Cleavage-resistant RIPK1-induced autoinflammatory syndrome-A report of three generations with periodic fever and clinical response to colchicine.

The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.

Normative data for paediatric lymphocyte subsets: A pilot study from western India.

Background & objectives: Accurate diagnosis of immunodeficiencies requires a critical comparison of values with age-matched controls. In India, the existing reference values for rare lymphocyte subsets are currently not available and we rely on the data originating from other countries for the interpretation of the results. Furthermore, there is limited information on normal variation for these rare-subset parameters in Indian children. So, this study aimed to establish normative values for clinically important lymphocyte subsets in Indian children at different age groups. Methods: 148 children aged ≥16 yr were enrolled in this study. The study population included 61 per cent males and 39 per cent females and was divided into the following groups: cord blood (n=18), 0-6 months (n=9), 6-12 months (n=13), 1-2 yr (n=19), 2-5 yr (n=27), 5-10 yr (n=25) and 10-16 yr (n=37). The absolute and relative percentage of lymphocytes, T, B, natural killer cell, along with activated, naïve and memory subsets, was determined by flow cytometry. Results: Median values and the 10th and 90th percentiles were obtained for 34 lymphocyte sub-populations. The T and B naïve compartments showed a decreasing trend, whereas memory cells showed an increase with age. The activated T cell subset shows an increasing pattern up to one year and then declines gradually. Double negative T cells are relatively stable. TCRgd+T cell percentage increases with age. Interpretation & conclusions: This single-centre pilot study provides preliminary data that justifies the need for future large-scale multi centric studies to generate a reference range for interpreting extended immunophenotyping profiles in the paediatric age group, making it possible for clinicians to assess the immunological status in inborn errors of immunity, infectious and autoimmune diseases.

Assessment of Enterovirus Excretion and Identification of VDPVs in Patients with Primary Immunodeficiency in India: Outcome of ICMR-WHO Collaborative Study Phase-I.

The emergence of vaccine-derived polioviruses (VDPVs) in patients with Primary Immunodeficiency (PID) is a threat to the polio-eradication program. In a first of its kind pilot study for successful screening and identification of VDPV excretion among patients with PID in India, enteroviruses were assessed in stool specimens of 154 PID patients across India in a period of two years. A total of 21.42% of patients were tested positive for enteroviruses, 2.59% tested positive for polioviruses (PV), whereas 18.83% of patients were positive for non-polio enteroviruses (NPEV). A male child of 3 years and 6 months of age diagnosed with Hyper IgM syndrome was detected positive for type1 VDPV (iVDPV1) with 1.6% nucleotide divergence from the parent Sabin strain. E21 (19.4%), E14 (9%), E11 (9%), E16 (7.5%), and CVA2 (7.5%) were the five most frequently observed NPEV types in PID patients. Patients with combined immunodeficiency were at a higher risk for enterovirus infection as compared to antibody deficiency. The high susceptibility of PID patients to enterovirus infection emphasizes the need for enhanced surveillance of these patients until the use of OPV is stopped. The expansion of PID surveillance and integration with a national program will facilitate early detection and follow-up of iVDPV excretion to mitigate the risk for iVDPV spread.

Poliovirus surveillance in patients with primary immunodeficiencies, India.

Individuals with primary immunodeficiencies who are infected with vaccine-derived polioviruses may continue to shed poliovirus for months and go undetected by surveillance programmes of acute flaccid paralysis. These patients therefore pose a risk of initiating poliovirus outbreaks that jeopardize efforts towards global polio eradication. To identify these individuals, we designed a study protocol for the establishment of a network for surveillance of immunodeficiency-related vaccine-derived poliovirus in India. In the first step we identified recognized centres in India that could diagnose and enrol patients with primary immunodeficiency disorder into the study. Stool sample collection from study sites, culture, isolation, characterization of enteroviruses and reporting to study sites was carried out at the National Institute of Virology Mumbai Unit, as per the WHO national polio surveillance project protocol. In the first phase of the study from January 2020 to December 2021, we implemented the protocol at seven study sites at different medical institutes to determine the proportion of poliovirus infections in primary immunodeficiency disorder patients of India. We later expanded the study by including an additional 14 medical institutes across the country in the second phase running from January 2022 to December 2023. We believe this study protocol will help other countries to initiate immunodeficiency-related vaccine-derived poliovirus surveillance to identify and follow up patients who are long-term excretors of vaccine-derived poliovirus. Integration of immunodeficiency-related poliovirus surveillance with acute flaccid paralysis surveillance of the existing poliovirus network will enhance continuous screening of patients with primary immunodeficiency disorder in the future.

Certains individus qui présentent des immunodéficiences primaires et sont infectés par des poliovirus dérivés d'une souche vaccinale pourraient continuer à excréter le poliovirus pendant des mois sans que ce dernier ne soit détecté par le biais d'une surveillance de la paralysie flasque aiguë. Ces patients risquent donc de déclencher des épidémies de poliovirus qui mettent en péril les efforts visant à éradiquer la poliomyélite dans le monde. En vue d'identifier ces individus, nous avons élaboré un protocole d'étude pour établir, en Inde, un réseau de surveillance du poliovirus d'origine vaccinale lié à une immunodéficience. Au cours de la première étape, nous avons repéré des centres reconnus dans le pays, capables de diagnostiquer des patients atteints d'un syndrome d'immunodéficience primaire et de les recruter dans le cadre de l'étude. Le prélèvement des échantillons de selles auprès des sites participant à l'étude, la culture, l'isolement, la caractérisation des entérovirus et la communication des résultats à ces sites ont été pris en charge par le National Institute of Virology Mumbai Unit, conformément au protocole du Projet national de surveillance de la poliomyélite de l'OMS. Nous avons consacré la première phase de l'étude, qui s'est déroulée entre janvier 2020 et décembre 2021, à la mise en œuvre du protocole au sein de différents établissements médicaux sur sept sites participants, afin de déterminer le nombre d'infections au poliovirus chez les patients souffrant d'un syndrome d'immunodéficience primaire en Inde. Nous avons ensuite, durant la deuxième phase comprise entre janvier 2022 et décembre 2023, élargi l'étude en incluant 14 établissements supplémentaires à travers le pays. Nous sommes convaincus que ce protocole d'étude aidera d'autres pays à instaurer une surveillance du poliovirus dérivé d'une souche vaccinale et lié à une immunodéficience, qui leur servira à identifier et suivre les patients responsables d'une excrétion prolongée du poliovirus d'origine vaccinale. L'intégration, au sein du réseau existant dédié au poliovirus, d'une surveillance de ce type couplée à une surveillance de la paralysie flasque aiguë améliorera le dépistage systématique des patients atteints d'un syndrome d'immunodéficience primaire à l'avenir.

Las personas con inmunodeficiencias primarias infectadas por los poliovirus de origen vacunal pueden seguir excretando poliovirus durante meses sin que la vigilancia de la parálisis flácida aguda los detecte. Por lo tanto, estos pacientes suponen un riesgo de iniciar brotes de poliovirus que pongan en peligro los esfuerzos hacia la erradicación mundial de la poliomielitis. Para identificar a estas personas, diseñamos un protocolo de estudio para el establecimiento de una red de vigilancia de poliovirus de origen vacunal relacionados con inmunodeficiencias en la India. En el primer paso identificamos centros reconocidos en la India que pudieran diagnosticar e inscribir en el estudio a pacientes con trastorno de inmunodeficiencia primaria. La recogida de muestras de heces de los centros de estudio, el cultivo, el aislamiento, la caracterización de los enterovirus y la notificación a los centros de estudio se llevaron a cabo en el Instituto Nacional de Virología, Unidad de Mumbai, según el protocolo del Proyecto Nacional de Vigilancia de la Poliomielitis de la OMS. En la primera fase del estudio, de enero de 2020 a diciembre de 2021, aplicamos el protocolo en siete centros de estudio de diferentes institutos médicos para determinar la proporción de infecciones por poliovirus en pacientes con trastorno de inmunodeficiencia primaria de la India. A continuación, ampliamos el estudio con la inclusión de otros 14 institutos médicos de todo el país en la segunda fase, de enero de 2022 a diciembre de 2023. Creemos que este protocolo de estudio ayudará a otros países a iniciar la vigilancia de poliovirus de origen vacunal relacionados con la inmunodeficiencia para identificar y hacer un seguimiento de los pacientes que son excretores a largo plazo de poliovirus de origen vacunal. La integración de la vigilancia del poliovirus asociado a la inmunodeficiencia con la vigilancia de la parálisis flácida aguda de la red de poliovirus existente mejorará el cribado continuo de pacientes con trastorno por inmunodeficiencia primaria en el futuro.

Monogenic inborn errors of immunity in autoimmune disorders.

To estimate the prevalence of monogenic inborn errors of immunity in patients with autoimmune diseases (AID), the study included 56 subjects (male:female ratio: 1.07) with mean age of onset of autoimmunity 7 years (4 months-46 years). 21/56 had polyautoimmunity. 5/56 patients met the JMF criteria for PID. The different AID referred were hematological (42%) > gastrointestinal (GI) (16%) > skin (14%) > endocrine (10%) > rheumatological (8%) > renal (6%) > neurological (2%). 36/56 reported recurrent infections. 27/56 were on polyimmunotherapy. 18/52 (35%) had CD19 lymphopenia, 24/52 (46%) had CD4 lymphopenia, 11/52 (21%) had CD8 lymphopenia, and 14/48 (29%) had NK lymphopenia. 21/50 (42%) had hypogammaglobinemia; 3 of whom were given rituximab. 28/56 were found to have pathogenic variants among PIRD genes. These 28 patients had 42 AID among which hematological was most common (50%) > GI (14%) = skin (14%)> endocrine (9%) > rheumatological (7%) > renal and neurological (2%). Hematological AID was the most common AID (75%) in children with PIRD. Positive predictive value (PPV) of abnormal immunological tests was 50% and sensitivity of 70%. JMF criteria had specificity of 100% in identifying PIRD and sensitivity of 17%. Polyautoimmunity had a PPV of 35% and sensitivity of 40%. 11/28 of these children were offered transplant. 8/28 were started on sirolimus, 2/28 on abatacept, and 3/28 on baricitinib/ruxolitinib after diagnosis. In conclusion, 50% of children with AID have underlying PIRD. LRBA deficiency and STAT1 GOF were the most common PIRD. Age at presentation, number of autoimmunity, routine immunological tests, and JMF criteria are not predictive of underlying PIRD. Early diagnosis with exome sequencing alters the prognosis and opens new therapeutic avenue.

Clinical, immunological and molecular findings of patients with DOCK-8 deficiency from India.

DOCK8 deficiency affects various cell subsets belonging to both the innate and adaptive immune systems. Clinical diagnosis is challenging, as many cases present with severe atopic dermatitis as the only initial manifestation. Though flow cytometry helps in the presumptive diagnosis of DOCK8-deficient patients by evaluating their DOCK8 protein expression, it requires subsequent confirmation by molecular genetic analysis. Currently, haematopoietic stem cell transplantation (HSCT) is the only curative treatment option available for these patients. There is a paucity of data from India on the clinical diversity and molecular spectrum of DOCK8 deficiency. In the present study, we report the clinical, immunological and molecular findings of 17 DOCK8-deficient patients from India diagnosed over the last 5 years.

SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency.

The energy metabolism of myeloid cells depends primarily on glycolysis. 1,5-Anhydroglucitol (1,5AG), a natural monosaccharide, is erroneously phosphorylated by glucose-phosphorylating enzymes to produce 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a powerful inhibitor of hexokinases. The endoplasmic reticulum transporter (SLC37A4/G6PT) and the phosphatase G6PC3 cooperate to dephosphorylate 1,5AG6P. Failure to eliminate 1,5AG6P is the mechanism of neutrophil dysfunction and death in G6PC3-deficient mice. Sodium glucose cotransporter 2 (SLGT2) inhibitor reduces 1,5AG level in the blood and restores the neutrophil count in G6PC3-deficient mice. In the investigator-initiated study, a 30-year-old G6PC3-deficient woman with recurrent infections, distressing gastrointestinal symptoms, and multi-lineage cytopenia was treated with an SLGT2-inhibitor. A significant increase in all the hematopoietic cell lineages and substantial improvement in the quality of life was observed.

Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.

Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India.

Background: Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed. Results: In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months). Conclusions: We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Results: Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India.

Background: Chronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India. Objective: To describe infection patterns, immunological, and molecular features of CGD from multiple centers in India. Methods: A detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed. Results: Of the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)-CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%), and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up. Conclusions: In India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.

Clinical Profile of Hyper-IgE Syndrome in India.

Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES. Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis. Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12. Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.