Presentation and outcome of pediatric lupus nephritis from a large single centre contemporary cohort in Eastern India.

BACKGROUND: We present clinical, biochemical, and histopathological characteristics and treatment outcomes of biopsy proven childhood lupus nephritis (LN) from a low/middle income setting treated in the current era of increased use of Mycophenolate Mofetil (MMF) and biologics. METHODS: Retrospective observational study of children (1-18 years) with biopsy proven LN treated from 01.01.2010 to 31.01.2020. RESULTS: 60 children met our inclusion criteria (80%, n = 48 were females). The median age at diagnosis was 11 (IQR: 9-12) years. The most common extra-renal manifestation was mucocutaneous (n = 54, 90%) and the most common kidney manifestation was edema (n = 50, 83.3%). The median 24-h urinary protein excretion was 1117.8 (IQR: 795.4-1941.7) mg/m2/day with 67% (n = 40) having nephrotic range proteinuria (>1000 mg/m2/day). 75% (n = 45) children had eGFR <90 mL/min/1.73 m2 (median eGFR = 71; IQR: 56-90 mL/min/1.73 m2). Anti-Nuclear Antibody was positive in all, both complement three and four were low in 82% (n = 49) and anti-double stranded DNA antibodies were positive in 63% (n = 38). 85% (n = 51) had proliferative LN with majority being class IV (57%, n = 34). All children received steroids for induction therapy. MMF was given as the sole induction agent in 48% (n = 29) and cyclophosphamide in 27% (n = 16). Rituximab was added in 17% (n = 10) as a rescue agent. Median follow up duration was 50 (IQR: 28-82) months. Six children (10%) died as a result of serious infections and none of them had shown complete response (CR). Out of the 52 children who had a follow up duration of at least 2 years, CR was achieved in 46 children (88%) and partial response (PR) or no response (NR) in three children (6%) each. Although children who were in CR/PR at last follow up had lower proteinuria, higher eGFR, and lower histopathology activity index at onset; low numbers in the NR group precluded us from subjecting them to any statistical correlation tests. 36% (n = 22) of children developed 36 episodes of renal flares with overall incidence of 0.14/person-year. CONCLUSION: Our study on a contemporary cohort of childhood LN highlights the importance of achieving CR and its feasibility.

A comparative study of IL-6, CRP and NT-proBNP levels in post-COVID multisystem inflammatory syndrome in children (MISC) and Kawasaki disease patients.

BACKGROUND: Post-COVID multisystem hyperinflammatory syndrome in children (MISC) has clinical and laboratory similarities with Kawasaki disease (KD). Inflammatory markers like C-reactive protein (CRP), interleukin 6 (IL6) as well as N-terminal probrain natriuretic peptide (NT-proBNP) are elevated in both. This study attempts a comparative analysis of the 3 markers in an attempt at early differentiation for planning appropriate management. METHODOLOGY: This analytical study conducted at the Institute of Child Health, Kolkata, India compared the levels of the above 3 markers at admission between 72 patients with KD, 30% of whom had coronary artery lesions (CALs) collected over a period of 18 months (Jan 2017-June 2018), with 71 MISC patients over a period of 6 months (July 2020-December 2020). The non-parametric Mann-Whitney U test was used to test for similarity in distributions of the samples of CRP, NT-proBNP and IL6 in KD and MISC patients using correction factor for similar ranks. The 3 parameters were compared using receiver operating characteristic (ROC) curve analysis. RESULTS: Mean IL6 value in KD was 83.22 pg/mL and in MISC 199.91 pg/mL, which was not found to be statistically significant (P = .322 > .05).However mean NT-proBNP (914.91 pg/mL) with CRP level (96.32 mg/L) in KD was significantly lower (P < .05 for both cases) than that in MISC (9141.16 pg/mL and 145.66 mg/L respectively). ROC analysis showed NT-proBNP has the best sensitivity and specificity in predicting MISC. CONCLUSION: NT-proBNP and CRP are significantly higher among MISC patients; ROC analysis shows levels >935.7 pg/mL and >99.55 mg/L respectively might act as a guide to differentiate between them.

Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.

OBJECTIVE: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. METHODS: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. RESULTS: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. CONCLUSION: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.

Experience with Cidofovir as an adjunctive therapy in a patient of adenovirus-induced macrophage activation syndrome in systemic arthritis.

A 5-year-old female child, with known systemic juvenile idiopathic arthritis diagnosed at 18 months of age (on low dose Prednisolone + Methotrexate + Leflunomide + Tocilizumab), presented with fever for 1 day, vomiting, drowsiness followed by seizures. On admission to PICU, she was drowsy, tachycardic, tachypneic, with rashes, and hepatosplenomegaly. Lab findings showed thrombocytopenia, leucopenia, low ESR, normal CRP, elevated liver enzymes, high ferritin, LDH, and triglycerides suggestive of macrophage activation syndrome (MAS). Chest X-ray showed left basal pneumonia and DNA PCR of throat swab revealed adenovirus. She was diagnosed as adenovirus-triggered MAS and was initiated on pulse methylprednisolone (6 mg/kg). Because of suboptimal response after 2 doses, manifested by increasing drowsiness, further fall in platelets and rising ferritin, methylprednisolone dosage was increased to 30 mg/kg/day with the addition of oral cyclosporine (4 mg/kg/day). In view of worsening of the chest X-ray and increasing oxygen requirement, Cidofovir infusion (1 mg/kg thrice weekly) was also started simultaneously considering increased activity of the adenoviral infection concurrent to immunosuppression. Within 48 h, the child showed signs of recovery with improved consciousness, lower oxygen requirements, and improving lab parameters. She was discharged after 3 weeks of IV Cidofovir, on oral prednisolone and cyclosporine. To the best of our knowledge, this is the first reported use of Cidofovir in adenovirus-induced MAS.

IgG4-related Disease at Rectovesical Pouch Mimicking Inflammatory Myofibroblastic Tumor.

Fever of unknown origin frequently remains a diagnostic challenge. Immunological diseases account for about 20- 30% cases of these fevers. We report the case of a boy who presented with high fever for 2 months and was finally diagnosed as a case of IgG4-related disease at the rectovesical pouch.

A comparison of serum IL6 and CRP levels with respect to coronary changes and treatment response in Kawasaki disease patients: a prospective study.

To evaluate serum levels of IL6 in patients with Kawasaki disease and compare it with CRP, and to assess the role of these biomarkers in predicting coronary changes and resistance to the first-line therapy of this disease in a subset of Indian population. A single centre prospective observational study was conducted amongst all Kawasaki disease patients for a period of 18 months from January 2017 at Institute of Child Health, Kolkata. Serum IL6 and CRP were compared at diagnosis and after 48 h of administering IVIG in patients who developed coronary changes with those who did not and also among the responders and non-responders to IVIG, the first-line therapy given to these patients. Out of total 72 patients of KD [mean age of presentation: 24 months, M:F = 1.22:1], 30% (n = 22) had coronary artery involvement (CALs), and 15% (n = 11) were IVIG non-responders. Mean IL6 prior to IVIG in those with CALs was 143.60 pg/ml, which was about three times higher than in those without CALs (mean = 52.90 pg/ml), the difference being significant (p < 0.01). Mean CRP values also were significantly raised in patients with CALs (p < 0.01) whereas post-IVIG levels of mean serum IL6 was found to be 108.15 pg/ml in non-responders which was about 17 times raised than that in the responders (mean IL6 = 6.22),the difference again was statistically significant (p < 0.001).Also, ROC analysis revealed a sensitivity and specificity of 81.0% and 82.0%, respectively, for IL6; 72% and 74%, respectively, for CRP for predicting CALs. This study also shows a sensitivity of 72% and specificity of 68% for IL6 in predicting IVIG resistance whereas that of CRP being 90% sensitive and 36% specific. These results suggest that higher levels of IL-6 and CRP at diagnosis are associated with occurrence of CALs and IVIG resistance in KD patients. Using the cutoff for IL6 and CRP from our study, chances of developing CALs and IVIG resistance can be predicted, which might prevent the development of future complications like aneurysms in such patients.

A Young Child with Eosinophilia, Rash, and Multisystem Illness: Drug Rash, Eosinophilia, and Systemic Symptoms Syndrome After Receipt of Fluoxetine.

Drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome is a severe systemic hypersensitivity reaction that usually occurs within 6 weeks of exposure to the offending drug. Diagnosis is usually straightforward in patients with pyrexia, skin rash, hepatitis, and eosinophilia with a preceding history of exposure to agents often associated with DRESS syndrome, such as aromatic anticonvulsants and sulfa drugs, but diagnosis of DRESS may still be a challenge. We report a 4-year-old child with probable DRESS syndrome complicated by multiple hematologic complications that developed 1 month after exposure to fluoxetine, a drug not known to be associated with such severe reactions.

Two cases of non-cystic fibrosis (CF) bronchiectasis with allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction in patients with asthma or cystic fibrosis (CF), which is associated with bronchi colonized by the fungus Aspergillus species, most often Aspergillus fumigatus. ABPA is an important consideration for asthmatics that do not respond to asthma management or with recurrent chest infections and deteriorating lung function in children with cystic fibrosis. We present two cases of non CF bronchiectasis associated with ABPA who presented to our hospital with recurrent hospitalisations of undiagnosed aetiology.

Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients.

OBJECTIVE: To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). METHODS: In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. RESULTS: A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. CONCLUSION: This study provides information on the clinical spectrum and current management of systemic JIA-associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Dengue associated hemophagocytic lymphohistiocytosis: a case series.

Hemophagocytic lymphohistiocytosis is a rare complication of dengue. We present 8 cases of dengue associated hemophagocytic lymphohistiocytosis diagnosed in our hospital during the dengue outbreak of 2012. All the cases were treated with a short (4 weeks) course of steroids along with supportive measures, and showed an excellent response.

Childhood Polyarteritis Nodosa: a prospective multicentre study from eastern India.

OBJECTIVE: To delineate the spectrum of clinical presentation and system involvement in childhood Polyarteritis Nodosa (PAN) in a multicentre follow up. METHODS: This prospective observational study included all children less than 12 y attending pediatric rheumatological clinic of four different institutes in West Bengal or admitted with rheumatological symptoms and were diagnosed as childhood PAN by ACR and EULAR/PRES/PRINTO criteria. During the study period of 8 y, 15 cases were categorized as childhood PAN with organ involvement. The children diagnosed as microscopic polyangiitis or cutaneous PAN were excluded. RESULTS: The mean age of presentation was 8.6 ± 2.09 y with male to female ratio of 7:8. All had prolonged fever, severe myalgia, skin involvement and elevated acute phase reactants. Hypertension (93 %) and peripheral neuropathy (46 %) were notable findings. Nine had typical peripheral gangrene with ulceration, whereas rash of livedo reticularis was seen in 6 patients. None had renal, pulmonary or testicular involvement. Diagnosis was established in all patients by skin biopsy which showed necrotizing vasculitis of the medium sized vessels. The clinical presentations and diagnostic parameters were compared between the genders and no statistically significant difference was noted. All patients required corticosteroids while 10 patients needed additional immunosuppressives where there were uncontrolled symptoms of peripheral neuropathy or progressive gangrene despite treatment with corticosteroids. Cyclophosphamide was used most commonly (n = 7). Two required methyl prednisolone. Two children were lost to follow up. One patient had two relapses within three years. No mortality was observed. CONCLUSIONS: This multicentric study on childhood PAN, first of its kind from India, demonstrated a distinctive pattern of system involvement and clinical presentations.

Infection-associated haemophagocytic lymphohistiocytosis: a case series using steroids only protocol for management.

Haemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of clinical syndromes characterised by activation and subsequent uncontrolled non-malignant proliferation of T lymphocytes and macrophages, leading to a cytokine storm that accounts for most of its clinical features such as acute febrile illness, hepatosplenomegaly, multi-organ dysfunction and fulminant pancytopenia-resembling severe sepsis. Here, we present a series of 23 cases of infection-associated HLH diagnosed in our hospital within a time period of last three and half years. Though the presentation and progression of disease was variable, the patients shared some common features like prolonged fever unresponsive to broad spectrum antibiotics, organomegaly and cytopenias. In most of the cases, however, the triggering infectious agent could not be identified. They were treated using a steroid only protocol along with supportive measures and showed an excellent response.

Infantile systemic hyalinosis.

Infantile systemic hyalinosis is a rare disorder characterized by widespread deposition of hyaline. They usually present with skin lesions, joint contractures, and intractable diarrhea. We report a 2 year 4 month old boy with growth retardation, typical facial appearance, gingival enlargement, generalized stiff skin, joint contractures, and intermittent diarrhea. Skin biopsy revealed deposition of hyaline.

Childhood cutaneous polyarteritis nodosa: an unusual presentation.

A 6-year-old boy presented with post-burn like cutaneous scars over the buttocks and the back of thighs, following skin ulceration. Cutaneous polyarteritis (CPA) was diagnosed based on the histopathological examination of the skin biopsy specimen from one of the scars. Such a presentation of childhood CPA, to our knowledge, is not documented in the English literature.

Benign angiopathy of central nervous system.

Benign angiopathy of central nervous system (BACNS) is rare in children. We report a seven-year-old boy presenting with sudden severe headache and progressive external ophthalmoplegia. Magnetic resonance angiography (MRA) showed diffuse segmental narrowing of major cerebral arteries. Following a course of glucocorticoid, there was complete resolution of vascular lesions and follow-up MRA did not show any evidence of new lesions.

Reactive haemophagocytic lymphohistiocytosis.

We present a series of five cases diagnosed and treated as reactive haemophagocytic lymphohistiocytosis (HLH) in three tertiary referral centers of Kolkata, within a time frame of 3 months. The initial presentations were very variable, the most prominent clinical feature being--acute renal failure in the first patient, convulsions in the second, encephalopathy the third, marked cervical lymphadenopathy in the fourth and polyserositis in the fifth. All had a history of prolonged fever preceding admission and hepatosplenomegaly on examination. Investigations revealed multi-organ involvement with pancytopenia; haemophagocytosis was eventually diagnosed by bone marrow examination. These cases highlight the diagnostic challenge posed by infection associated haemophagocytosis and the need for maintaining a high index of suspicion to promptly diagnose and treat this potentially life threatening condition.