A novel mutation of adenosine deaminase causing SCID presenting as hemophagocytic lymphohistiocytosis with acute kidney injury

Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes’ reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients’ long-term recovery.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review

Fratini,

Migliavacca,

Barzaghi

et al. 2023

“…With the available literature, the most common types of SCID to develop HLH or HLH-like manifestations are X-linked SCID followed by RAG defects. However, features of HLH have also been described with JAK3 , CD3D , ADA , and ORAI1 defects also ( 13 ) ( 15 ) ( 16 ) ( 18 ), ( 20 ). In India, autosomal forms of SCID are more common than X-linked SCID.…”

Section: Discussionmentioning

confidence: 99%

Features of Hemophagocytic Lymphohistiocytosis in Infants With Severe Combined Immunodeficiency: Our Experience From Chandigarh, North India

Vignesh

Anjani²,

Kumrah³

et al. 2022

BackgroundHemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive inflammation leading to high mortality. Aetiology of HLH can be primarily due to genetic causes or secondarily due to infections or rheumatological illness. However, rarely T-cell deficiencies like severe combined immunodeficiency (SCID) can develop HLH.ObjectiveTo describe clinical and laboratory features of SCID cases who developed HLH.MethodsWe collected clinical, laboratory, and molecular details of patients with SCID who developed HLH at our center at Chandigarh, North India.ResultsOf the 94 cases with SCID, 6 were noted to have developed HLH-like manifestations. Male-female ratio was 5:1. Median (inter-quartile range) age of onset of clinical symptoms was 4.25 months (2-5 months). Median (inter-quartile range) delay in diagnosis was 1 month (1-3.5 months). Family history of deaths was seen in 4 cases. Molecular defects in IL2RG were seen in 5 out of 6 cases. Documented infections include disseminated bacillus calmette-guerin (BCG) infection (n=2), blood stream infections (n=3) with Staphylococcal aureus (n=1), Klebsiella pneumonia (n=1), and Pseudomonas aeruginosa (n=1), pneumonia (influenza H1N1 strain, and K. pneumoniae (n=1).ConclusionChildren with SCID can present with HLH-like manifestations secondary to fulminant infections. A high index of suspicion of SCID is needed in infants who present with HLH who have an associated infection or a suggestive family history. Occurrence of HLH-like manifestations in SCID suggests that T-lymphocytes may not have a significant role in immunopathogenesis of HLH.

“…Tubulointerstitial damage may arise from hemodynamic shifts and coagulation disorders during the acute phase of severe sepsis. While glomerular involvement is infrequent, it can lead to collapsed glomerulopathy, focal segmental glomerulosclerosis, microscopic lesions, and thrombotic microangiopathy ( 3 , 42 – 44 ). A direct deleterious effect of pro-inflammatory cytokines on the kidney is evident.…”

Section: Pathophysiologymentioning

confidence: 99%

Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis

Zhao,

Guan,

Lin

et al. 2024

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.