Abstract
Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.
Highlights
Chronic granulomatous disease (CGD) is a primary immune deficiency caused by defects in one of the five subunits of the NADPH oxidase complex leading to impaired phagocyte respiratory burst and increased susceptibility to infections, especially with catalase-positive organisms
Primary HLH refers to genetic disorders associated with HLH and includes a group of autosomal recessive genetic disorders entitled familial hemophagocytic lymphohistiocytosis (FHL) due to mutations in PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5)
Other hereditary disorders associated with primary HLH include Griscelli syndrome type 2 (RAB27A), Chediak-Higashi syndrome (LYST), and X-linked lymphoproliferative syndromes type 1 and 2 (SH2D1A and XIAP, respectively) [8, 9]
Summary
Chronic granulomatous disease (CGD) is a primary immune deficiency caused by defects in one of the five subunits of the NADPH oxidase complex leading to impaired phagocyte respiratory burst and increased susceptibility to infections, especially with catalase-positive organisms. Patients with CGD are at increased risk of inflammatory bowel disease, inflammatory respiratory disease, and systemic autoimmune disease [1]. They may be at increased risk of systemic inflammatory disorders, such as hemophagocytic lymphohistiocytosis (HLH) [2, 3]. HLH may present clinically indistinguishable from sepsis or systemic inflammatory response syndrome (SIRS). A diagnosis of HLH is established by meeting five of eight clinical criteria (Table 1) [5]. Patients with CGD may present with secondary HLH due to inflammatory disease or infection, the latter being more common [2]. Treatment of secondary HLH in CGD should include broad spectrum antimicrobials, including coverage for Burkholderia, but may be complicated by the need for immune suppression to treat hyperinflammation
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