|Year : 2020 | Volume
| Issue : 2 | Page : 216-219
Myelofibrosis: An unusual presentation of disseminated tuberculosis
Neha Sharma1, Siddharda Venkat Bikkina1, Monica Gupta1, Anita Tahlan2
1 Department of General Medicine, Government Medical College Hospital, Chandigarh, India
2 Department of Pathology, Government Medical College Hospital, Chandigarh, India
|Date of Web Publication||29-May-2020|
Department of General Medicine, Government Medical College and Hospital, Level 4 D Block, Sector 32, Chandigarh - 160 030
Source of Support: None, Conflict of Interest: None
Disseminated tuberculosis (DTB) often presents with protean clinical manifestations that often leads to potential diagnostic dilemmas. The nonspecific features may include pyrexia of unknown origin, hepatosplenomegaly, lymphadenopathy, meningitis, and a variety of hematological abnormalities, namely anemia, pancytopenia, and leukemoid reaction. Tuberculosis is one of the nonhematopoietic diseases that has been reported in conjunction with myelofibrosis. We, hereby, report a case of DTB with massive splenomegaly, severe pancytopenia, and marrow fibrosis.
Keywords: Myelofibrosis, secondary, tuberculosis
|How to cite this article:|
Sharma N, Bikkina SV, Gupta M, Tahlan A. Myelofibrosis: An unusual presentation of disseminated tuberculosis. Int J Mycobacteriol 2020;9:216-9
|How to cite this URL:|
Sharma N, Bikkina SV, Gupta M, Tahlan A. Myelofibrosis: An unusual presentation of disseminated tuberculosis. Int J Mycobacteriol [serial online] 2020 [cited 2021 Aug 3];9:216-9. Available from: https://www.ijmyco.org/text.asp?2020/9/2/216/285228
| Introduction|| |
Disseminated tuberculosis (DTB) refers to the concurrent involvement of at least two nonadjacent organs or sites of the body or involvement of the blood or bone marrow. Hematological abnormalities associated with extrapulmonary TB include anemia of different types, leukemoid reaction, and rarely pancytopenia., Pancytopenia could be ascribed to hypersplenism, maturation arrest, hemophagocytic lymphohistiocytosis (HLH), or infiltration of the bone marrow by caseating or noncaseating granulomas causing reversible or irreversible fibrosis. Myelofibrosis is generally idiopathic in origin, but among nonhematopoietic diseases, tuberculosis (TB) is an important cause of secondary myelofibrosis. Patients presenting with pyrexia of unknown origin, massive splenomegaly, and peripheral cytopenia in an endemic region must alert the physician to the possibility of DTB.
| Case Report|| |
We report a case of a 45-year-old male who presented to the medicine emergency in November 2018 with a history of fever for 4 months. The pyrexia was intermittent, documented up to 103°F, associated with chills and rigors, night sweats, and evening rise of temperature. During this period, he had marked loss of appetite and had a significant weight loss of up to 10 kg. He denied any long-standing history of cough, alteration of bowel habits, or headache. His past medical history was unremarkable. He was a shopkeeper by profession, a chronic smoker, and a social drinker. He denied any past history of substance abuse or contact history of TB. He had not received any prior blood transfusion or hematinic supplementation.
On general physical examination, he was conscious and oriented to time, place, and person. He was febrile with a temperature of 39.8°C, had tachycardia with pulse rate of 112/min, and blood pressure was 100/60 mmHg. He had severe pallor but no icterus, clubbing, lymphadenopathy, or sternal tenderness. There were no peripheral stigmata of chronic liver disease. The tongue was not bald, there was no knuckle hyperpigmentation, and Romberg's sign was negative. Neck rigidity and other meningeal signs were absent. His abdominal examination revealed a soft, nontender abdomen with mild hepatomegaly and massive splenomegaly which was firm in consistency. There was no evidence of free fluid or any other lump. A detailed cardiovascular, respiratory, and neurological examination, including higher functions, was unremarkable.
Hemogram revealed pancytopenia with Hb: 7.9 g/dl, platelet count: 79,000/uL, and total leukocyte count: 1900 (N/L: 82/16). Peripheral smear examination was consistent with leukoerythroblastic picture nucleated red blood cell/white blood cells (03/100) in conjunction with moderate anisopoikilocytosis, elliptical cells, pencil cells, and few fragmented cells. Erythrocyte sedimentation rate was 80 mm (1st h) and C-reactive protein was 117 mg/dl. Serum electrolytes, renal functions, and liver function test were within the limits. Lipid profile showed triglycerides of 244 mg/dl (reference range: 10–190 mg/dl); other fractions are normal. Initial sputum and blood cultures showed no growth. Mantoux (tuberculin) test, hepatitis profile and human immunodeficiency virus serology, monospot test for Epstein–Barr virus, rapid diagnostic test, IgM antibodies for malaria, and recombinant kinesin antigen (rK39) for Kala-Azar were also negative. Serum ferritin, B2-microglobulin, and lactate dehydrogenase (LDH) levels were within the normal range. Anti-nuclear antibody (ANA) andanti-double stranded DNA antibodies (anti-dsDNA) were noncontributory. Stool examination for parasitic cyst/ova/occult blood was unhelpful. Ophthalmoscopic examination was normal. Echocardiography showed no evidence of pericardial effusion or vegetations.
Chest radiograph was suggestive of bilateral non-homogenous nodular infiltrates suggestive of miliary tuberculosis. A subsequent contrast-enhanced computed tomography chest was suggestive of multiple randomly distributed nodules in bilateral lung field likely miliary TB [Figure 1]. Later sputum Cartridge based nucleic acid amplification test (CBNAAT) report came out to be positive and sensitive to rifampicin. However, in view of pancytopenia and massive splenomegaly, a bone marrow examination from bilateral iliac It revealed hypercellular marrow spaces with large, dysplastic, clustered megakaryocytes and excess granulocytes; increased reticulin around clusters of megakaryocytes; megakaryocytes having aberrant nuclear-cytoplasmic ratio and hyperchromatic irregularly folded nuclei along with marked fibrosis and fibroblastic proliferation as revealed by 3+reticulin stain and increased Masson's Trichrome positivity, thereby supporting a diagnosis of myelofibrosis [Figure 2]. No granulomas were seen, and Ziehl–Neelsen staining for acid-fast bacilli (AFB) was negative. Further cytogenetic studies were not meeting criteria for essential thrombocythemia, polycythemia vera or chronic myeloid leukemia, myelodysplastic syndromes, or other myeloid neoplasms, as the BCR-ABL1, JAK2, MPL, and CALR mutations were not detected.
|Figure 1: Contrast-enhanced computed tomography chest-axial section showing multiple variable size nodules in the bilateral lung field|
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|Figure 2: Bone marrow aspirate (×10) showing hypercellular marrow with an increase in megakaryocytes with marrow fibrosis|
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Before making a diagnosis of secondary myelofibrosis as a cause of massive splenomegaly, other common causes of a large splenomegaly need to be excluded. For patients living in tropical endemic regions, protozoal infections such as chronic malaria, Kala-Azar, and tropical splenomegaly syndrome need to be considered. Hematological conditions such as thalassemia and malignancies such as chronic myeloid leukemia, hairy cell leukemia, lymphoma, and myelodysplastic syndrome should be kept in mind. Infiltrative disorders such as Gaucher's disease and Niemann–Pick disease are rare.
Fever with pancytopenia would merit workup for other infections such as brucellosis, AIDS, Ebstein–Barr, and cytomegalovirus virus. HLH should be considered in the differential diagnosis of patients with TB who present with cytopenia, organomegaly, and coagulopathy. Pancytopenia with massive splenomegaly may be uncommonly due to hypersplenism, chronic liver disease, and connective tissue diseases. The list of differential diagnosis is quite exhaustive; therefore, clinical and diagnostic acumen is essential. When the diagnosis of myelofibrosis is inferred, primary myelofibrosis must always be ruled out by cytogenetic studies.
The patient was started on standard anti-TB treatment, including isoniazid, rifampicin, pyrazinamide, and ethambutol. He was given blood transfusion for anemia. The patient demonstrated good clinical improvement and his blood counts improved over the next 2 weeks. A diagnosis of DTB with secondary myelofibrosis was made, and he was referred to DOTS clinic for the continuation of antitubercular treatment. Two months later as outpatient, his complete blood count showed a hemoglobin level of 11 g/dl, white blood cell count of 7000/μl, and a platelet count of 215 × 103/μl. He was advised to continue Anti-tubercular treatment (ATT). However, he failed to visit the following month and very likely stopped his medications.
Outcome and follow-up
Subsequently, he presented in the emergency department in February 2019 with altered sensorium with meningeal signs and Grade II–III papilledema. An magnetic resonance imaging (MRI) brain at this time revealed meningeal enhancement with multiple ring-enhancing lesions in bilateral cerebral and left cerebellar hemispheres suggestive of tuberculomas. In addition, obstructive hydrocephalus with periventricular edema in left parietal, temporal, and occipital lobes with midline shift was observed [Figure 3] and [Figure 4]. Guarded lumbar puncture was done which revealed 42 cells with lymphocytic pleocytosis (95% lymphocytes), protein level of 623 mg/dl and low glucose 38 mg/dl, adenosine deaminase (ADA) of 56 IU/L and negative AFB and gram stain. He was restarted on antitubercular therapy, moxifloxacin, and a high dose of intravenous steroids. A ventriculoperitoneal shunting was done in view of obstructive hydrocephalus, but he succumbed to his illness after 2 days.
|Figure 3: Magnetic resonance imaging brain-axial section T1-weighted showing two ring-enhancing lesion in the lateral ventricle likely tuberculoma with midline shift|
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|Figure 4: Magnetic resonance imaging brain-axial section T2-weighted showing perilesional edema with hydrocephalus|
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| Discussion|| |
Singh et al. described various hematological manifestations in patients with both pulmonary and extrapulmonary TB. DTB can present with variable hematologic abnormalities including anemia of various types, leukopenia, leukocytosis, thrombocytopenia, thrombocytosis and monocytosis, and rarely pancytopenia.,, Further, literature has documented various other atypical features associated with TB such as leukoerythroblastic anemia, leukemoid reaction and infrequently disseminated intravascular coagulation, and myelofibrosis. Myelofibrosis, also known as myelosclerosis, is a rare hematologic disorder characterized by extensive fibrosis of the bone marrow. When it appears as a histological feature associated with various malignant or benign diseases of hematopoietic or nonhematopoietic origin, myelofibrosis is considered to be secondary. Among nonhematopoietic diseases, TB is reported as a cause of secondary myelofibrosis. Transforming growth factor–β is involved in the pathophysiologic process linking bone marrow fibrosis and TB. Verma et al. found that Mycobacterium tuberculosis induced interleukin-1 secretion and pro-fibrotic responses by fibroblasts.
Given the fact that TB is a great mimic, it is also well known that DTB can virtually involve any/multiple organ systems, masquerade hematological malignancies, or rarely may present as an autoimmune phenomenon as idiopathic thrombocytopenic purpura.,
Histopathological changes in the bone marrow can range from normal marrow to typical granuloma formation, marrow hypoplasia, reversible or irreversible bone marrow fibrosis, and necrosis of the marrow. In a study by Mert et al., pancytopenia was seen only in 8% in a series of 38 patients with miliary TB. Granulomas were found in 56% of patients in bone marrow tissue specimen, and polymerase chain reaction was positive in 47% of specimens with granuloma. The presence of AFB detected by Ziehl–Neelsen staining is rare. Various theories have been put forward to explain the occurrence of pancytopenia in DTB which includes hypersplenism, histiocytic hyperplasia, maturational arrest, or infiltration of the bone marrow by caseating or noncaseating granulomas.
In cases of bone marrow TB, high mortality has been reported in the range of 50% to nearly 100% in the literature. Various factors are thought to contribute to the variable outcome such as disease severity, other underlying pathologies leading to immunocompromised state, immunosuppressive therapies, and delay in initiation of appropriate treatment. Another contributing factor to poor outcome is the development of macrophage-activating syndrome (MAS). MAS or HLH should be considered in the differential diagnosis of patients with TB who present with fever, cytopenias, and organomegaly. The diagnosis is made on the basis of a constellation of fever, organomegaly, cytopenias, elevated serum ferritin, and triglyceride levels with or without lower plasma fibrinogen and demonstration of histiocytic hemophagocytosis on bone marrow examination. Our patient did not fulfill the criteria of HLH.
Whether TB stimulates a secondary fibrotic reaction or develops in patients with preexisting myeloproliferative disorders is still debatable. Pancytopenia secondary to myelosuppressive effects of TB has been supported by cases where recovery of peripheral blood counts with antituberculous therapy has been accepted as evidence of a normal bone marrow. Viallard et al., Rosenberg and Rumans, and Jin et al. each described one case where TB was proven and pancytopenia and bone marrow fibrosis recovered the completion of ATT.,, Our patient initially showed good subjective response with subsidence of symptoms within a few weeks following the initiation of the treatment. The unfavorable outcome in our patient is thought to be due to probable noncompliance and nonadherence to therapy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]