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.

Radiation dose analysis of computed tomography coronary angiography in Children with Kawasaki disease.

BACKGROUND: There is evolving role of computed tomography coronary angiography (CTCA) in non-invasive evaluation of coronary artery abnormalities in children with Kawasaki disease (KD). Despite this, there is lack of data on radiation dose in this group of children undergoing CTCA. AIM: To audit the radiation dose of CTCA in children with KD. METHODS: Study (December 2013-February 2018) was performed on dual source CT scanner using adaptive prospective electrocardiography-triggering. The dose length product (DLP in milligray-centimeters-mGy.cm) was recorded. Effective radiation dose (millisieverts-mSv) was calculated by applying appropriate age adjusted conversion factors as per recommendations of International Commission on Radiological Protection. Radiation dose was compared across the groups (0-1, 1-5, 5-10, and > 10 years). RESULTS: Eighty-five children (71 boys, 14 girls) with KD underwent CTCA. The median age was 5 years (range, 2 mo-11 years). Median DLP and effective dose was 21 mGy.cm, interquartile ranges (IQR) = 15 (13, 28) and 0.83 mSv, IQR = 0.33 (0.68, 1.01) respectively. Mean DLP increased significantly across the age groups. Mean effective dose in infants (0.63 mSv) was significantly lower than the other age groups (1-5 years 0.85 mSv, 5-10 years 1.04 mSv, and > 10 years 1.38 mSv) (P < 0.05). There was no significant difference in the effective dose between the other groups of children. All the CTCA studies were of diagnostic quality. No child required a repeat examination. CONCLUSION: CTCA is feasible with submillisievert radiation dose in most children with KD. Thus, CTCA has the potential to be an important adjunctive imaging modality in children with KD.

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.

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.

Kawasaki Disease and Inborn Errors of Immunity: Exploring the Link and Implications.

The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature.

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.

Emerging role of computed tomography coronary angiography in evaluation of children with Kawasaki disease.

Coronary artery abnormalities are the most important complications in children with Kawasaki disease (KD). Two-dimensional transthoracic echocardiography currently is the standard of care for initial evaluation and follow-up of children with KD. However, it has inherent limitations with regard to evaluation of mid and distal coronary arteries and, left circumflex artery and the poor acoustic window in older children often makes evaluation difficult in this age group. Catheter angiography (CA) is invasive, has high radiation exposure and fails to demonstrate abnormalities beyond lumen. The limitations of echocardiography and CA necessitate the use of an imaging modality that overcomes these problems. In recent years advances in computed tomography technology have enabled explicit evaluation of coronary arteries along their entire course including major branches with optimal and acceptable radiation exposure in children. Computed tomography coronary angiography (CTCA) can be performed during acute as well as convalescent phases of KD. It is likely that CTCA may soon be considered the reference standard imaging modality for evaluation of coronary arteries in children with KD.

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.

Acute kidney injury following multisystem inflammatory syndrome associated with SARS-CoV-2 infection in children: a systematic review and meta-analysis.

INTRODUCTION: Multisystem inflammatory syndrome (MIS-C) is a rare paediatric hyper-inflammatory disorder that occurs following SARS-CoV-2 infection. Acute kidney injury (AKI) occurs in approximately one-quarter to one-third of the patients with MIS-C and is associated with poor prognosis in critically ill children. This systematic review is aimed to evaluate the incidence of AKI, mortality, and the need for kidney replacement therapy (KRT) in patients with MIS-C. METHODS: We searched databases from Medline, EMBASE, Cochrane Register, and Google Scholar from December 2019 to December 2021 with our search strategy. Studies meeting the following criteria were included in this systematic review: (1) articles on AKI in MIS-C; (2) studies providing AKI in MIS-C and COVID-19 infection separately; (3) studies reporting outcomes such as mortality, KRT, serum creatinine; length of hospital/ICU stay. QUALITY ASSESSMENT: The quality of the included studies was independently assessed by using the National Heart Lung and Blood Institute (NHLBI) quality assessment tool for cohort studies and case series. STATISTICAL ANALYSIS: Outcomes and their 95% confidence intervals (CI) were reported if a meta-analysis of these outcomes was conducted. Heterogeneity was reported using I2 statistics, and heterogeneity ≥ 50% was considered high. We used Baujat's plot for the contribution of each study toward overall heterogeneity. In sensitivity analysis, the summary estimates were assessed by repeating meta-analysis after omitting one study at a time. Forest plots were used for reporting outcomes in each study and with their 95% CI. All statistical tests were performed using R software version 4.0.3. RESULTS: A total of 24 studies were included in this systematic review and of these, 11 were included in the meta-analysis. The pooled proportion of patients with MIS-C developing AKI was 20% (95% CI: 14-28%, I2 = 80%). Pooled proportion of death in children with MIS-C was 4% (95% CI: 1-14%; I2 = 93%). The odds of death in patients with AKI were 4.68 times higher than in patients without AKI (95% CI: 1.06-20.7%; I2 = 17%). The overall pooled proportion of MIS-C-induced AKI patients requiring KRT was 15% (95% CI: 4-42%; I2 = 91%). CONCLUSION: Approximately one-fifth of children with MIS-C develop AKI which is associated with higher odds of death. PROSPERO registration: CRD42022306170 A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

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.

Kawasaki disease and the environment: an enigmatic interplay.

Kawasaki disease (KD) is a common systemic vasculitis of childhood. Although it has been almost 6 decades since Dr. Tomisaku Kawasaki reported the first case series of KD, the underlying cause remains a mystery. KD is a self-limiting disease. However, a dreaded complication is development of coronary artery abnormalities (CAAs). KD is the most common cause of acquired heart disease in children in the developed world and is being increasingly reported from developing countries too. Over the years, significant observations have been made about epidemiology of KD. It usually affects children below 5, has male preponderance and has significantly higher incidence in North East Asian countries. While several hypotheses have been proffered for etiology of KD, none have been conclusive. These include associations of KD epidemics in Japan and the United Stated with changes in tropospheric wind patterns suggesting wind-borne agents, global studies showing peaks of incidence related to season, and increased rates in populations with a higher socioeconomic profile related to hygiene hypothesis and vaccination. Furthermore, the self-limiting, febrile nature of KD suggests an infectious etiology, more so with sudden decline noted in cases in Japan with onset of COVID-19 mitigation measures. Finally, single nucleotide polymorphisms have been identified as possible risk alleles in patients with KD and their significance in the pathogenesis of this disease are also being defined. The purpose of this review is to elucidate the puzzling associations of KD with different environmental factors. Looking at patterns associated with KD may help us better predict and understand this disease.

Challenges in the diagnosis of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome in developing countries-A decade of experience from North India.

Background: Reports of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome from developing countries are sparse. Recognizing PFAPA is often challenging in these regions due to a higher incidence of infectious illnesses and significant resource constraints. Herein, we present our experience from North India regarding the diagnosis and management of PFAPA syndrome. Methods: We reviewed cases of non-monogenic periodic fever syndrome diagnosed at our center from January 2011 to December 2021. A total of 17 children who fulfilled the Marshall criteria for PFAPA syndrome were included. Data regarding basic clinical features, treatment/outcome, and performance of the recently proposed Eurofever/PRINTO and Takeuchi criteria were analyzed. Results: Besides recurrent fever, the triad of oral aphthae, pharyngitis, and adenitis was noted in only 18% of patients. Episodes of exudative pharyngitis/tonsillitis were documented in 24%. These figures were lower than the values reported from developed countries. The Takeuchi and Eurofever/PRINTO criteria were fulfilled in 76% and 71% cases, respectively. In addition to antipyretics and supportive care, intermittent steroid therapy was the main treatment modality used. Additional treatment with colchicine (n = 3) and thalidomide (n = 1) was used successfully in a few patients. Before the diagnosis of PFAPA, all patients had received multiple courses of antimicrobials (without microbiological confirmation). These included multiple courses of antibacterials for fever, pharyngotonsillitis, and/or cervical adenitis in all patients and antivirals for fever and aphthous stomatitis in a patient. Empiric antitubercular therapy had also been administered in two patients. Conclusions: A significant proportion of patients with PFAPA seem to remain undiagnosed in the Indian subcontinent. Increased awareness and improvement in basic healthcare facilities are crucial in enhancing the recognition of PFAPA, which would eliminate the unprecedented scale of undesirable antimicrobial use in such children.