Expanding the Clinical Phenotype with CD79A Mutation and Refractory Helicobacter Bilis Infection.

Autosomal recessive agammaglobulinemia is a severe primary antibody deficiency disorder typically presenting in infancy. We present a rare case of an 8-year-old boy with AR agammaglobulinemia due to a homozygous splice site variant (c.499-1G > A) in the CD79A gene. Despite monthly intravenous immunoglobulin replacement and prophylactic antibiotics, he developed refractory Helicobacter bilis leg ulcers. Helicobacter species are known for extracellular colonization and are challenging to culture, necessitating molecular diagnostics for identification. The patient required prolonged treatment with intravenous meropenem followed by oral metronidazole and doxycycline for resolution of the ulcers over two years. The patient also exhibited persistent asymptomatic thrombocytopenia, an atypical finding in CD79A mutation cases. This case underscores the importance of genetic diagnosis and targeted antimicrobial therapy in managing rare infections associated with primary immunodeficiencies like autosomal recessive agammaglobulinemia due to CD79A mutation.

Somatic reversion in Wiskott-Aldrich syndrome: Case reports and mechanistic insights.

This report describes two brothers from India and a Chinese patient with somatic reversion of an inherited deleterious mutation in the WAS gene. Both the Indian siblings had inherited a single nucleotide deletion causing a frameshift mutation (c.1190del, p.Pro397Argfs*48) (variant 1: marked in blue) from the mother. Another variant (variant 2: marked in red), a 12-nucleotide deletion at position 1188-1199 (c.1188_1199del, p.P401_P404del) was also found, which resulted in restoration of the frame and subsequent rescue of the protein sequence. DNA sequencing from buccal mucosal cells revealed only the inherited variant (variant 1), while no reversion mutation was identified in the mucosal cells. Similarly, the Chinese patient was found to have a novel germline 14-base duplication (ACGAAAATGCTTGG) c.120_132 + 1dup (variant 1). This resulted in abolishment of the original splice junction coupled with the creation of a new junction 14 bases 3' and a frameshift mutation with predicted protein truncation p. Thr45Aspfs*. DNA from the patient's PBMC showed co-existence of wild-type and mutated sequences, but only the mutant was present in the buccal cells. Genomic and mRNA analysis of the isolated CD3+ T lymphocytes, CD3- mononuclear cells, and EBV-transformed B lymphocytes indicated that the reverant variant (germline variant was restored to wild-type sequence) were selectively found in CD3+ T lymphocytes.

Profile of patients with Juvenile Dermatomyositis and Anti-MDA5 autoantibodies.

BACKGROUND: Anti-MDA5 autoantibody-positive dermatomyositis (MDA5-DM) is associated with clinically amyopathic forms and rapidly progressive interstitial lung disease (ILD); however, data in children are limited. In this study, we described our cohort of anti-MDA5-positive juvenile DM (MDA5-JDM) from a tertiary care center in North India. METHODS: We performed a retrospective analysis of children with MDA5-JDM who were diagnosed and followed up at our center and compared them with our anti-MDA5-negative cohort. We also compared the published literature on MDA5-DM with the juvenile cohort. RESULTS: Of 66 children with JDM who underwent testing for MSA, 10(15.5%) had anti-MDA5 positivity. The mean age at onset of clinical manifestations was 8.4 years; male: female ratio was 7:3. Five of nine patients who underwent screening HRCT chest had ILD; one amongst them had a fatal rapidly progressive disease. Children with MDA5-JDM had significantly more arthralgia/arthritis (p = 0.006) and ILD (p = 0.0005) compared to anti-MDA5 negative JDM in our cohort. While MDA5-DM had high rates of Raynaud's phenomenon (p = 0.04) and pulmonary involvement (p = 0.001), juvenile patients had a higher prevalence of constitutional symptoms (p = 0.01), skin manifestations (p = 0.003), arthritis (p = 0.001), and muscle weakness (p = 0.001). CONCLUSIONS: Arthritis and ILD are commonly seen with MDA5-JDM; however, the frequency of ILD and clinically amyopathic forms are less common compared to adult counterparts. IMPACT: The frequency of anti-MDA5 antibodies in a North Indian cohort of JDM is much lower (15.5%) compared to adult studies in dermatomyositis from Southeast Asia (~25%). Incidence of interstitial lung disease (ILD) and arthritis is high in anti-MDA5 autoantibody-positive JDM. Rates of a rapidly progressive form of ILD and clinically amyopathic dermatomyositis are much lower in children compared to adults with anti-MDA5-associated dermatomyositis.

Wiskott-Aldrich syndrome protein expression in female WAS carriers: A flow cytometry study from North India.

INTRODUCTION: Wiskott-Aldrich syndrome (WAS) is a rare X-linked inborn error of immunity characterized by microthrombocytopenia, infections, eczema, and increased predisposition to develop autoimmunity and malignancy. Flow cytometric assay for determining WAS protein (WASp) is a rapid and cost-effective tool for detecting patients. However, very few studies described WASp expression in female carriers. Most WAS carriers are clinically asymptomatic. Active screening of female family members helps identify female carriers, distinguish de novo mutations, and to select appropriate donor prior to curative stem cell transplantation. This study was undertaken to evaluate the diagnostic capability of flow cytometry-based WASp expression in peripheral blood cells to identify carriers and compare WASp expression in different blood cell lineages. PATIENTS AND METHODS: Female patients, heterozygous for WAS gene, were enrolled in this study conducted at Pediatric Allergy Immunology Unit, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Flow cytometric assessment of WASp expression in lymphocytes, monocytes, and neutrophils was carried out and compared with healthy control and affected patients. The results were expressed in delta (Δ) median fluorescence intensity (MFI) as well as stain index (SI), which is the ratio of ΔMFI of patient and ΔMFI of control. RESULTS: Thirteen mothers and two sisters of genetically confirmed WAS patients were enrolled in the study. All enrolled females were clinically asymptomatic and did not have microthrombocytopenia. Low WASp expression (SI < 1) was seen in lymphocytes and monocytes in 10 (66.6%) carriers. Females with variants in proximal exons (exons 1 and 2) were found to have lesser expression than those with distal (exons 3-12) variants. CONCLUSION: Flow cytometry is a rapid, easily available, cost-effective tool for WASp estimation. Lymphocytes followed by monocytes are the best cell lineages for WASp estimation in carrier females. However, genetic testing remains the gold standard, as carrier females with variants in distal exons may have normal WASp expression.

Delay in diagnosis is the most important proximate reason for mortality in hereditary angio-oedema: our experience at Chandigarh, India.

BACKGROUND: Hereditary angio-oedema (HAE) is a rare autosomal dominant disorder characterized clinically by recurrent episodes of nonpruritic subcutaneous and/or submucosal oedema. Laryngeal oedema is the commonest cause of mortality in patients with HAE. Prior to the availability of first-line treatment options for the management of HAE, mortality was as high as 30%. Mortality has significantly declined in countries where first-line treatment options are available and patients can access these therapies. There is a paucity of literature on the outcomes of patients with HAE in developing countries where availability of and access to first-line treatment options are still a challenge. OBJECTIVES: To report our experience on mortality in patients with HAE and to report factors associated with the death of these patients. METHODS: We carried out a record review of all patients diagnosed with HAE between January 1996 and August 2022. Families with HAE who had reported the death of at least one family member/relative from laryngeal oedema were studied in detail. RESULTS: Of the 65 families (170 patients) registered in the clinic, 16 families reported the death of at least one family member/relative from laryngeal oedema (total of 36 deaths). Of these 16 families, 14 reported that 1 or more family members had experienced at least 1 attack of laryngeal oedema. One patient died during follow-up when she was taking long-term prophylaxis with stanozolol and tranexamic acid, while the remaining 35 patients were not diagnosed with HAE at the time of their death. At the time of death of all 36 patients, at least 1 other family member had symptoms suggestive of HAE, but the diagnosis was not established for the family. CONCLUSIONS: To our knowledge, this is the largest single-centre cohort of patients with HAE in India reporting mortality data and factors associated with death in these families. The delay in diagnosis is the most important reason for mortality.

Expanding the clinical and immunological phenotype of prolidase deficiency: A case report.

Prolidase deficiency (PD) is a rare autosomal recessive disorder associated with recurrent infections, immune dysregulation, and autoimmunity. PD is characterized by persistent dermatitis, skin fragility, and non-healing ulcerations on the lower limbs as its main dermatologic characteristics. Herein, we report a boy with PD due to a novel variant in PEPD who had abnormal facies, cognitive impairment, corneal opacity, recurrent infections, and persistent non-healing leg ulcers. Th17 lymphocyte counts and phosphorylated-STAT5 expression following IL-2 stimulation were reduced in our patient as compared to healthy control.

Infections due to Salmonella sp. in children with chronic granulomatous disease: Our experience from North India.

Infections with non-typhoidal Salmonella sp. have been documented in children with chronic granulomatous disease (CGD), but the prevalence of salmonella infection in children with CGD in underdeveloped countries is unknown. We assessed the clinical profiles of CGD patients diagnosed at our tertiary care centre in north India and had Salmonella sp.infections. We found three patients with Salmonella sp. bloodstream infections (2-proven, 1-probable) among the 99 CGD patients. After receiving cotrimoxazole prophylaxis following a CGD diagnosis, we noted that none of our patients experienced non-typhoidal salmonella infection. One patient experienced severe typhoidal bacteremia despite receipt of cotrimoxazole prophylaxis. This patient required numerous hospital admissions and prolonged intravenous antibiotic regimen. We suggest that vaccination with killed typhoidal vaccines should be regularly given to children with CGD in order to avoid typhoidal bacteremia, in addition to cotrimoxazole prophylaxis and a focus on good hand and food hygiene.

Clinico-Etiological Profile of Children with Pericardial Effusion in a Tertiary Care Hospital in Eastern India.

INTRODUCTION: Pericardial effusion may be due to various causes. With the changing scenario of newer generation antibiotics and robust immunization program our aim is to identify the change, if any, in etiology and disease menifestations. METHODOLOGY: This is a hospital-based uni-center prospective study with a population of 30 children for a period of 1½ year. Clinico-epidemiological features, investigations, complications and short-term outcome were assessed. RESULTS: We found 13 (43.33%) patients having mild, 11 (36.67%) had moderate and 6 (20%) had severe pericardial effusion. Cardiac tamponade was present in six cases. Among the study population 9 (30%) patients were diagnosed as having pyogenic pericardial effusion and 8 (26.67%) had tubercular effusion. The predominant symptoms of pericardial effusion in our children were fever and tachycardia (83.33%).Other symptoms at presentation were tachycardia (76.67%), cough (63.33%), chest pain (50%), orthopnea (43.33%) and skin rash (16.67%). Pericardiocentesis was done in 14 cases (46.67%) of which 4 patients (13.33%) required pig tail catheterization. DISCUSSION: Infectious etiology still remains the primary cause of pericardial effusion in our country. The presenting clinical signs are very much nonspecific and also not so prominent unless hemodynamic compromisation occurs. CONCLUSION: This study showed that bacterial and tubercular pericardial effusions are still two most prevalent etiological diagnosis in this part of country. Early diagnosis and treatment has good outcome.

Clinical Profile and Therapeutic Response of Scrub Typhus in Children: A Recent Trend from Eastern India.

OBJECTIVE: The aim of this study was to assess the clinico-laboratory parameters, complications and therapeutic responses in children with scrub typhus in Eastern India. MATERIALS AND METHODS: In this prospective, observational study, all children (age, <12 years) with suspected scrub typhus with a compatible clinical scenario were enrolled consecutively over six months. Cases confirmed by means of a positive IgM serology or a positive Weil-Felix reaction (OXK = 1/80 or above) were administered enteral doxycycline (4.5 mg/kg/day). RESULTS: Out of 94 recruited children, 61 had confirmed scrub typhus (mean age = 6.1 years, M:F = 1.1:1) with or without complications and having a considerably higher incidence of neurological presentation (meningoencephalistis n = 21, 34.4%). The most frequent manifestations included vomiting (n = 39, 63.9%), abdominal pain (n = 33, 54.1%), lymphadenopathy (n = 36, 59%), hepatosplenomegaly (n = 32, 52.5%), pedal edema (n = 32, 52.5%) and eschar formation (n = 30, 49.2%). Low hemoglobin levels, leukocytosis, thrombocytopenia, hypoalbuminemia, hyponatremia, increased liver enzymes and increased C-reactive protein were associated with delayed defervescence (>48 h). CONCLUSION: Scrub meningoencephalitis, with a notably higher incidence, showed favorable therapeutic response. Prompt and empiric doxycycline therapy could be lifesaving.

Membranous nephropathy with Kimura's disease: A case report and review of literature.

Kimura's disease (KD) is a chronic inflammatory disorder characterized by nontender lymphadenopathy involving the head and neck region. Renal involvement in KD is rare, especially in children. We report a 12-year-old boy who had been previously treated for classical KD and had presented with anasarca and oliguria after 4 years. There were no swellings or lymphadenopathy. The kidney biopsy revealed membranous nephropathy. Remission was achieved with oral prednisolone and tacrolimus therapy. This patient highlights the need to regularly monitor patients with KD for the evolution of renal diseases, even if lymphadenopathy regresses. Serial monitoring for eosinophilia, inflammatory markers, and urine examination is needed to help identify subclinical disease early and prompt initiation of specific therapy.

Immunoglobulin replacement therapies in inborn errors of immunity: a review.

Immunoglobulins (Ig) were used as a therapeutic modality for the first time in a patient with X-linked agammaglobulinemia in 1952 by Colonel Ogden Bruton, decades before the molecular mechanisms causing the disease were unraveled. In many autoimmune and inflammatory illnesses, human immunoglobulin has been employed as a significant immunomodulatory and immunosuppressive drug. In patients with inborn errors of immunity (IEI), immunoglobulin remains a cornerstone of management. IEIs are notable causes of recurrent infections and autoimmunity due to inheritable single-gene defects in genes encoding for different components of the immune system. As there is decreased immunoglobulin production in IEIs with antibody defects, immunoglobulin replacement is the mainstay of therapy in these disorders. Although serum immunoglobulin levels may not be low in combined immune defects, immunoglobulin replacement is still necessary in these disorders due to a deficiency of functional antibodies and qualitative defects of immunoglobulins. Commercial immunoglobulin preparations are generated from plasma donated by thousands of donors. Immunoglobulin preparations are usually available in two forms: intravenous and subcutaneous immunoglobulins. In the developed world, both intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) are available, and SCIg is preferred over IVIg for replacement therapy in patients with IEIs. In developing countries, IVIg remains the mainstay of replacement therapy. The rate of adverse events has significantly reduced over the last few years due to advancements in the production process. In this review article, we discuss different aspects of the use of Ig (indications, dosing, mechanism of action, route, adverse effects) in patients with IEIs.

Incidence of Kawasaki disease among children in Chandigarh, India during 2015-2019: a trend analysis.

Background: Only limited information exists regarding the epidemiology of Kawasaki disease (KD) in low-income and middle-income countries. The present study provides the incidence of KD during 2015-2019 in Chandigarh, north India. Our centre follows the largest KD cohort in India. Methods: Children with KD at Chandigarh diagnosed during January 2015-December 2019 were enrolled in the study. Annual incidence rates were determined using decadal growth rates of the National Census 2011. We computed the incidence of KD in children aged <5, and <15 years. We also undertook linear trend analysis using our incidence data from 1994 to 2019. Findings: During 2015-2019, 83 patients (66 males, 17 females) were diagnosed with KD in Chandigarh. Incidence rates during these 5 years were 5.64, 9.25, 9.11, 9.87, and 9.72/100,000 in children aged <5 years, and 2.65, 4.44, 3.86, 5.07, 4.74/100,000 in children aged <15 years. The median age at diagnosis was 48 months (range: 12 days to 15 years). Compared to previous data (2009-2014), there was a 53.1% increase in annual incidence of KD in children aged <5 years, and a 53.7% increase in children aged <15 years. Coronary artery abnormalities during acute phase were noted in 16.9%, and in 7.2% of patients at 6 weeks of follow-up. The trend analysis indicated a monthly rise of 0.002 cases per 100,000 children aged <5 years, and 0.0165 cases per 100,000 children aged <15 years. Interpretation: The incidence of KD has continued to show an upward trend in Chandigarh over the period 2015-2019. This may indicate a true rise in the occurrence of KD or may reflect better disease ascertainment as a result of greater awareness about KD amongst healthcare professionals. Funding: None.

Epstein-Barr virus-driven lymphoproliferation in inborn errors of immunity: a diagnostic and therapeutic challenge.

INTRODUCTION: Inborn errors of immunity (IEI) are a group of genetically heterogeneous disorders with a wide-ranging clinical phenotype, varying from increased predisposition to infections to dysregulation of the immune system, including autoimmune phenomena, autoinflammatory disorders, lymphoproliferation, and malignancy. Lymphoproliferative disorder (LPD) in IEI refers to the nodal or extra-nodal and persistent or recurrent clonal or non-clonal proliferation of lymphoid cells in the clinical context of an inherited immunodeficiency or immune dysregulation. The Epstein-Barr virus (EBV) plays a significant role in the etiopathogenesis of LPD in IEIs. In patients with specific IEIs, lack of immune surveillance can lead to an uninhibited proliferation of EBV-infected cells that may result in chronic active EBV infection, hemophagocytic lymphohistiocytosis, and LPD, particularly lymphomas. AREAS COVERED: We intend to discuss the pathogenesis, diagnosis, and treatment modalities directed toward EBV-associated LPD in patients with distinct IEIs. EXPERT OPINION: EBV-driven lymphoproliferation in IEIs presents a diagnostic and therapeutic problem that necessitates a comprehensive understanding of host-pathogen interactions, immune dysregulation, and personalized treatment approaches. A multidisciplinary approach involving immunologists, hematologists, infectious disease specialists, and geneticists is paramount to addressing the diagnostic and therapeutic challenges posed by this intriguing yet formidable clinical entity.

Transmission patterns of C1-INH deficiency hereditary angioedema favors a wild-type male offspring: Our experience at Chandigarh, India.

BACKGROUND: Deficiency of C1-inhibitor (C1-INH) protein, caused by pathogenic variants in the Serpin family G member 1 (SERPING1) gene, is the commonest pathophysiological abnormality (in ∼95 % cases) in patients with hereditary angioedema (HAE). C1-INH protein provides negative control over kallikrein-kinin system (KKS). Although the inheritance of the HAE-C1-INH is autosomal dominant, female predominance has often been observed in patients with HAE. OBJECTIVE: To analyze the risk of transmission of SERPING1 gene variant from father or mother to their offspring. METHODS: Pedigree charts of 42 families with a confirmed diagnosis of HAE-C1-INH and a pathogenic variant in the SERPING1 gene were analysed. Patients with HAE who had had at least one child were included for analyses to assess the risk of transmission from the father or mother to their offspring. RESULTS: Overall, 49 % (189/385) of all offspring inherited the genetic defect. In the subgroup analyses, 54.8 % (90/164) female offspring and 44.8 % (99/221; p < 0.02) male offspring inherited the genetic defect. Inheritance of the genetic defect was significantly lower in male offspring. Fathers with SERPING1 gene variant had a statistically significant skewed transmission of the wild type to the male offspring as compared to the variant (57.8 % wild type vs. 42.1 % variant; p < 0.02), whereas no statistically significant difference was found when a father transmitted the variant to a female offspring. Mothers with SERPING1 gene variant had no statistically significant difference in variant transmission to male or female offsprings. CONCLUSION: Results of the study suggest that the transmission pattern of SERPING1 gene variant favours the transmission of wild-type alleles in males, especially when the father is the carrier; hence, overall, fewer males and more female offspring inherited the variant. This could be because of a selection of wild-type male sperms during spermatogenesis, as the KLK system has been reported to play a crucial role in the regulation of spermatogenesis. Although, a similar pattern was observed in the maternal transmission of the SERPING1 gene variant; the difference was not statistically significant, likely because of a small sample size.

Clinical profile and management of pediatric hereditary angioedema in resource-constrained settings: our experience from a single centre in North India.

Hereditary angioedema (HAE) is a rare genetic disorder. The pattern of HAE is different in children as compared to adults. There is limited literature from developing countries where all first-line treatments are either unavailable or not easily accessible. Data of children with HAE were retrieved from medical records of patients registered in the Pediatric Immunodeficiency Clinic at our institute. Of the 206 patients with HAE, 61 were diagnosed before the age of 18 years. Male: female ratio was 1.1:1. Median age at onset of symptoms and diagnosis were 6.2 years (range 1-17 years) and 10.7 years (range 1.5-18 years) respectively. Median delay in diagnosis was 4.9 years (range 0-16 years). The commonest presentation was facial swelling (51/61) followed by swelling of extremities (47/61). Laryngeal edema and abdominal symptoms were reported in 28/61 and 31/61 patients respectively. Abdominal attacks were found to be less common in children as compared to adults. Most patients in our cohort received fresh-frozen plasma (n = 5/61) as on-demand therapy. Long-term prophylaxis included attenuated androgens (n = 25/61) and tranexamic acid (n = 23/61). Median duration of follow-up was 2242 patient months. One patient died on follow-up in this cohort. This is the largest single-centre cohort of pediatric HAE from resource-constrained settings. Facial attacks were more common, and there were significant delays in diagnosis when the age of onset of symptoms was younger. Gastrointestinal symptoms were less common in children than adults. HIGHLIGHTS: One of the largest single-centre cohorts of pediatric HAE and the only one from resource-constrained settings. There were significant delays in diagnosis when the age of onset of symptoms was younger. Abdominal attacks were found to be less common in children as compared to adults.