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Clinical Infection & Immunity

Case Report

Volume 6, Number 2, June 2021, pages 51-54

Disseminated Tuberculosis on an Acute Myeloid Leukemia Patient

Tuberculosis (TB) is an indolent infectious disease caused by Mycobacterium tuberculosis (MT), and it can infect any organ, although it mainly causes lung disease. Most symptomatic cases of TB are due to reactivation of a latent infection which, in high prevalence countries, may occur in immune competent patients. Although TB incident is falling about 2% per year (between 2015 and 2019) globally, it remains a major cause of death worldwide, and the primary cause from a single infectious agent [1]. Even in less prevalent countries, cases of TB continue to occur, due to globalization, which allows the widespread of infectious diseases. Therefore, TB is still an important differential diagnosis to account for.

Extrapulmonary and disseminated tuberculosis (DTB) may present themselves with several different clinical scenarios, without respiratory symptoms, posing a diagnostic challenge [2]. DTB is associated with human immunodeficiency virus (HIV) or other immunosuppressive conditions, although the latter may not always be evident at initial presentation [2-4]. In a non-HIV patient with no apparent immune compromising disease, less common disseminated infections are seldom considered for differential diagnostics of an unspecific clinical picture. We present a case of DTB in a patient with few comorbid conditions, and aim to bring awareness to this disease and to the possible underlying condition. Comorbid conditions that affect the immune response, such as hematologic diseases, may neither be apparent previously nor at initial presentation [5, 6].

A 66-year-old man, with prior alcoholic liver disease, abstinent and stable for the past 8 years, and chronic renal disease stage 3a of New York Kidney Foundation, was admitted to our medical ward, due to severe pancytopenia (hemoglobin 4.2 g/dL, neutrophils 380/µL and platelets 8,200/µL), fever, asthenia, anorexia and weight loss, for the past 2 months. He also reported a mild dry cough during the previous 15 days, which was resolved at hospital admission, and had no night sweats. He was healthy until then, and had no knowledge of previous infectious or neoplastic diseases.

On physical examination, he was febrile, pale, had a normal chest examination, and ascites on abdominal examination. His initial and follow-up laboratory results are detailed in Table 1. Of note, HIV, hepatitis C and B were excluded, and blood and urine cultures were negative. His chest X-ray was normal, and his abdominal ultrasound showed ascites and bilateral small-sized pleural effusion. Ascitic fluid analysis showed a clear liquid, with leukocytes of 986/µL, of which lymphocyte was 823/µL, a serum to albumin gradient (SAAG) was > 1.1 and adenosin deaminase (ADA) was 54 U/L. He was further investigated with a thoraco-abdomino-pelvic computed tomography (CT) scan, which showed a diving goiter but no supraclavicular or axillary lymphadenopathies; mediastinal lymphadenopathies; normal lung parenchyma with few millimetric subpleural nodules limited to upper right lobe, right-sided mild non-loculated pleural effusion associated with non-specific mild pleural enhancement; slightly irregular hepatomegaly and splenomegaly; permeable but distended portal vein; retroperitoneal and retrocrural lymphadenopathies, ascites, and epiploic densification resembling carcinomatous dissemination. Thyroid function was normal.

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Table 1. Laboratory Data

He underwent both a bone marrow (BM) aspirate and a biopsy which was pauci-cellular but otherwise normal. We also performed a peritoneal biopsy that had non-caseating granulomas. Thyroid was not biopsied. At this point, blood, ascitic fluid and sputum samples were collected to test for TB, all of which were positive (auramine, PCR and Lowenstein media). A multi-sensitive MT was isolated, and he was started on classical tuberculous scheme (isoniazid, rifampicin, ethambutol and pyrazinamide). The BM aspirate had not been tested for TB but, since blood cultures were positive, pancytopenia was assumed to be secondary to BO MT invasion.

After 1 month treatment, the patient’s blood counts (Table 1) had improved, he was asymptomatic, and had gained weight. The patient was discharged to an outpatient clinic, where he maintained treatment and follow-up.

At 6 months treatment, the patient had a new fall in blood counts (Table 1), and we performed another BM biopsy and aspirate: he maintained cellular hypoplasia with no evidence of hematologic disease, and no MT invasion. Pharmacologic toxicity was the most probable diagnosis, and he was started on a different scheme, associated with blood transfusion support, epoetin and hematopoietic growth-stimulating factors.

Eight months after starting treatment, TB antibiotics had been stopped for a month, but the patient maintained pancytopenia. He was submitted to another BM aspirate, which showed 21% blasts with 14% ring sideroblasts, and BM biopsy for which immunohistochemistry showed 20% positive CD34 blasts, all compatible with acute myeloid leukemia (AML). The patient had worsened his general condition, had severe pancytopenia, and was oriented to palliative care. The first hemogram that had circulating blast cells was 11 months after his initial hospital admission, and he died 1 year after this first admission.

Portugal still has TB prevalence above European average, and MT may cause lung infection in immune competent individuals. That is not the case for DTB, as in most cases, it occurs in HIV patients. DTB, in non-HIV patients, is associated with some form of immune debilitating condition such as immunosuppressive therapy, diabetes mellitus, alcoholism (mainly with liver cirrhosis), or hematologic diseases [2, 3].

DTB is defined as TB infection in two non-contiguous locations, caused by hematologic or lymphatic dissemination of MT, either during a primary infection or, more frequently, after reactivation of a latent infection. DTB is difficult to diagnose, because its clinical scenario is frequently non-specific and may affect several different organs [2, 3]. DTB, on its own, rarely causes pancytopenia due to medullary invasion [2, 3, 7, 8]. TB is also a known cause of fever of unknown origin. In our case, DTB mimics advanced cancer, and presents itself with scarce respiratory symptoms as well as an innocent lung image (both X-ray and CT scan). An important clue to the diagnosis was the elevated ADA in ascitic fluid, which is highly suggestive of peritoneal TB [9].

With patient partial recovery during the first 6 months, no additional diagnosis was proposed. He had a known chronic alcoholic liver disease, which was considered to be his immune debilitating condition. After the first relapse, with aggravating pancytopenia but a normal BO biopsy and aspirate, the most probable diagnosis was BM toxicity due to the administration of antibiotics, which were stopped. The main diagnosis was evident only after 8 months. Looking back, it was unusual to observe such a massively disseminated TB in an HIV-negative patient, with such stable comorbid conditions, and no alcohol consumption in the past 8 years.

TB may precede or accompany the diagnosis of hematologic malignancies, and may also complicate its treatment. TB infection may be associated with both AML and myelodysplastic syndrome (MDS), or other hematologic malignancies [6, 10, 11]. Taking into account the presence of ring sideroblasts [12] and the absence of medical follow-up in the previous 3 years, it is possible that this patient had a previously unnoticed MDS. Mishra et al [6] reviewed TB infection in leukemia patients for 2 years, and described two cases of TB preceding AML diagnosis for 2 months, with no evidence of leukemia at the time of TB diagnosis. This study was conducted on an Indian hospital, where TB has also an elevated incidence, and it was postulated that in such countries there may be a more frequent association between acute leukemia (mainly AML) and TB infection. Another study found that, within the hematologic patients, DTB was more common, and caused febrile neutropenia more frequently, in AML patients [11]. Thus, in this case, the DBT was probably due to a previously unknown MDS, which was not initially recognized because of infection-induced cytopenia, which latter evolved to an AML. It may also be questioned if the presentation with febrile severe pancytopenia may have been due to leukemic transformation.

Literature on DTB is limited, and even more scarce in hematologic patients. There is an apparent susceptibility for TB infection in AML and MDS patients. Moreover, DTB appears to manifest itself more frequently as febrile neutropenia in AML patients. The initial diagnostic of DTB reflects a compromised immune system. Hematologic diseases such as MDS, and especially AML, should be considered as a possible underlying condition in these cases, as DTB may precede or accompany them. Furthermore, it should be considered that globalization may allow for this infection to appear in less affected countries, and go undiagnosed, as they tend to mimic other diseases.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Not applicable.

Author Contributions

Case review and writing: Marta R. Alves, Filipa Rodrigues. Literature review and writing: Marta R. Alves, Tania A. Ferreira, Catarina A. Costa. Paper review: Claudia Pereira, Daniela Barroso.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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