We report the case of a 43-year-old Dominican man with no medical history or regular medication who was admitted for a 1-month history of fever in the evening, low back pain radiating to the lower limbs, and constitutional symptoms. Computed tomography showed left laterocervical lymphadenopathies, central lobular nodules in the middle pulmonary lobe, collections in the left psoas-iliac muscle extending to the obturator and adductor, and L1–L2 spondylodiscitis. Magnetic resonance imaging revealed intravertebral collections in L1 and L2 and another perivertebral collection.

Ultrasound-guided puncture of the psoas abscess was performed. The sample was sent to the microbiology lab for culture and auramine staining: sputum smear revealed 1–9 acid-alcohol-resistant bacilli per 10 fields at 250X. PCR was positive for Mycobacterium tuberculosis, and no rifampicin resistance was detected by GeneXpert MTB/RIF. The adductor muscle abscess was drained surgically. HIV serology was negative.

Treatment began with isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z), and continued for 3 months due to the extensive involvement and the existence of undrained intra- and perivertebral collections. Culture of the abscess grew HREZ and streptomycin-sensitive Mycobacterium tuberculosis. The patient tolerated treatment well, with normal liver function and blood counts.

At the end of the third month, E-Z was discontinued, and H-R was maintained. At month 5 of treatment, the patient presented neutropenia that progressed to 500 neutrophils/μL (2,780 leukocytes/μL) by month 6. He also developed a severe adverse reaction to granulocyte colony-stimulating factor (sudden dyspnea). Initially, neutropenia due to R was suspected, so this drug was withdrawn and, in order not to continue treatment with H alone, E and moxifloxacin (MFX) were added. Neutropenia worsened, falling a week later to 370 neutrophils/μL. All treatment was discontinued, and a bone marrow aspirate was performed that ruled out central neutropenia. PCR for Mycobacterium tuberculosis in the bone marrow was negative.

Neutropenia resolved 1 week after complete discontinuation of treatment. Only R was restarted because it was the most important drug in the treatment of tuberculosis1 and because the patient’s neutropenia had worsened with H-E-MFX. In order to determine whether R was also involved in neutropenia, it was prescribed in increasing doses until the ideal dose was reached within a week. Two weeks after this reintroduction, the patient once again showed a progressive reduction of neutrophils, that fell to 570/μL, so R was definitively discontinued.

Three weeks later, once the blood count was normalized, H was reintroduced. There were no incidents with respect to blood count and E-MFX was added. The combination of these 3 drugs was maintained for the following 4 months, and neutrophil levels remained above 800/μL, allowing for a total of 12 months of treatment. At all times the neutropenia was asymptomatic and the patient remained afebrile. The collections on the magnetic resonance imaging disappeared and neutropenia resolved after completing treatment. Given the good clinical and radiological progress, drainage of most of the collections, treatment with R for almost 6 months, and the persistent neutropenia, we decided not to prolong the treatment for 18 months, as recommended in cases of R intolerance.2

Treatment of tuberculosis requires combinations of 3–4 drugs for long periods of time (6–9 months is recommended in the case of vertebral involvement).2 The combined use of several drugs increases the chances of adverse reactions. In the case of the standard HRZE scheme, hepatotoxicity is the most frequent adverse effect, but there are other less common but serious issues, such as hematological events and, in this case in particular, neutropenia.3

The incidence of leukopenia observed in the seminal studies on H-R regimens is between 2% and 10%,4,5 but less than 1% in the specific case of neutropenia.4 In fact, since Ferguson first described the association between H and neutropenia during treatment in a patient with tuberculosis in 1952,6 isolated cases have been reported.7

Among the first-line drugs, H may be the one most frequently associated with neutropenia,8 but it has also been described with R9 and E10; among second-line drugs, linezolid is the one most frequently involved.3

It should be noted that the onset of neutropenia in this patient was late, which justifies the recommendations of the SEPAR 2010 guidelines for performing complete blood counts both at the beginning of treatment and at months 2, 4, and 6.11 The fact that it occurs after a long exposure time suggests an immune mechanism rather than direct bone marrow damage.12

Different courses have been described in the literature: in some cases, the therapeutic regimen had to be modified, while in others, neutrophil concentrations stabilized at safe levels, so treatment could be completed. In fact, in the study by Lee et al. of 825 patients with no hematological history who started first-line treatment for tuberculosis, 185 developed leukopenia, 109 of whom continued treatment: neutropenia resolved during treatment in 30% and in the rest, it normalized after completion.13 The use of colony-stimulating factors to induce medullary neutrophil production has been proposed as an alternative.14

Our patient’s neutropenia reappeared unequivocally after isolated reintroduction of R and in the absence of other drugs, so its association with neutropenia can be defined as “certain” according to the WHO causality classification.15 However, his neutrophil count did not completely normalize until the antituberculous treatment including H was completed, so it is reasonable to think that both drugs contributed to the etiology of the neutropenia.

In short, our intention is to warn of this hematological toxicity that may appear with tuberculosis treatment (especially H and R) and to share our particular experience on its progress and management, in case it could be of help to the rest of the scientific community.