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Diagnostic Utility of Bone Marrow Sampling in HIV-Infected Patients Since the Advent of Highly Active Antiretroviral Therapy

Posted on: Saturday, 29 October 2005, 03:02 CDT

By Llewelyn, M J; Noursedeghi, M; Dogan, A; Edwards, S G; Miller, R F

Summary: We investigated the diagnostic value of bone marrow (BM) sampling in investigation of HIV-infected patients presenting to a major London HIV treatment centre between 1999 and 2004. One hundred and fourteen consecutive patients underwent 130 BM samplings. The majority of BM aspirates were normal or showed non-diagnostic changes; microscopy revealed lymphoma in one and mycobacterial infection in two. Subsequent culture identified mycobacterial infection in nine samples. BM trephine had a diagnostic yield of 26% in patients with fever and cytopaenia (including mycobacteriosis in 14%, lymphoma in 6%, Castleman disease in 3% and 'drug effect' in 3%), a yield of 20% in patients with fever, but no cytopaenia (mycobacteriosis in each case), and a yield of 19% in patients with cytopaenia in the absence of fever (lymphoma in 5% and 'drug effect' in 14%). In investigation/staging of lymphoma, the diagnostic yield was 36%. The overall yield from BM sampling was 30% in patients receiving highly active antiretroviral therapy (HAART) and 23% in those not receiving HAART. In this study, BM sampling was of most diagnostic value in HIV-infected patients where fever and cytopaenia coexisted in the absence of localizing signs of infection, and in the staging/investigation of lymphoma. BM sampling had less diagnostic value in the investigation or fever without cytopaenia or cytopaenia without fever.

Keywords: bone marrow, HIV, lymphoma, mycobacteria, pyrexia of undetermined origin

Introduction

In 1997, we described the diagnostic utility of bone marrow (BM) sampling in patients with HIV infection attending our treatment centre.1 We found that BM sampling was performed in four main clinical settings: investigation of pyrexia, staging/ investigation of lymphoma, investigation of pancytopaenia and investigation of isolated cytopaenia. In patients from the first three groups BM sampling provided useful diagnostic information, but contributed little to the diagnosis of isolated cytopaenia.1

Since 1997, the clinical manifestations and associated pathology of HIV disease have changed significantly, primarily due to the widespread introduction of combination highly active antiretroviral therapy (HAART).2 In our treatment centre, since 1997 the majority of new HIV diagnoses have been in patients from sub-Saharan Africa with heterosexually acquired infection. In the light of these changes, our earlier observations might not apply to the current patient population. We investigated the clinical value of BM sampling in our patient population over a period of 4.5 years, since HAART became routinely available.

Methods

The study was performed in an inner London specialist HIV/AIDS inpatient unit. All HIV-infected patients undergoing BM sampling between December 1999 and July 2004 were identified from patients' case-notes, discharge summaries and computer records. Patient characteristics, indications for performing BM sampling, results of microscopic examination of the marrow and other concurrent investigations, final diagnosis and the value of the marrow sample in achieving a diagnosis were recorded, as previously described.1

Indications for BM sampling were investigation of (1) fever without localizing signs, (2) pancytopaenia or single lineage cytopaenia and (3) lymphoma, as a suspected diagnosis, for staging, or for investigation of possible relapse. All BM aspirates and trephines were processed, as previously described.1 BM trephines were reported by several pathologists, using a standard protocol.

For comparison of patients' CD4 counts and viral loads between groups, medians and 25-75% interquartile ranges are given and differences analysed using the Mann-Whitney rank sum test. The frequency of discontinuous variables was analysed using the two- tailed Fisher exact test. Analyses were performed using SigmaStat software (SPSS Inc.). A value of P <0.05 was taken to be statistically significant.

Results

One hundred and thirty-five BM samples (125 aspirates and 120 trephines) were obtained from 119 patients. Five patients for whom no clinical data were available were excluded from analysis. Thus, 130 BM samples were obtained from 114 patients, 88 of whom were men. The mode of HIV transmission was men who have sex with men (MSM) in 63 (55%), heterosexual in 44 (39%) and injection drug use (IDU) in seven (6%). No adverse events as a result of BM sampling were reported in this series.

Diagnostic yield of BM sampling

Eighty-eight (73%) of BM trephines were normal or showed non- specific changes. Abnormal trephines included lymphoma in 13 (11%), mycobacterial infection in 12 (10%), drug-induced changes (of minor dysplasia) in five (4%) and Castleman disease in two (2%).

The majority of BM aspirates were either normal or showed non- diagnostic changes. Three showed diagnostic features on microscopy (mycobacterial infection in two and lymphoma in one).

Lymphoma: Thirteen samples from 12 patients showed lymphoma on histology. Eight of these samples were taken from seven patients with previously diagnosed lymphoma. Six were taken for staging, one for assessment of treatment response and one for investigation of relapse. In five patients BM sampling made a new diagnosis of lymphoma. All five were anaemic and neutropenic; additionally, four had fever, peripheral lymphadenopathy and thrombocytopaenia.

Table 1 Detection of mycobacteria by type of bone marrow (BM) sampling

Mycobacterial infection: Twelve BM trephine samples showed mycobacterial infection. Microscopy of the corresponding BM aspirate in two samples also demonstrated mycobacteria. Mycobacteria were cultured from the BM aspirate in eight of 12 (Mycobacterium tuberculosis in two and M. avium complex (MAC) in six). Additionally, MAC was cultured once from a BM which showed only reactive changes on histology (Table 1). All 13 patients were febrile; in six BMs sampling provided the first evidence of mycobacterial infection.

Drug effect: Histology of BM showed druginduced changes on five occasions. All these patients were taking HAART; in four the regimen included zidovudine. Three patients were also taking co-trimoxazole as prophylaxis. All were anaemic. Other lineages were either normal or demonstrated mild thrombocytopaenia.

Impact of HAART

In 53 episodes (43%) patients were taking HAART. Patients taking HAART were a little older (mean = 41.8 years) than those not taking HAART (mean = 37.4 years), but no differences were found in either the proportion of men (78% versus 81%) or mode of HIV acquisition (MSM:heterosexual:IDU [%]) = 52:40:8 in patients taking HAART and 69:29:2 in those who were not. Viral loads were significantly lower in patients taking HAART median (interquartile range) = 1000 (80- 87,225) copies/mL compared with those who were not 125,500 (125,100- 336,450)copies/mL, P<0.001, but CD4 counts were not significantly higher. In those taking HAART, CD4 counts (median [interquartile range]) were 110 (40-280) cells/L, and in those not taking HAART were 70 (40-240) cells/L. Only 12 patients taking HAART had undetectable viral loads. In this subgroup, the median CD4 count = 340 (interquartile range = 215-485) cells/ L, and was significantly higher than in patients not receiving HAART (P = 0.002).

The impact of HAART on the diagnostic yield of BM sampling is outlined in Table 2. BM sampling made a specific diagnosis in 16 of 71 (23%) sampling episodes where the patient was not receiving HAART, and in 16 of 53 (30%) where the patient was receiving HAART.

Table 2 Influence of HAAHT on diagnosis made by bone marrow (BM) sampling

Table 3 Findings from bone marrow (BM) trephine histology by clinical indication

Diagnostic yield by indication for BM sampling

Fever without localizing signs: Eighty BM trephine samples were performed to investigate fever without localizing signs (Table 3). Ih 65 episodes, cytopaenia was present. Of the 80 samples, 55 (69%) were normal or showed non-specific change. Of these 55 samples, 53 BM aspirates were obtained, one of which grew MAC (the only site from which MAC was cultured in this patient). Histology of 12 samples showed mycobacterial infection. Culture of the corresponding BM aspirates grew MAC in seven and M. tuberculosis in two. In four of 12 episodes, the diagnosis of mycobacterial infection was dependant solely on BM sampling.

Four trephine samples showed lymphoma; in one the diagnosis also made by contemporaneous lymph node biopsy. Two samples showed drug- induced changes. Both patients were receiving zidovudine and one also co-trimoxazole prophylaxis. Two samples showed Castieman disease. Five trephine samples were inadequate for histological analysis; in none of these were the corresponding BM aspirates diagnostic

Fifteen BM samples were performed to investigate fever without cytopaenia. In three, mycobaoterial infection was identified. In all the three patients M. tuberculosis was also diagnosed from lymph node histology and culture, whereas BM culture was negative. Of the remaining 12 episodes, BM histology showed only reactive changes or normal appearances. Of these, disseminated M. tuberculosis was diagnonpd on four occasions by other means. In all of these instances, culture of BM aspirate was negative.

Diagnosis of cytopaenia: Twenty-one BM samp\les were performed to investigate cytopaenia without fever: pancytopaenia (n=7), two lineage cytopaenia (n=8), isolated anaemia (n=4) and isolated thrombocytopaenia (n=2). Four specific diagnoses were made: three of drug-induced changes and one of lymphoma. In all instances the patient was anaemic.

Ten of the 21 BM samplings were for diagnosis of cytopaenia without fever in patients receiving HAART; of these only two had undetectable viral loads. Drug-induced changes were found in three patients. Reactive changes were found in six and one marrow was normal. Of 11 samples where patients were not receiving HAART, normal or non-specific changes were found in eight marrows and in two no results were available. One patient with isolated anaemia, not receiving HAART, had lymphoma diagnosed only on BM histology.

Table 4 Indications for and diagnostic yield from bone marrow sampling in HIV-infected patients in the current study (1999-2004) and in an earlier study (1987-1996) at University College London Hospitals

Diagnosis and staging of lymphoma: Six of 18 BM biopsies performed for staging of lymphoma showed BM involvement. One BM sample taken to assess treatment response showed lymphoma infiltration, as did one of six samples taken because lymphoma relapse was suspected clinically. BM sampling in these cases made no additional diagnoses.

Overall diagnostic yield: Overall, BM sampling made a specific positive diagnosis on 33 of 130 (25%) occasions. This diagnostic yield increased to 44 (34%) in all instances in which biopsies performed for staging of lymphoma were considered to have made a positive impact on management.

The diagnostic yield from BM sampling in the present patient group compared with a preHAART cohort from this treatment centre is shown in Table 4.

Discussion

The epidemiology of HIV disease seen in a developed-world specialist centre such as ours has changed markedly since the early 1990s. Two factors have contributed to this change. First, the increases in numbers of patients with heterosexually acquired HIV infection, particularly those from sub-Saharan Africa, and second, the widespread introduction of HAART.2 Potentially, both these factors have had an impact on the diagnostic utility of BM sampling. In this study, 55% of patients acquired HIV via MSM and 38% by heterosexual sex. In the previous study from our centre 91% were white men; in almost all the mode of acquisition was MSM and only 9% were heterosexual black Africans.1

A striking feature of the data presented in this study is the greater diagnostic yield from histology of BM trephine compared with that from BM aspirate, 27% of trephines being histologically abnormal with only nine diagnoses (7%) being made by aspirate and subsequent culture, all of mycobacterial disease. This is in keeping with the results of our previous study in which mycobacteria were cultured on 18 occasions from a total of 246 BM samples (7% yield).1 Other studies have reported higher diagnostic yields from BM aspirate irrespective of HAART use. In a study from Spain of HIV- infected patients with prolonged fever, where IDU was the most common route of transmission, 55% of BM aspirates showed mycobacterial infection, and a further 14% showed leishmaniasis.3 Similarly, in a study of HIV-infected adults from South Africa, mycobacterial infection was the most common diagnosis made by BM sampling and yield from culture was accordingly high.4 We conclude that the observed comparatively low diagnostic yield from BM aspirate in our study arises from the comparatively low incidence, in our patient population, mycobacterial infection and leishmaniasis, which target the BM, and is not related to patients' use of antiretroviral therapy.

Our data demonstrate that the overall diagnostic yield of BM sampling is similar in patients receiving HAART (30%) or not (23%). This overall yield is comparable to other published studies.4"8 Of note, our data demonstrate that patients' use of HAART is associated with two differences in specific diagnoses made by BM sampling. First, drug-induced changes were only found in five patients receiving HAART, four of whom were receiving zidovudine. Second, lymphoma was diagnosed more commonly in patients not receiving HAART. This is in keeping with reported changes in the epidemiology of HIV-related neoplasia associated with use of HAART.9,10

In comparing the present patient group with that in our previous study, the most striking change in indication for BM biopsy is the absence of patients with isolated thrombocytopaenia. In the previous study, 10% of BM samples were performed for isolated thrombocytopaenia; in 95% of these the final diagnosis was of HIV- associated immune thrombocytopaenic purpura (ITP).1 It is unlikely that this change has arisen directly because of antiretroviral use since only 40% of BM samplings in the present study were performed in patients receiving HAART. It is more likely that BM sampling is no longer indicated in HIV-infected patients presenting with isolated thrombocytopaenia. Instead, the diagnosis of ITP is made on the basis of a peripheral blood film and is interpreted in the light of the previous study.1

As in our previous study, the single group of HIV-infected patients in which BM sampling makes the most clearly defined diagnostic impact remains those patients who already have a diagnosis of lymphoma, and in whom treatment is affected by the presence or absence of marrow infiltration. These patients made up 19% of the BM sampling episodes in this study compared with 15% in our previous series.1 Apart from this group of patients, the greatest diagnostic yield (26%) was found among patients who underwent BM sampling for investigation of fever with cytopaenia, the predominant diagnosis being mycobacterial infection. Thus, our current study mirrors the findings of our previous study.1

Fever in the absence of localizing signs or cytopaenia was a comparatively uncommon indication for BM sampling in the present study. The diagnostic yield in these patients was low, which is not surprising. Only three patients had a diagnosis of mycobacterial infection made by BM examination, and in each case the diagnosis was also made by other investigations. A similarly low yield from BM sampling has been reported recently from a retrospective study of 72 HIV-infected patients with pyrexia of undetermined origin from Miami, USA.11 The data from this study and our study suggest that, in investigating an HIV-infected patient presenting with fever in the absence of cytopaenia, attempts should be made to identify mycobacteria from other sources, e.g. blood cultures, before proceeding to BM sampling.

The data in this study show that cytopaenia in the absence of fever is rarely associated with any specific diagnosis made by BM sampling. In patients receiving HAART who have good suppression of HIV viral load, cytopaenia is likely to be due to a drug effect. This observation suggests that in this patient group modification of the regimen of HAART should be considered, before carrying out BM sampling. The identification of lymphoma in one patient presenting with isolated anaemia serves as a reminder that even in the face of a low diagnostic yield, BM sampling may still be worthwhile.

References

1 Brook MG, Ayles H, Harrison C, Rowntree C, Miller RF. Diagnostic utility of bone marrow sampling in HIV positive patients. Genitourin Med 1997;73:117-21

2 Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000;30:55-14

3 Fernandez-Aviles F, Ribera JM, Romeu J, et al. The usefulness of the bone marrow examination in the etiological diagnosis of prolonged fever in patients with HIV infection. Med Clin (Barc) 1999;112:641-5

4 Karstaedt AS, Pantanowitz L, Omar T, Sonnendecker HE, Patel M. The utility of bone-marrow examination in HIV-infected adults in South Africa. QJM 2001;94:101-5

5 Riley UB, Crawford S, Barrett SP, Abdalla SH. Detection of mycobacteria in bone marrow biopsy specimens taken to investigate pyrexia of unknown origin. J Clin Pathol 1995;48:706-9

6 Engels E, Marks PW, Kazanjian P. Usefulness of bone marrow examination in the evaluation of unexplained fevers in patients infected with human immunodeficiency virus. Clin Infect Dis 1995;21:427-8

7 Benito N, Nunez A, de Gorgolas M, et al. Bone marrow biopsy in the diagnosis of fever of unknown origin in patients with acquired immunodeficiency syndrome. Arch Intern Med 1997;157:1577-80

8 Keiser P, Rademacher S, Smith JW. Utility of bone marrow culture and biopsy in the diagnosis of disseminated infections in AIDS. Am J Hematol 1997;56:1-4

9 Vilchez RA, Finch CJ, Jorgensen JL, Butel JS. The clinical epidemiology of Hodgkin lymphoma in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. Medicine (Baltimore) 2003;82:77-81

10 Thirlwell C, Sarker D, Stebbing J, Bower M. Acquired immunodeficiency syndrome-related lymphoma in the era of highly active antiretroviral therapy. Clin Lymphoma 2003;4:86-92

11 Santos ES, Raez LE, Eckardt P, Decesare T, Whitcombe CC, Byrne Jr GE. The utility of a bone marrow biopsy in diagnosing the source of fever of unknown origin in patients with AIDS. J Acquir Immune Defic Syndr 2004;37:1599-603

(Accepted 19 April 2005)

M J Llewelyn MRCP1,3*, M Noursedeghi MRCP1,3, A Dogan FRCPath2[dagger], S C Edwards FRCP1,4 and R F Miller FRCP1,3

1 Patrick Manson Unit, University College London Hospitals (NHS) Trust, London WC1E 6AU; 2 Department of Histopathology, Royal Free and University College Medical School; 3 Department of Primary Care and Population Sciences, Centre for Sexual Health and HIV Research, Royal Free and University College Medical School, University College London, London WC1E 6JJ; 4 Department of Genitourinary Medicine, Camden PCT, Mortimer Mark\et Centre, off Capper Street, London WC1E 6AU, UK

Correspondence to: Dr R F Miller

Email: rmiller@gum.ucl.ac.uk

* Current address: Division of Medicine, Brighton and Sussex Medical School, Palmer, Sussex BN1 9PS, UK

[dagger] Current address: Mayo Clinic, Department of Pathology, 200 First Street SW, Rochester, MN 55905, USA

Copyright Royal Society of Medicine Press Ltd. Oct 2005

Source: International Journal of STD & AIDS

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