the presence of noncaseating granulomas on examination of the lung-biopsy specimens assists in narrowing the differential diagnosis. Cancer Differ en t i a l Di agnosis Dr. Josalyn L. Cho: This patient presented with constitutional symptoms that had lasted for several weeks, as well as a cough with intermittent hemoptysis and pulmonary infiltrates. Repeated imaging studies of the chest showed subpleural reticulations and ground-glass opacities. The patient was treated with high doses of systemic glucocorticoids, but his condition worsened both clinically and radiographically. Although the symptoms and radiographic findings are non- In patients with weight loss and cough with hemoptysis, cancer involving the lung should be considered. A number of neoplastic conditions can cause ground-glass opacities to be present on chest CT, including atypical adenomatous hyperplasia, adenocarcinoma in situ (previously termed bronchoalveolar carcinoma), and lymphangitic carcinomatosis. Granulomas are seen with both primary pulmonary lymphoma and lymphomatoid granulomatosis.1,2 However, neither of these conditions fits well with the radiographic findings seen in this case. Therefore, n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 2165 The n e w e ng l a n d j o u r na l of m e dic i n e A A B B Figure 2. Chest CT Scans. Axial CT scans of the chest show diffuse ground‑glass opacities with subpleural reticulations in the lower lobes bilaterally (Panel A, arrowhead), as well as subcu‑ taneous emphysema related to the recent lung biopsy (Panels A and B, arrows). Figure 1. Chest Radiographs. A frontal chest radiograph that was obtained on ad‑ mission to the other hospital (Panel A) shows a patchy opacity in the right midzone. A follow‑up frontal chest radiograph that was obtained 5 days later (Panel B) shows a persistent patchy opacity in the right midzone and diffuse reticular opacities in the lung bases. is typically caseating.3 Alveolar hemorrhage can occur with Goodpasture’s syndrome and connective-tissue diseases, but granulomas are not seen with these disorders. In this case, the results of bronchoscopy ruled out alveolar hemorrhage; furthermore, there is no sinus or renal involvement, and tests for antineutrophil cytocancer is not likely to be the underlying cause of plasmic antibodies, antinuclear antibodies, rheuthis patient’s illness. matoid factor, and anti–glomerular basement membrane antibodies are negative. Thus, we can Inflammatory and Idiopathic Disorders rule out this group of disorders. Vasculitis and Alveolar Hemorrhage Hemoptysis and ground-glass opacities can occur as a result of pulmonary vasculitis and alveolar hemorrhage. Pulmonary vasculitides, including granulomatosis with polyangiitis and the Churg–Strauss syndrome, cause granulomatous inflammation of the lung, but the inflammation 2166 n engl j med 373;22 Idiopathic Interstitial Pneumonias Patients with idiopathic interstitial pneumonia often present with respiratory symptoms and ground-glass opacities. Of the idiopathic interstitial pneumonias, lymphoid interstitial pneumonia is the only disorder that is associated nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital with granulomas. Lymphoid interstitial pneumonia is often diagnosed in patients with immunologic disorders, such as Sjögren’s syndrome, hypogammaglobulinemia, and HIV infection. This patient had mildly suppressed levels of IgG and IgM; an HIV test was negative. Lymphoid interstitial pneumonia typically has an insidious onset, and the clinical presentation tends to be dominated by dyspnea, often with a dry cough. Hemoptysis is rare, but constitutional symptoms occur in about one third of patients.4 This patient did not present with dyspnea, and thus a diagnosis of lymphoid interstitial pneumonia is unlikely. Sarcoidosis Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases.5 Symptoms include fatigue, fever, anorexia, weight loss, cough, dyspnea, chest pain, and hemoptysis. Disease onset does not commonly occur in this patient’s age group. The radiographic findings associated with sarcoidosis include bilateral hilar and mediastinal lymphadenopathy, as well as parenchymal opacities that may be nodular, reticular, or ground-glass in nature. The radiographic features in this case are not classic for sarcoidosis, but this diagnosis must be considered because of the presence of noncaseating granulomas. In the United States, sarcoidosis is the most common noninfectious cause of granulomatous disease of the lung.6 However, sarcoidosis is a diagnosis of exclusion, since no specific diagnostic test is available. The efficacy of glucocorticoids in the treatment of sarcoidosis is unclear, but they remain the first-line therapy for this condition. Therefore, worsening of the patient’s symptoms after the administration of high-dose systemic glucocorticoids should prompt strong consideration of an alternative diagnosis. Infection Bacterial, viral, fungal, and mycobacterial diseases can cause fever, cough, and hemoptysis and should be considered in the differential diagnosis. This patient’s clinical course was not consistent with a typical bacterial or viral pneumonia, and granulomatous inflammation is not a feature of these infections. Cultures of blood and bronchoalveolar lavage fluid were negative, as were tests for influenza and cytomegalovirus. This patient is mildly immunocompromised on the basis of his older age, underlying diabetes, and recent history of cancer. Thus, we should consider fungal and mycobacterial lung infections, both of which can cause pulmonary granulomas and can result in the bronchiolocentric and lymphangitic distributions seen on examination of the patient’s biopsy specimens. Fungi that are endemic in this region can cause symptomatic disease with fever, cough, hemoptysis, and pulmonary infiltrates. Pneumocystis jirovecii can also cause cough, fever, hypoxemia, and bilateral symmetric reticular and groundglass opacities. However, this patient did not have obvious risk factors for pneumocystis; his symptoms developed before the administration of glucocorticoid therapy. Finally, atypical mycobacterial infection and tuberculosis should always be considered in patients who present with fever, night sweats, weight loss, and cough with hemoptysis. Exposures The final category of diseases that should be considered is occupational, environmental, and drug exposures. There is an extensive list of medications associated with granulomatous lung disease, including methotrexate and etanercept; this patient did not receive any of these medications. Injection of crushed tablets can also result in deposition of talc in the lung, which can cause granulomatous inflammation.7 The patient had a history of occupational exposure to asbestos but not to talc or beryllium. Thus, drug and occupational exposures can be ruled out as a cause of this patient’s illness. Hypersensitivity pneumonitis should be strongly considered in this case. This condition is an immunologic reaction to an inhaled organic antigen.8 The list of specific antigens that cause hypersensitivity pneumonitis is lengthy but can be categorized into microbial agents, animal proteins, and low-molecular-weight chemicals. In this case, the patient reported exposure to chickens, which is a known cause of hypersensitivity pneumonitis. Fever, malaise, weight loss, and cough are consistent with a diagnosis of subacute hypersensitivity pneumonitis, but hemoptysis is uncommon. This patient had a negative panel for precipitating IgG antibodies against potential antigens associated with hypersensitivity pneumonitis. A positive serum test for n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 2167 The n e w e ng l a n d j o u r na l A of m e dic i n e B B D C Figure 3. Lung-Biopsy Specimen (Hematoxylin and Eosin). A wedge‑biopsy specimen of the lung was obtained at the other hospital. Panel A shows a solid area of inflamma‑ tion (outlined) and small nodules of inflammation. Panel B shows a bronchiole (B) with histiocytic inflammation involving the peribronchiolar interstitium, with multinucleated histiocytes (arrow). Panel C shows an area of histio‑ cytic inflammation in linear array (oval), which reflects the lymphocytic distribution. Panel D shows a non‑necrotizing granuloma (oval) with a multinucleated histiocyte (arrow). precipitins can be helpful in confirming the diagnosis, but a negative test should not be used to rule it out.8 The mainstay of therapy for hypersensitivity pneumonitis is elimination of the causative antigen from the patient’s environment. Severe cases may necessitate treatment with systemic glucocorticoids, although we are unaware of any controlled trials to support this treatment.8 This patient received 1 g of methylprednisolone daily for 3 days, followed by high-dose prednisone, which was presumably administered as empirical treatment for hypersensitivity pneumonitis. Unfortunately, the patient’s condition worsened after this therapy, and thus it was appropriate to perform a lung biopsy. May we review the results of the pathological examination? 2168 n engl j med 373;22 Pathological Examination Dr. Eugene J. Mark: Before the patient was transferred to this hospital, he underwent a lung biopsy. In consultation with the referring facility, we have reviewed the slides of the biopsy specimen (Fig. 3). The specimen contained extensive granulomatous inflammation, which involved the peribronchiolar interstitium and interalveolar walls. Modest fibrosis was present, as were numerous histiocytic giant cells. No necrosis was present. The peribronchiolar distribution and granulomatous aspects of the process are suggestive of subacute hypersensitivity pneumonitis,9-11 which was the diagnosis I preferred in this case on the basis of the histopathological features alone. The pathological features were not char- nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital acteristic of sarcoidosis, aspiration, or active infection.6,12-15 Dr. Cho: The presence, type, and distribution of granulomas substantially narrow the differential diagnosis to include hypersensitivity pneumonitis and infection. Hypersensitivity Pneumonitis The histologic features of hypersensitivity pneumonitis typically include prominent chronic interstitial inflammation with scattered, small, poorly formed non-necrotizing granulomas that may be centered around bronchioles.16 Hottub lung, which is a response to Mycobacterium avium complex that is similar to hypersensitivity pneumonitis, can cause large, well-formed granulomas. Hot tubs provide an ideal temperature for the growth of M. avium complex and a means for aerosolization and inhalation. In both hypersensitivity pneumonitis and hot-tub lung, granulomas are found around airways and in air spaces.6 Although the histologic features in this case are consistent with hypersensitivity pneumonitis, the clinical worsening after glucocorticoid treatment argues against the diagnosis. Infection Fungal Infection The most common fungal causes of pulmonary granulomas include cryptococcus, histoplasma, coccidioides, and blastomyces. Cryptococcus is ubiquitous but very uncommonly associated with a symptomatic pulmonary disease. Coccidioides is endemic in the southwestern United States, parts of Mexico, Central America, and South America. This patient had traveled to Mexico, but the trip had not been taken recently, and thus infection with coccidioides is very unlikely. Histoplasma and blastomyces are primarily seen in the central and eastern United States. This patient’s clinical presentation is most consistent with a disseminated or progressive infection that is not adequately contained by the immune system. In such cases of fungal infection, granuloma formation is uncommon, and therefore, examination of the blood, sputum, and bronchoalveolar lavage fluid should have a high diagnostic yield.17,18 For these reasons, fungal infection is not likely to explain this patient’s presentation. Mycobacterial Infection The other major class of infection to consider is mycobacterial disease. Mycobacteria can be categorized as nontuberculous or tuberculous. Nontuberculous mycobacteria are ubiquitous and frequently cause pulmonary disease.19 In particular, nontuberculous mycobacterial infection can develop in older persons even in the absence of underlying lung disease. Symptoms include cough, fatigue, and occasionally hemoptysis, but these tend to be less severe in cases of nontuberculous mycobacterial infection than in cases of tuberculosis. Fever and weight loss are also less common in cases of nontuberculous mycobacterial infection than in cases of tuberculosis. The radiographic findings are diverse and can include infiltrates and cavities in the upper lobe, nodules, tree-in-bud opacities, and areas of bronchiectasis; none of these findings were observed in this case. Tuberculosis is caused by any one of the three mycobacterial pathogens that form the M. tuberculosis complex: M. tuberculosis, M. bovis, and M. africanum. M. tuberculosis causes most cases of tuberculosis and commonly results in infection through inhalation and deposition of the organism in the lung. M. tuberculosis can cause primary disease, latent infection, or reactivation disease in the lung. Reactivation of latent disease represents 90% of cases of tuberculosis in HIV-negative adults and typically involves the apicoposterior segments of the upper lobes or the superior segment of the lower lobes. Other radiographic patterns have been described and include infiltrates in the middle or lower lung zones and pleural effusions, features that were present in this patient.20 Hematogenous dissemination of M. tuberculosis is an infrequent complication of disease.21 More than 50% of patients with disseminated disease have pulmonary symptoms. Gastrointestinal symptoms are common and include abdominal tenderness and diarrhea, features that were present in this patient. Tuberculous meningitis has been reported in 10 to 30% of patients with disseminated disease.21 This patient had altered mentation late in his course, but results of lumbar puncture and of CT and MRI of the head were unremarkable. Laboratory evaluation frequently reveals hematologic abnormalities, including normocytic normochromic anemia. n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 2169 The n e w e ng l a n d j o u r na l Pancytopenia should prompt evaluation for tuberculosis with bone marrow involvement; this evaluation was performed in this case. The majority of patients have an elevated level of alkaline phosphatase (as this patient initially did), and almost half have mildly elevated aminotransferase levels. Anergy to tuberculin is common in disseminated disease and can be seen in more than half of patients.21 Thus, a negative tuberculin skin test does not rule out this disease. Similarly, a negative interferon-γ release assay does not rule out the possibility of active tuberculosis.22 This patient did not have risk factors that are often associated with M. tuberculosis infection. However, he had a history of transitional-cell carcinoma of the bladder and had completed a course of BCG therapy 7 months before this admission. BCG is a live attenuated strain of M. bovis and a mainstay of therapy for superficial bladder cancer. Systemic complications of intravesicular BCG therapy are rare, occurring in less than 1% of patients.23 Pulmonary complications of intravesicular BCG therapy include bilateral interstitial pneumonitis and non-necrotizing granulomas.24 The pathogenesis is incompletely understood, but it is thought that the organisms gain access to the lymphatics and blood through disruption of the uroepithelium and then disseminate to multiple sites. Granulomatous reactions in the absence of organisms (which are thought to represent hypersensitivity reactions) and active infection have been reported.25,26 There are case reports of infections occurring months and even years after BCG therapy. Tuberculosis due to M. bovis is clinically and radiographical ly indistinguishable from tuberculosis due to M. tuberculosis. In this patient, the clinical, radiographic, and pathological findings are most consistent with tuberculosis due to M. bovis. I suspect that the diagnostic test was a positive culture or nucleic acid test of either bronchoalveolar lavage fluid or sputum. Dr. Eric S. Rosenberg (Pathology): Dr. Tsibris, would you tell us your impression when you evaluated this patient? Dr. Athe M. Tsibris: We focused our differential diagnosis on the patient’s pancytopenia, the presence of noncaseating lung granulomas, and the fever of unknown origin. The granulomas 2170 of m e dic i n e suggested an intracellular pathogen, and we thought that a nontuberculous mycobacterial infection was likely. We considered the possibility of a disseminated M. bovis infection, but the time course of illness was atypical of this disease. Our preference was to confirm a microbiologic diagnosis before starting antimycobacterial therapy. We could not find a convincing link between the patient’s illness and his exposures to animals. Cl inic a l Di agnosis Hypersensitivity pneumonitis, possibly due to a nontuberculous mycobacterial infection. Dr . Jos a ly n L . Cho’s Di agnosis Tuberculosis (due to Mycobacterium bovis) after intravesicular therapy with bacille Calmette– Guérin. M a nagemen t a nd Fol l ow-up Dr. Tsibris: The patient remained febrile throughout the 10-day inpatient hospitalization. At the time of discharge, his cultures remained negative. Positron-emission tomography, which was performed as part of the workup for the fever of unknown origin, revealed diffuse uptake in the lungs; the leading diagnosis at this time was hypersensitivity pneumonitis. The patient was discharged with a prescription for oral glucocorticoids and a plan for close follow-up. After discharge, fevers persisted. Approximately 2 months after this admission, cultures of urine and sputum revealed growth of M. bovis (BCG type). The patient received a regimen of isoniazid, rifampin, and ethambutol, and the fevers resolved; the course of glucocorticoids was tapered. Pathol o gic a l Discussion Dr. Mark: We had concerns that BCG therapy had caused this patient’s reaction, and we also considered other forms of atypical mycobacterial infection. In addition, hot-tub lung was included in the differential diagnosis because the patient’s presentation at another hospital suggested the possibility of hypersensitivity pneumonitis.6,12-15 When the patient had positive cultures for n engl j med 373;22 nejm.org November 26, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on January 1, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital A B FN Figure 4. Bone Marrow–Biopsy Specimen (Hematoxylin and Eosin). A bone marrow–biopsy specimen shows several multi‑ nucleated histiocytes (Panel A, arrows); a multinucle‑ ated histiocyte (Panel B, arrow) is seen amid fat and fat necrosis (FN). were present. We asked the patient whether he had had possible exposure to atypical mycobacteria in the form of aerosolized organisms from a humidifier or sauna, but he reported no such exposure. Although sputum cultures grew the organisms, I could not confirm whether this patient had hypersensitivity pneumonitis, infection, or both. To further evaluate the dissemination of the mycobacteria, a needle biopsy of the bone marrow was performed. The bone marrow contained a few granulomas and a few small, scattered aggregates of histiocytes in the fat (Fig. 4). Acid-fast staining of this specimen for organisms was negative. Dr. Cho: Case reports of the systemic complications of BCG therapy describe both sterile granulomatous inflammation and active infection with identification of viable organisms. I think it is clear that this patient had M. bovis infection, but he probably had an extensive hypersensitivity reaction to the organism, as well. A Physician: Would you recommend any prophylactic treatments for patients who have received BCG therapy and are going to receive high-dose glucocorticoid therapy? Dr. Tsibris: It is generally assumed that patients who receive intravesicular BCG therapy will not have a latent M. bovis infection, since the rate of dissemination is less than 1%. Therefore, no specific prophylaxis is recommended. Fina l Di agnosis M. bovis, I asked the referring hospital to provide Disseminated Mycobacterium bovis infection. unstained recut sections of lung tissue in an atThis case was presented at the Medical Case Conference. tempt to visualize the mycobacterium. We atDisclosure forms provided by the authors are available with tempted this on six slides, and no mycobacteria the full text of this article at NEJM.org. References 1. 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Pulmonary disease following intravesical BCG treatment. Thorax 1990;45:709-10. 25.Gupta RC, Lavengood R Jr, Smith JP. Miliary tuberculosis due to intravesical bacillus Calmette–Guérin therapy. Chest 1988;94:1296-8. 26. Palayew M, Briedis D, Libman M, Michel RP, Levy RD. Disseminated infection after intravesical BCG immunotherapy: detection of organisms in pulmonary tissue. Chest 1993;104:307-9. Copyright © 2015 Massachusetts Medical Society. Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. 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