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Vacuolation of early erythroblasts with ring sideroblasts: a clue to the diagnosis of linezolid toxicity

While examining the bone marrow aspirates of a 72-year-old woman with knownmyelodysplastic syndrome with excess blasts 2 (controlled by azacitidine) we were struck by the remarkable number of vacuolated erythroblasts. Twenty-four days earlier, she had been hospitalised because of severe sepsis, renal dysfunction and right orbital cellulitis with purulent drainage from the right orbit caused by Staphylococcus aureus. Initial laboratory tests had shown a white blood cell count of 23 9 10/l (92% neutrophils), haemoglobin concentration (Hb) 126 g/l and platelet count 327 9 10/l. Intravenous linezolid (600 mg every 12 h) had been started and during the ensuing 17 days her condition improved. However, during the following week, she developed progressive hearing loss, abdominal distention, hypoactive bowel sounds and pancytopenia. On the 24th hospital day, Hb was 65 g/l, mean corpuscular volume (MCV) 82 fl, white blood cell count 2.6 9 10/l and platelet count 33 9 10/l. The absolute reticulocyte count was 1.2 9 10/l; serum vitamin B12 and folate levels were normal. Bone marrow aspiration was done because of the pancytopenia. Vacuolation was seen mainly in the proerythroblasts and basophilic erythroblasts, rarely in the late polychromatophilic cells. The vacuoles were present in the cytoplasm, and sometimes overlay the nucleus (left image). They showed no reaction with periodic acid–Schiff staining. The percentage of blasts was not elevated. Iron was abundant in fragments; 10% of the nucleated red cells were ring sideroblasts, 27% contained partial rings, 22% contained multiple coarse siderotic granules and 41% contained no granules (right image). In view of the vacuolation, we considered a toxic effect on the bone marrow. Linezolid was stopped, and intravenous glucose infusion for caloric support and vitamins of the B complex including thiamine, riboflavin, nicotinamide and pyridoxine were initiated. A repeat bone marrow aspirate performed 13 days later showed that vacuoles and ring sideroblasts were no longer present. Gradually, haematological abnormalities regressed, and there was improvement in hearing at midfrequencies but with persistent low-frequency sensorineural hearing loss. Vacuolation of early erythroblasts is well described in acute alcoholism, chloramphenicol toxicity, riboflavine deficiency, copper deficiency, acute erythroid leukaemia, phenylalaninedeficient states, marasmus and kwashiorkor. The mechanism of vacuole formation in our patient may be mitochondrial injury since linezolid disrupts mitochondrial protein synthesis. The occurrence of erythroid vacuoles synchronously with her hearing symptoms and gastrointestinal dysmotility suggests a common aetiology. Vacuolation of erythroid precursors with ring sideroblasts has been reported previously with linezolid. When confronted with a disturbance of haemopoiesis, the haematologist must determine whether it is due to a disorder primarily involving the haemopoietic system or is secondary to an underlying systemic disease or drug therapy. This case illustrates the significance of vacuolation of early erythroblasts together with ring sideroblasts as a clue to linezolid toxicity.