Bone marrow necrosis (BMN) is a rare clinicopathologic entity caused by hypoxemia after the failure of microcirculation that frequently manifests with bone pain, fever, and peripheral cytopenia. In most reported cases of BMN resulting from extrapulmonary tuberculosis (TB), the presence of marrow granulomas, pulmonary infiltrates and/or extrapulmonary involvement are common. We report a case of an extensive BMN from miliary TB whose initial presentation was only mild anemia and multiple bone lesions.
Keywords: Bone marrow necrosis (BMN), TB-polymerase chain reaction (TB-PCR), Tuberculosis (TB)
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Santosh T, Patro MK, Bal AK, Choudhury A. Extensive marrow necrosis due to miliary tuberculosis: A case report. Ann Trop Med Public Health 2015;8:293-5
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Santosh T, Patro MK, Bal AK, Choudhury A. Extensive marrow necrosis due to miliary tuberculosis: A case report. Ann Trop Med Public Health [serial online] 2015 [cited 2020 Sep 22];8:293-5. Available from: https://www.atmph.org/text.asp?2015/8/6/293/162657
Bone marrow necrosis (BMN) is defined as “necrosis of myeloid tissue and medullary stroma in large areas of the hematopoietic bone marrow (BM)”  that frequently manifests with bone pain, fever, and peripheral cytopenia. The underlying diseases of BMN are diverse, the most common being hematological malignancies followed by nonmalignant causes such as sickle cell disease, infections and drugs. Among the infectious etiologies, miliary tuberculosis can be diagnostically troublesome due to its variable hematological manifestations, i.e., anemia of different types, leukemoid reaction, and rarely pancytopenia. 
Bone marrow biopsy has been widely used as one of the diagnostic tools when blood counts show a picture of pancytopenia. Though considered a treatable condition of the bone marrow, TB has been reportedly associated with fatal outcome.  We report a case of extensive BMN in a 3-year-old child with multiple bone lytic lesions diagnosed to have TB by TB-polymerase chain reaction (TB-PCR).
A 3-year-old Hindu male boy presented with intermittent fever and weight loss for 1 year. On examination he was found to have bilateral cervical lymphadenopathy, swelling in his right elbow joint, and a nonhealing ulcerative lesion over the right outer canthus of his eye since 2 months [Figure 1]a and b]. He had no history of TB in any of his family members. X-ray of his chest showed a lytic expansile lesion in the posterior aspect of the left seventh rib. X-ray from the right elbow joint showed lytic expansile lesion in the lower end of the humerus [Figure 2]a and b. Fine-needle aspiration cytology of the cervical lymph node showed features of tubercular lymphadenitis. Ziehl-Neelsen (ZN) stain for acid-fast bacilli (AFB) and Gram stains were negative and the culture was sterile. Mantoux test was negative. Laboratory investigation showed hemoglobin (Hb) – 7.8 gm% and serum ferritin – 18.2 ng/mL. Human immunodeficiency virus (HIV) 1/2, hepatitis B antigen, and HCV were negative. Peripheral smear showed red cells with mild anisocytosis, predominantly normochromic with few microcytic hypochromic cells, leukopenia with absolute neutropenia and thrombocytopenia [Figure 3]a.
|Figure 1: (a and b) Nonhealing ulcerative lesion over the right outer canthus of the eye and swelling in right elbow joint since 2 months
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|Figure 2: (a and b) X-ray of the chest with lytic expansile lesion in the posterior aspect of the left seventh rib. X-ray of the right elbow joint showing lytic expansile lesion in the lower end of the humerus
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|Figure 3: (a and b) Peripheral smear showing pancytopenia and marrow aspirate with necrotic material, few epithelioid cells, polymorphs, and occasional giant cells. There was a suppression of all the hematopoietic lineages. (Leishmann, ×40)
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Considering a provisional diagnosis of pancytopenia, bone marrow aspiration was done which revealed reduced cellularity with abundant necrotic material alongwith few epithelioid cells, polymorphs and occasional giant cells. There were few scattered mononuclear cells with open nuclear chromatin, mature lymphocytes, and occasional plasma cells. All the hematopoietic cell lineages were conspicuously depressed [Figure 3]b. AFB stain of bone aspirate was negative for TB bacilli. Cell block was prepared from the remaining aspirate material followed by trephine biopsy that showed epithelioid cell granuloma with Langhans type giant cells and focal necrosis [Figure 4]. TB-PCR of the marrow aspirate confirmed the presence of Mycobacterium tuberculosis. The patient was put on antitubercular treatment (ATT), steroid, phenytoin, along with intravenous (IV) administration of fluids and two units of whole blood transfusion. He showed gradual improvement in the hematological as well as clinical profiles. He is under strict follow-up for the proper completion of ATT since last 5 months.
|Figure 4: (a and b) Cell block preparation and trephine biopsy showing epithelioid cell granuloma with Langhans type giant cells and focal necrosis. (H&E;, ×40)
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TB is a chronic bacterial infection caused by Mycobacterium tuberculosis. This ancient infection has plagued humans through the ages. Its elimination has remained extremely difficult as long as poverty, overpopulation, and HIV infection exist in large portions of the earth. It is an index of social organization and the standard of living in the community.  TB can affect any organ. The lung is the usual site involved. The extrapulmonary sites involved are the lymph nodes, pleura, genitourinary tract, bones, joints, meninges, and peritoneum. Today as a result of hematogenous dissemination in HIV infection, extrapulmonary TB is seen more commonly than in the past. 
Hematologic changes in disseminated TB are protean and reversible only when TB is treated adequately. The predominant variations are the following:
- Different degrees of anemia (morphologically normocytic, normochromic, hypochromic, and dimorphic) with some apparently refractory,
- High erythrocyte sedimentation rate,
- Lymphomononuclear cell preponderance with atypicity in peripheral blood films,
- Hypocellular marrow and depressed normoblastic erythropoiesis, lymphomononuclear cell preponderance with atypicity, and increased plasma cells and reticuloendothelial (RE) cells,
- Defective ferrokinetics. 
The mechanism of BMN appears to involve a diversity of events, among which the failure of microcirculation is the most critical.  The other critical events contributing to BMN include the toxic effects of chemotherapy, irradiation, bacterial endotoxins, tumor cell involvement in marrow microvasculature, and aberrant cytokine production, particularly tumor necrosis factor (TNF) that is a well-known vascular disrupting agent. 
Miliary TB should always be considered in patients with extensive BMN even in the absence of granulomas or pulmonary/extrapulmonary presentations, particularly in areas of high prevalence of TB. Magnetic resonance imaging (MRI) and TB-PCR are useful diagnostic tools for such patients. PCR has been shown to have a good sensitivity and specificity in detecting Mycobacterium tuberculosis in pulmonary as well as extrapulmonary specimens including bone marrow. PCR by amplifying the MPB64 gene of Mycobacterium tuberculosis is able to detect up to 5-10 mycobacteria with results within 2 days. , There were no other possible infectious etiologies and no hematological malignancies identified in our case.
The incidence of bone marrow granuloma ranges 0.38-2.2%.  In contrast to a good prognosis of pulmonary TB, the literature review of various similar reported cases of bone marrow TB has revealed high mortality in the range of 50-100%. Certain factors are thought to contribute to the variable outcome such as disease severity, other underlying pathologies leading to an immunocompromised state, immunosuppressive therapies, and delay in the initiation of appropriate treatment.  Another contributing factor to poor outcome is macrophage-activation syndrome (MAS) that is a nonspecific clinical syndrome comprising pancytopenia, hypertriglyceridemia, and hyperferritinemia. A retrospective study carried out by Eid et al. during the period of 1990-2002 showed a mortality rate of 50%. The high mortality rate in that study was attributed to the delay in presentation. 
Although certain poor prognostic factors such as bone involvement, chronicity and caseating tubercular granulomas in the bone marrow were present with negative ZN stain and culture reports, our patient showed good subjective response with subsidence of the symptoms within a few weeks following the initiation of treatment. The favorable outcome in our patient is thought to be due to an early diagnosis by TB-PCR, rapid start of the treatment, good compliance with ATT and a thorough follow-up.
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Bernard C, Sick H, Boilletot A, Oberling F. Bone marrow necrosis: Acute microcirculation failure in myelomonocytic leukemia. Arch Intern Med 1978;138:1567-9.
Lee YH, Hong YC, Yang CF, Wu HT, Huang LJ, Tzeng CH, et al. Severe Extensive Bone marrow necrosis from miliary tuberculosis without granulomas and pulmonary presentations. J Chin Med Assoc 2010;73:208-11.
Alghamdi AA, Awan FS, Maniyar IH, Alghamdi NA. Unusual manifestation of extrapulmonary tuberculosis. Case Rep Med 2013;3:1-3.
Hungund BR, Sangolli SS, Bannur HB, Malur PR, Pilli GS, Chavan RY, et al. Blood and bone marrow findings in tuberculosis in adults – A cross sectional study. Al Ameen J Med Sci 2012;5:362-6.
Chakrabarti AK, Dutta AK, Dasgupta B, Dhiman G, Ghosal AG. Haematological changes in disseminated tuberculosis. Ind J Tub 1995;42:165-8.
Janssens AM, Offner FC, Van Hove WZ. Bone marrow necrosis. Cancer 2000;88:1769-80.
Singh UB, Bhanu NV, Suresh VN, Arora J, Rana T, Seth P. Utility of polymerase chain reaction in diagnosis of tuberculosis from samples of bone marrow aspirate. Am J Trop Med Hyg 2006;75:960-3.
Escobedo-Jaimes L, Cicero-Sabido R, Criales-Cortez JL, Ramirez E, Romero M, Rivero V, et al. Evaluation of the polymerase chain reaction in the diagnosis of miliary tuberculosis in bone marrow smear. Int J Tuberc Lung Dis 2003;7:580-6.
Avasthi R, Mohanty D, Chaudhary SC, Mishra K. Disseminated tuberculosis: Interesting hematological observations. J Assoc Physicians India 2010;58:243-4.
Eid A, Carion W, Nystrom JS. Differential diagnoses of bone marrow granuloma. West J Med 1996;164:510-5.
Source of Support: None, Conflict of Interest: None
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