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. 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.

Treatment intensification in Kawasaki disease - current perspectives.

INTRODUCTION: Intravenous immunoglobulin is the standard of care in Kawasaki disease. However, a subset of patients exhibits resistance to intravenous immunoglobulin treatment, even when Kawasaki disease is promptly diagnosed and managed. While intravenous immunoglobulin reduces the occurrence of coronary artery abnormalities from 15-25% to 3-5%, it does not entirely eliminate the risk. Besides, management guidelines for non-coronary complications of Kawasaki disease, for instance, myocarditis, remain speculative. AREAS COVERED: Recent literature suggests that a subset of patients with Kawasaki disease may benefit from treatment intensification with drugs, such as corticosteroids, infliximab, anakinra, and/or ciclosporin. In this manuscript, we have reviewed recent advances in the management of Kawasaki disease, especially with regard to preemptive intensification of therapy in children at high risk of cardiac complications. A comprehensive search was made using Web of Science, Scopus, and PubMed databases to gather English articles published from 1967 to 2023 on the treatment of Kawasaki disease. We incorporated the following words in the search strategy: 'Kawasaki disease,' 'intravenous immunoglobulin/IVIg,' 'intravenous immunoglobulin/IVIg-resistant Kawasaki disease,' 'treatment intensification,' or 'primary intensification of treatment/therapy.' EXPERT OPINION: The 'high-risk' group in Kawasaki disease needs to be identified with early intensification of primary therapy for better coronary and myocardial outcomes.

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, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India.

BACKGROUND: Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. OBJECTIVES: To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. METHODS: Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. RESULTS: Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. CONCLUSIONS: DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

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.

Pediatric Lupus Retinopathy: A Rare Manifestation of a Grave Systemic Disorder.

We describe a rare case of pediatric systemic lupus erythematosus (pSLE) and its successful management. A nine-year-old female presented with bilateral diminution of vision, fever, and rash in the malar region, chest, abdomen, back, and arms for three months. Clinical examination and multimodal imaging revealed bilateral extensive retinal vasculitis with macular edema. Laboratory investigations revealed anemia, leucopenia, positive serum antinuclear antibody (ANA), and anti-extractable nuclear antigen (ENA) antibodies. A diagnosis of pediatric lupus retinopathy was made. Ocular and systemic manifestations responded well to intense systemic immunosuppression (pulse intravenous {IV} methylprednisolone, oral prednisolone and hydroxychloroquine {HCQ}, six cycles of IV cyclophosphamide, and oral azathioprine) along with topical steroids and laser photocoagulation, over the next 10 months. Though ocular manifestations are not a part of the diagnostic criteria for SLE, they may be markers of active systemic disease. Ophthalmologists and rheumatologists must treat this complex disease in tandem in order to provide optimum patient care.

Impact of COVID-19 Pandemic on Clinical Care of Patients and Psychosocial Health of Affected Families with Chronic Granulomatous Disease: an Observational Study from North India.

Day-to-day clinical management of patients with inborn errors of immunity, including chronic granulomatous disease (CGD), has been affected by the coronavirus disease-2019 (COVID-19) pandemic. There is a dearth of information on impact of this pandemic on clinical care of children with CGD and psychological profile of the caretakers. Among the 101 patients with CGD followed up in our center, 5 children developed infection/complications associated with COVID-19. Four of these children had a mild clinical course, while 1 child developed features of multisystem inflammatory syndrome in children (MISC) requiring intravenous glucocorticoids. Parents and caretakers of CGD patients (n = 21) and 21 healthy adults with similar ages and genders were also evaluated on the following scales and questionnaires: COVID-19 Fear Scale (FCV 19S), Impact of Event Scale (IES-R), Depression, Anxiety, and Stress Scale (DASS 21), Preventive COVID-19 Behavior Scale (PCV 19BS), and a "COVID-19 Psychological wellbeing questionnaire." Median age of the parents/caregivers was 41.76 years (range: 28-60 years). Male:female ratio was 2:1. In the study group, 71.4% had higher IES scores compared to 14.3% in controls. The caregivers had a high prevalence of stress, anxiety, avoidance behavior, and depression compared to controls (p < 0.001). Children with CGD have had predominantly mild infection with COVID-19; however, caregivers/parents of these children were at risk of developing psychological distress. The COVID-19 pandemic has brought to light the importance of patients' and caretakers' mental health which needs periodic assessment and appropriate interventions.

Juvenile dermatomyositis associated with autoantibodies to small ubiquitin-like modifier activating enzyme: a report of 4 cases from North India and a review of literature.

BACKGROUND: Juvenile dermatomyositis (JDM) is the commonest inflammatory myositis in children. The clinical phenotype is often characterized by the presence of myositis-specific antibodies (MSA). Antibodies to small ubiquitin-like modifier activating enzyme (SAE) are amongst the rarest MSA reported in children. MATERIALS AND METHODS: A review of medical records of all patients diagnosed to have JDM during the period January 1992-April 2022 in our institute was done. Case records of children with JDM who had significant positivity for anti-SAE antibody by myositis immunoblot were analysed in detail. RESULTS: Of the 140 children with JDM, MSA immunoblot was carried out in 53 patients-4 (7.5%) amongst these had significant positivity for anti-SAE antibodies. Median age of onset of symptoms was 5.5 years (range: 5-11 years). Clinical features at presentation included fever, photosensitivity, heliotrope rash, and Gottron papules. Clinically significant proximal muscle weakness was noted in 3/4 patients; 1 had no discernible weakness but had radiological evidence of myositis. None of the 4 patients had evidence of interstitial lung disease or calcinosis. All patients were treated with intravenous pulse methylprednisolone: subcutaneous weekly methotrexate and hydroxychloroquine. One patient received mycophenolate mofetil because of a relapse of muscle disease, while none received cyclophosphamide or biologics. Median follow-up duration was 21.5 months (range: 6-39 months). CONCLUSION: Anti-SAE antibodies were found in 4/53 (7.5%) of North Indian children with JDM. All 4 patients had predominant cutaneous manifestations followed by muscle disease. Response to treatment was brisk and sustained. None had developed calcinosis in the follow-up. KEY MESSAGES: 1. We report high prevalence of anti-SAE antibody positivity (7.5%) in North Indian cohort of JDM. 2. Cutaneous disease precedes muscle weakness in children with anti-SAE positive JDM. 3. No evidence of interstitial lung disease/calcinosis was seen in these children.

Phenotype and Genotype Profile of Children with Primary Distal Renal Tubular Acidosis: A 10-Year Experience from a North Indian Teaching Institute.

Primary distal renal tubular acidosis (dRTA) or Type 1 RTA in children is caused by a genetic defect (involved genes ATP6V0A4 , ATP6V1B1 , SLC4A1 , FOXI1 , or WDR72 ), which causes tubular transport defects characterized by an inability to appropriately acidify urine with resultant persistent hyperchloremic metabolic acidosis. Retrospective analysis of 28 children (14 males) under the age of 14 years with dRTA seen from 2010 to 2019 was reviewed, and detailed clinic records were analyzed. The clinical features, investigations, and response to treatment were recorded. The median age of the children at presentation was 30 months (range: 9.25-72 months), and the median age at onset of symptoms was 2 months. All the children had growth failure, polyuria, and polydipsia at presentation. Mean serum potassium, pH, bicarbonate, and anion gap at presentation was 2.3 ± 0.5 mmol/L, 7.22 ± 0.09, 13.28 ± 4.37 mmol/L, and 9.3 ± 2.18, respectively. Mean serum potassium, pH, bicarbonate at follow-up was 3.88 ± 0.6 mmol/L, 7.35 ± 0.06, and 20.13 ± 4.17 mmol/L, respectively. The median z-score for the weight for age and height for age at initial presentation was -4.77 (-7.68 to -3.74) and -4.21 (-5.42 to -2.37) and at follow-up was -3.35 (-5.29 to -1.55) and -3.84 (-5.36 to -1.63), respectively. Twenty-two (78.6%) children had medullary nephrocalcinosis. Four children had sensorineural hearing loss. Seven children had genetic testing done, and six had pathogenic or likely pathogenic variants in ATP6V1B1 and ATP6V0A4 gene. Children with dRTA have a guarded prognosis and ATP6V1B1 and ATP6V0A4 mutations are the most common implicated genetic defect in Indian children with distal RTA.

Cardiovascular Abnormalities in Juvenile Dermatomyositis: A Scoping Review for the Clinical Rheumatologists.

Juvenile dermatomyositis (JDM) is a common form of inflammatory myositis in children. Vasculopathy and endothelial dysfunction play significant roles in the pathogenesis of JDM. Cardiac involvement in JDM is often underestimated, and it may be a potential indicator of poor prognosis. Cardiac dysfunction in JDM can occur both in the acute and chronic stages of the disease. Amongst the acute complications, acute congestive heart failure (CHF), myocarditis, arrhythmia, and complete heart block are common. However, these remain unrecognized due to a lack of overt clinical manifestations. Increased rates of cardiovascular abnormalities have been noted with anti-SRP and anti-Jo 1 auto-antibody positivity. Long-term follow-up studies in JDM have shown an increased prevalence of hypertension, atherosclerosis, coronary artery disease, and metabolic syndrome in adolescence and adulthood. Monitoring of body-mass index, blood pressure, and laboratory evaluation of fasting glucose and lipid profile may help in identifying metabolic syndrome in children with JDM. Steroid-sparing agents, daily exercise, and a healthy diet may reduce such long-term cardiac morbidities. Current use of multimodality imaging such as stress-echocardiography, contrast-enhanced echocardiography, cardiac magnetic resonance imaging, and positron emission tomography has increased the diagnostic yield of subclinical heart disease during acute and chronic stages of JDM. This review elaborates on different aspects of cardiac dysfunction in JDM. It also emphasizes the importance of cardiac screening in long-term follow-up of children with JDM.

Autoimmune Cytopenias in Common Variable Immunodeficiency Are a Diagnostic and Therapeutic Conundrum: An Update.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). CVID is a heterogenous condition and clinical manifestations may vary from increased susceptibility to infections to autoimmune manifestations, granulomatous disease, polyclonal lymphoproliferation, and increased risk of malignancy. Autoimmune manifestations may, at times, be the first and only clinical presentation of CVID, resulting in diagnostic dilemma for the treating physician. Autoimmune cytopenias (autoimmune haemolytic anaemia and/or thrombocytopenia) are the most common autoimmune complications seen in patients with CVID. Laboratory investigations such as antinuclear antibodies, direct Coomb's test and anti-platelet antibodies may not be useful in patients with CVID because of lack of specific antibody response. Moreover, presence of autoimmune cytopenias may pose a significant therapeutic challenge as use of immunosuppressive agents can be contentious in these circumstances. It has been suggested that serum immunoglobulins must be checked in all patients presenting with autoimmune cytopenia such as immune thrombocytopenia or autoimmune haemolytic anaemia. It has been observed that patients with CVID and autoimmune cytopenias have a different clinical and immunological profile as compared to patients with CVID who do not have an autoimmune footprint. Monogenic defects have been identified in 10-50% of all patients with CVID depending upon the population studied. Monogenic defects are more likely to be identified in patients with CVID with autoimmune complications. Common genetic defects that may lead to CVID with an autoimmune phenotype include nuclear factor kappa B subunit 1 (NF-kB1), Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA), cytotoxic T lymphocyte antigen 4 (CTLA4), Phosphoinositide 3-kinase (PI3K), inducible T-cell costimulatory (ICOS), IKAROS and interferon regulatory factor-2 binding protein 2 (IRF2BP2). In this review, we update on recent advances in pathophysiology and management of CVID with autoimmune cytopenias.

Mechanisms of Immune Dysregulation in COVID-19 Are Different From SARS and MERS: A Perspective in Context of Kawasaki Disease and MIS-C.

Coronaviruses have led to three major outbreaks to date-Severe Acute Respiratory Syndrome (SARS; 2002), Middle East Respiratory Syndrome (MERS; 2012) and the ongoing pandemic, Coronavirus Disease (COVID-19; 2019). Coronavirus infections are usually mild in children. However, a few children with MERS had presented with a severe phenotype in the acute phase resulting in progressive pneumonic changes with increasing oxygen dependency and acute respiratory distress requiring ventilatory support. A subset of children with a history of SARS-CoV-2 infection develops a multisystem hyper-inflammatory phenotype known as Multisystem Inflammatory Syndrome in Children (MIS-C). This syndrome occurs 4-6 weeks after infection with SARS-CoV-2 and has been reported more often from areas with high community transmission. Children with MIS-C present with high fever and often have involvement of cardiovascular, gastrointestinal and hematologic systems leading to multiorgan failure. This is accompanied by elevation of pro-inflammatory cytokines such as IL-6 and IL-10. MIS-C has several similarities with Kawasaki disease (KD) considering children with both conditions present with fever, rash, conjunctival injection, mucosal symptoms and swelling of hands and feet. For reasons that are still not clear, both KD and MIS-C were not reported during the SARS-CoV and MERS-CoV outbreaks. As SARS-CoV-2 differs from SARS-CoV by 19.5% and MERS by 50% in terms of sequence identity, differences in genomic and proteomic profiles may explain the varied disease immunopathology and host responses. Left untreated, MIS-C may lead to severe abdominal pain, ventricular dysfunction and shock. Immunological investigations reveal reduced numbers of follicular B cells, increased numbers of terminally differentiated CD4+T lymphocytes, and decreased IL-17A. There is still ambiguity about the clinical and immunologic risk factors that predispose some children to development of MIS-C while sparing others. Host-pathogen interactions in SARS, MERS and COVID-19 are likely to play a crucial role in the clinical phenotypes that manifest. This narrative review focuses on the immunological basis for development of MIS-C syndrome in the ongoing SARS-CoV-2 pandemic. To the best of our knowledge, these aspects have not been reviewed before.

Management of pregnancy in hereditary angioedema in a resource constrained setting: Our experience at Chandigarh, North India.

Hereditary angioedema (HAE) is a rare genetic disorder distinguished clinically by recurrent episodes of non-pruritic swelling. Although pregnancy has been considered a trigger, it may have variable effect on frequency of attacks of HAE. C1-inhibitor (C1-INH) is the treatment of choice for management of HAE during pregnancy. However, because of non-availability of C1-INH therapy in developing countries, fresh-frozen plasma (FFP) and tranexamic acid remain the drugs of choice in pregnancy for treatment of acute attacks and for prophylaxis respectively. There is paucity of data on outcome of pregnancy with patients with HAE from developing countries such as India where all the first line medications are not available. A retrospective review was done including four HAE patients who conceived (with a total of 9 pregnancies). Our results suggest that frequency of attacks may increase during pregnancy especially during second trimester and post-delivery (during breastfeeding). However, HAE attacks are rare at the time of delivery. In resource limited settings, treatment with FFP/tranexamic acid needs to be individualised.