Diagnostic utility of bone marrow examination in evaluation of fever: a descriptive study on 98 immunocompetent adults from a tertiary care institute in south India

Abstract

Five-year clinico-laboratory data from 99 (one HIV seropositive) adults (mean age = 41.3 ± 20.4 years) who underwent bone marrow examination for fever persisting for ≥ 1 week were analysed and correlated with microbiological characteristics. Infections, reactive marrow changes and haematolymphoid malignancies were most commonly associated with fever. A high concordance rate of 71% was noted between aspiration and trephine biopsies. Bone marrow granulomas (BMG) were seen exclusively on sections and were most commonly of tubercular and typhoidal in origin (two Salmonella Typhi, one Salmonella Paratyphi A). The common aetiologies associated with fever and cytopenia(s) were BMG, acute leukaemia and haemophagocytic lymphohistiocytosis (HLH; n = 3). The yield from bone marrow culture was inferior compared to other body fluids. In conclusion, bone marrow histology is superior to smears in the evaluation of prolonged fever. Marrow culture may not be useful in immunocompetent individuals other than if Salmonellosis is suspected.

Keywords

Bone marrow culture immunocompetent pyrexia

Introduction

The diagnosis of prolonged fever continues to pose immense diagnostic dilemma for treating physicians as well as laboratory personnel. The diagnosis may still remain obscure for several weeks or even months in spite of exhaustive clinical, radiological, microbiological, serological and/or biochemical investigations. One investigation that stands tall among the recent scientific advancements in diagnosis of prolonged fever is bone marrow examination (BME).

Among almost 200 causes of prolonged fever, many are known to involve the bone marrow. The diagnostic yield of both bone marrow aspiration (BMA), bone marrow trephine biopsy (BMBx) and microbial culture in these patients still remains unknown.^1,2 Previous studies have shown that BMBx is a safe and useful procedure in laboratory investigation of fever in patients with human immunodeficiency virus (HIV) infection.^3–5 However, its usefulness in apparently immunocompetent hosts has not been thoroughly assessed. Moreover, the diagnostic yield from both morphology and microbial culture, as well as the indications of BME in this setting have been controversial.^6,7 In this manuscript, we describe the diagnostic yield of bone marrow examination from 98 cases of immunocompetent adults with prolonged fever along with culture correlation.

Materials and methods

Our Institutional Ethics Committee approved the study protocol; this study was carried out according to the Declaration of Helsinki standards. Standard hospital protocols for informed consent had been obtained and recorded in the case records (in the retrospective group), while consent was obtained for cases in the prospective group.

This descriptive cross-sectional study was conducted in the Department of Pathology at Pondicherry Institute of Medical Sciences, Pondicherry, India over a period of five years (May 2010 to June 2015). During this period, 395 cases underwent BME in the Department of Pathology, of whom 99 (25.06%) were referred from the Department of Internal Medicine and other allied specialities solely for ‘evaluation of fever’. We included in the study all referral cases where fever (≥38.3℃) persisted for ≥1 week before BME without any established clinical, radiological and/or microbiological/serological diagnosis. Clinical and pathology records of 26 fever cases (in 2010–2011) were reviewed retrospectively; those of the remaining 73 cases (seen in 2012–2015) were reviewed prospectively.

Data pertaining to age, gender, underlying immune status and serology (retroviral status, hepatitis B surface antigen, anti-hepatitis C antibody), nature of fever, associated symptoms and signs, organomegaly, lymphadenopathy, routine complete blood count, erythrocyte sedimentation rate, antinuclear antibody titre, C-reactive protein (CRP), rheumatoid factor and other relevant radiological and biochemical parameters were collected from case records before the bone marrow procedure. BMA and BMBx were performed by a trained pathologist (SKS, SP) from the posterior superior iliac spine under 2% xylocaine infiltration anaesthesia and maintaining strict aseptic precautions. In addition, according to protocol, 5 mL each of bone marrow aspirate samples were collected in the same sitting for anaerobic and aerobic culture by an automated BAC-T culture system. Fungal and mycobacterial cultures of aspirate were also performed manually. Morphological analysis of May Grunewald Giemsa-stained BMA and trephine imprint smears was performed according to International Council of Standardization in Haematology (ICSH 2008) guidelines.⁸ Similarly, BMBx cores were fixed in 10% neutral buffered formalin, decalcified in 14% EDTA solutions. Thin (4 µm) paraffin-embedded sections were routinely stained with haematoxylin and eosin (H&E), periodic acid Schiff (PAS) and reticulin stain in all cases. Special stains such as Ziehl Nielsen (ZN) and Gomori methenamine silver (GMS) stains were used as and when required for the purpose of demonstration of acid-fast bacilli (AFB) and fungi, respectively. BMA smears and BMBx sections were independently reviewed by two pathologists (SP, RGV), blinded for bias; the findings were correlated with clinico-laboratory parameters for a final opinion (Figure 1).

Figure 1.

Laboratory investigations in cases with prolonged fever. BME, bone marrow examination. *Leucocytosis (LC), thrombocytosis (TC), blasts (BL) and their combinations; **Anaemia (A), leucopenia (L), thrombocytopenia (T), pancytopenia (P) and their combinations. ^#Isolation of organisms from different body fluids such as blood, urine and bone marrow aspirate (BMA). CBC, complete blood count; ESR, erythrocyte sedimentation rate; BMBx, bone marrow trephine biopsy; BMC, bone marrow aspirate culture; TORCH, toxoplasmosis, rubella, cytomegalovirus and herpes; CRP, C-reactive protein; RA factor, rheumatoid factor.

Concordance between BMA and BMBx findings was confirmed using kappa statistics. Cellular and morphological changes in the bone marrow were analysed by descriptive statistics. Bone marrow morphology was correlated with various clinico-laboratory parameters for determination of positive predictive parameters in prolonged fever using the χ² test.

Results

There were 68 men and 31 women with a mean age of 41.3 ± 20.4 years. Of these, 39 patients (40%) had fever which persisted for > 21 days; in 51 patients (51%) it was described as a low-grade type. A total of 44 patients (45%) had associated hepatomegaly (n = 16), splenomegaly (n = 8), hepatosplenomegaly (n = 16) or lymphadenopathy (n = 5). Pallor and chills/rigor were the most common signs and symptoms accounting for 41% and 38%, respectively.

Of the 99 individuals, bone marrow alone was aspirated in five cases; in seven cases, the bone marrow was reported as inadequate for definitive opinion. Finally, correlational analysis was done in 87 cases. The following were the observed diagnostic patterns: reactive marrow change (n = 37, 47.53%); granulomatous (n = 17, 19.54%); acute leukaemia (n = 8, 9.2%); hypocellular/hypoplastic marrow (n = 8, 9.2%); megaloblastic anaemia (n = 7, 8.04%); plasma cell myeloma and haemophagocytic lymphohistiocytosis (HLH) (n = 2 each, 2.3%); and marrow involvement by lymphoma, myelodysplastic syndrome, primary myelofibrosis, immune thrombocytopenic purpura (ITP), HIV and histoplasmosis (n = 1 each, 1.1%). There was no statistically significant association between the grade (P = 0.717), duration (P = 0.699) and pattern (P = 0.990) of pyrexia, presence or absence of organomegaly (P = 0.758) or cytopenia(s) (P = 0.228). The most common pathologies associated with fever and cytopenia(s) were reactive marrow change, granulomas, acute leukaemia and HLH (P = 0.228). On the other hand, the association between leucocytosis and reactive marrow change was statistically very significant (P < 0.002). We found no significant difference in diagnostic trend in regard to duration of fever (≤21 vs. > 21 days; P = 0.699) (Table 1, Figure 2).

Figure 2.

Major diagnostic trends in cases with fever undergoing bone marrow examination in regard to duration of fever (≤21 vs. > 21days). HLH, haemophagocytic lymphohistiocytosis.

Table 1.

Association of fever, organomegaly and cytopenia(s) with various diagnostic patterns on bone marrow trephine biopsy (n = 87/99).*

			Reactive	Granulomas	HLH	Leukaemia	Aplastic	Megaloblastic	Myeloma	MDS	Myelofibrosis	Dimorphic	Hypocellular	Lymphoma	ITP	Histoplasma	HIV	P value
Fever	Grade^†	High (n = 48)	19	11	1	3	1	1	–	1	–	1	2	–	–	–	1	0.717
	Grade^†	Low (n = 50)	17	6	1	5	1	2	2	–	1	3	4	1	1	1	–	0.717
	Duration	< 21 days (n = 60)	22	8	2	4	1	2	1	–	1	3	4	1	1	1	–	0.699
	Duration	> 21 days (n = 39)	15	9	–	4	1	1	1	1	–	1	2	–	–	–	1	0.699
	Pattern^†	Continuous (n = 12)	3	3	–	1	–	–	–	–	–	1	1	–	–	–	–	0.990
	Pattern^†	Intermittent (n = 86)	33	14	2	7	2	3	2	1	1	3	5	1	1	1	1	0.990
Organomegaly^†		Present (n = 44)	10	12	2	7	–	–	1	–	1	3	1	–	–	–	1	0.758
Organomegaly^†		Absent (n = 54)	27	5	–	1	2	3	1	1	–	1	4	1	1	1	–	0.758
Cytopenia(s)^†		Present (n = 80)	27	12	2	8	2	3	2	1	1	4	5	1	1	–	1	0.228
Cytopenia(s)^†		Absent (n = 18)	9	5	–	–	–	–	–	–	–	–	1	–	–	1	–	0.228
Cytosis^‡		Present (n = 31)	17	3	–	6	–	–	4	–	–	–	–	–	1	–		<0.005

Table excludes cases with inadequate sample (n = 7) for opinion and cases where procedure not done (n = 5).

*Bone marrow biopsy was not performed (n = 5/99) or inadequate for opinion (n = 7/99).

^†Data not available for one case.

^‡Association between leucocytosis and reactive marrow diagnosis was statistically significant (P < 0.05).

On BMA evaluation, non-specific changes such as normal to increased cellularity, along with normal to mildly dyspoietic trilineage hematopoiesis, plasmacytosis and lymphohistiocytosis typically characterised the reactive marrow pattern (P < 0.05). Similarly, of all the lineages, megakaryocyte hyperplasia with normal to mild dyspoietic morphology was well represented with both aspirate smears and BMBx (Table 2).

Table 2.

Cellular changes in various diagnostic patterns on bone marrow aspirate smears (n = 93/99*).

	Cellularity			Morphology					Plasma cells		Lymphohistiocytic cells
	N	↑	↓	N	Dyspoietic	Toxic	Giant	Blast	N (n = 64)	↑ (n = 35)	N (n = 60)	↑ (n = 39)
Reactive (n = 57)	34	20	3	50	4	1	1	1	35	22	35	22
HLH (n = 5)	3	1	1	5	–	–	–	–	4	1	–	5
Leukaemia (n = 9)	1	0	8	–	–	–	–	9	8	1	9	–
Aplastic anaemia (n = 1)	–	–	1	1	–	–	–	–	–	1	–	1
Megaloblastic (n = 7)	6	1	–	7	–	–	–	–	4	3	4	3
Myeloma (n = 2)	–	1	1	2	–	–	–	–	–	2	1	1
Dimorphic (n = 4)	2	1	1	3	–	–	1	–	3	1	3	1
Hypocellular (n = 4)	1	–	3	2	2	–	–	–	1	3	1	3
Histoplasma (n = 1)	–	–	1	1	–	–	–	–	1	–	1	–
Dyspoietic (n = 3)	1	1	1	2	1	–	–	–	2	1	1	2
P value	<0.05			<0.05					>0.05		0.005

↑, increased; N, normal; ↓, decreased.

In 6/99 cases, bone marrow aspirate smears were inadequate for opinion.

HLH; haemophagocytic lymphohistiocytosis.

A high concordance of 71% (n = 62/87) was achieved between the various diagnostic patterns on BMA and BMBx. A high concordance was observed for an individual diagnosis of reactive marrow, leukaemia and multiple myeloma. Bone marrow granuloma and megaloblastic anaemia were few diagnostic patterns with low concordance with the former being diagnosed solely on BMBx and the latter mostly on BMA (Table 3).

Table 3.

Concordance between important diagnostic patterns in bone marrow aspirate (BMA) and trephine biopsy (BMBx).

serial no	Diagnostic patterns	BMA	BMBx
1	Reactive marrow	57	37
2	Bone marrow granuloma	0	17
3	Leukaemia	9	8
4	Dimorphic anaemia	4	4
5	Multiple myeloma	2	2
6	Megaloblastic anaemia	7	3

The detailed microbial culture findings and utility of bone marrow examination in prolonged fever are presented in Table 4 and Figure 3. The overall number of cases diagnosed based on BME was more than the diagnosis obtained just based on culture study alone (Figure 3). Serological data were available in 19/98 cases; notable among these were the following: Hepatitis B surface antigen positive (n = 6; non-specific/reactive in three and one each reported as granulomatous, HLH and hypocellular on BME); IgM ELISA against Orientia tsutsugamushi + (n = 4; one case each of reactive marrow, associated HLH and granuloma; non-contributory in one). No definite cause was identified in 26 culture-negative cases where BME was reported as non-diagnostic.

Figure 3.

Diagnostic utility of bone marrow study in culture positive and culture negative cases. *Data not available for one case. **Two cases were inadequate for opinion.

Table 4.

Microbial organisms isolated from various body fluid samples in patients with prolonged fever and correlation between bone marrow diagnostic patterns with positive microbial culture (n = 26).

	Source of isolation	Common isolates	Diagnostic patterns	Remarks
Culture-positive cases (n = 26)	Urine (n = 5) > blood (n = 4) > urine + blood (n = 1)	E. coli (n = 2) ESBL E. coli (n = 3) E. faecalis (n = 2) B. pseudomallei (n = 1) Candida albicans (n = 1) E. faecium (n = 1)	Reactive (n = 10)	Bone marrow was non-diagnostic in these cases whereas the culture of various other sources yielded diagnosis
	Urine (n = 3) > blood (n = 2) > blood + BMA (n = 2)	Salmonella (n = 3) (Typhi 2 and Paratyphi 1) E. coli (n = 2) Candida, ESBL E. coli, coagulase-negative S. aureus (n = 1 each)	Granulomatous (n = 7)	Out of 7 cases with BMGs, only 3 were correlating with the culture (Salmonellosis). In the remaining 4 cases, specific diagnosis was obtained only on BMS and not in culture. Histiocytic erythrophagocytosis was a clue for Salmonella granulomas (Figure 4).
	Blood Blood Blood Urine Blood Urine BMA + urine Urine	B. pseudomallei E. coli E. coli C. albicans Enterobacter species Candida Klebsiella species E. faecalis Candida	Others: Leukaemia (n = 1) Megaloblastic (n = 1) Dimorphic anaemia (n = 2) Hypocellular (n = 1) HLH (n = 1) MDS (n = 1) BMA inadequate/ not done (n = 2)	Among others, three cases yielded a definitive diagnosis on BMS whereas in the rest of the cases BMS was non-specific.

The numbers in parentheses in column 1 (source of isolation) represent the number of positive cases.

Overall, the most common isolates were E. coli (n = 6), Candida (n = 5), ESBL E. coli (n = 4), Enterococcus (n = 4), Salmonella (n = 3), B. pseudomallei (n = 2), Enterobacter (n = 1), Klebsiella species (n = 1) and coagulase-negative S. aureus (n = 1).

BMS, bone marrow study; BMGs, bone marrow granulomas; HLH, haemophagocytic lymphohistiocytosis; MDS, myelodysplastic syndrome.

Discussion

Though the outcomes of our studies were in accordance with some previous Indian and Western literature, it must be noted that in countries such as Australia, where tuberculosis (TB) is a rare entity, causes of marrow granulomas are expected to be significantly different, as was evident from a recent publication where B cell non-Hodgkin lymphoma, sarcoidosis and autoimmune diseases were more common.^7,9

In contrast to the above, Wang et al. reported the highest incidence of infective aetiologies of BMGs (80/110 cases [72.8%]) from China.¹⁰ TB was the most common cause (n = 62), followed by fungi (n = 4), typhoid or paratyphoid fever (n = 3), and brucellosis (n = 2). In 27 of 62 cases of tubercular granulomas, the diagnosis was based on marrow morphology in correlation with clinical presentation and excellent response to anti-tubercular therapy. However, a definitive aetiology was not identified in 30 cases, which accounted for 27.2% of the total.¹⁰ These findings highlight the fact that while TB still remains the commonest aetiology of pyrexia and BMGs, especially in the high prevalence Southeast Asian region, Salmonellosis should also be considered as a close differential in such cases. As previously reviewed by our own group, erythrophagocytosis within histiocytic granulomas on trephine biopsy sections should be correlated with culture characteristics to confirm a typhoidal granuloma and prevent unnecessary, potentially toxic anti-tubercular therapy (Figure 4).¹¹ In addition, the good concordance between BMA and BMBx findings in our study was similar to those published in the literature.^12–14

Figure 4.

Paraffin-embedded decalcified bone marrow trephine biopsy sections from a case with culture-proven typhoid fever which showed epithelioid and histiocytic granulomas in the interstitial and paratrabecular loci. Note the presence of erythrophagocytosis by benign histiocytes (black arrow) in the granulomas (H&E stain: 400 × (a) and 1000 × (b)). Reproduced with permission from Muniraj et al.¹¹

A comparative review of literature describing the microbial yield of organisms from different sources in prolonged pyrexia is presented in Table 5.^6,7,15–20 Typhoid fever is one of the bacterial infections where bone marrow examination is routinely recommended; the yield of bone marrow aspirate culture has been found to be superior to blood, rectal swab or stool culture in the diagnosis of typhoid fever in various studies.^20,21 Overall, the yield of microorganisms from different culture samples is in the range of 0–40% in different series. There has been a varied opinion regarding the diagnostic utility of BMA culture compared to other body fluids in cases with pyrexia. Barring two reports of HIV associated pyrexia, none of the studies have reported the isolation of the Mycobacteria, as was also our experience.

Table 5.

A comparative review of literature describing the microbial yield of organisms from different sources in prolonged pyrexia.

Sample no.	Author (year)	Cases (n)	Culture-positive cases (n (%))	Source of isolates	Culture isolates (n)	Remarks
1	Hot et al. (2009)⁶	130	0 (0)	BM	No pathogens	No growth even in suspected TB cases
2	Chin et al. (2006)⁷	94	4/8 endocarditis cases (4.3)	Blood	S. oralis, S. bovis serotype I, S. sanguinis, S. viridans and S. epidermidis	TB was most common cause of PUO (culture for TB not mentioned)
3	Labrador et al. (2014)¹⁵	45	0 (0)	BM	–	BMC not a useful tool
4	Zafar et al. (2012)¹⁶	495	6 (1.2)	BM	Salmonellosis (n = 6)	–
5	Duong et al. (2008)¹⁷	367	12 (3.3)	BM Blood (Bact T - Myco/F lytic medium)	E. faecium (BM) MAC (3%) (blood)	To be advised only in infectious aetiology cases; no big difference between blood culture and BMA culture yield
6	Volk et al. (1998)¹⁸	61	1 (1.6)	BM	MAC (HIV associated)	BM not to be sent routinely
7	Jha et al. (2009)¹⁹	57	12 (21.1)	BM (n = 9) Blood culture (n = 3)	BM: S. typhi (n = 3), S. aureus (n = 2), E. coli (n = 1), Enterococci (n = 1), S. paratyphi A (n = 1), gram-negative bacilli (n = 1). Blood: S. typhi (n = 2) and S. paratyphi (n = 1)	BM better than BC, BM yield unlikely in immunocompetent individuals
8	Tanyigna et al. (2001)²⁰	84 (288 specimens)	Blood 24/84 (28.6) Stool 27/84 (32.1) BM 14/36 (38.9)	BM > blood > stool WIDAL was positive in only 25%	Salmonella yield alone was considered	BM better for Salmonella in conjunction with WIDAL BMC superior than blood culture
9	Present study	93	26 (28)	Urine (n = 14) > blood (n = 11) > BM (n = 4)	Urine: C. albicans (n = 5), E. coli (n = 3), E. faecalis (n = 2) Blood: E. coli (n = 3), B. pseudomallei (n = 2), S. typhi (n = 1) BM: S. typhi, S. paratyphi, Coagulase-negative S. aureus, Klebsiella species (n = 1 each)	Yield from bone marrow was less compared to blood and urine

BM, bone marrow; TB, tuberculosis; PUO, pyrexia of unknown origin; BMC, bone marrow aspirate (BMA) culture; MAC, Mycobacterium avium complex; BC, blood culture; S. typhi, Salmonella typhi; S. aureus, Staphylococcus aureus; E. coli, Escherichia coli; B. pseudomallei, Burkholderia pseudomallei.

In our study, the yield of organisms from bone marrow was inferior compared to that from blood and urine (Table 5). This might be explained by the fact that most of our patients were apparently immunocompetent with no significant co-morbidities. Besides this, the volume of BMA inoculated in to the appropriate culture media might also have influenced the outcome. In the best of laboratories, the yield of organisms from BMA is not very high. Automated blood culture systems using enriched media; media for anaerobes have resulted in increased yield. However, prior antibiotic therapy in most cases of prolonged fever precludes isolation by culture. With the introduction of multiplex polymerase chain reaction and other advanced molecular techniques, it is expected to give a definitive diagnosis in fevers due to infectious aetiology.

To summarise, BMA and BMBx are essential, cost-effective tools in the laboratory evaluation of prolonged pyrexia in resource-poor settings. Appropriate microbial culture and serological findings should supplement the morphological analysis of bone marrow for accurate diagnosis and appropriate patient management.

Footnotes

Acknowledgements

The authors thank Dr Sudhagar Mookappan from the Department of General Medicine at Pondicherry Institute of Medical Sciences, Pondicherry for his valuable contribution in evaluation and management of patients with prolonged fever.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Arnow

Flaherty

. Fever of unknown origin. Lancet 1997; 350: 575–580.

Cunha

. Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination, and laboratory tests. Infect Dis Clin North Am 2007; 21: 1137–1187.

Quesada

Tholpady

Wanger

et al.

Utility of bone marrow examination for workup of fever of unknown origin in patients with HIV/AIDS. J Clin Pathol 2015; 68: 241–245.

Pande

Bhattacharyya

Pain

et al.

Diagnostic yield of bone marrow examination in HIV associated FUO in ART naïve patients. J Infect Public Health 2010; 3: 124–129.

Hot

Schmulewitz

Viard

et al.

Fever of unknown origin in HIV/AIDS patients. Infect Dis Clin North Am 2007; 21: 1013–1032.

Hot

Jaisson

Girard

et al.

Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Arch Intern Med 2009; 169: 2018–2023.

Chin

Chen

Lee

et al.

Fever of unknown origin in Taiwan. Infection 2006; 34: 75–80.

Lee

Erber

Porwit

et al.

ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol 2008; 30: 349–364.

Crispin

Holmes

. Clinical and pathological feature of bone marrow granulomas: a modern Australian series. Int J Lab Hem 2018; 40: 123–127.

10.

Wang

Tang

X-Y

Yuan

et al.

Bone marrow granulomas in a high tuberculosis prevalence setting: a clinicopathological study of 110 cases. Medicine (Baltimore) 2018; 97(4): e9726–e9726.

11.

Muniraj

Padhi

Phansalkar

et al.

Bone marrow granuloma in typhoid fever: a morphological approach and literature review. Case Rep Infect Dis 2015; 2015: 628028–628028.

12.

Chandra

. Comparison of bone marrow aspirate cytology, touch imprint cytology and trephine biopsy for bone marrow evaluation. Hematol Reports 2011; 3: 65–68.

13.

Toi

Varghese

Rai

. Comparative evaluation of simultaneous bone marrow aspiration and bone marrow biopsy: an institutional experience. Indian J Hematol Blood Transfus 2010; 26: 41–44.

14.

Kaur

Rana

APS

Kapoor

et al.

Diagnostic value of bone marrow aspiration and biopsy in routine hematology practice. J Clin Diagnostic Res 2014; 8: 13–16.

15.

Labrador

Pérez-López

Martín

et al.

Diagnostic utility of bone marrow examination for the assessment of patients with fever of unknown origin: a 10-year single-centre experience. Intern Med J 2014; 44: 610–612.

16.

Zafar

Imran

Dodhy

et al.

Value of bone marrow examination in diagnosis of patients having different types of fever. ISRA Med J 2012; 4: 244–251.

17.

Duong

Dezube

Desai

et al.

Limited utility of bone marrow culture: a ten-year retrospective analysis. Lab Med 2008; 40: 37–38.

18.

Volk

Miller

Kirkley

et al.

The diagnostic usefulness of bone marrow cultures in patients with fever of unknown origin. Am J Clin Pathol 1998; 110: 150–153.

19.

Jha

Sarda

Gupta

et al.

Bone marrow culture vs blood culture in FUO. J Nepal Med Assoc 2009; 48: 135–138.

20.

Tanyigna

Bello

Okeke

et al.

Comparison of blood, bone marrow aspirate, stool and urine cultures in the diagnosis of enteric fever. Niger J Med 2001; 10: 21–24.

21.

Wain

Bay

Vinh

. Quantitation of bacteria in bone marrow from patients with typhoid fever: relationship between counts and clinical features. J Clin Microbiol 2001; 39: 1571–1576.