caso clinico 37 2015 nejm

n engl j med 373;22 nejm.org November 26, 20152162

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Pr esen tation of C a se

Dr. Christopher J. Danford (Medicine): A 76-year-old man with multiple medical prob-lems 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 admis-sion, 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), con-gestive heart failure, peripheral vascular disease (with previous aortofemoral by-pass surgery), non–insulin-dependent diabetes mellitus, gout, and benign pros-tatic 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.

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/NEJMcpc1504839Copyright © 2015 Massachusetts Medical Society.

Founded by Richard C. Cabot Eric S. Rosenberg, M.D., Editor Nancy Lee Harris, M.D., Editor Jo‑Anne O. Shepard, M.D., Associate Editor Alice M. Cort, M.D., Associate Editor Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

Case 37-2015: A 76-Year-Old Man with Fevers, Leukopenia, and Pulmonary

InfiltratesJosalyn L. Cho, M.D., Shaunagh McDermott, M.D., Athe M. Tsibris, M.D.,

and Eugene J. Mark, M.D.

Case Records of the Massachusetts General Hospital

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Case Records of the Massachusetts Gener al Hospital

There was abdominal distention, with tender-ness in the right upper quadrant. Results of co-agulation tests and blood levels of total and di-rect bilirubin were normal; other test results are shown in Table 1. Abdominal ultrasonography revealed a horseshoe kidney and a mildly hetero-geneous liver. A chest radiograph showed a patchy opacity in the right midzone (Fig. 1A). Transthoracic echocardiography reportedly re-vealed 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 phagocyto-philum, babesia, rickettsia (Rocky Mountain spot-ted 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 pulmo-nary 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 reticu-lar 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 rheumatolo-gist, methylprednisolone (1 g daily) was admin-istered for 3 days, followed by prednisone (60 mg daily). The fevers initially improved but then re-curred. On the 15th day, video-assisted thoracic surgery was performed. Pathological examina-tion of a lung-biopsy specimen reportedly re-vealed extensive noncaseating granulomatous inflammation and granulomas in both bronchi-olocentric 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 bi-lateral 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 associ-ated myoclonus during sleep and a temperature of 38.9°C. Lumbar puncture and CT and mag-netic 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 glucocorti-coid 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 ad-ministered. Laboratory test results are shown in Table 1. The patient was transferred and admit-ted to this hospital.

The patient was allergic to contrast dye. He lived alone and had retired from the construc-tion industry, with past exposure to asbestos. He had a 46-pack-year history of smoking and had stopped 10 years earlier; he had stopped drink-ing 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 re-spiratory rate was 18 breaths per minute, and the oxygen saturation 93% while he was breath-ing ambient air; the other vital signs were nor-mal. 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 coagu-lation tests and blood levels of phosphorus and total and direct bilirubin were normal; testing for antibodies to the Goodpasture antigen was





VariableReference

Range, Adults†Days 1–3,

Other HospitalDays 7–9,

Other HospitalDay 20,


Other HospitalOn Admission, This 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

White‑cell count (per mm3) 4500–11,000 3500 (day 1), 1900 (day 3)

(ref 4000–11,000)

2100 4000 2600 2900

Differential count (%)

Neutrophils 40–70 76.0 84.2 84.0 84.8

Band forms 0–10 8.0 3.0

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

Metamyelocytes 1

Platelet count (per mm3) 150,000–400,000

138,000 121,000 139,000

Mean corpuscular volume (μm3) 80–100 86 91.0 (ref 86–99)

89.9 85.3

Erythrocyte count (per mm3) 4,500,000–5,900,000

3,500,000 3,540,000

Peripheral smear Normochromic, normocytic,

minimal aniso‑poikilocytosis, rare platelet

clumps

Erythrocyte sedimentation rate (mm/hr)

0–13 3 15 25

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

Urea nitrogen (mg/dl) 8–25 23 14 27 (ref 7–26)

21 26

Creatinine (mg/dl) 0.60–1.50 1.20 0.93 1.39 (ref 0.0–1.4)

1.21 1.48

Estimated glomerular filtration rate (ml/min/1.73 m2)

≥60 >60 51 60 46

Glucose (mg/dl) 70–110 148 140 (ref 70–109)

104 101

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 1.7 1.5

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

Table 1. Laboratory Data.*





negative, as were the results of a lung panel for hypersensitivity pneumonitis. Other test results are shown in Table 1. Antibiotic agents and glu-cocorticoids were not administered. On the third day, a diagnostic test was performed.

Differ en ti a l Di agnosis

Dr. Josalyn L. Cho: This patient presented with constitutional symptoms that had lasted for sev-eral 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-

specific, the presence of noncaseating granulo-mas on examination of the lung-biopsy speci-mens assists in narrowing the differential diagnosis.

Cancer

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 lym-phangitic carcinomatosis. Granulomas are seen with both primary pulmonary lymphoma and lymphomatoid granulomatosis.1,2 However, neither of these conditions fits well with the radio-graphic findings seen in this case. Therefore,

VariableReference

Range, Adults†Days 1–3,

Other HospitalDays 7–9,



Other HospitalOn Admission, This Hospital

Aspartate aminotransferase (U/liter) 10–40 72 36 23 24 27

Alanine aminotransferase (U/liter) 10–55 61 43 24 23 25

C‑reactive protein (mg/liter) <8.0 77 (ref 0–5)

94.4 45.3 86.5

Lactate dehydrogenase (U/liter) 110–210 235 (ref 121–225)

Lactate (mmol/liter) 0.5–2.2 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 Negative

Antinuclear antibodies Negative Negative

Rheumatoid factor Negative Negative

Immunoglobulins (mg/dl)

IgG 614–1295 447

IgA 69–309 86

IgM 53–334 41

Serum protein electrophoresis and immunofixation

Normal pattern

Normal pat‑tern, no M component

* 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.

Table 1. (Continued.)





cancer is not likely to be the underlying cause of this patient’s illness.

Inflammatory and Idiopathic Disorders Vasculitis and Alveolar Hemorrhage

Hemoptysis and ground-glass opacities can oc-cur as a result of pulmonary vasculitis and alveo-lar hemorrhage. Pulmonary vasculitides, includ-ing granulomatosis with polyangiitis and the Churg–Strauss syndrome, cause granulomatous inflammation of the lung, but the inflammation

is typically caseating.3 Alveolar hemorrhage can occur with Goodpasture’s syndrome and con-nective-tissue diseases, but granulomas are not seen with these disorders. In this case, the re-sults of bronchoscopy ruled out alveolar hemor-rhage; furthermore, there is no sinus or renal involvement, and tests for antineutrophil cyto-plasmic antibodies, antinuclear antibodies, rheu-matoid factor, and anti–glomerular basement membrane antibodies are negative. Thus, we can rule out this group of disorders.

Idiopathic Interstitial PneumoniasPatients with idiopathic interstitial pneumonia often present with respiratory symptoms and ground-glass opacities. Of the idiopathic inter-stitial pneumonias, lymphoid interstitial pneu-monia is the only disorder that is associated

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.

A

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).

A

B





with granulomas. Lymphoid interstitial pneu-monia is often diagnosed in patients with immu-nologic 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 pa-tient 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 radio-graphic findings associated with sarcoidosis in-clude bilateral hilar and mediastinal lymphade-nopathy, 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 diag-nostic test is available. The efficacy of glucocor-ticoids 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 dis-eases can cause fever, cough, and hemoptysis and should be considered in the differential di-agnosis. This patient’s clinical course was not consistent with a typical bacterial or viral pneu-monia, 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 infec-tions, both of which can cause pulmonary granulomas and can result in the bronchiolocen-tric and lymphangitic distributions seen on ex-amination of the patient’s biopsy specimens. Fungi that are endemic in this region can cause symptomatic disease with fever, cough, hemop-tysis, and pulmonary infiltrates. Pneumocystis jir-ovecii can also cause cough, fever, hypoxemia, and bilateral symmetric reticular and ground-glass opacities. However, this patient did not have obvious risk factors for pneumocystis; his symptoms developed before the administration of glucocorticoid therapy. Finally, atypical myco-bacterial infection and tuberculosis should al-ways 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 medica-tions. Injection of crushed tablets can also result in deposition of talc in the lung, which can cause granulomatous inflammation.7 The pa-tient 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 strong-ly 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 hypersensi-tivity pneumonitis. Fever, malaise, weight loss, and cough are consistent with a diagnosis of subacute hypersensitivity pneumonitis, but he-moptysis is uncommon. This patient had a nega-tive panel for precipitating IgG antibodies against potential antigens associated with hyper-sensitivity pneumonitis. A positive serum test for





precipitins can be helpful in confirming the diag-nosis, 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 an-tigen 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 empiri-cal 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?

Pathological Examination

Dr. Eugene J. Mark: Before the patient was trans-ferred to this hospital, he underwent a lung bi-opsy. In consultation with the referring facility, we have reviewed the slides of the biopsy speci-men (Fig. 3). The specimen contained extensive granulomatous inflammation, which involved the peribronchiolar interstitium and interalveo-lar walls. Modest fibrosis was present, as were numerous histiocytic giant cells. No necrosis was present.

The peribronchiolar distribution and granu-lomatous 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-

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).

A B

B

DC





acteristic of sarcoidosis, aspiration, or active infection.6,12-15

Dr. Cho: The presence, type, and distribution of granulomas substantially narrow the differ-ential diagnosis to include hypersensitivity pneumonitis and infection.

Hypersensitivity Pneumonitis

The histologic features of hypersensitivity pneu-monitis typically include prominent chronic interstitial inflammation with scattered, small, poorly formed non-necrotizing granulomas that may be centered around bronchioles.16 Hot-tub lung, which is a response to Mycobacterium avium complex that is similar to hypersensitiv-ity pneumonitis, can cause large, well-formed granulomas. Hot tubs provide an ideal tempera-ture 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 glu-cocorticoid treatment argues against the diag-nosis.

InfectionFungal 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, granu-loma formation is uncommon, and therefore, examination of the blood, sputum, and bron-choalveolar lavage fluid should have a high diag-nostic yield.17,18 For these reasons, fungal infec-tion is not likely to explain this patient’s presentation.

Mycobacterial InfectionThe other major class of infection to consider is mycobacterial disease. Mycobacteria can be cate-gorized as nontuberculous or tuberculous.

Nontuberculous mycobacteria are ubiquitous and frequently cause pulmonary disease.19 In particular, nontuberculous mycobacterial infec-tion can develop in older persons even in the absence of underlying lung disease. Symptoms include cough, fatigue, and occasionally hemop-tysis, 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 tuber-culosis. 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. tuber-culosis complex: M. tuberculosis, M. bovis, and M. afri-canum. M. tuberculosis causes most cases of tu-berculosis and commonly results in infection through inhalation and deposition of the organ-ism in the lung. M. tuberculosis can cause primary disease, latent infection, or reactivation disease in the lung. Reactivation of latent disease repre-sents 90% of cases of tuberculosis in HIV-nega-tive adults and typically involves the apicoposte-rior segments of the upper lobes or the superior segment of the lower lobes. Other radiographic patterns have been described and include infil-trates 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. Gastrointes-tinal symptoms are common and include ab-dominal tenderness and diarrhea, features that were present in this patient. Tuberculous menin-gitis 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.





Pancytopenia should prompt evaluation for tu-berculosis with bone marrow involvement; this evaluation was performed in this case. The ma-jority of patients have an elevated level of alka-line phosphatase (as this patient initially did), and almost half have mildly elevated amino-transferase levels. Anergy to tuberculin is com-mon 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 dis-ease. 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 intra-vesicular 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 dis-seminate to multiple sites. Granulomatous reac-tions 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

suggested an intracellular pathogen, and we thought that a nontuberculous mycobacterial infection was likely. We considered the possibil-ity of a disseminated M. bovis infection, but the time course of illness was atypical of this dis-ease. Our preference was to confirm a microbio-logic diagnosis before starting antimycobacteri-al therapy. We could not find a convincing link between the patient’s illness and his exposures to animals.

Clinic 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 Foll ow-up

Dr. Tsibris: The patient remained febrile through-out the 10-day inpatient hospitalization. At the time of discharge, his cultures remained nega-tive. 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 glucocor-ticoids and a plan for close follow-up. After dis-charge, fevers persisted. Approximately 2 months after this admission, cultures of urine and spu-tum 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 con-sidered 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





M. bovis, I asked the referring hospital to provide unstained recut sections of lung tissue in an at-tempt to visualize the mycobacterium. We at-tempted this on six slides, and no mycobacteria

were present. We asked the patient whether he had had possible exposure to atypical mycobac-teria 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, infec-tion, or both.

To further evaluate the dissemination of the mycobacteria, a needle biopsy of the bone mar-row was performed. The bone marrow con-tained a few granulomas and a few small, scat-tered aggregates of histiocytes in the fat (Fig. 4). Acid-fast staining of this specimen for organ-isms was negative.

Dr. Cho: Case reports of the systemic compli-cations of BCG therapy describe both sterile granulomatous inflammation and active infec-tion with identification of viable organisms. I think it is clear that this patient had M. bovisinfection, but he probably had an extensive hy-persensitivity reaction to the organism, as well.

A Physician: Would you recommend any pro-phylactic treatments for patients who have re-ceived BCG therapy and are going to receive high-dose glucocorticoid therapy?

Dr. Tsibris: It is generally assumed that pa-tients 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

Disseminated Mycobacterium bovis infection.

This case was presented at the Medical Case Conference.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.

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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).

A

B

FN





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