Hematopathology / ORIGINAL ARTICLE
The Diagnostic Usefulness of Bone Marrow Cultures
in Patients With Fever of Unknown Origin
Emily E. Volk, MD, Michaell. Miller, DO, Barbara A. Kirkley,
and John A. Washington, MD
Key Words: Bone marrow cultures; Fever of unknown origin; Mycobacterium avium complex
Abstract
Bone marrow cultures (BMCs) and blood cultures
(BCs) are frequently obtained in the evaluation of fever
of unknown origin (FUO). However, the low yield of
clinically significant isolates leads to questions about
their cost-effectiveness. We retrospectively compared
BMC with BC and studied the usefulness of bone
marrow trephine biopsy (BMTB) histopathology in
detecting infection in an unselected population of 61
patients with FUO, among whom 215 BMCs had been
performed. For patients who had undergone BMTB, the
histopathology was evaluated for granulomas and
microorganisms. Only 1 BMC had a clinically
significant isolate, Mycobacterium avium complex
(MAC), which was also identified by BC. Rhodotorula
rubra was found in the BMC of another patient and
classified as a contaminant. Both patients had HIV
infection. No growth occurred in BCs for the other 59
patients. Culture results for all 26 BMTB specimens
were negative; 4 contained nonnecrotizing granulomas,
including the case with MAC. BMCs are probably not
justified for routine initial evaluation of FUO, but may
be valuable after culture results for blood and easily
obtainable tissues have been negative. Bone marrow
histopathology and special stains for microorganisms in
the absence of granulomas
were noncontributory.
150 Am J Clin Pathol 1998,110:150-153
MT(ASCP),
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Bone marrow cultures (BMCs) are commonly obtained
in the evaluation of fever of unknown origin (FUO), partic-
ularly for patients who are immunosuppressed. In the effort
to identify the cause of systemic infection, BMCs are often
performed in conjunction with blood cultures (BCs) and
cultures of other body fluids and tissues. The tradition of
performing BMC and BC is long-standing, but the medical
necessity is questionable. Given the importance of cost
containment, such practices must be assessed on the basis
of their cost-benefit to patient outcomes. We compared the
value of BMC with BC and studied the usefulness of the
histopathologic features of bone marrow trephine biopsy
specimens in detecting the cause of systemic infection in an
unselected patient population with FUO.
Materials and Methods
A retrospective review was performed of the medical
records of all patients who had undergone BMC and BC
during one hospital episode occurring from January 1994
to July 1995, but excluding those obtained as part of a
bone marrow transplantation protocol and those obtained
in evaluations for osteomyelitis. Patients with FUO were
selected for the study, and their clinical diagnosis and
immunocompetence status was determined. An FUO was
defined by using the definition of Petersdorf and Beeson1:
"An elevation in temperature greater than 101 °F (38.3°C)
for a prolonged period (at least two to three weeks) and in
which the diagnosis cannot be made during at least one
week of intensive study." Immunosuppressed patients
were defined as follows: (1) HIV positive with absolute
CD4 cell counts less than 400/uL (0.40 x 109/L); (2)
moderate to severe leukopenia; and (3) receiving immuno-
suppressive chemotherapy.
© American Society of Clinical Pathologists
 Hematopathology / ORIGINAL ARTICLE

The bone marrow aspiration, biopsy, and blood cultures ITable II

specimens were obtained using standard techniques. Summary of Clinical Diagnoses
Cultures for bacterial, fungal, and acid-fast bacilli were Diagnosis No. of Cases
performed. Blood specimens were inoculated in an aerobic
(Organon Teknika, Durham, NC) fastidious antibiotic AIDS 10
Non-Hodgkin's lymphoma 10
neutralization bottle and a standard anaerobic (Organon Acute myelogenous leukemia 10
Teknika) bottle. Blood cultures were held on an Organon Myelodysplastic syndrome 5
Teknika BacT/Alert system at 35°C for 5 days. When the Systemic lupus erythematosus or connective
tissue disease not otherwise specified 4
system identified growth within a specimen bottle, the spec- Hodgkin's disease 4
imen bottle was removed, and a direct Gram stain of the Carcinoma 4
Chronic myelogenous leukemia 3
organisms was evaluated. The specimen was then subcul- Multiple myeloma 2
tured on the appropriate media depending on the Gram stain Hepatitis C 2
Acute lymphocytic leukemia
morphology, including blood agar for gram-positive cocci

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or MacConkey agar for gram-negative, rod-shaped organ-
isms. Blood cultures for mycobacteria were performed with
the BACTEC 13A bottle (Becton Dickinson Diagnostic
Instrument Systems, Sparks, Md), which after inoculation
was held at 37°C for 6 weeks. The specimen was evaluated
for evidence of growth using the BACTEC 460 (Becton
Dickinson) instrument. If growth was identified, an acid-fast
stain was performed to confirm the presence of acid-fast
bacteria, and a DNA probe (GenProbe, San Diego, Calif)
test was used to further classify the Mycobacterium species.
The bone marrow specimens for bacterial culture were
inoculated onto trypticase soy blood agar and a chocolate
agar plate. Bone marrow specimens for fungal culture were
inoculated onto a blood brain heart infusion agar plate
and a potato dextrose agar plate. A BACTEC 13A bottle
also was inoculated for recovery of mycobacteria. The
bone marrow biopsy specimens were fixed in B5 solution,
decalcified, processed by standard methods, embedded in
paraffin, sectioned at 3 to 4 urn, and stained with H&E.
The biopsy specimens were reviewed for granuloma forma-
tion and stained for fungi and acid-fast bacilli, using the
Gomori methenamine silver and Fite or Ziehl-Neelsen
methods, respectively.
Results
During the 18-month study period, 215 bone marrow
cultures were performed on 61 patients with FUO. The
patients ranged in age from 20 to 80 years (mean, 48 years)
and had a variety of primary diagnoses ITable II. Thirty-
seven patients (61%) were immunosuppressed at the time of
admission. Multiple cultures were obtained on many
patients, with an average of 3.4 BMCs performed on each
patient (range, 1-9). Only 2 of the BMCs exhibited growth.
No fungal organisms were found. Mycobacterium avium
complex (MAC) was isolated from 1 (0.5%) of the BMCs
and a concomitant BC. Rhodotorula rubra was identified in
the other BMC with a positive result from another patient.
Chronic lymphocytic leukemia
Posttransplantation lymphoproliferative
disorder
Aplastic anemia
Polyarteritis nodosa
Sarcoidosis
Mycosis fungoides
Total 61
This was classified as a contaminant. The BC results for this
patient were negative. Both patients were immunosuppressed
and had HIV infection. The BCs performed on the other 59
patients demonstrated no growth. ITable 21 summarizes the
relevant clinical findings and BMC and BC culture results.
Bone marrow trephine biopsy specimens were
obtained on 26 patients (43%), and all culture results were
negative for pathogenic organisms by special stains. Of the
26 biopsy specimens, 4 (15%) contained nonnecrotizing
granulomas, including the specimen from the patient with
systemic MAC demonstrated by BMC and BC.
Discussion
The finding in this study of only 0.5% of the BMCs
having a clinically significant isolate is low but consistent
with the observations of other studies that have found
considerable variation in the percentage of BMCs with posi-
tive results, depending on the patient population studied.
Many of the previous studies focused on assessing the value
of BMCs to diagnose mycobacterial and/or fungal infec-
tions in immunosuppressed patients with HIV infection. It is
clear from the results of these studies that the immunosup-
pressed patient population, particularly patients who have
HIV infection, has a considerably higher yield of positive
results of BMCs and BCs. Our study, in contrast, reviewed
BMCs and BCs from all patients with FUO, including HIV-
positive patients, accounting for a comparatively low
percentage of positive culture results. Mycobacterial isolates
from BMCs have been reported to range from less than 1 %

© American Society of Clinical Pathologists Am J Clin Pathol 1998;110:150-153 1 5 1

Volk et al / THE DIAGNOSTIC USEFULNESS OF BONE MARROW CULTURES

to 11.7%.2-6 Marsh et al2 and Riley et al5 found the highest
percentages of mycobacterial isolates, 3.2% and 11.7%,
respectively. Both studies were limited to immunosup-
pressed patients with HIV infection. Fungal isolates were
identified in 3 of the 5 earlier studies reviewed. The
percentage of fungal isolates from BMCs ranged from less
than 1% to 3.7%.2•;'•6 These studies assessed patients with
cancer and HIV infection. Our study identified no fungal
isolates. ITable 31 summarizes the results of previous
studies assessing the use of BMC to detect mycobacterial
and fungal infections in patients with FUO.
A definitive statement about the value of BMC vs BC
disseminated mycobacteria or fungi, but that BC should
probably be the initial test performed. Studies by Riley et al5
and Nichols et al4 compared the results of BMC and BC for
mycobacteria in an HIV-positive patient population. Riley
et al5 found that 10 (33%) of 30 patients had concomitant
positive BC and BMC results. However, 3 patients had
mycobacteria isolated by BMC, but BC results were nega-
tive, and 1 patient had a positive BC result and no growth
on BMC. Nichols et al4 found that BMC results were posi-
tive in 54% of HIV-positive patients known to have a
mycobacterial or fungal infection. They also found discrep-
ancies between the BMC and BC results similar to the find-
ings of Riley et al5 ITable 41.

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cannot be made based on our data owing to the paucity of
positive culture results. However, the findings of other Four (15%) of our patients who underwent bone
studies indicate that neither method will detect all cases of marrow trephine biopsies had granulomas, but none had

ITable 21
Summary of Bone Marrow and Blood Culture Results
Bone Marrow Corresponding Blood Bone Marrow Pertinent
Culture Results Culture Results Histopathologic Features Clinical History
Negative (n = 213) Negative 22/26 without granulomas; 37/63 immunosuppressed;
4/26 with granulomas 26/63 not immunosuppressed
Rhodotorula rubra No growth No granulomas or 44-year-old man, HIV positive;
organisms identified culture result indicated probable contaminant
Mycobacterium M avium-intracellulare Single nonnecrotic granuloma; 21-year-old man, HIV positive;
avium-intracellulare no organisms identified culture result indicated clinically significant
disseminated M avium-intracellulare

ITable 31
Summary of Studies Evaluating Detection of Mycobacteria and Fungi by Bone Marrow Culture in Patients
With Fever of Unknown Origin
No. (%) of Specimens With
No. of Mycobacteria or Fungi Isolated Species Patient
Study Cultures From Bone Marrow Culture (No. of Cases) Population

Volketal 215 1 (0.5) Mycobacterium avium-intracellulare (1) Nonrestricted

Marsh et al2 124 4 (3.2) M avium-intracellulare (4) HIV
Riley et al5 433 51 (11.8) M avium-intracellulare (42) HIV
Mycobacterium tuberculosis (5)
Mycobacterium kansasii (2)
Mycobacterium xenopi (1)
Mycobacterium fortuitum (1)
Nichols et al4 342 59(17.3) M avium-intracellulare (36) HIV
M tuberulosis (13)
Histoplasma capsulatum (8)
Cryptococcus neoformans (2)
Fainstein et al6 1,542 6 (0.4) Mycobacterial species Cancer; not otherwise
specified
Candida albicans (4)
H capsulatum (3)
Coccidioides immitus (1)
Aspergillus fumigatus (1)
Trichosporon cutaneum (1)
Smith7 133 2(1.5) M avium-intracellulare (1) All patients with fever
of undetermined origin
H capsulatum (1)
Hughes8 187 7 (3.7) H capsulatum (3) Children with leukemia
C albicans (2)
C neoformans (2)

152 Am J Clin Pathol 1998; 110:150-153 © American Society of Clinical Pathologists


organisms identifiable by special stains. Similarly, Riley et
al 5 found granulomas in 23% of their patients, but in
contrast, acid-fast bacilli were identified in 19%. Nichols et
al4 found 64% of their HIV-positive patients with known
mycobacterial or fungal infections to have granulomas;
35% had organisms identified by special stains. It is not
uncommon to find that organisms are absent by special
stains despite positive BMC results and the presence of
granulomas. In fact, organism are rarely seen in the absence
of granulomas. Our experience gives further credence to
the practice of performing only stains for organisms when
granulomas are present, rather than ordering them prospec-
tively on biopsy specimens.
An important consideration in the current medical-
economic environment when assessing the value of BMC is
the cost-effectiveness of the procedure. Assuming there is no
hematologic justification for a bone marrow evaluation,
BMCs added to BCs in a clinical workup substantially
increase the cost of the evaluation of FUO. The additional
costs incurred include the professional and technical fees of
obtaining and processing the bone marrow specimen and the
additional costs associated with the microbiologic evaluation.
This cost is increased further with each additional culture, as
noted in our study in which an average of 3.4 BMCs per
patient were performed, despite repeatedly negative BC and
BMC results. Moreover, there is the potential for morbidity,
and, of course, the obvious discomfort inflicted on the patient
during a bone marrow procedure. It is difficult to justify
performing BMCs on all patients with FUO given the low
yield of positive results demonstrated in our study.
BMCs are probably not justified as part of the routine
initial evaluation of a patient with FUO, regardless of
immunologic status, given the cost, the low yield of clini-
cally significant isolates, and the comparable BC results.
Therefore, recognizing that neither BMCs or BCs will
detect the causes of all systemic infections, an algorithm
that conserves resources should be followed in which
BMCs are performed if blood and other more easily
obtained tissues have been cultured and results are repeat-
edly negative, as suggested by other studies. In our study,
the histopathologic features of the bone marrow specimens
and stains for microorganisms did not contribute to the
identification of the cause of a systemic infection, even in
the presence of granulomas, although it is well known that
there is a strong correlation between the presence of bone
marrow granulomas and systemic infection. Therefore, our
© American Society of Clinical Pathologists
Hematopathology / ORIGINAL ARTICLE
ITable 41
Comparison of the No. (%) of Mycobacterial Isolates by Blood
and Bone Marrow Cultures
No. of Blood and
Study Cultures Blood Bone Marrow Bone Marrow
Volk et al 215 1 (0.5) 1 (0.5) 1 (0.5)
Riley et al5 433 11 (2.5) 13(3.0) 10(2.3)
Nichols et al4 77 3 (3.9) 8(10.4) 10(13.0)
experience and that of others support the practice of
performing stains for microorganisms only when granu-
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lomas are present.
From the Cleveland Clinic Foundation, Cleveland, Ohio.
Address reprint requests to Dr Miller: Head, Section of
Hematopathology, Department of Clinical Pathology, Cleveland
Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
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