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Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 257-259

Linezolid-induced ringed sideroblastic anemia and thrombocytopenia in a child with extensively drug-resistant tuberculosis

1 Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Pune, Maharashtra, India
2 Department of Pathology, Bharati Vidyapeeth Medical College and Hospital, Pune, Maharashtra, India

Date of Submission16-Apr-2021
Date of Decision29-Sep-2021
Date of Acceptance12-Nov-2021
Date of Web Publication29-Nov-2021

Correspondence Address:
Dr. Bhakti U Sarangi
Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Pune - 411 043, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_117_21

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Background: With the ever-evolving guidelines and changing drug regimens for pediatric tuberculosis (TB), it is paramount for treating physicians to understand the efficacy and safety profiles of the drugs being used. Linezolid is included in the treatment of multidrug-resistant and extensively drug-resistant (XDR) TB in the intensive, as well as continuation phases. Clinical Description: A 12-year-old child with XDR central nervous system TB was treated with second- and third-line anti-tubercular drugs including linezolid. Three weeks after therapy started the boy presented with progressive pallor for a week, lethargy for few days, and rapid breathing since that morning. He was severely pale, acidotic, and in hypotensive shock. Investigations revealed severe anemia, thrombocytopenia, reticulocytopenia, normal liver and renal function, and no evidence of sepsis. He also had severe metabolic acidosis and hyperlactatemia. Management: The child was mechanically ventilated and administered red blood cell and platelet transfusions. The presence of ringed sideroblasts in the bone marrow confirmed acquired sideroblastic anemia. The clinical, hematological, and metabolic toxicities were considered most likely due to linezolid. It was discontinued and his drug regime was modified. There was a rapid symptomatic improvement with supportive therapy and gradual increase in hematological parameters with cessation of linezolid. Conclusions: Clinicians are used to treating Gram-positive infections with short courses of linezolid. Regular and planned monitoring is required when linezolid is used at higher doses and longer durations.

Keywords: Linezolid, ring sideroblasts, sideroblastic anemia, extensively drug resistant tuberculosis

How to cite this article:
Sippy S, Nisal A, Sarangi BU. Linezolid-induced ringed sideroblastic anemia and thrombocytopenia in a child with extensively drug-resistant tuberculosis. Indian Pediatr Case Rep 2021;1:257-9

How to cite this URL:
Sippy S, Nisal A, Sarangi BU. Linezolid-induced ringed sideroblastic anemia and thrombocytopenia in a child with extensively drug-resistant tuberculosis. Indian Pediatr Case Rep [serial online] 2021 [cited 2022 Jan 20];1:257-9. Available from: http://www.ipcares.org/text.asp?2021/1/4/257/331363

The burden of pediatric multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has been recognized as a major public health concern in India. While diagnosing drug-resistant TB is challenging and requires costly laboratory services, access to effective treatment of these conditions is also sometimes difficult. Establishing drug-resistant TB therapeutic regimens is arduous with several of the available drugs being expensive and toxic, and their efficacy uncertain.[1] Efforts have been made towards exploring the role of additional drugs and regimens.

Linezolid, the first oxazolidinone to be developed and approved for clinical use, has emerged as a viable option for the treatment of resistant TB.[2] It is active against a range of bacteria, especially aerobic Gram-positive drug-resistant organisms, such as vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus. and penicillin-resistant pneumococci.[2] After initially being included in “Group 5 drugs” of the World Health Organization treatment guidelines of MDR-TB (i.e., has unclear efficacy, or unclear role), it was upgraded to “Group A” (Fluoroquinolones) in the 2018 New classification of antitubercular therapy (ATT) reserved for MDR and XDR-TB,[3] with caution for close monitoring of adverse events. A variety of dosing strategies have been used for linezolid for drug-resistant TB,[3] and most treatment durations are long.

Though hematological and nonhematological adverse events are common following prolonged Linelozid use, the occurrence of sideroblastic anemia is rare.[4] We report a patient with XDR-TB on second- and third-line ATT who developed ringed sideroblastic anemia with thrombocytopenia following prolonged linezolid therapy.

  Clinical Description Top

A 12-year-old boy, presented with multiple episodes of generalized tonic-clonic seizures for a day. There was no history of fever, vomiting, loose motions, preceding trauma, or ingestion of any drugs or other substances. There was no history of any altered or loss of consciousness, severe headache, projectile vomiting, abnormal posturing, or any recent unusual change in behavior, temperament, or sleep pattern. The child had a significant history of receiving chemotherapy and a stem cell transplant for Hodgkin's lymphoma 2 years earlier. There was no history of Koch's contact or epilepsy in the family. The child was completely immunized.

At admission, the child was afebrile with normal blood pressure and other vital parameters. He was underweight with a body mass index of 17.1 kg/m2. There was no pallor, jaundice, rashes, petechiae, or significant lymphadenopathy. The sensorium was normal. No papilledema was detected in the fundus. There were no cranial or focal neurological deficits or meningeal signs. Plantar reflexes were flexor. The respiratory system was normal and there was no hepatosplenomegaly. Routine investigations were performed to rule of common causes of seizures. The blood sugar, serum electrolytes, liver, and kidney function tests were within normal limits. The hemogram was not suggestive of an acute bacterial infection. Normal platelet counts and coagulation profile ruled out risk factors for an intracranial bleed. At this point, given the background of the lymphoma and a possible immunosuppressed state postchemotherapy, two other differentials were considered; relapse of the malignancy or an indolent infection, involving the brain.

Management and outcome

Magnetic resonance imaging of the brain revealed communicating hydrocephalus with periventricular ooze, suggestive of tubercular meningitis. He was treated with anti-convulsant drugs (intravenous [IV] Leveracetam and Fosphenytoin), hyperosmolar therapy, and other neuroprotective measures. Pleocytosis and elevated proteins were reported in the cerebrospinal fluid. No acid-fast bacilli were detected in the sputum and the chest radiograph was normal. First-line ATT was started with pyridoxine considering central nervous system (CNS) TB. The human immunodeficiency virus status was nonreactive. Subsequently, the nucleic acid amplification test was positive for XDR-TB, and the diagnosis was modified to XDR CNS TB.

ATT was changed to second- and third-line drugs as per standard guidelines; pyrazinamide, cycloserine, clofazimine, ethionamide, and meropenem. After 3 weeks, the mycobacteria growth indicator tube culture report became available, demonstrating resistance to pyrazinamide. Hence, it was omitted and linezolid was added (600 mg twice a day) instead. The child underwent a ventriculoperitoneal shunt insertion in the 4th week, and was discharged within 7 days. The family was counseled regarding ATT and the need for close follow-up.

After 3 weeks he returned with progressive pallor for a week, lethargy for a few days, and fast breathing since that morning. There was no history of any fever, bleed from any site, seizures, headache, vomiting, diarrhea, or abdominal pain. At admission, he had tachypnea (acidotic breathing) and features of hypotensive shock (tachycardia, bounding pulses, and blood pressures <5th percentile for age). The child was severely pale, but there was no icterus, or signs of cutaneous bleeds. There was no evidence of congestive heart failure or any other salient findings on the systemic examination.

A clinical diagnosis of severe anemia in acute respiratory failure with hypotensive shock was kept. Severe metabolic acidosis and high levels of lactate were detected on arterial blood gas analysis. The child was started on IV fluids with adrenaline infusion and electively ventilated. Salient hemogram findings were hemoglobin (Hb) of 2.8 g/dl, mean corpuscular volume 81 fL normal total leukocyte counts, platelets 25,000/cmm, and reticulocyte count 0.5%. The peripheral blood smear showed predominantly normocytic normochromic erythrocytes, absence of hemolysis. Direct Coomb's test was negative. Blood sugar, serum electrolytes, liver, and renal function tests were normal. Biomarkers for infection and cultures were negative. The child was transfused with 2 units of packed cell volume (PCV). Once he became symptomatically better, ventilation was discontinued.

Bone marrow aspiration was done [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, considering the possibility of drug-induced myelosuppression. The erythroid series showed relative hyperplasia with normoblastic erythropoiesis, and a few macronormoblasts displaying features of dyserythropoesis. Ring sideroblasts were present. The myeloid series showed normal maturation, whereas megakaryocytes were reduced. The most likely candidate was linezolid, given the combination of sideroblastic anemia, thrombocytopenia, metabolic acidosis, and elevated lactates, all known associations with its therapy. Linezolid was stopped and oral clofazimine, cycloserine, ethambutol and clarithromycin were continued. The child received another PCV transfusion and platelet transfusion. Over the next 2 weeks, serial hemograms demonstrated an increasing trend in the levels of Hb and platelet counts. Though isoniazid (INH) and cycloserine can also cause sideroblastic anemia,[5] we did not consider them seriously as the duration of INH had been brief, and hematological parameters improved despite continuing cycloserine. Thus, the final diagnosis was Linelozid induced sideroblastic anemia and thrombocytopenia. He was discharged on the revised ATT. A month afterward the Hb had increased to 9.6 g/dl and platelet count to 1.2 lakhs/cmm.
Figure 1: (a and b) Pearls Prussian blue stain showing many ringed sideroblasts (c and d) relative erythroid hyperplasia with normoblastic erythropoiesis. Few macronormoblasts are seen with features of dyserythropoiesis in the form of irregular nuclear contours, bilobed nuclei, karryorhexsis, and nuclear budding

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  Discussion Top

Sideroblastic anemias are a heterogeneous group of disorders characterized by ring sideroblasts in the bone marrow and impaired heme biosynthesis.[5] The ring sideroblast is a pathological erythroid precursor that contains excessive deposits of nonheme iron in the mitochondria. These cells are identified on Prussian blue staining of the bone marrow aspirate, in which bluish-green inclusions (siderosomes) can be seen as a “ring” around the nucleus.[6] Sideroblastic anemia may be secondary to alcohol, drugs (i.e., chloramphenicol, pyrazinamide, D-penicillamine, and progesterone), toxins (arsenic and lead), nutritional deficiencies (copper and pyridoxine), myelodysplastic syndrome, or idiopathic in origin.[5]

With the increasing burden of XDR-TB in low- and middle-income countries, several new treatment options are being explored. Since the duration of treatment is longer than first-line ATT, the safety and tolerability of these require thorough investigation. The National TB Elimination Program prescribes Linezolid in MDR, as well as XDR-TB, in both intensive and continuation phases.[7] It has been recognized as a promising drug.[8] However, there are reports of variation in safety profiles related to dosage and duration of therapy.[9] The spectrum of adverse effects is hematological (anemia, leukopenia, and thrombocytopenia), neurological and gastrointestinal.

The anti-bacterial mechanism of action of Linezolid is the disruption of protein synthesis by the binding of the drug to the 70S initiation complexes in the bacterial ribosomes. However, the same mechanism also allows it to bind to human mitochondria and inhibit protein synthesis, resulting in its toxicity.[3] Ring sideroblasts develop due to abnormal intracellular iron metabolism with deposition within the mitochondria. Thrombocytopenia is attributed to the suppression of the final step of platelet release from mature megakaryocytes, as well as immune-mediated platelet destruction.[10] The mainstay of treatment is the withdrawal of the drug and supportive therapy.

Clinicians are used to treating Gram-positive infections with short courses of linezolid. Regular and planned monitoring is required when linezolid is used at higher doses and longer durations. When this drug is used in ATT, the treating physician should be aware of its side effects, tell parents about warning signs and regularly monitor clinical, hematological, and metabolic parameters for early detection to avoid life-threatening situations.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Chang KC, Yew WW. Management of difficult multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis: Update 2012. Respirology 2013;18:8-21.  Back to cited text no. 1
Ballow CH, Jones RN, Biedenbach DJ. A multicenter evaluation of linezolid antimicrobial activity in North America. Diagn Microbiol Infect Dis 2002;43:75-83.  Back to cited text no. 2
Singh B, Cocker D, Ryan H, et al. Linezolid for drug-resistant pulmonary tuberculosis. Cochrane Database Syst Rev 2019;3:CD0128.  Back to cited text no. 3
Willekens C, Dumezy F, Boyer T, et al. Linezolid induces ring sideroblasts. Haematologica 2013;98:e138-40.  Back to cited text no. 4
Bottomley SS, Muller-Eberhard U. Pathophysiology of heme synthesis. Semin Hematol 1988;25:282-302.  Back to cited text no. 5
Montpetit MC, Shammo JL, Loew J, et al. Sideroblastic anemia due to linezolid in a patient with a left ventricular assist device. J Heart Lung Transplant 2004;23:1119-22.  Back to cited text no. 6
Singh V, Parakh A. What is new in the management of childhood tuberculosis in 2020? Indian Pediatr 2020;57:1172-6.  Back to cited text no. 7
Zhang X, Falagas ME, Vardakas KZ, et al. Systematic review and meta-analysis of the efficacy and safety of therapy with linezolid containing regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis. J Thorac Dis 2015;7:603-15.  Back to cited text no. 8
Sotgiu G, Centis R, D'Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: Systematic review and meta-analysis. Eur Respir J 2012;40:1430-42.  Back to cited text no. 9
Tajima M, Kato Y, Matsumoto J, et al. Linezolid-induced thrombocytopenia is caused by suppression of platelet production via phosphorylation of myosin light chain 2. Biol Pharm Bull 2016;39:1846-51.  Back to cited text no. 10


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