Ethambutol-Associated Thrombocytopenia: A Rare Case Report of Drug-Induced Platelet Decline in Tuberculosis Treatment

Introduction

Ethambutol (EMB), in combination with isoniazid, rifampin, and pyrazinamide, is recommended during the initial treatment of tuberculosis (TB) pending susceptibility results, particularly to limit the selection of isoniazid-resistant bacteria in cases of rifampin-resistant strains [1]. EMB is also a cornerstone for the treatment of atypical mycobacteria and is considered the best companion drug for preventing the emergence of macrolide resistance [2]. Apart from ocular and occasional cutaneous reactions, EMB is seldom associated with toxicity [3]. We report a case of EMB-induced thrombocytopenia in a patient with lymph node TB requiring discontinuation of the drug.

Case Report

A 41-year-old man presented to Cayenne Hospital in July 2023 with a progressive enlargement of cervical lymph nodes that had been present since April. He arrived in French Guiana in January 2023, following a 2-year migration from Afghanistan. His medical history included pulmonary TB, treated for only 2 months, 20 years earlier, without any reported adverse effects. He also had hypertension, renal colic, and stage 5 chronic kidney disease (CKD) [4]. He did not report any drug allergy. His treatment consisted of darbepoetin alfa 100 μg subcutaneously once weekly, amlodipine 10 mg/day, pantoprazole 40 mg twice daily, sevelamer 800 mg 3 times daily, folic acid, polystyrene sulfonates, ferrous sulfate, calcium, and sodium bicarbonate. Physical examination revealed bilateral basilar cervical lymph nodes that were soft, tender to palpation, up to 6 cm in maximum diameter, and not adherent to the skin or deep tissues.

Mycobacterium tuberculosis complex was detected in lymph node aspiration fluid by Xpert MTB/RIF Ultra assay, without rpoB gene resistance mutations. There was no clinical or imaging evidence of TB elsewhere. Standard anti-TB treatment was initiated on August 19 (DantiTB 0). Daily doses were weight-adjusted (59 kg) and modified for renal function, with an estimated glomerular filtration rate of 7 mL/min/1.73 m2 (CKD-EPI), as follows: isoniazid 300 mg/day, rifampin 600 mg/day, ethambutol 1000 mg every other day, pyrazinamide 2000 mg every other day, and pyridoxine 250 mg/day, while continuing his usual medications (Figure 1). At baseline, the patient had CKD-related anemia (hemoglobin 7.1 g/dL) and a platelet count of 304×109/L.

During follow-up on August 31 (DantiTB 12), a significant reduction in cervical lymph nodes was noted, confirming good treatment compliance. The patient reported the onset of pruritic papules on the lateral surfaces of the fingers beginning August 26 (DantiTB 7). He self-medicated with cetirizine and prednisone (1 mg/kg) on August 30. Dyshidrotic eczema was considered the most likely diagnosis, and systemic corticosteroids and cetirizine were discontinued. Blood test results on August 28 (DantiTB 10) were stable. On September 8 (DantiTB 20), the patient reported improvement of his skin lesions and good compliance and clinical tolerability of the anti-TB treatment. However, on September 4 (DantiTB 16), he developed thrombocytopenia, with a platelet count 120×109/L, confirmed by blood smear and a second blood test performed on September 6 showing a platelet count of 86×109/L. He did not report headache, fever, or other concomitant events suggesting a concomitant viral infection. Therefore, given the patient’s geography and good clinical outcome after 3 weeks of appropriate treatment, our estimate of the probability of isoniazid resistance was low. Given the described, albeit rare, cases of EMB-induced thrombocytopenia, we decided to stop EMB on September 9 (DantiTB 21, Dstop 0) but maintain the same regimen otherwise. In September, the patient presented to the Emergency Department with hypertensive pulmonary edema and suspected acute coronary syndrome, due to chest pain, elevated troponin levels, and electrocardiographic abnormalities. He was admitted to the Intensive Care Unit and received isosorbide dinitrate, furosemide, and lercanidipine for pulmonary edema, and aspirin, clopidogrel, and unfractionated heparin for suspected coronary syndrome. Thrombocytopenia stabilized between 72 and 108×109/L on September 11 (DantiTB 23, Dstop 2). Coronary syndrome was eventually ruled out, and the final diagnosis was acute pulmonary edema secondary to hypervolemia with ion imbalance. On September 14 (DantiTB 26, Dstop 5), the patient had a platelet count of 131×109/L. He was eventually discharged from the hospital on September 26 with a platelet count of 274×109/L, which had been maintained through the last follow-up on January 31, 2024.

Discussion

To the best of our knowledge, only 2 cases of thrombocytopenia secondary to EMB have been published [5,6]. In both reports, an isolated thrombocytopenia occurred within the first week of treatment, with no evidence of overdose. Discontinuation of EMB resulted in normalization of platelet levels within 1 week, which strongly supports drug toxicity caused solely by EMB. In the present case, given the antibiogram results, no EMB reintroduction test was performed. The Naranjo causality score was +6 (Figure 2), indicating that EMB was probably responsible for the adverse reaction [7]. In a reported case in which reintroduction was attempted, a rapid relapse occurred [6]. The mechanism of thrombocytopenia remains unknown. In 1 case [5], the authors suggested an immune mechanism. However, the rapid onset and normalization of thrombocytopenia suggests a toxic mechanism. Nevertheless, it is important to note that rifampin remains the most common cause of anti-TB treatment-related thrombocytopenia and should be the first consideration in cases of thrombocytopenia [8]. In our case, we suspected a sensitive strain (later confirmed by antibiogram) that does not require EMB in regions where drug-resistant TB is not endemic [9]. This allowed easy identification of EMB involvement without the need for sequential reintroduction. Of note, the dyshidrotic eczema may have been secondary to EMB, as its association with EMB has been suggested previously [10].

Conclusions

Although rare, EMB-induced thrombocytopenia appears to be a real phenomenon, occurring within the first 2 weeks of treatment and resolving rapidly after EMB discontinuation.