Autor :Flores, Verónica1,2,,Trullas, María Florencia1,2, Jajati, Mónica1,2, Sívori, Martín1,2
1 Pulmonology University Center “Dr. J. M. Ramos Mejía”, Faculty of Medicine, University of Buenos Aires 2 Pulmonology and Tisiology Unit. Hospital General de Agudos “Dr. J. M. Ramos Mejía”, Autonomous City of Buenos Aires
https://doi.org/10.56538/ramr.UGWO1087
Correspondencia : Verónica Flores, Urquiza 609, Zip code: 1405, Buenos Aires, Argentina; e-mail: vero.fmn@gmail.com
ABSTRACT
The leading cause of death from a
contagious infectious disease worldwide is attributable to Mycobacterium
tuberculosis infection. Extrapulmonary tuberculosis
accounts for 20-25% of cases of tuberculous disease.
Frequently, in order to reach the diagnosis of these sites, invasive diagnostic
tests have to be used.
We present the case of a
17-year-old patient with extrapulmonary tuberculosis
with bone marrow involvement. The patient wasn’t immunocompromised,
and had the following symptoms: fever, asthenia, weight loss, tricytopenia and hepatosplenomegaly,
without other significant clinical findings. The diagnosis was reached by
positive culture for tuberculosis in bone marrow puncture aspiration/biopsy
material
After one month of treatment with
isoniazid, pyrazinamide, ethambutol and rifampicin,
the patient evolved with fever episodes, even after having received antibiotics
for urinary tract infection caused by Klebsiella
pneumoniae. Thus, oral corticosteroid therapy was
started, with good response. The patient discontinued treatment after three and
a half months due to poor adherence.
Key words: Extrapulmonary tuberculosis, Bone marrow, Cytopenia,
Tuberculosis
RESUMEN
La
primera causa de muerte por enfermedad infecto-contagiosa a nivel mundial es
atribuible a la infección por Mycobacterium tuberculosis.
La tuberculosis extrapulmonar representa entre un
20-25% de los casos de enfermedad tuberculosa. Frecuentemente, para arribar al
diagnóstico de dichas localizaciones, se debe recurrir a pruebas diagnósticas
invasivas.
Se
presenta el caso de un paciente de 17 años de edad con compromiso extrapulmonar de tuberculosis en médula ósea sin inmunocompromiso conocido, con síntomas de fiebre, astenia,
pérdida de peso, tricitopenia y hepatoesplenomegalia,
sin otros hallazgos clínicos significativos.
Se
arriba al diagnóstico por cultivo positivo para tuberculosis en material de
punción/ biopsia de médula ósea.
Luego
de un mes de tratamiento con Isoniacida, Pirazinamida, Etambutol y Rifampicina evoluciona con registros febriles, aún después
de recibir antibióticos por infección urinaria por Klebsiella
pneumoniae, por lo cual se inicia corticoterapia
oral con buena respuesta. El paciente abandona tratamiento luego de tres meses
y medio por mala adherencia al mismo.
Palabras
clave: Tuberculosis
extrapulmonar, Médula ósea, Citopenias,
Tuberculosis
Received: 09/29/2023
Accepted: 11/25/2023
INTRODUCTION
Infection by Mycobacterium
tuberculosis (MTB) still remains the leading cause of death from a contagious
infectious disease worldwide.1 Up to 25% of
the tuberculosis cases show extrapulmonary involvement.2-3 It is caused by hematogenous and
lymphatic dissemination of the MTB bacillus to other organs. The most frequent
extrapulmonary sites are the lymph node, pleural and osteo-articular sites.2-3
The problem with these forms of tuberculosis (TB) lies in the
difficulty in reaching a definitive diagnosis, since both clinical symptoms and
direct bacteriological (paucibacillary forms) and imaging
tests can be non-specific. Most of the time it is necessary to resort to
invasive diagnostic tests for the collection of biological samples for the genotypic
diagnosis, culture in liquid or solid media or anatomic pathology.2-3
In immunocompetent
and immunocompromised patients, the presentation in
the bone marrow as the only form of extrapulmonary
involvement is very rare, and there is little information in the literature.4-10 In general,
it is associated with disseminated miliary forms.7-11
The aim of this presentation is
to describe the case report of a patient in whom bone marrow involvement was
the only extrapulmonary site of tuberculosis.
CASE REPORT
Male patient, 17 years old, with
no relevant history. The patient was admitted with one month of clinical
evolution characterized by fever episodes, unquantified
weight loss, night sweats, and adding in the last four days epistaxis and
bleeding flictenas in the jugal
mucosa. He did not report cough or expectoration. He had no close contact with
people with respiratory symptoms.
He presented tricytopenia
in the admission laboratory tests, so it was decided to admit him to the
General Medicine Ward. There were no significant findings on physical
examination. There was no history of immunocompromised
disease.
Complementary tests were
performed, blood cultures and urine culture (without bacteriological rescue),
negative serological testing for human immunodeficiency virus, hepatitis A, B
and C, cytomegalovirus and Parvovirus B19; negative PPD (purified protein
derivative); echocardiogram with no vegetations,
abdominal ultrasound showing hepatosplenomegaly
without pathological findings, chest X-ray without pleuropulmonary
pathology. A full body CT scan was performed and the only relevant finding was
homogeneous hepatosplenomegaly. A positron emission
tomography was requested with evidence of splenomegaly without pathological
uptake. As the patient continued with fever episodes and tricytopenia,
a consultation was made with the Hematology Department: a bone marrow puncture
aspiration and biopsy were performed, showing hypercellularity
for age with dysplasia in the erythroid and
megakaryocytic series. A sample was sent for culture in Lowenstein Jensen’s
solid medium, which reported growth of Mycobacterium tuberculosis, so
self-administered treatment was started with isoniazid 5 mg/kg/day, rifampicin
10 mg/kg/day, pyrazinamide 25 mg/kg/day and ethambutol
20 mg/kg/day orally. The antibiogram reported
sensitivity to isoniazid and rifampicin. The patient evolved with daily fever
episodes despite receiving anti-tuberculous
treatment, so blood cultures without rescue, and urine
culture (Klebsiella pneumoniae)
were performed. He completed seven days of treatment with imipenem
without changes in the thermal curve. After being evaluated by the Hematology
Department, other causes of hematological involvement were discarded. On day 32
of anti-tuberculous treatment, it was decided that
the patient should be started on oral corticosteroid therapy (meprednisone 40 mg/day orally) with good response. The
patient evolved afebrile and without complications, with improvement of
hematological parameters twenty days after starting meprednisone.
He was discharged from hospital after 52 days of anti-tuberculous
treatment and on replacement therapy with hydrocortisone. He continued
treatment on an outpatient basis with regular adherence and clinical
improvement. Subsequently, he discontinued anti-tuberculous
treatment after three and a half months. A bone marrow biopsy was still
pending.
DISCUSSION
Due to the biological
characteristics of the MTB bacillus, it is able to affect almost any tissue. Extrapulmonary TB can present with various hematological
manifestations frequently associated with the involvement of other organs,
including pancytopenia.2-3 Pancytopenia
could be due to hypersplenism, maturation arrest, hemophagocytic lymphohistiocytosis,
and infiltration of the bone marrow by caseating or noncaseating granulomas that cause reversible or
irreversible fibrosis.10-13
Extrapulmonary TB is defined according to the classification criteria of the World
Health Organization as an infection produced by MTB that affects tissues and
organs outside the pulmonary parenchyma. It accounts for 20-25% of the cases of
tuberculous disease.1
It is the result of hematogenous
and lymphatic dissemination of the MTB bacillus. As a result of this
dissemination and thanks to the development of specific cellular immunity,
including the formation of anti-tumor necrosis factor antibodies,
interleukin-12 and interferon gamma, protective immunity is created against
the bacterium, with the consequent formation of encapsulated granulomas
containing viable bacilli inside.1
In our service between 1979 and
2019, 4,283 patients were diagnosed with various forms of TB presentation, but
there was only one case with bone marrow involvement as unique site of disease
presentation (prevalence 0.02%). We present the case of a 17-year-old patient
with hematological alterations (tricytopenia), asthenia,
fever and weight loss, with no other positive findings on physical examination,
no known immunocompromise,
negative cultures, negative serology and hepatosplenomegaly.
Bone marrow puncture aspiration was performed and Lowenstein Jensen’s solid
medium culture allowed the diagnosis of TB.
Extrapulmonary TB can present with various hematological manifestations. Various
hematological manifestations in patients with pulmonary and extrapulmonary TB have been described.7-11 Normochromic normocytic anemia was the most
common abnormality observed in all studies.7,11 Other hematological abnormalities of white
blood cells include leukopenia, neutropenia, lymphocytopenia,
monocytopenia, leukocytosis, neutrophilia,
lymphocytosis and monocytosis.3,7 Pancytopenia
was observed only in patients with disseminated TB and can be explained by
granulomatous TB infiltration, macrophage activation syndrome or hemophagocytic lymphohistiocytosis
syndrome.5-6 This often
fatal syndrome responds to an ineffective inflammatory response, characterized
by excessive macrophage and T-cell activation, as well as decreased activity of
natural killer and cytotoxic lymphocytes to attack infected cells. This results
in uncontrolled histiocytic phagocytosis of mature
blood cells and their precursors in the reticuloendothelial
system. Our patient had hepatosplenomegaly. This
disproportionate response leads to cytokine-mediated multiple organ
dysfunction.5-6 Another
explanation that we ruled out which could explain hepatosplenomegaly
is as a clinical form of presentation of disseminated TB.7,11 In general, when there is hepatic involvement
due to TB, liver enzymes tend to be elevated (this was not the case in our
patient), and if the spleen is also involved, hepatosplenic
radiological lesions can often be observed (for example, single or multiple
nodules) on abdominal CT scan or abdominal ultrasound (again, this was not the
case).
In a series of 22 cases in Saudi
Arabia reported by Hakawi et al, 55% had no history
of immunocompromise, as did some reported cases and
our patient.8,11
Thrombocytopenia was also very
common in patients with disseminated TB and thrombocytosis in patients with
pulmonary TB.6,7
Bone marrow puncture aspiration or biopsy are useful to confirm
the bacteriological and/or histological diagnosis.9
Late diagnosis of extrapulmonary forms
is frequent and leads to increased morbidity and mortality. Symptoms and signs
can be relatively vague and sometimes present on normal chest X-rays and in
patients with negative bacilloscopy, making it
difficult to consider the disease in the initial approach.3
In many case reports or the
Indian series of 32 cases with disseminated forms and 23 pulmonary cases with
bone marrow involvement, evolution with anti-TB treatment was favorable, but in
the series of 22 cases of Hakawi et al 45% of
patients died probably due to immunocompromise associated
with disseminated forms.7-11 Our patient
began treatment with four first-line drugs for TB and due to the lack of response
after the first month, systemic corticosteroids were added, and the patient
evolved until the fever disappeared. Unfortunately, follow-up was lost after
multiple dropouts due to poor adherence and social vulnerability of the
patient.
Regarding the use of
corticosteroid therapy in TB, only with a high level of evidence it can be
recognized for the treatment of tuberculous
meningitis and pericarditis.13 There is in
vitro evidence that corticosteroids in MTB infection can protect pulmonary
fibroblasts from mycobacterial death and reduce intracellular bacterial growth
in human monocyte-derived macrophages.14-16 They would prevent necrotic cell death of
MTB-infected cells by facilitating mitogen-activated protein kinase-dependent dephosphorylation. These findings could explain how the use
of corticosteroids could be beneficial in specific cases of TB treatment.12-14 However, there is no evidence for their use in a clinical
situation as that of our patient.
In conclusion, we present a very
rare case of extrapulmonary TB with bone marrow
involvement without known immunocompromise. A high
index of suspicion of TB is required and other hematological diseases must be
discarded. In our case report the diagnosis was made by culturing bone marrow
puncture aspiration/biopsy material for TB in a patient presenting with tricytopenia under study and symptoms of fever, asthenia
and weight loss without any other significant clinical finding.
Conflict of interest: Authors have no conflicts of interest to declare.
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