Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Risk factors of post-transplant autoimmune cytopenia in primary immunodeficiency: the most significant risk factors were the use of alemtuzumab (figure A) and the presence of GvHD (figure B). * indicates p<0.05 on Gray's test and ** indicates p<0.05 on Fine-and-Gray's test AIC: autoimmune cytopenia; ATG: An thymocyte globulin; CI: cumula ve incidence/confidence interval; GvHD: gra -versus-host disease HCT: haematopoie c cell trnasplanta on A B Post-transplant autoimmune cytopenia in primary immunodeficiency Study cohort: 502 children The cumula ve incidence of post-transplant autoimmune cytopenia = 9.4%

Chronic granulomatous disease (CGD), an inherited immunodeficiency resulting from defects in the reduced NAD phosphate oxidase complex rendering phagocytes deficient in producing the superoxide anion necessary for normal killing of bacterial and fungal microorganisms, leads to severe and recurrent infections, inflammatory granulomatous complications, and autoimmune diseases. 1 It is associated with substantial morbidity and premature death. Hematopoietic cell transplantation (HCT) is the only long-term curative therapy; however, historically, utility was limited by high rates of graft failure and transplant-related morbidity and mortality. Transplant survival and graft outcome have improved dramatically over the past 10 years as a result of reduced-toxicity conditioning (RTC) regimens, detailed graftselection hierarchy, superior HLA-matching technology, better cell-dosed grafts, greater availability of grafts, improved supportive care, and more effective antimicrobial therapy. We studied transplant survival post-HCT for CGD in a supraregional immunology transplant center in the United Kingdom.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)–specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

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Aim This study aims to evaluate the utility of genetic testing of patients diagnosed with periodic fever syndromes and to assess the validity of existing scoring criteria. Methods This study retrospectively reviewed the clinical history of patients diagnosed with periodic fever syndromes at Queensland Children's Hospital between November 2014 and June 2018. Results Forty‐three patients were diagnosed with periodic fever syndromes. Diagnoses in the cohort included periodic fever, adenitis, pharyngitis and aphthous stomatitis (10), tumour necrosis factor receptor‐associated periodic syndrome (9), cryopyrin‐associated periodic syndrome (6), mevalonate kinase deficiency (4) while 14 remained unspecified. No presenting symptoms were uniquely associated with any particular diagnosis. Genetic testing of between 1 and 26 genes was performed in 26 (60%) patients. Two (7.7%) patients had pathogenic variants identified. Variants of uncertain significance which were insufficient to confirm a monogenic disorder were identified in a further 7 (27%) patients. The Eurofever classification criteria correlated with clinical diagnosis for patients diagnosed with cryopyrin‐associated periodic syndrome (P = 0.046) and tumour necrosis factor receptor‐associated periodic syndrome (P = 0.025) but not for patients diagnosed with mevalonate kinase deficiency (P = 0.47); however, the Eurofever classification criteria were often positive for more than one diagnosis in these patients. Conclusion The European classification criteria can form a potentially useful tool to guide diagnosis; however, clinical judgement remains essential, because the score is often positive for multiple diagnoses. The diagnostic yield of genetic testing in this cohort was low and genetic testing may be more useful to confirm a strong clinical suspicion than to clarify a diagnosis for patients with less clear symptoms.

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