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Rosário Perry1, Graça Seves2, Maria João Brito3, Gabriela Pereira4, Steve Holland5, Ana Isabel Cordeiro1, João Farela Neves1, Conceição Neves1

1Unidade de Imunodeficiências Primárias; 2 Unidade Local de Saúde do Baixo Alentejo; 3 Unidade de Infecciologia; 4 Unidade de Cuidados Intensivos Pediátricos
Área de Pediatria Médica, Hospital Dona Estefânia - CHLC EPE. Lisboa - Portugal
5 National Institute of Health, Bethesda, Maryland, USA

V Reunião de Imunodeficiências Primárias. Estoril, 9 de Novembro 2013

Introduction: Hemophagocytic syndrome is characterized by a dysregulated immune response and inefficient mediated cytokine storm, including IFN- γ and TNF- α. IFN- γ receptor 2 deficiency, although much less frequent than the receptor 1 deficiency, has been linked to mendelian susceptibility to mycobacteria (4% of the described patients).

Case Report: Six weeks-old girl, born of first cousins parents, admittedwith hepatosplenomegaly, intermittent fever,  generalized macular rash,leukemoid reaction and hypereosinophilia (95,000 leukocytes/mm3 and 45,000 eosinophils/mm3). No microorganism was identified in the initial investigation. Regarding mycobacteria, PCR and direct test was negative in bone marrow, peripheral blood and liver biopsy and cultural exams were ongoing. Excluded DRESS syndrome, primary hypereosinophilicssyndromes, Omenn syndrome, as well as lympho/myeloproliferative disease andhistiocytosis.Also excluded primary immunodeficiencieswith hyperleukocytosis, such as chronic granulomatous disease or leukocyte adhesion deficiency.MSMD mutations were searched. In the 3rd week of admission, she develops hemophagocyticsyndrome (HLH) secondary to CMV infection. She started treatment with dexamethasone and ganciclovir, and foscarnetand cyclosporine were associated because of lack of control of the disease (and viral load). After confirmation of the existence of a related-matched donor, ATG (5x5 mg/kg/day) was associated because of ongoing disease. Despite achieving partial remission, she developed acute respiratory failure with progression to ARDS with isolation of BCG and CMV in respiratory secretions (cultural examination of the bone marrow would eventually be also positive for BCG). Despite achieving an effective control of the inflammatory/immune response and of the infections, she evolved to irreversible and fatal respiratory (despite several weeks on extracorporeal membrane oxygenation, ECMO).Genetictesting later confirmed an IFN-γ receptor-2 deficiency.

Comments: The presence of CMV-induced HLH requiring immunosupression before the diagnosis of disseminated BCG led to major difficulties in the disease(s)  control. The development of a condition mediated largely, but not exclusively, by IFN- γin the absence of receptor 2 for this interleukin raises serious doubts about its pathophysiology and therapeutic targetting.

Key-words:Hemophagocytic syndrome, IFN-γreceptor2 deficiency