Reactive haemophagocytic syndrome in a patient with adult-onset Still’s disease: beta-lactams as trigger?

Abstract

Reactive haemophagocytic syndrome (RHS) is a severe and acquired form of haemophagocytic lymphohistiocytosis that may overlap with adult-onset Still’s disease (AOSD) [1]. The diagnosis of RHS, particularly in its early phase, may be confused with other clinical conditions, such as sepsis, malignancy and rheumatological flare. In November 2012, a 27-year-old woman presented to our hospital with a 3-day history of alternating fever and low back pain. Neurological examination was normal. Tenderness of the lumbar spine on percussion was reported. Blood tests showed a white cell count of 24,130/lL with a normal C-reactive protein (CRP \1.00 mg/L) and erythrocyte sedimentation rate (ESR; 10 mm/h). Hepatic and renal function were normal. Examination of the blood smear did not reveal blasts, and the platelet count and coagulation indices were normal. Urinalysis showed no abnormalities. Procalcitonin (PCT) was 5.7 ng/mL. Fever persisted ([39 C) for 2 days following presentation, and the patient developed signs of haemodynamic instability. Empirical oxacillin was begun awaiting the results of the blood cultures. Emergency imaging scans were performed. A symmetrical oligoarthritis and an intermittent macular–papular rash that extended to the trunk and extremities were detected (Fig. 1). Concomitantly, the levels of CRP (247.6 mg/L), ferritin (up to 15,000 lg/L), lactate dehydrognase (LDH; 2,670 U/L), triglycerides (403 mg/dL), aspartate transaminase (AST; 474 U/L), alanine transaminase (ALT; 171 U/L) started to increase, as did the prothrombin time (12.7 s) and activated partial thromboplastin time (32.4 s). Pancytopenia and reduced fibrinogen levels were also detected. A magnetic resonance imaging (MRI) scan of the spine ruled out epidural abscess and vertebral osteomyelitis. Transthoracic echocardiography did not reveal any valvular vegetations. Positron emission tomography–computed tomography imaging showed no abscess or solid malignancy. Blood and urine cultures grew no bacterial and mycobacterial pathogens. Autoimmunity screening was negative, and radiographs of all involved joints did not reveal marginal erosions. At this point a presumptive diagnosis of AOSD (5/8 criteria) [1] with RHS (4/8 criteria) [1] was strongly considered, and we ruled out infective triggers. Examination of the bone marrow confirmed haemophagocytosis. After the suspension of betalactam treatment, PCT (and other blood tests) progressively normalized. A literature search revealed 34 reported cases of RHS in AOSD in which an active infection was clearly not identified as a potential trigger [1–7]. The authors of these studies proposed that anti-tuberculosis, nonsteroidal antiinflammatory drugs (NSAIDS), sulfasalazine, hydroxychloroquine, gold salts, etanercept and adalimumab, respectively, could have elicited the RHS. In our patient, oxacillin was suspected of acting as the RHS trigger. She received penicillinase-resistant penicillin as a unique medication; moreover, the ‘‘switch-off’’ began just with its suspension. Takeshita [8] and Motegi [9] are the only two authors who advocated treatment with beta-lactams (penicillin G) as the triggering factor for RHS, but in these two F. Mearelli, P. Vinci and M. Gigli were the clinicians involved in the management of the patient.