Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases.

Autoinflammatory diseases include disorders with a genetic cause and also complex syndromes associated to polygenic or multifactorial factors. Eye involvement is present in many of them, with different extent and severity. The present review covers ophthalmological lesions in the most prevalent monogenic autoinflammatory diseases, including FMF (familial Mediterranean fever), TRAPS (TNF receptor-associated periodic syndrome), CAPS (cryopyrin-associated periodic syndromes), Blau syndrome, DADA2 (deficiency of adenosine deaminase 2), DITRA (deficiency of the interleukin-36 receptor antagonist), other monogenic disorders, including several ubiquitinopathies, interferonopathies, and the recently described ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Among polygenic autoinflammatory diseases, ocular manifestations have been reviewed in Behçet's disease, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome, Still's disease and autoinflammatory bone diseases, which encompass CRMO (chronic recurrent multifocal osteomyelitis) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome.

Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses.

BACKGROUND: After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients developed unusual often fatal pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: We sought to facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not-stopping IL-1/IL-6-inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6-inhibitors to 37 cases not-stopping these drugs. RESULTS: Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 weeks after initiating IL-1/IL-6-inhibition. In drug-reaction cases stopping versus not-stopping IL-1/IL-6-inhibitor treatment, reaction related features were indistinguishable, including pulmonary complication rates [75%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6-inhibitors significantly improved outcomes.

Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

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

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

Treatment adherence and its determinants among the rheumatic fever/rheumatic heart disease patients during COVID 19 pandemic - A cross sectional study from Chandigarh, India.

Background: Rheumatic heart disease/Rheumatic fever is a non - communicable disease being a major neglected health problem. Recurrent attacks of rheumatic fever can have catastrophic outcomes, therefore regular administration of antibiotics is recommended. During COVID 19 pandemic, people were afraid to approach hospitals hence the compliance and follow up of patients were affected. This study had planned to assess the treatment adherence of patients diagnosed with rheumatic fever/rheumatic heart disease during COVID 19 pandemic and to describe the socio demographic factors, clinical characteristics. This study also determines the factors associated with the treatment adherence. Methods: A cross sectional study was conducted among Rheumatic Fever/Rheumatic Heart Disease patients, attending Outpatient department at tertiary care hospital during COVID 19 pandemic. Mean score with confidence interval was calculated for quantitative data. P value less than 0.05 is significant. Results: The Mean (SD) age of the study participants was 41 ± 14.17 years. Treatment adherence was found to be 94.5 percent among Rheumatic Fever/Rheumatic Heart Disease patients during COVID 19 pandemic. 89.5% of injection benzathine penicillin users had an adherence rate above 80 percent. It was found that the presence of comorbidities (Diabetes/Hypertension/both Diabetes and Hypertension) had a statistically significant association with treatment adherence. Conclusions: Rheumatic Heart Disease is a disease of young and middle -age population affecting predominantly females. The overall adherence rate among Rheumatic Fever/Rheumatic Heart Disease patients was high. High time to maintain hospital-based registry to have follow up of patients.

DRESS syndrome due to first-line antitubercular therapy - A diagnostic imbroglio!

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after the use of first-line antitubercular drugs (ATDs) is rare and literature regarding DRESS syndrome due to ATDs is scarce in children. We report a young boy with tuberculosis who developed DRESS syndrome after exposure to isoniazid. A 9-year-old boy, diagnosed clinically as pulmonary tuberculosis, presented with fever, fast breathing, maculopapular rash, and one episode of gross hematuria. He had been on 4-drug ATD therapy (isoniazid, rifampicin, ethambutol, and pyrazinamide) for the past 4 weeks. In view of multiorgan involvement and absence of a microbiological diagnosis of tuberculosis, vasculitis was considered and he was treated with steroids. As the child recovered, both corticosteroids and ATD therapy were stopped. At 6 months of follow-up, he was presented with pneumonia. Microbiological diagnosis of tuberculosis was made and 4-drug ATD therapy was reinitiated. After 15 days, he again developed a high-grade fever and rash. On evaluation, isoniazid-induced DRESS syndrome was diagnosed. Subsequently, he received a modified regimen of ethambutol, pyrazinamide, levofloxacin, and linezolid. DRESS syndrome did not recur on these ATDs and the child became asymptomatic. Linezolid was stopped after 3 months of therapy and ethambutol, pyrazinamide, and levofloxacin are being continued. Currently, he has completed 15 months of modified ATD therapy. As a high index of suspicion is required for early diagnosis and management that are crucial to reducing morbidity and mortality, DRESS syndrome should be among the differentials in children with unexplained febrile illnesses.

An Autopsy Case of Wiskott-Aldrich Syndrome Revealing "FDC-Only Lymphoid Follicles" in Lymphoid Tissue: A Morphologic Correlate of Defective Immune Synapse.

Wiskott-Aldrich Syndrome (WAS) is an inherited disorder characterized by the classical triad of eczema, micro-thrombocytopenia, and immune deficiency. This disease affects the hematopoietic cells to a variable extent. The spectrum of clinical and laboratory data for WAS has been well described in the literature though there is a paucity of its histopathologic and immunohistochemical correlates. The current case describes the autopsy findings of this rare entity in an 8-year old male child with specific recognition of altered histology noticed in the lymphoreticular tissues. The predominant morphological finding in lymphoid tissue was atretic hyalinized germinal centers labeled as "the follicular dendritic cell (FDC)-only lymphoid follicles." Immunohistochemistry revealed a reduction in germinal-center B-cells, T-follicular helper cells, attenuated mantle zone, FDC proliferation, and paracortical plasmacytosis. This case highlights the crippled immune cell population in WAS, ultimately leading to the morphology of atretic follicles rich in FDCs.

Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India.

Background: Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed. Results: In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months). Conclusions: We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.

Successful Management of Catastrophic Thrombotic Storm in a Young Boy: A Case Report From Northern India.

Thrombotic storm is a rare clinical entity characterized by acute to subacute thrombosis developing at multiple sites over a few days to a few weeks. An 11-year-old boy presented with headache and facial nerve palsy. He was found to have cortical sinus venous thrombosis and was initiated on low molecular weight heparin, but rapidly progressed with thromboses involving the pulmonary arteries and deep veins of the legs. Thereafter managed on high-dose unfractionated heparin, he eventually stabilized after a hospital stay of 34 days. Genetic analysis showed potentially pathogenic variants in the factor V and stabilin-2 genes.

Novel SERPING1 gene mutations and clinical experience of type 1 hereditary angioedema from North India.

BACKGROUND: There is paucity of literature on long-term follow-up of patients with hereditary angioedema (HAE) from developing countries. OBJECTIVE: This study was carried out to analyze the clinical manifestations, laboratory features, and genetic profile of 32 patients (21 male and 11 female) from 23 families diagnosed with HAE between January 1996 and December 2019. METHODS: Data were retrieved from medical records of Paediatric Immunodeficiency Clinic, Postgraduate Institute of Medical Education and Research, Chandigarh, India. RESULTS: Median age at onset of symptoms was 6.25 years (range 1-25 years), and median age at diagnosis was 12 years (range 2-43 years). Serum complement C4 level was decreased in all patients. All patients had low C1-esterase inhibitor (C1-INH) quantitative level (type 1 HAE). SERPING1 gene sequencing could be carried out in 20 families. Of these, 11 were identified to have a pathogenic disease-causing variant in the SERPING1 gene. While 2 of these families had a previously reported mutation, remaining 9 families had novel pathogenic variants in SERPING1 gene. Because of non-availability of C1-INH therapy in India, all patients were given long-term prophylaxis (attenuated androgens or tranexamic acid (TA) or a combination of the 2). Life-threatening episodes of laryngeal edema were managed with fresh-frozen plasma (FPP) infusions. We recorded one disease-related mortality in our cohort. This happened in spite of long-term prophylaxis with stanozolol and TA. CONCLUSIONS: We report largest single-center cohort of patients with HAE from India. Attenuated androgens, fibrinolytic agents, and FPP may be used for management of HAE in resource-limited settings.

LINEZOLID-INDUCED MITOCHONDRIAL TOXICITY PRESENTING AS RETINAL NERVE FIBER LAYER MICROCYSTS AND OPTIC AND PERIPHERAL NEUROPATHY IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE.

PURPOSE: To report a case with unique changes in the retinal nerve fiber layer observed on optical coherence tomography in a 22-year-old patient on chronic linezolid therapy for recurrent pyogenic liver abscesses with underlying chronic granulomatous disease. METHODS: History and clinical examination, laboratory evaluation, fluorescein angiography, and optical coherence tomography. RESULTS: The patient presented with best-corrected visual acuity of 20/200 in the right eye and 20/125 in the left eye. He had moderate optic disk edema and superotemporal field defects bilaterally. Swept-source optical coherence tomography revealed the presence of retinal nerve fiber layer microcystic spaces. Laboratory tests showed no positive findings except for an elevated lactic acid level. Linezolid-induced optic neuropathy was suspected, and the drug was discontinued. Six weeks after termination of oral linezolid therapy, the optic disk edema and the microcystic spaces in the retinal nerve fiber layer resolved, and the best-corrected visual acuity improved to 20/50 in the right and 20/40 in the left eye, respectively. CONCLUSION: Linezolid is a widely used antibiotic with broad-spectrum action. However, chronic use can lead to mitochondrial toxicity that may have protean manifestations. Ocular examination, particularly of the optic nerve and nerve fiber layer using multimodal imaging, is critical in diagnosing such toxicity.

An updated review on phenocopies of primary immunodeficiency diseases.

Primary immunodeficiency diseases (PIDs) refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections, autoimmunity and increased risk of malignancies. These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as "Phenocopies of PIDs". These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines. In this review, we provide an update on clinical manifestations, diagnosis and management of these diseases.

Sun Exposure in Children: Balancing the Benefits and Harms.

There is a common belief among the laity and even physicians that sun exposure is a useful source of vitamin D. However, despite the fact that sun exposure occurs almost throughout the year in India, vitamin D deficiency is widely prevalent. Although several authors have reported on the duration of sun exposure required to synthesize adequate amounts of vitamin D in the human body, they have not followed a standard and uniform protocol for measurement of sun exposure and vitamin D synthesis. For these and many other reasons, the results are difficult to interpret. The American Academy of Pediatrics (AAP) has clearly stated that infants should be protected from the sun as much as possible and vitamin D requirements should be met through diet and fortified foods rather than deliberate sun exposure. However, this recommendation is frequently ignored in clinical practice. This review aims to summarize the available literature on benefits and harm of unprotected sun exposure in infants and children with a focus on skin phototype IV to VI. Dermatologists and pediatricians in India should counsel parents about the need for sun protection, especially in fair-skinned infants and children.

Complex interventions of abdominal aorta and its branches in children with Takayasu arteritis: Clinical experience from a tertiary care center in north-west India.

AIM: To report our experience on complex percutaneous interventions of the abdominal aorta and its branches in six children with Takayasu arteritis (TA). METHODS: A review of records of children with TA, who underwent percutaneous interventions of the abdominal aorta and its major branches. RESULTS: In this analysis, we included six children with TA who underwent intervention of the abdominal aorta and its major branches. The endovascular interventions were performed mostly for treatment-resistant renovascular hypertension and mesentery artery ischemia. Mean age (±SD) at time of intervention was 10.6 ± 2.5 years (four boys and two girls). Percutaneous interventions included stenting of abdominal aorta (n = 2), renal arteries (n = 4), mesenteric arteries (n = 2), repeat stenting for renal artery in-stent restenosis (n = 1), and renal autotransplantation (n = 4). All 13 interventions were successful and enabled us to obtain good control of blood pressure. CONCLUSION: We hereby report six children with TA who were successfully managed with complex percutaneous interventions of the abdominal aorta and its major branches. Balloon dilatation and stent placement constitutes the mainstay of management of TA with stenosis of the large vessels.

Autoantibody profile in children with Kawasaki disease on long-term follow-up: A prospective study from North India.

AIM: To study the profile of autoantibodies on long-term follow-up of children with Kawasaki disease (KD). PATIENTS AND METHODS: In this single-center observational cohort study, 50 children who had been diagnosed and treated for KD with a minimum follow-up period of 3 years were enrolled. The organ-specific autoantibodies that were assessed in the study included anti-thyroid microsomal antibody (TMA), anti-parietal cell antibody (PCA) and anti-liver kidney microsomal (LKM) antibody. The organ-nonspecific autoantibodies that were studied included anti-endothelial cell antibody (AECA), anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), anti-mitochondrial antibody (AMA) and anti-smooth muscle antibody (SMA). RESULTS: The sample for assessment of serology was taken at a mean follow-up period of 6.41 years (±1.95 SD) after diagnosis. Autoantibodies were detected in 11/50 (22%) patients. ANA was detected in three patients, TMA was positive in seven and ANCA was positive in one. CONCLUSIONS: These autoantibodies likely develop in children with KD during the acute stage and may persist for many years. There is no concrete evidence to suggest that these children are at increased risk of developing an autoimmune disease in the future. However, there is some justification for prolonged surveillance for development of autoimmune manifestations.