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

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. Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J
2002;20:750-62.
2. Lee JS, Tuder R, Lynch DA. Lymphomatoid granulomatosis: radiologic features
and pathologic correlations. AJR Am J
Roentgenol 2000;175:1335-9.
3. Gaudin PB, Askin FB, Falk RJ, Jennette
JC. The pathologic spectrum of pulmonary
lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for antiproteinase 3 and anti-myeloperoxidase.
Am J Clin Pathol 1995;104:7-16.
4. Cha SI, Fessler MB, Cool CD, Schwarz
MI, Brown KK. Lymphoid interstitial
pneumonia: clinical features, associations and prognosis. Eur Respir J 2006;
28:364-9.
5. Judson MA. The clinical features of
sarcoidosis: a comprehensive review. Clin
Rev Allergy Immunol 2015;49:63-78.
6. Mukhopadhyay S, Gal AA. Granulomatous lung disease: an approach to the
differential diagnosis. Arch Pathol Lab
Med 2010;134:667-90.
7. Low SE, Nicol A. Talc induced pulmonary granulomatosis. J Clin Pathol 2006;
59:223.
n engl j med 373;22
nejm.org
8. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit
Care Med 2012;186:314-24.
9. Hariri LP, Mino-Kenudson M, Shea B,
et al. Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum Pathol 2012;43:
660-8.
10. Kahana LM, Kay JM, Yakrus MA,
Waserman S. Mycobacterium avium complex
infection in an immunocompetent young
adult related to hot tub exposure. Chest
1997;111:242-5.
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.
2171
Case Records of the Massachuset ts Gener al Hospital
11. Rickman OB, Ryu JH, Fidler ME, Kalra
S. Hypersensitivity pneumonitis associated with Mycobacterium avium complex and
hot tub use. Mayo Clin Proc 2002;​77:​1233-7.
12.Khoor A, Leslie KO, Tazelaar HD,
Helmers RA, Colby TV. Diffuse pulmonary disease caused by nontuberculous
mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001;​
115:​755-62.
13. Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub
lung: presenting features and clinical
course of 21 patients. Respir Med 2006;​
100:​610-5.
14.Sood A, Sreedhar R, Kulkarni P, Nawoor AR. Hypersensitivity pneumonitislike granulomatous lung disease with nontuberculous mycobacteria from exposure
to hot water aerosols. Environ Health
Perspect 2007;​115:​262-6.
15. Barrios RJ. Hypersensitivity pneumonitis: histopathology. Arch Pathol Lab Med
2008;​132:​199-203.
16. Grunes D, Beasley MB. Hypersensitiv-
ity pneumonitis: a review and update of
histologic findings. J Clin Pathol 2013;​66:​
888-95.
17. Saccente M, Woods GL. Clinical and
laboratory update on blastomycosis. Clin
Microbiol Rev 2010;​23:​367-81.
18.Smith JA, Kauffman CA. Pulmonary
fungal infections. Respirology 2012;​17:​
913-26.
19. Griffith DE, Aksamit T, Brown-Elliott
BA, et al. An official ATS/IDSA statement:
diagnosis, treatment, and prevention of
nontuberculous mycobacterial diseases. Am
J Respir Crit Care Med 2007;​175:​367-416.
20. Krysl J, Korzeniewska-Kosela M, Müller NL, FitzGerald JM. Radiologic features
of pulmonary tuberculosis: an assessment
of 188 cases. Can Assoc Radiol J 1994;​45:​
101-7.
21.Maartens G, Willcox PA, Benatar SR.
Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in
109 treated adults. Am J Med 1990;​89:​291-6.
22.Sester M, Sotgiu G, Lange C, et al.
Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J 2011;​
37:​100-11.
23.Lamm DL, Stogdill VD, Stogdill BJ,
Crispen RG. Complications of bacillus
Calmette–Guérin immunotherapy in 1,278
patients with bladder cancer. J Urol 1986;​
135:​272-4.
24.Kesten S, Title L, Mullen B, Grossman
R. 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. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].
2172
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.