Systemic chloroquine intoxication: a hint from the peripheral blood smear.

Abstract

A 49-year-old female with a 14-year history of systemic lupus erythematosus (SLE) was treated with hydroxychloroquine (HCQ) since the diagnosis was established. In 2017, she was switched to chloroquine (CQ, 300 mg per day) because of refractory discoid lupus. During the following year, she progressively developed renal failure, cardiomyopathy, retinal changes and neutropenia. Kidney biopsy did not reveal any sign of lupus nephritis (negative immunofluorescence staining), but instead a Fabry-like disease compatible with the diagnosis of systemic CQ intoxication (including eye, heart, skeletal muscle and kidney involvement). Genetic testing for Fabry disease was negative. A peripheral blood smear performed during a phase of neutropenia (lowest neutrophil count: 0.59 × 109/L) revealed structural abnormalities of polymorphonuclear cells, monocytes and lymphocytes (Image 1). Most of the neutrophils had abnormally clustered cytoplasmic granules, and minor nuclear abnormalities such as thin chromatin bridges. Absolute lymphocyte count was normal (1.83 × 109/L) but most of the lymphocytes were vacuolated, often with azurophilic granulations surrounding the vacuoles. These morphological aspects were similar to those generally observed in storage diseases, like mucopolysaccharidosis. While no structural abnormalities were found in erythrocytes nor in platelets in the peripheral blood smear, transient anemia (hemoglobin lowest value: 7.2 g/dL) and thrombocytopenia (lowest value: 117 × 109/L) were also noted in the absence of any SLE activity. For comparison, a peripheral blood smear from the same patient analyzed in 2016, before CQ introduction, revealed no cytologic abnormalities. Moreover, after CQ interruption the neutropenia and all cytologic abnormalities disappeared. In order to further investigate these abnormalities, we conducted an electron microscopic analysis of the leukocytes which confirmed a pattern of lysosomal storage disease (Image 2). Phospholipidosis is a pathological condition in which phospholipid excessively accumulates in cells and tissues.1, 2 Chloroquine and HCQ have been shown to induce a wide spectrum of organ toxicity (bull's eye retinopathy, cardiomyopathy, Fabry-like renal disease) associated with histopathological lesions characteristic of phospholipidosis.3, 4 Many reports suggest that CQ is far more toxic than HCQ.5 Chloroquine-induced structural abnormalities on white blood cells have been previously described in both experimental6, 7 and clinical settings.8, 9 This case highlights several novel considerations. First, the structural changes observed in white blood cells were associated with systemic CQ intoxication involving multiple organs. The resolution of these abnormalities paralleled the improvement of others organs involved (especially heart and kidney function). Second, the structural cellular abnormalities were associated with a reversible neutropenia, anemia and thrombocytopenia suggesting that CQ toxicity may generally affect bone marrow function. Furthermore, in the setting of SLE, a new-onset neutropenia should raise concerns about HCQ/CQ toxicity and not solely be attributed to ethnicity or SLE activity itself. Finally, we propose that the structural changes observed in leukocytes may serve as a noninvasive tool to further elucidate suspected systemic CQ intoxication. The value of a peripheral blood smear as a diagnostic tool for HCQ/CQ toxicity in other organs needs to be further evaluated. MPdC, CS, AM and ZA participated in the concept and the design of the study, data acquisition, analysis and the interpretation of data; they drafted, revised and provided final approval of the manuscript. All other authors substantially contributed to the data acquisition and provided final approval of the manuscript. None.