Microvascular changes on nailfold capillaroscopy in acute stage of Kawasaki disease: a new diagnostic paradigm for an enigmatic condition.

OBJECTIVES: Kawasaki disease (KD) is a medium vessel vasculitis with a predilection to involve coronary arteries. However, there is a paucity of literature on microvascular changes in patients with KD. METHODS: Children diagnosed with KD based on American Heart Association guidelines 2017 were enrolled prospectively. Demographic details and echocardiographic changes in coronaries were recorded. Nailfold capillaries were assessed using Optilia Video capillaroscopy and data were analysed using Optilia Optiflix Capillaroscopy software at acute (prior to IVIG administration) and subacute/convalescent phase. RESULTS: We enrolled 32 children with KD (17 boys) with a median age of 3 years. Nailfold capillaroscopy (NFC) was performed in 32 patients in the acute phase (compared with 32 controls) and in 17 during the subacute/convalescent phase at a median follow-up of 15 (15-90) days after IVIG treatment. The following findings were seen in NFC in the acute phase of KD: reduced capillary density (n = 12, 38.6%), dilated capillaries (n = 3, 9.3%), ramifications (n = 3, 9.3%) and capillary haemorrhages (n = 2, 6.2%). Capillary density was reduced significantly in the acute phase of KD (38.6%) as compared with the subacute/convalescent phase (25.4%) (P-value <0.001) and controls (0%) (P-value = 0.03). We observed no correlation between coronary artery involvement and mean capillary density (P = 0.870). CONCLUSION: Results show that patients with KD have significant nailfold capillary changes in the acute phase. These findings may provide a new diagnostic paradigm for KD and a window to predict coronary artery abnormalities.

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.

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.

Evening versus morning dosing regimen drug therapy for hypertension.

BACKGROUND: Variation in blood pressure levels display circadian rhythms. Complete 24-hour blood pressure control is the primary goal of antihypertensive treatment and reducing adverse cardiovascular outcomes is the ultimate aim. This is an update of the review first published in 2011. OBJECTIVES: To evaluate the effectiveness of administration-time-related effects of once-daily evening versus conventional morning dosing antihypertensive drug therapy regimens on all-cause mortality, cardiovascular mortality and morbidity, total adverse events, withdrawals from treatment due to adverse effects, and reduction of systolic and diastolic blood pressure in people with primary hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register via Cochrane Register of Studies (17 June 2022), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 6, 2022); MEDLINE, MEDLINE In-Process and MEDLINE Epub Ahead of Print (1 June 2022); Embase (1 June 2022); ClinicalTrials.gov (2 June 2022); Chinese Biomedical Literature Database (CBLD) (1978 to 2009); Chinese VIP (2009 to 7 August 2022); Chinese WANFANG DATA (2009 to 4 August 2022); China Academic Journal Network Publishing Database (CAJD) (2009 to 6 August 2022); Epistemonikos (3 September 2022) and the reference lists of relevant articles. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the administration-time-related effects of evening with morning dosing monotherapy regimens in people with primary hypertension. We excluded people with known secondary hypertension, shift workers or people with white coat hypertension. DATA COLLECTION AND ANALYSIS: Two to four review authors independently extracted data and assessed trial quality. We resolved disagreements by discussion or with another review author. We performed data synthesis and analyses using Review Manager Web for all-cause mortality, cardiovascular mortality and morbidity, serious adverse events, overall adverse events, withdrawals due to adverse events, change in 24-hour blood pressure and change in morning blood pressure. We assessed the certainty of the evidence using GRADE. We conducted random-effects meta-analysis, fixed-effect meta-analysis, subgroup analysis and sensitivity analysis. MAIN RESULTS: We included 27 RCTs in this updated review, of which two RCTs were excluded from the meta-analyses for lack of data and number of groups not reported. The quantitative analysis included 25 RCTs with 3016 participants with primary hypertension. RCTs used angiotensin-converting enzyme inhibitors (six trials), calcium channel blockers (nine trials), angiotensin II receptor blockers (seven trials), diuretics (two trials), α-blockers (one trial), and ß-blockers (one trial). Fifteen trials were parallel designed, and 10 trials were cross-over designed. Most participants were white, and only two RCTs were conducted in Asia (China) and one in Africa (South Africa). All trials excluded people with risk factors of myocardial infarction and strokes. Most trials had high risk or unclear risk of bias in at least two of several key criteria, which was most prominent in allocation concealment (selection bias) and selective reporting (reporting bias). Meta-analysis showed significant heterogeneity across trials. No RCTs reported on cardiovascular mortality and cardiovascular morbidity. There may be little to no differences in all-cause mortality (after 26 weeks of active treatment: RR 0.49, 95% CI 0.04 to 5.42; RD 0, 95% CI -0.01 to 0.01; very low-certainty evidence), serious adverse events (after 8 to 26 weeks of active treatment: RR 1.17, 95% CI 0.53 to 2.57; RD 0, 95% CI -0.02 to 0.03; very low-certainty evidence), overall adverse events (after 6 to 26 weeks of active treatment: RR 0.89, 95% CI 0.67 to 1.20; I² = 37%; RD -0.02, 95% CI -0.07 to 0.02; I² = 38%; very low-certainty evidence) and withdrawals due to adverse events (after 6 to 26 weeks active treatment: RR 0.76, 95% CI 0.47 to 1.23; I² = 0%; RD -0.01, 95% CI -0.03 to 0; I² = 0%; very low-certainty evidence), but the evidence was very uncertain. AUTHORS' CONCLUSIONS: Due to the very limited data and the defects of the trials' designs, this systematic review did not find adequate evidence to determine which time dosing drug therapy regimen has more beneficial effects on cardiovascular outcomes or adverse events. We have very little confidence in the evidence showing that evening dosing of antihypertensive drugs is no more or less effective than morning administration to lower 24-hour blood pressure. The conclusions should not be assumed to apply to people receiving multiple antihypertensive drug regimens.

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.

Immune and metabolic perturbations in COVID-19-associated pulmonary mucormycosis: A transcriptome analysis of innate immune cells.

BACKGROUND AND OBJECTIVES: The mechanisms underlying COVID-19-associated pulmonary mucormycosis (CAPM) remain unclear. We use a transcriptomic analysis of the innate immune cells to investigate the host immune and metabolic response pathways in patients with CAPM. PATIENTS AND METHODS: We enrolled subjects with CAPM (n = 5), pulmonary mucormycosis (PM) without COVID-19 (n = 5), COVID-19 (without mucormycosis, n = 5), healthy controls (n = 5) without comorbid illness and negative for SARS-CoV-2. Peripheral blood samples from cases were collected before initiating antifungal therapy, and neutrophils and monocytes were isolated. RNA sequencing was performed using Illumina HiSeqX from monocytes and neutrophils. Raw reads were aligned with HISAT-2 pipeline and DESeq2 was used for differential gene expression. Gene ontology (GO) and metabolic pathway analysis were performed using Shiny GO application and R packages (ggplot2, Pathview). RESULTS: The derangement of core immune and metabolic responses in CAPM patients was noted. Pattern recognition receptors, dectin-2, MCL, FcRγ receptors and CLEC-2, were upregulated, but signalling pathways such as JAK-STAT, IL-17 and CARD-9 were downregulated; mTOR and MAP-kinase signalling were elevated in monocytes from CAPM patients. The complement receptors, NETosis, and pro-inflammatory responses, such as S100A8/A9, lipocalin and MMP9, were elevated. The major metabolic pathways of glucose metabolism-glycolysis/gluconeogenesis, pentose phosphate pathway, HIF signalling and iron metabolism-ferroptosis were also upregulated in CAPM. CONCLUSIONS: We identified significant alterations in the metabolic pathways possibly leading to cellular iron overload and a hyperglycaemic state. Immune responses revealed altered recognition, signalling, effector functions and a pro-inflammatory state in monocytes and neutrophils from CAPM patients.

Optochiasmatic Cavernomas: Updated systematic review and proposal of a novel classification with surgical approaches.

Cavernomas are histologically benign vascular malformations found at different sites in the brain. A rare site for such cavernomas, however, is the anterior optic pathway, comprising the optic nerve, chiasma, and optic tract-called optochiasmatic cavernomas (OCC). These lesions usually present with sudden onset or progressive vision loss, headache, and features mimicking pituitary apoplexy. In this paper, we describe a case of OCC operated at our center. We carry out an updated review of literature depicting cases of OCC, their clinical presentation, management, and postoperative complications. We also propose a novel classification system based on lesion location and further analyze these cavernoma types with respect to the surgical approach used and visual outcome. A 30-year-old lady had presented with a 3-week history of progressive bilateral vision loss and headache. Based on imaging, she was suspected to have a cavernous angioma of the chiasma and left optic tract. Due to progressive vision deterioration, the lesion was surgically excised using pterional craniotomy. Postoperatively, her visual symptoms improved, but she developed diabetes insipidus. Clinical and radiological follow-up has been done for 18 months after surgery. A total of 81 cases have been described in the literature, including the present case. Chiasmal apoplexy is the most common presentation. Surgical excision is the standard of care. Our analysis based on lesion location shows the most appropriate surgical approach to be used for each cavernoma type. Visual outcome correlates with the preoperative visual status. Visual outcome is good in patients presenting with acute chiasmal apoplexy, and when complete surgical excision is performed. The endonasal endoscopic approach was found to provide the best visual outcome. In addition to preoperative visual status, complete surgical excision predicts favorable visual outcomes in OCC. Our proposed classification system guides the appropriate surgical approach required for a particular location of the cavernoma.

Systematic review analyzing significance of endometrial cavity fluid during assisted reproductive techniques.

OBJECTIVE: The objective of our study is to estimate the prevalence of endometrial cavity fluid (ECF) in Assisted Reproductive Techniques (ART) cycles and analyze its effects on pregnancy outcome in such cycles. DATA SOURCES: PubMed, Cochrane Central, Scopus, and clinicaltrials.gov were searched for articles. The reference lists of relevant publications were explored for other studies. STUDY ELIGIBILITY CRITERIA: Studies that had assessed the pregnancy outcome in ART cycles and had commented on ECF accumulation were included. Pregnancy outcomes were assessed in all ART cycles where ECF was observed and were compared to the non-ECF cycles. RESULTS: A total of nine studies were included in the meta-analysis for a total of 28,210 cycles. Pooled analysis of the prevalence of ECF cycles out of total cycles in females undergoing ART using a fixed effect model showed that it was 14% (95% CI is 13% to 14%; I2 = 99%, p = < 0.01). The random effect model prevalence of ECF cycles was around 7% (95% CI: 4% to 10%). There was a statistically significant (25%) decrease in pregnancy rates per cycle transfer in the ECF cycle versus the non-ECF cycle group during ART [OR = 0.75, 95% CI = 0.67-0.84), p < 0.001; moderate quality evidence]. When ECF size was compared, there was a statistically significant increase in pregnancy rates if ECF size was less than 3.5 mm versus greater than or equal to 3.5 mm [OR = 13.67, 95% CI = 1.43-130.40), p = 0.02; high quality evidence]. Sub-group analysis revealed that the ECF present at the time of embryo transfer significantly decreased the pregnancy rates by 26% as compared to the group where the ECF was not present at the time of embryo transfer [OR = 0.74, 95% CI = 0.65-0.85), p < 0.001]. CONCLUSIONS: This meta-analysis proposes that the presence of ECF significantly decreases the implantation and pregnancy rates of ART cycles, and even more so if its size is greater than 3.5 mm. Interventions to decrease ECF formation or treat it have enhanced the pregnancy outcome in ART cycles. PROSPERO REGISTRATION: Date: 17th September 2020; Number: CRD42020182262.

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.

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.

Distal coronary artery abnormalities in Kawasaki disease: experience on CT coronary angiography in 176 children.

OBJECTIVE: Precise evaluation of coronary artery abnormalities (CAAs) in Kawasaki disease (KD) is essential. The aim of this study is to determine role of CT coronary angiography (CTCA) for detection of CAAs in distal segments of coronary arteries in patients with KD. METHODS: CTCA findings of KD patients with distal coronary artery involvement were compared with those on transthoracic echocardiography (TTE) during the period 2013-21. RESULTS: Among 176 patients with KD who underwent CTCA (128-Slice Dual Source scanner), 23 (13.06%) had distal CAAs (right coronary-15/23; left anterior descending-14/23; left circumflex-4/23 patients). CTCA identified 60 aneurysms-37 proximal (36 fusiform; 1 saccular) and 23 distal (17 fusiform; 6 saccular); 11 patients with proximal aneurysms had distal contiguous extension; 9 patients showed non-contiguous aneurysms in both proximal and distal segments; 4 patients showed distal segment aneurysms in absence of proximal involvement of same coronary artery; 4 patients had isolated distal CAAs. On TTE, only 40 aneurysms could be identified. Further, distal CAAs could not be identified on TTE. CTCA also identified complications (thrombosis, mural calcification and stenosis) that were missed on TTE. CONCLUSIONS: CAAs can, at times, occur in distal segments in isolation and also in association with, or extension of, proximal CAAs. CTCA demonstrates CAAs in distal segments of coronary arteries, including branches, in a significant number of children with KD-these cannot be detected on TTE. CTCA may therefore be considered as a complimentary imaging modality in children with KD who have CAAs on TTE.

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.

Rate and anchorage loss during en-masse retraction between friction and frictionless mechanics: A randomized clinical trial.

OBJECTIVE: To compare rate and anchorage loss during en-masse retraction of anterior maxillary teeth between friction mechanics (FM) and frictionless mechanics (FLM). SETTING AND SAMPLE POPULATION: Thirty-eight patients requiring en-masse retraction of protruded anterior maxillary teeth were randomly allocated into FM and FLM groups. METHODS: En-masse retraction with sliding mechanics (FM) using an elastomeric chain was compared with continuous mushroom loop archwire mechanics (FLM). Study models and lateral cephalograms were taken before (T1) and immediately after retraction (T2). The primary outcome was the rate of en-masse retraction. Anchorage loss was the secondary outcome. Intergroup comparison was performed using an independent t test (P < .05). RESULTS: Baseline characteristics were similar between groups. Thirty-six patients completed the trial. Two patients were lost to follow-up in the FLM group. The rate of en-masse retraction did not differ significantly (P = .625) between FM (0.7 mm/mo) and FLM (0.8 mm/mo) groups. The intragroup comparison showed significant anchorage loss in FM (2.28 mm) and FLM (1.13 mm) groups; however, the intergroup comparison showed no statistically significant difference (P = .093). Maxillary first molar showed a statistically significant change in angulation between the two mechanic groups (P < .001). Vertical movement of the maxillary incisor and first molar showed no significant difference between FM and FLM groups (P = .143, P = .546, respectively). CONCLUSIONS: The rate of en-masse retraction and anchorage loss was comparable between the FM and FLM groups. Significant anchorage loss was seen with both mechanics. The result suggests that both the mechanic group require external reinforcement to prevent anchorage loss.

Long-term vascular dysfunction in Kawasaki disease: systematic review and meta-analyses.

BACKGROUND: Long-term physiological dysfunction in coronary/systemic vasculature may persist in individuals with Kawasaki disease even in the absence of coronary artery abnormalities. We perform a systematic review and meta-analyses of studies assessing long-term vascular function in Kawasaki disease. METHODS: PubMed, Embase, and Web of Science databases were searched for relevant literature published till May 2021. Patients with Kawasaki disease were included as cases and healthy age/sex-matched individuals as controls. Newcastle Ottawa Scale was used to assess the study quality. Outcome measures were differences in markers of vascular function 1 year after diagnosis of Kawasaki disease. Data were analysed using Review Manager software. Comprehensive meta-analysis software was used for meta-regression. To assess the certainty of evidence, GRADE Profiler software was utilised. RESULTS: Of 2280 citations, 49 case-control studies (comprising 2714 cases and 2118 controls) were included for data synthesis. Decreased flow-mediated dilatation [3.83, 95%CI 0.94-6.72] and increased pulse-wave velocity [39.34 cm/sec, 95%CI 20.86-57.83], arterial stiffness [0.35, 95%CI 0.11-0.59], and common carotid artery intima-media thickness were noted in patients with Kawasaki disease. No significant difference was observed for nitroglycerine-mediated dilatation and endothelial peripheral artery tonometry (endo-PAT). Significant inter-study heterogeneity was observed for flow-mediated dilatation, arterial stiffness, carotid artery intima-media thickness, and endo-PAT. The GRADE evidence was of 'very low quality' for all outcome measures except 'moderate quality' for pulse-wave velocity. CONCLUSIONS: Evidence suggests the presence of long-term endothelial dysfunction in patients with Kawasaki disease even in the absence of coronary artery abnormalities. Avoidance of development of other cardiovascular risk factors seems prudent in patients with Kawasaki disease.

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.

Utility of Immunohistochemistry and Immunofluorescence in Determining the Pathogenic Variants of Chronic Granulomatous Disease.

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes due to defects in any of the five subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. An initial diagnosis of CGD is made by flow cytometry-based dihydrorhodamine assay or nitro blue tetrazolium test, which is further confirmed by molecular assays. Expression of five subunits of NADPH oxidase components by either flow cytometric or western blot analysis provides clues toward the potential gene targets which are subsequently confirmed by various genetic assays. Immunohistochemistry (IHC) and immunofluorescence (IF) have never been earlier used to determine the expression of different subunits of NADPH oxidase system. We evaluated the utility of IHC and IF in determining the underlying pathogenic variants of CGD. MATERIALS AND METHODS: Twelve genetically confirmed cases of CGD, comprising of biopsy specimens (n = 6), tissue blocks from autopsy cases (n = 3), and cellblocks of cell pellet prepared from peripheral blood (n = 4) were included. IHC for p67phox and p47phox subunits and IF for cytochrome b558 were performed. RESULTS: All 4 cases with pathogenic variation of NCF2 gene showed loss of expression for p67phox subunit. Two cases with pathogenic variation of NCF1 gene showed loss of expression for p47phox subunit. Five cases, except a single case with CYBB gene pathogenic variation, showed loss of expression for cytochrome b558 on IF. Thus, loss of expression consistently matched with the underlying genetic defects assessed by sequencing. CONCLUSIONS: Our results confirm our hypothesis that IHC and IF are two rapid, economical, pathologist-friendly techniques providing pertinent information regarding the underlying pathogenic variants and such immuno-analysis can be easily performed on the tissue.

A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia.

PURPOSE: Specific granule deficiency (SGD) is a rare inborn error of immunity resulting from loss-of-function variants in CEBPE gene (encoding for transcription factor C/EBPε). Although this genetic etiology has been known for over two decades, only a few patients with CEBPE variant-proven SGD (type I) have been reported. Herein, we describe two siblings with a novel homozygous CEBPE deletion who were noted to have profound neutropenia on initial evaluation. We aimed to evaluate the immunohematological consequences of this novel variant, including profound neutropenia. METHODS: Light scatter characteristics of granulocytes were examined on various automated hematology analyzers. Phagocyte immunophenotype, reactive oxygen species generation, and Toll-like receptor (TLR) signaling were assessed using flow cytometry. Relative expression of genes encoding various granule proteins was studied using RT-PCR. Western blot analysis and luciferase reporter assay were performed to explore variant C/EBPε expression and function. RESULTS: Severe infections occurred in both siblings. Analysis of granulocyte light scatter plots revealed automated hematology analyzers can provide anomalously low neutrophil counts due to abnormal neutrophil morphology. Neutrophils displayed absence/marked reduction of CD15/CD16 expression and overexpression (in a subset) of CD14/CD64. Three distinct populations of phagocytes with different oxidase activities were observed. Impaired shedding of CD62-ligand was noted on stimulation with TLR-4, TLR-2/6, and TLR-7/8 agonists. We demonstrated the variant C/EBPε to be functionally deficient. CONCLUSION: Homozygous c.655_665del variant in CEBPE causes SGD. Anomalous automated neutrophil counts may be reported in patients with SGD type I. Aberrant TLR signaling might be an additional pathogenetic mechanism underlying immunodeficiency in SGD type I.

Association of ITPKC gene polymorphisms rs28493229 and rs2290692 in North Indian children with Kawasaki disease.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of several genes are linked to the etiopathogenesis of Kawasaki disease (KD). Association of SNPs of inositol 1,4,5-triphosphate-3-kinase C (ITPKC) gene with susceptibility to KD and coronary artery lesions (CALs) has been observed in children of certain ethnicities, but not from others. The present study was planned to explore this genetic association in the North Indian cohort. METHODS: Fifty children with KD and 50 age- and sex-matched controls were studied for two SNPs (rs28493229 and rs2290692) of the ITPKC gene using polymerase chain reaction and restriction fragment length polymorphism. Findings were confirmed by Sanger sequencing. A meta-analysis was also carried out for GG and CC genotypes of the SNPs. RESULTS: There was significant association between KD susceptibility and CG + GG genotype of rs2290692 (p = 0.015, odds ratio = 4.1, 95% confidence interval = 1.38-13.83). None of the single alleles or genotypes of the SNPs of ITPKC were, however, significantly associated with KD susceptibility. A meta-analysis also did not show any significant association of these SNPs to KD susceptibility. CONCLUSIONS: Our findings suggest that ITPKC gene SNPs (rs28493229 and rs2290692) did not have a significant association with susceptibility to KD in children from North India. Larger multicentric studies incorporating different ethnicities are required to understand the genetic basis of KD. IMPACT: While SNP rs28493229 of the ITPKC gene is not found to be associated with susceptibility to KD, the combined genotype of SNP rs2290692 is shown to be associated. Impact of ITPKC gene SNP on KD is different across different races and ethnicities. We could find an association of the combined genotype of rs2290692 with it in the Indian population. This study highlights that phenotype and genotypic association of KD varies with ethnicities. Larger multicentric studies are required to reach a conclusion regarding the genetic association of KD.