Abstract: Reactive hemophagocytic syndrome has various causes (1Reiner A.P. Spivak J.L. Hematophagic histiocytosis: a report of 23 new patients and a review of the literature.Medicine. 1988; 67: 369-388Crossref PubMed Scopus (389) Google Scholar). We report two cases of hemophagocytosis in the setting of severe drug hypersensitivity syndrome related to glycopeptide and trimethoprim-sulfamethoxazole. The first case was a 45-year-old woman who had been admitted for an inflammatory scar 1 month after changing a dysfunctional pacemaker. A superficial abscess was incised, and a coagulase-negative Staphylococcus was recovered. Intravenous vancomycin was started. On the 10th day of treatment, fever (39°C) occurred, accompanied by a pruriginous maculopapulous rash. The patient's white blood cell count was 2300/mm3. Vancomycin was replaced with teicoplanin, but the fever persisted. The rash developed into a large urticaria, and painful cervical lymphadenopathies appeared. Teicoplanin was stopped after 5 days, but symptoms persisted. Three days after glycopeptide therapy was stopped, the patient was transferred to our unit for investigation of the fever. On examination, the patient's temperature was 39.4°C; she had a weight loss of 2 kg, sweats, 1- to 2-cm cervical bilateral lymphadenopathies, and a discrete maculous rash on the trunk. Abnormal laboratory tests showed an inflammatory syndrome and a white blood cell count of 2240/mm3, with 1380 neutrophils/mm3. A transesophageal echocardiographic and an abdominothoracic computed tomographic (CT) scan were normal. Pancytopenia developed progressively (white blood cell count, 1000/mm3, with 100 neutrophils/mm3; hemoglobin, 8 g/dL; platelets, 100,000/mm3, with cytolysis [alanine aminotransferase and aspartate aminotransferase, 6N]). Fibrinogen level decreased to 1.6 g/L. A bone marrow biopsy revealed hemophagocytosis associated with a maturation blockade of the myeloid lineage. Three days after admission, the patient received methylprednisolone (32 mg/d) for 2 days, which is the standard preparation for CT scan in our hospital. Complete apyrexia occurred overnight. The biological evolution was slowly favorable, without treatment other than folic acid. One month later, results of the clinical and biological examinations were normal. The second patient was a 53-year-old woman who had been admitted for recent weight loss, cough, and dyspnea. She had congenital dyskeratosis. On examination, she was thin and polypneic, with a few crackles in the lungs; her temperature was 38.5°C. Chest radiograph and thoracic CT scan showed a bilateral interstitial infiltrate. Main laboratory investigations were unremarkable (white blood cell count, 5320/mm3). The bronchoalveolar lavage showed cysts of Pneumocystis carinii. Treatment with trimethoprim (960 mg/d) and sulfamethoxazole (4800 mg/d) in the form of six double-strength tablets per day, and folic acid was started. The patient's temperature normalized, dyspnea improved, and she was discharged. Four days later, and 9 days after beginning treatment with trimethoprim-sulfamethoxazole, fever (39°C) reappeared suddenly, accompanied by a morbilous rash and painful cervical lymphadenopathies. She was readmitted and was diagnosed as having hypersensitivity syndrome related to trimethoprim-sulfamethoxazole. Abnormal laboratory investigations showed a white blood cell count of 3300/mm3, with 2370 neutrophils/mm3, 146,000 platelets/mm3, and moderate cytolysis. Treatment with trimethoprim-sulfamethoxazole was replaced with atovaquone, but cytopenias worsened (white blood cell count, 1700/mm3, with 500 neutrophils/mm3; hemoglobin, 7.3 g/dL; platelets, 17,000/mm3; and cytolysis [aspartate aminotransferase and alanine aminotransferase, 10N]). A myelogram showed extensive hemophagocytosis (Figure). Polyvalent intravenous immunoglobulins (1 g/kg/d) were given for 2 days. Apyrexia was observed within 48 hours, accompanied by marked clinical improvement. Biological abnormalities disappeared within a month. In both cases, extensive search for an infectious, malignant, or autoimmune cause of the hemophagocytosis remained negative. Both patients presented with the classic symptomatology of drug hypersensitivity syndrome (2Knowles S.R. Uetrecht J. Shear N.H. Idiosyncratic drug reactions: the reactive metabolite syndromes.Lancet. 2000; 356: 1587-1591Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar): abrupt onset of fever 9 to 10 days after beginning the drug, with exanthema, cervical lymphadenopathies, and cytolysis. Interestingly, these symptoms were characterized by pancytopenia, which is not a usual feature of the syndrome (3Callot V. Roujeau J.C. Bagot M. et al.Drug-induced pseudolymphoma and hypersensitivity syndrome.Arch Dermatol. 1996; 132: 1315-1321Crossref PubMed Google Scholar). In the same manner, these symptoms strongly suggested hemophagocytosis, which was observed in both cases. The mechanisms of cytopenias in drug hypersensitivity syndrome are unknown. Cell destruction by cytotoxic antibodies (4Kiefel V. Santoso S. Schmidt S. et al.Metabolite-specific (IgG) and drug-specific antibodies (IgG, IgM) in two cases of trimethoprim-sulfamethoxazole–induced immune thrombocytopenia.Transfusion. 1987; 27: 262-265Crossref PubMed Scopus (59) Google Scholar) and a reversible depression of stem cell activity (5Keisu M. Wiholm B.E. Palmblad J. Trimethoprim-sulphamethoxazole–associated blood dyscrasias. Ten years' experience of the Swedish spontaneous reporting system.J Intern Med. 1990; 228: 353-360Crossref PubMed Scopus (81) Google Scholar) with myeloid maturation blockade have been suggested. The occurrence of hemophagocytosis is possible because drug hypersensitivity syndrome may lead to a systemic inflammatory response, with activation of macrophages that produce inflammatory cytokines. Hemophagocytosis is probably underdiagnosed because both syndromes share nonspecific symptoms, bone marrow cytology is usually not required in a characteristic drug hypersensitivity syndrome (5Keisu M. Wiholm B.E. Palmblad J. Trimethoprim-sulphamethoxazole–associated blood dyscrasias. Ten years' experience of the Swedish spontaneous reporting system.J Intern Med. 1990; 228: 353-360Crossref PubMed Scopus (81) Google Scholar), and hemophagocytosis pictures can be missed on bone marrow aspiration (6Tiab M. Mechinaud F. Hamidou M. et al.Syndromes hémophagocytaires.Ann Med Interne (Paris). 1996; 147: 138-144PubMed Google Scholar).
Publication Year: 2002
Publication Date: 2002-05-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 55
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