Caso clinico 37 2015 nejm

n engl j med 373;22 nejm.org November 26, 20152162
The new engl and jour nal of medicine
Presentation of Case
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/NEJMcpc1504839
Copyright © 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
Infiltrates
Josalyn 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
The New England Journal of Medicine
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n engl j med 373;22 nejm.org November 26, 2015 2163
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

Variable
Reference
Range, Adults†
Days 1–3,
Other Hospital
Days 7–9,
Other Hospital
Day 20,
Other Hospital
Day 22,
Other Hospital
On 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.
Differential Diagnosis
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,
Variable
Reference
Range, Adults†
Days 1–3,
Other Hospital
Days 7–9,
Other Hospital
Day 20,
Other Hospital
Day 22,
Other Hospital
On 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 Pneumonias
Patients 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.
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, 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 Infection
The 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.
Clinical Diagnosis
Hypersensitivity pneumonitis, possibly due to a
nontuberculous mycobacterial infection.
Dr. Josalyn L. Cho’s Diagnosis
Tuberculosis (due to Mycobacterium bovis) after
intravesicular therapy with bacille Calmette–
Guérin.
Management and Follow-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.
Pathological 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. bovis
infection, 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.
Final Diagnosis
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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