RESIDENTS’ CLINIC
RESIDENTS’ CLINIC
68-Year-Old Man With Fatigue, Fever, and Weight Loss
NASEEMA GANGAT, MD*; YI LIN, MD, PHD*; AND PETER L. ELKIN, MD†
A 68-year-old man presented to our institution with a 3-
week history of fatigue, fever, and weight loss. He
described his fever as low-grade and intermittent. He de-
nied night sweats but reported weight loss of 5 kg in 3
weeks. He also experienced problems with attention and
concentration, increased drowsiness, and unsteady gait. He
denied recent travel, outdoor recreational activities, tick
bites, or contact with sick persons. His medical history
included rheumatoid arthritis, bilateral lower extremity
deep venous thromboses, and a prior infected right knee
prosthesis. The patient had smoked a pack of cigarettes per
day for 45 years but had quit 11 months previously. He
denied use of alcohol or recreational drugs. His father had
died of a brain tumor. Medications and supplements in-
cluded methotrexate at 20 mg/wk for more than 5 years,
prednisone at 5 mg/d, valdecoxib at 10 mg/d, levofloxacin
at 500 mg/d, warfarin at 5 mg/d, and calcium at 1000 mg/d.
On physical examination, the patient appeared lethargic.
His blood pressure was 134/70 mm Hg, his pulse rate was
75/min, and he was afebrile. Conjunctival pallor and dry
mucous membranes were appreciated. No lymphadenopa-
thy was noted, and findings on lung and cardiac examina-
tions were unremarkable. The patient’s abdomen was dis-
tended but nontender with a palpable spleen tip. On mental
status examination, the patient had difficulties with atten-
tion and calculation. On neurologic examination, his gait
was unsteady, but he showed no focal neurologic deficits.
Laboratory test results were as follows (reference ranges
shown parenthetically): hemoglobin, 11.0 g/dL (13.5-17.5
g/dL); white blood cells, 2.6 × 109/L (3.5-10.5 × 109/L); and
platelets, 68 × 109/L (150-450 × 109/L). This was a substan-
tial change from the normal complete blood cell count
obtained 2 weeks previously. Other results included so-
dium, 131 mEq/L (135-145 mEq/L); potassium, 5.4 mEq/L
(3.6-4.8 mEq/L); creatinine, 1.1 mg/dL (0.9-1.4 mg/dL);
total calcium, 12.3 mg/dL (8.9-10.1 mg/dL); ionized cal-
cium, 6.60 mg/dL (4.65-5.30 mg/dL); parathyroid hormone
*Resident in Internal Medicine, Mayo Graduate School of Medicine, Mayo
Clinic College of Medicine, Rochester, Minn.
†Adviser to residents and Consultant in General Internal Medicine, Mayo
Clinic College of Medicine, Rochester, Minn.
See end of article for correct answers to questions.
Address reprint requests and correspondence to Peter L. Elkin, MD, Division
of General Internal Medicine, Mayo Clinic College of Medicine, 200 First St
SW, Rochester, MN 55905 (e-mail: elkin.peter@mayo.edu).
© 2005 Mayo Foundation for Medical Education and Research
Mayo Clin Proc. • July 2005;80(7):939-942
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
(PTH), 10 pg/mL (10-55 pg/mL); PTH-related peptide
(PTHrP), 1.3 pmol/L (<2.0 pmol/L); and calcitriol (1,25-
dihydroxyvitamin D3), 72 pg/mL (10-65 pg/mL). Chest
radiography showed a vague nodular opacity in the left mid
lung. Chest computed tomography (CT) confirmed an ill-
defined, uncalcified, angular, 1.2-cm pulmonary nodule
located peripherally in the superior aspect of the lower lobe
of the left lung. Left hilar adenopathy and a prominent right
paratracheal lymph node were noted.
1. Which one of the following is the best test to establish a
diagnosis for our patient?
a. Purified protein derivative (PPD) skin test
b. Biopsy of the lung nodule
c. Positron emission tomography
d. Serum angiotensin-converting enzyme (ACE) level
e. Serum protein electrophoresis (SPEP), urinary protein
electrophoresis, and skeletal bone survey
The PPD skin test has limited utility in the diagnosis of
symptomatic patients; it is used primarily for detection of
latent tuberculous infection (LTBI). Knowledge of a
patient’s tuberculin skin test reactivity facilitates the diag-
nosis of LTBI in selected patients. Annual testing of high-
risk patients with negatve results from skin testing allows
the detection of new skin test converters who require LTBI
therapy regardless of age. Our patient was immunocom-
promised due to low-dose methotrexate; thus, obtaining a
PPD skin test is reasonable but is not diagnostic.
Our clinical suspicion for lung malignancy was ex-
tremely high because our patient had been a smoker; hence,
biopsy of the lung nodule would be the best test to establish
the diagnosis for this patient. Lesion size and location are
the strongest determinants of the diagnostic yield in a soli-
tary pulmonary nodule.1 The yield of flexible fiberoptic
bronchoscopy is particularly low in 2-cm or smaller lesions
that are located in the outer third of the lung.1 Our patient
had a peripherally located 1.2-cm nodule, making CT-
guided biopsy of the lung nodule the preferred procedure
for obtaining tissue for histological studies, routine and
acid-fast bacillus and fungal stains, and culture. Positron
emission tomography has been shown to be of benefit, in
concert with CT, to assess potential resectability of early-
stage lung cancer. It can be helpful after a histopathological
diagnosis has been obtained.
We considered a diagnosis of sarcoidosis in our patient.
Testing the serum ACE level, which is elevated in 75% of
• www.mayoclinicproceedings.com 939
RESIDENTS’ CLINIC
untreated patients with sarcoidosis, is considered useful.2
Because up to 10% of elevated ACE levels are caused by
nonsarcoidosis conditions, biopsy of affected tissue for
confirmation of diagnosis is definitive.2
Serum protein electrophoresis, urinary protein electro-
phoresis, and skeletal bone survey are reasonable tests to
obtain as part of the work-up for multiple myeloma but are
not diagnostic.
Our patient underwent CT-guided biopsy of the lung
nodule. Pathologic findings showed lung parenchyma with
necrosis and fungal organisms consistent with Histoplasma
capsulatum (Grocott methenamine silver–positive). The
diagnosis of disseminated histoplasmosis was confirmed
subsequently by detection of histoplasma antigen in the
urine. Also, culture from the bronchial washings was posi-
tive for the fungus. The serum ACE level was within
normal limits; SPEP showed biclonal spikes measuring 0.6
g/dL and 1.1 g/dL; and a skeletal bone survey showed no
lytic lesions.
2. Which one of the following is the most helpful test to
evaluate pancytopenia in our patient?
a. Peripheral blood smear
b. Serum ferritin concentration
c. Bone marrow aspiration biopsy
d. Serum vitamin B12 and folate levels
e. Blood methotrexate level
A peripheral blood smear would be a reasonable test
because it would provide insight about red blood cell and
white blood cell morphology and the presence of blasts or
large granular lymphocytes (LGLs). Occasionally, Histo-
plasma can be seen within monocytes on a peripheral blood
smear.
Serum ferritin concentration is an excellent indicator of
iron stores in healthy adults. Ferritin is an acute phase reac-
tant with serum levels increasing in liver disease, inflamma-
tion, infection, and malignancy. Because our patient has
rheumatoid arthritis, he may have a falsely normal ferritin
concentration even if he is iron deficient. Iron deficiency
would not explain pancytopenia in our patient; hence, a test
for serum ferritin concentration would not be helpful.
Bone marrow aspiration biopsy is the most helpful test
to evaluate pancytopenia in our patient. We were con-
cerned about a diagnosis of both disseminated histoplas-
mosis and multiple myeloma. Pancytopenia can be caused
by bone marrow infiltration due to either an infectious or a
neoplastic process. Thus, a bone marrow aspiration biopsy
is important along with fungal stains and cultures. Bone
marrow cultures are positive in more than 75% of patients
with disseminated histoplasmosis.3 Because our patient had
biclonal spikes on SPEP, bone marrow biopsy is warranted
in the work-up for multiple myeloma.
940 Mayo Clin Proc. • July 2005;80(7):939-942
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Low levels of vitamin B12 and folate can cause pancy-
topenia. Our patient was taking methotrexate, a dihydro-
folate reductase inhibitor that can cause folate deficiency
leading to secondary anemia. Hence, measuring serum vi-
tamin B12 and folate levels is reasonable.
Pancytopenia is a dose-limiting toxicity of methotrex-
ate. It occurs about 5 to 7 days after high-dose methotrexate
therapy and resolves within 2 weeks. Because our patient
was taking low-dose methotrexate, a test of his blood meth-
otrexate level would not be valuable.
We obtained a peripheral blood smear that showed hy-
pochromic normocytic anemia, absolute neutropenia, and
thrombocytopenia. Peripheral blood flow cytometry re-
vealed no increase in B cells, T cells, or blasts. Serum
vitamin B12 and folate levels were within normal limits.
Bone marrow aspiration biopsy findings revealed multifocal
noncaseating granulomas. Grocott methenamine silver–
positive organisms with morphologic features suggestive of
Histoplasma were present within the granulomas. Also, 10%
biclonal plasma cells were identified in the bone marrow.
3. Which one of the following is the most likely cause of
pancytopenia in our patient?
a. Multiple myeloma
b. Methotrexate
c. LGL leukemia
d. Lymphoma
e. Disseminated histoplasmosis
Multiple myeloma is an unlikely cause of pancytopenia
in our patient because he had only 10% biclonal plasma
cells in his bone marrow.
Methotrexate in high doses is a well-recognized cause
of pancytopenia. However, our patient had been taking
low-dose methotrexate for more than 5 years; thus, this
drug is less likely to be the cause of his acute pancytopenia.
Large granular lymphocyte leukemia is a clonal prolif-
eration of cytotoxic T cells, characterized by neutropenia,
anemia, thrombocytopenia, and modest lymphocytosis.4
Rheumatoid arthritis is present in one third of patients with
LGL leukemia. However, no LGLs were identified on the
peripheral smear, flow cytometry revealed no increase in
T-cell population, and T-cell gene rearrangement studies
were normal, making LGL leukemia an extremely unlikely
cause of pancytopenia in our patient.
The risk of lymphoma is increased in patients with
rheumatoid arthritis, and spontaneous reporting suggests
that methotrexate and anti–tumor necrosis factor therapy
may be associated independently with an increased risk of
lymphoma.5 In our patient, bone marrow biopsy findings
showed no lymphoma cells.
Therefore, disseminated histoplasmosis with bone mar-
row involvement is the most likely cause of our patient’s
• www.mayoclinicproceedings.com

pancytopenia. Disseminated histoplasmosis was con-
firmed on bone marrow biopsy and later on bone marrow
culture.
4. Which one of the following is the most likely cause of
our patient’s hypercalcemia?
a. Primary hyperparathyroidism
b. Hypercalcemia of malignancy
c. High calcium intake
d. Disseminated histoplasmosis
e. Familial hypocalciuric hypercalcemia
Parathyroid-mediated hypercalcemia generally is re-
ferred to as primary hyperparathyroidism. In this con-
text, PTH levels are elevated or inappropriately normal
for the increase in calcium. Our patient’s PTH level
was suppressed, making primary hyperparathyroidism
unlikely.
Certain cancers, particularly squamous cell carcinoma,
lead to hypercalcemia through ectopic elaboration of
PTHrP, which shares remarkable homology with PTH as
well as many of the metabolic actions of PTH.
Neoplasms such as multiple myeloma, breast cancer,
and lymphomas lead to hypercalcemia through local inva-
sion into bone with bone resorption (local osteolytic hyper-
calcemia). In this circumstance, tumor cells within bone
itself produced locally active cytokines that stimulated re-
sorptive activity of osteoclasts with systemic release of
calcium. Our patient had no evidence of malignancy, the
PTHrP level was within normal limits, and the skeletal
bone survey showed no lytic lesions.
High calcium intake alone rarely causes hypercal-
cemia because the initial elevation in serum calcium con-
centration inhibits both the release of PTH and the syn-
thesis of calcitriol. However, increased calcium intake
combined with decreased urinary excretion can cause hy-
percalcemia. This can occur in both chronic renal failure
and milk-alkali syndrome. Because our patient did not
have chronic renal failure and did not report high milk
intake, high calcium intake is an unlikely cause of his
hypercalcemia.
Granulomatous diseases such as disseminated fungal
infections, sarcoidosis, and tuberculosis cause hypercalce-
mia due to unregulated production of calcitriol by the
granulomas. Our patient’s calcitriol level was elevated,
making disseminated histoplasmosis the most likely cause
of his hypercalcemia.
In familial hypocalciuric hypercalcemia, urinary ex-
cretion of calcium is decreased. Our patient’s 24-hour
urinary calcium excretion level was elevated. Hence, fa-
milial hypocalciuric hypercalcemia is an unlikely cause of
his hypercalcemia. Our patient was treated with intrave-
nous fluids and pamidronate for his hypercalcemia, after
Mayo Clin Proc. • July 2005;80(7):939-942
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RESIDENTS’ CLINIC
which our attention turned to treatment of his disseminated
histoplasmosis.
5. Which one of the following is the most appropriate
initial therapy for our patient?
a. Amphotericin B
b. Itraconazole
c. Fluconazole
d. Ketoconazole
e. Voriconazole
Amphotericin B or one of its lipid-bound formulations
is recommended for patients who are immunocompro-
mised, hypoxic, or hypotensive or have impaired mental
status, weight loss greater than 10% of body weight, el-
evated hepatic enzyme level of more than 5 times the upper
limit of normal, serum creatinine level greater than 2.5
times normal, coagulopathy, or meningitis.6 If any of these
symptoms are present, the patient should receive intrave-
nous amphotericin B therapy. Because our patient was
immunocompromised, amphotericin B is the most appro-
priate initial therapy.
Itraconazole is the treatment of choice in patients with
mild to moderately severe symptoms who do not require
hospitalization for their treatment course. This drug also is
used for maintenance therapy in patients who have re-
sponded to amphotericin B.6
Fluconazole is not as active in vitro against H capsula-
tum as itraconazole and has not been as effective when used
for treatment, in part because fungemia is cleared more
slowly. Another problem with fluconazole is the develop-
ment of drug resistance. Thus, fluconazole should be re-
served for treatment of histoplasmosis in patients who can-
not take itraconazole or who have meningitis. Fluconazole
has a unique effect in the treatment of meningitis because
it achieves excellent concentrations in the cerebrospi-
nal fluid. In contrast, itraconazole, although more active
than fluconazole against H capsulatum, does not enter
the cerebrospinal fluid and therefore is used for mainte-
nance therapy after use of amphotericin B in Histoplasma
meningitis.6
In noncomparative trials, itraconazole was more suc-
cessful (85%-100%) than ketoconazole (56%-85%).7
Itraconazole appears to be the most active of the azole
drugs.
Voriconazole is active against H capsulatum, but animal
studies have not been conducted, and experience in com-
passionate-use studies in humans is too limited to assess its
activity.
Our patient was treated initially with amphotericin B at
1 mg/kg per day intravenously for 5 days followed by
itraconazole at a loading dose of 200 mg orally 3 times
daily for 3 days to achieve steady-state serum concentra-
• www.mayoclinicproceedings.com 941
RESIDENTS’ CLINIC
tions more rapidly, and then 200 mg orally twice daily.
Itraconazole capsules require gastric acidity for absorp-
tion; therefore, they should not be taken with antacids.
Capsule absorption is best if taken with food; thus,
itraconazole should be taken after meals. The optimal
duration of itraconazole therapy is unknown. However, a
course of 1 year is preferred because it reduces the risk of
relapse.8
At 3-month follow-up, our patient was doing well with
resolution of his constitutional symptoms of fatigue, fever,
and weight loss, as well as his pancytopenia and hyper-
calcemia.
DISCUSSION
H capsulatum is a dimorphic fungus that ordinarily causes
a self-limiting or slowly progressive chronic infection. Dis-
seminated histoplasmosis is a well-recognized complica-
tion in immunocompromised patients with acquired immu-
nodeficiency syndrome, leukemia, or lymphoma and in
those who receive long-term corticosteroid therapy. Low-
dose methotrexate therapy is used for numerous conditions
including rheumatoid arthritis and psoriasis. There are
many reports of disseminated histoplasmosis developing in
patients such as ours who receive prolonged low-dose
methotrexate therapy.9-11
Constitutional symptoms such as fever, fatigue, and
weight loss are presenting features of disseminated histo-
plasmosis. Various laboratory abnormalities may provide
clues to the sites of involvement. Pancytopenia suggests
bone marrow infection, whereas elevated levels of serum
aminotransferases, alkaline phosphatase, lactate dehydro-
genase, and bilirubin suggest hepatic involvement. Chest
x-ray films are abnormal in 70% of patients, usually show-
ing diffuse interstitial or reticulonodular infiltrates. Two
types of tests are available for rapid diagnosis of dissemi-
nated histoplasmosis: antigen determination and histo-
pathological examination of tissue samples. Tests for anti-
gen in urine and serum should be performed in patients
with suspected disseminated histoplasmosis. Histoplasma
antigen can be detected in the urine in 90% of patients with
the disease and appears to be the most sensitive rapid assay.
Serologic tests for antibodies to H capsulatum and culture
of the organism are less rapid methods but can aid in
942 Mayo Clin Proc. • July 2005;80(7):939-942
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
making the diagnosis. Serologic antibody tests are positive
in 70% to 80% of patients. Fungal blood cultures should be
performed in all patients with suspected disseminated his-
toplasmosis and are positive in 50% to 70% of those with
the disease.12 Disseminated histoplasmosis is treatable even
in immunocompromised patients. The major therapeutic
choices are amphotericin B, one of its lipid formulations, or
an azole drug, particularly itraconazole.6
Methotrexate therapy is the only immunosuppressive
agent we found that could have predisposed our patient to
the development of disseminated histoplasmosis. This case
serves as a reminder that patients taking low-dose metho-
trexate can be immunocompromised to a clinically impor-
tant degree. A high index of suspicion for opportunistic
infections should be maintained, especially when such pa-
tients develop fever or other constitutional symptoms.
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Correct answers: 1. b, 2. c, 3. e, 4. d, 5. a
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