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.

Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

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.

X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India.

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

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.

CD40 gene polymorphism and its expression in children with Kawasaki disease from North India: a preliminary case-control study and meta-analysis.

Introduction: CD40 gene single-nucleotide polymorphisms (SNPs) have been associated with susceptibility and development of coronary artery abnormalities (CAAs) in children with Kawasaki disease (KD) in Japanese, Chinese, and Taiwanese populations. However, data on SNPs of the CD40 gene in patients with KD from the Indian subcontinent are not available. We studied the CD40 gene polymorphisms and its expression in children with KD from North India. Methods: SNPs of the CD40 gene (rs4810485, rs1535045) were studied using Sanger sequencing. CD40 expression was studied by flow cytometry. Meta-analysis was carried out to assess the role of both SNPs of the CD40 gene in KD. GRADEpro GDT software (v.3.2) was used to assess the "certainty of evidence." Results: Forty-one patients with KD and 41 age-, sex-matched febrile controls were enrolled. However, none of the alleles and genotypes of the CD40 gene were found to be associated with KD. CD40 expression was higher in KD and in KD with CAAs compared to controls, but it failed to reach statistical significance. In a meta-analysis, the T allele of rs153045 was found to be significantly associated with KD (OR = 1.28; 95% confidence interval (: 1.09-1.50; p = 0.002). The GRADE of evidence for this outcome, however, is of " very low certainty." Conclusion: The present study found no association between SNPs (rs4810485 and rs153045) and susceptibility to KD. This could be a reflection of a modest sample size. CD40 expression was higher in KD and in KD with CAAs. In the meta-analysis, the T allele of rs153045 was significantly associated with KD. Our study confirms a significant genetic heterogeneity in KD among different ethnicities.

Tuberculosis and Bacillus Calmette-Guérin Disease in Patients with Chronic Granulomatous Disease: an Experience from a Tertiary Care Center in North India.

Chronic granulomatous disease (CGD) is a phagocytic defect characterized by recurrent bacterial and fungal infections. We report clinical profile of patients with CGD and mycobacterial infections in a cohort from North India. A review of clinical and laboratory records was carried out for patients with CGD registered at our center between 1990 and 2021. Of the 99 patients with CGD, 22 had mycobacterial infections-Mycobacterium tuberculosis and M. bovis-BCG in 11 each. Among the children with M. bovis-BCG infection, 6 had localized and 5 had disseminated BCG disease. Median age at onset of symptoms and diagnosis of BCG disease was 5 months and 15 months, respectively. While disseminated forms of BCG were noted only in CYBB defect, none of the patients with NCF1 defect developed complications due to BCG vaccine. A recurring radiological feature was left axillary lymph node calcification, which was present in around 50% of CGD patients with BCG infections. Of 11 patients with tuberculosis, pulmonary, pleuro-pulmonary, abdominal, and disseminated forms were present in 6, 1, 2, and 2, respectively. Median age at onset of symptoms and diagnosis of tuberculosis was 129 months and 130 months, respectively. Molecular defects were identified in CYBB (5), NCF1 (4), and CYBA (1). Incidence of tuberculosis and BCG-related complications in patients with CGD is higher than the normal population. Screening for CGD is warranted in any patient with adverse reactions to BCG vaccination, calcification of left axillary lymph node, and persistent, recurrent or disseminated forms of tuberculosis.

Occurrence of Kawasaki disease and neoplasms in temporal proximity-single-center experience and systematic review of literature.

Various factors (e.g., infections) have been postulated to trigger Kawasaki disease (KD) in genetically predisposed individuals. Whether neoplasms can trigger KD is largely unknown due to paucity of data. Herein, we provide a detailed account of KD occurring in temporal proximity (within 6 months) to neoplasms ('neoplasm-KD'). Patients with 'neoplasm-KD' diagnosed/treated at our center from January 1994 to May 2021 were included. Additionally, we performed a systematic literature review (as per PRISMA 2020 guidelines) utilizing PubMed, Web of Science and Scopus databases to retrieve details of all patients with 'neoplasm-KD' reported till June 2021. Patients with multisystem inflammatory syndrome in children were excluded. As all reports pertained to case description(s), risk of bias assessment was not performed. The details of patients with 'neoplasm-KD' were analyzed using SPSS software. Primary and secondary outcomes were occurrence of coronary artery abnormalities (CAAs) and clinical characteristics of 'neoplasm-KD', respectively. A total of 25 patients (data from 18 reports) were included in the 'neoplasm-KD' dataset. The most frequently diagnosed neoplasm was acute lymphoblastic leukemia followed by neuroblastoma and acute myeloblastic leukemia. Overall, CAAs were noted in 48% of patients. Interval between diagnoses of KD and neoplasm was shorter in patients with CAAs as compared to patients with normal coronary arteries (p-value = 0.03). Besides providing a comprehensive description of 'neoplasm-KD', this study raises a possibility that neoplasms might trigger KD. Also, 'neoplasm-KD' may be associated with a higher risk of development of CAAs. However, the small size of 'neoplasm-KD' dataset precludes definitive conclusions regarding this association. Funding: nil. Registration: PROSPERO (CRD42021270458).

This study is the first exhaustive description of cancers and Kawasaki disease (KD) occurring in close temporal proximity. Nearly half of these patients develop coronary artery abnormalities. In KD, persistent lymphadenopathy, enlargement of liver/spleen and development of low blood cell counts should trigger evaluation for cancer. Our study also raises a possibility that cancers might occasionally trigger KD.

A Well-Curated Cost-Effective Next-Generation Sequencing Panel Identifies a Diverse Landscape of Pathogenic and Novel Germline Variants in a Bone Marrow Failure Cohort in a Resource-Constraint Setting.

The current study is a 4-year experience in diagnosis and screening of inherited and immune bone marrow failure cases using a targeted sequencing panel. A total of 171 cases underwent targeted next-generation sequencing and were categorized as suspected inherited bone marrow failure syndrome (IBMFS) group (106; 62%) and immune/idiopathic aplastic anemia (IAA) group (65; 38%) based on clinical and laboratory criteria. A total of 110 (64%) were pediatric (aged 0 to 12 years) patients and 61 (36%) were adolescent and adult (aged 13 to 47 years) patients. In suspected IBMFS group, 47 (44%), and in IAA group, 8 (12%) revealed a likely germline pathogenic variation. Whole-exome sequencing performed in 15 of 59 suspected IBMFS group cases was negative on targeted panel, and revealed a clinically important variation in 3 (20%) cases. A total of 11 novel variants were identified. The targeted panel helped establish a diagnosis in 44% (27/61) of unclassified bone marrow failure syndrome cases and led to amendment of clinical diagnosis in 5 (4.7%) cases. Overall, diagnostic yield of this well-curated small panel was comparable to Western studies with larger gene panels. Moreover, this was achievable at a much lower cost, making it suitable for resource-constraint settings. In addition, high frequency (>10%) of cryptic pathogenic IBMFS gene variations in IAA cohort suggests routine incorporation of targeted next-generation sequencing screening in these cases.

Intravenous Immunoglobulin in Kawasaki Disease-Evolution and Pathogenic Mechanisms.

Kawasaki disease (KD) is an acute vasculitis of childhood that affects the medium vessels with a special predilection to the involvement of coronary arteries. The major morbidity of this disease is due to coronary artery aneurysm, which occurs in about 25-30% of untreated cases. For decades now, intravenous immunoglobulin (IVIg) has consistently been shown to reduce the risk of CAAs to less than 5%. However, the mechanism of immunomodulation remains unclear. Several studies on the role of IVIg in the modulation of toll-like receptor pathways, autophagy, and apoptosis of the mononuclear phagocytic system, neutrophil extracellular trap, and dendritic cell modulation suggest a modulatory effect on the innate immune system. Similarly, certain studies have shown its effect on T-cell differentiation, cytokine release, and regulatory T-cell function. In this review, we discuss the potential mechanisms underlying the immunomodulatory actions of IVIg in patients with Kawasaki disease. Furthermore, we provide a summary of the evidence regarding various infusion protocols and dosages utilized in the treatment of KD patients.

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.

Management of hereditary angioedema in resource-constrained settings: A consensus statement from Indian subcontinent.

Hereditary angioedema (HAE) is an uncommon disorder characterized clinically by recurrent episodes of nonitchy subcutaneous and/or submucosal swellings. The estimated prevalence of HAE is ~ 1: 10,000 to 1: 50,000. There are no prevalence data from India, however, estimates suggest that there are 27,000 to 135,000 patients with HAE in India at present. The majority of these, however, remain undiagnosed. Replacement of plasma-derived or recombinant C1-esterase inhibitor (C1-INH) protein, administered intravenously, is the treatment of choice during the management of acute episodes of angioedema (i.e., "on-demand treatment") and is also useful for short-term prophylaxis (STP) and long-term prophylaxis (LTP). This has been found to be effective and safe even in young children and during pregnancy. Until recently, none of the first-line treatment options were available for "on-demand treatment," STP or LTP in India. As a result, physicians had to use fresh frozen plasma for both "on-demand treatment" and STP. For LTP, attenuated androgens (danazol or stanozolol) and/or tranexamic acid were commonly used. These drugs have been reported to be useful for LTP but are associated with a significant risk of adverse effects. Intravenous pd-C1-INH, the first-line treatment option, is now available in India. However, because there is no universal health insurance, access to pd-C1-INH is a significant challenge. HAE Society of India has developed these consensus guidelines for India and other resource-constrained settings where plasma-derived C1-INH therapy is the only available first-line treatment option for the management of HAE and diagnostic facilities are limited. These guidelines have been developed because it may not be possible for all patients to access the recommended therapy and at the recommended doses as suggested by the international guidelines. Moreover, it may not be feasible to follow the evaluation algorithm suggested by the international guidelines.

Evaluation of immunodominant peptides of in vivo expressed mycobacterial antigens in an ELISA-based diagnostic assay for pulmonary tuberculosis.

Non-sputum-based biomarker assay is urgently required as per WHO's target product pipeline for diagnosis of tuberculosis. Therefore, the current study was designed to evaluate the utility of previously identified proteins, encoded by in vivo expressed mycobacterial transcripts in pulmonary tuberculosis, as diagnostic targets for a serodiagnostic assay. A total of 300 subjects were recruited including smear+, smear- pulmonary tuberculosis (PTB) patients, sarcoidosis patients, lung cancer patients and healthy controls. Proteins encoded by eight in vivo expressed transcripts selected from previous study including those encoded by two topmost expressed and six RD transcripts (Rv0986, Rv0971, Rv1965, Rv1971, Rv2351c, Rv2657c, Rv2674, Rv3121) were analyzed for B-cell epitopes by peptide arrays/bioinformatics. Enzyme-linked immunosorbent assay was used to evaluate the antibody response against the selected peptides in sera from PTB and controls. Overall 12 peptides were selected for serodiagnosis. All the peptides were initially screened for their antibody response. The peptide with highest sensitivity and specificity was further assessed for its serodiagnostic ability in all the study subjects. The mean absorbance values for antibody response to selected peptide were significantly higher (p<0.001) in PTB patients as compared to healthy controls; however, the sensitivity for diagnosis of PTB was 31% for smear+ and 20% for smear- PTB patients. Thus, the peptides encoded by in vivo expressed transcripts elicited a significant antibody response, but are not suitable candidates for serodiagnosis of PTB.

Granulomatous inflammation and hypogammaglobulinemia: Clinical conundrum of familial hemophagocytic lymphohistiocytosis type 5.

Familial hemophagocytic lymphohistiocytosis (HLH) is an inherited disorder characterized by systemic hyperinflammation caused by an uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. Most children with familial HLH present within first 2 years of life and can have fatal disease unless hematopoietic stem cell transplant (HSCT) is performed (1). However, few patients may have late presentation and prolonged survival. With increasing awareness and facilities to identify HLH these disorders are being identified beyond infancy (2-4). Clinical and laboratory features are often similar to other primary immune deficiency diseases and pose diagnostic challenges (4-6). We report two patients who presented beyond the first decade of life with HLH, granulomatous inflammation, hypogammaglobulinemia, reduced B cells and were diagnosed to have familial HLH type 5 due to defect in STXBP2 gene.

Trend of pediatric cryptococcosis in a tertiary care centre and review of literature.

PURPOSE: Cryptococcosis is one of the most significant systemic fungal infections worldwide. Epidemiological data for pediatric cryptococcosis is very limited. Therefore, we planned this study to determine the burden of cryptococcosis in the pediatric population at our tertiary care center and performed review of literature. MATERIAL AND METHODS: In this retrospective study, all the patients less than 18 years of age were diagnosed with cryptococcosis, from January 2015-June 2021 were included. Demographic, clinical, and laboratory details of all the patients were noted. Furthermore, PubMed and MedLine databases were comprehensively searched for cases of pediatric cryptococcosis till June 2021. RESULTS: Of the total 5420 samples from suspected cryptococcosis cases processed at mycology laboratory, a total of 21 episodes of cryptococcosis (0.39%) were identified in 15 pediatric patients. The majority of the patients were apparently immunocompetent (10/15). Central nervous system (CNS) cryptococcosis was the most common presentation, followed by disseminated disease. All the isolates were identified as Cryptococcus neoformans (formerly referred to as C. neoformans var grubii), except one that was identified as Papiliotrema laurentii (formerly referred to as Cryptococcus laurentii). A standard treatment regimen inclusive of induction and maintenance therapy was provided in only five patients. The literature review revealed a total of 125 studies describing 1134 cases, of which 76.4% are reported from outside Asia, the majority (65.7%) restricted to CNS with C. neoformans as the commonest species. The management profile divulged a significantly higher use of standard drug regimen in Asia as compared to the rest of the world. Mortality of 13.32% was noted worldwide. CONCLUSION: To the best of our knowledge, this is the first clinico-epidemiological study of pediatric cryptococcosis from India and the largest retrospective study worldwide. The rising incidence among immunocompetent individuals, especially in Asia, is a matter of concern. Clinical suspicion and early diagnosis are the cornerstones for the management of cases.

Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

PURPOSE: To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. MATERIALS AND METHODS: Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. RESULTS: Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. CONCLUSION: These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

Juvenile localized scleroderma: A single-centre experience from India.

BACKGROUND: Juvenile localized scleroderma (JLS) or morphoea, a rare chronic autoimmune disease predominantly affects skin, subcutaneous tissue and occasionally the adjacent muscle, fascia and bone. We report the largest single-centre cohort of patients with JLS from India. METHODS: Patients who were diagnosed to have JLS were enrolled from the Paediatric Dermatology Clinic and the Paediatric Rheumatology Clinic of a tertiary care referral hospital in India. Collected data included details of the clinical profile, laboratory investigations and management. RESULTS: We analysed 84 patients with Juvenile localized scleroderma. Median age of disease onset was 5 years, and median age at diagnosis was 8 years. Commonest subtype was linear scleroderma (57 patients, 67.7%) followed by plaque morphoea and generalized morphoea. Fourteen patients (16.6%) were noted to have extracutaneous manifestations (ECMs). These included arthritis in eight (33.3%), brain parenchymal abnormalities in four (4.7%) and pulmonary involvement in two (8.3%) patients. Antinuclear antibody (ANA) was positive in eight/25 patients (32%; diffuse and speckled pattern in four patients each). One amongst these also had elevated anti-dsDNA titres. Positive ANA was found to have no association with ECMs (p 1.000). Patients were treated using methotrexate (61 patients; 72.6%), dexamethasone oral mini-pulse (OMP; 35 patients; 41.6%), calcipotriol (39 patients; 46.4%), topical corticosteroids (32 patients; 38%) and topical tacrolimus (three patients; 3.7%). Using linear regression analysis, administration of dexamethasone OMP and calcipotriol was found to be a predictor of good treatment response (p 0.034 and 0.019, respectively). CONCLUSION: Early use of systemic corticosteroids along with methotrexate may be more beneficial than methotrexate therapy alone.