Seroconversion in asymptomatic COVID-19 pediatric patients with rheumatic diseases of one tertiary referral hospital

Abstract Objectives: To evaluate seroconverted asymptomatic COVID-19 in pediatric Autoimmune Rheumatic Diseases (ARDs) patients and to identify the risk factors related to contagion. Methods: A cross-sectional study was conducted in March 2021, before vaccination of children and adolescents in Brazil, including 77 pediatric ARDs patients, followed at a tertiary hospital and 45 healthy controls, all of them without a previous diagnosis of COVID-19. Data was obtained by a questionnaire with demographic data, symptoms compatible with COVID-19 over the previous year, and contact with people with confirmed COVID-19. Patient's medical records were reviewed to access data regarding disease and current medications. A qualitative immunochromatographic SARS-CoV-2 test was performed on all participants. Results: Patients and controls were similar in terms of female gender (70.1% vs. 57.8%, p = 0.173), age (14 vs. 13 years, p = 0.269) and SARS-CoV-2 positive serology (22% vs. 15.5%, p = 0.481). 80.5% of rheumatic patients were in use of immunosuppressive drugs: 27.3% of them used corticosteroids (33.3% in high doses), and 7.8% on immunobiologicals. No statistical differences were found between positive (n = 17) and negative serology (n = 60) patients regarding demographic/socioeconomic data, contact with people with confirmed COVID-19, use and number of immunosuppressive drugs, use and dose of corticosteroids, use of hydroxychloroquine and immunobiological drugs (p > 0.05). Conclusions: Pediatric rheumatic disease patients were infected at the same rate as healthy ones. Neither the underlying pathology nor its immunosuppressive treatment seemed to interfere with contagion risk.

Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19) METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Poor Sleep quality and health-related quality of life impact in adolescents with and without chronic immunosuppressive conditions during COVID-19 quarantine

OBJECTIVE: To assess the possible factors that influence sleep quality in adolescents with and without chronic immunosuppressive conditions quarantined during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This cross-sectional study included 305 adolescents with chronic immunocompromised conditions and 82 healthy adolescents. Online surveys were completed, which included questions on socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and the following validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0), and Pediatric Outcome Data Collection Instrument (PODCI). RESULTS: The median current age [14 (10-18) vs. 15 (10-18) years, p=0.847] and frequency of female sex (62% vs. 58%, p=0.571) were similar in adolescents with chronic conditions compared with healthy adolescents. The frequency of poor sleep quality was similar in both groups (38% vs. 48%, p=0.118). Logistic regression analysis, including both healthy adolescents and adolescents with chronic conditions (n=387), demonstrated that self-reported increase in screen time (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.3-6.8; p=0.008) and intrafamilial violence report (OR 2.1; 95% CI 1.2-3.5; p=0.008) were independently associated with poor sleep quality in these adolescents. However, the PODCI global function score was associated with a lower OR for poor sleep quality (OR 0.97; 95% CI 0.94-0.99; p=0.001). Further logistic regression, including only adolescents with chronic conditions (n=305), demonstrated that self-reported increase in screen time (OR 3.1; 95% CI 1.4-6.8; p=0.006) and intrafamilial violence report (OR 2.0; 95% CI 1.2-3.4; p=0.011) remained independently associated with poor quality of sleep, whereas a lower PODCI global function score was associated with a lower OR for sleep quality (OR 0.96; 95% CI 0.94-0.98; p<0.001). CONCLUSION: Self-reported increases in screen time and intrafamilial violence report impacted sleep quality in both healthy adolescents and those with chronic conditions. Decreased health-related quality of life was observed in adolescents with poor sleep quality.

Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial.

BACKGROUND: The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV. METHODS: We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18-59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422. FINDINGS: Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4. INTERPRETATION: Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing. FUNDING: Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Fundação Butantan.

Panniculitis in childhood-onset systemic lupus erythematosus: a multicentric cohort study.

OBJECTIVE: To evaluate prevalence, clinical manifestations, laboratory abnormalities, treatment and outcome in a multicenter cohort of childhood-onset systemic lupus erythematosus (cSLE) patients with and without panniculitis. METHODS: Panniculitis was diagnosed due to painful subcutaneous nodules and/or plaques in deep dermis/subcutaneous tissues and lobular/mixed panniculitis with lymphocytic lobular inflammatory infiltrate in skin biopsy. Statistical analysis was performed using Bonferroni correction(p < 0.004). RESULTS: Panniculitis was observed in 6/847(0.7%) cSLE. Painful subcutaneous erythematosus and indurated nodules were observed in 6/6 panniculitis patients and painful subcutaneous plaques in 4/6. Generalized distribution was evidenced in 3/6 and localized in upper limbs in 2/6 and face in 1/6. Cutaneous hyperpigmentation and/or cutaneous atrophy occurred in 5/6. Histopathology features showed lobular panniculitis without vasculitis in 5/6(one of them had concomitant obliterative vasculopathy due to antiphospholipid syndrome) and panniculitis with vasculitis in 1/6. Comparison between cSLE with panniculitis and 60 cSLE without panniculitis with same disease duration [2.75(0-11.4) vs. 2.83(0-11.8) years,p = 0.297], showed higher frequencies of constitutional involvement (67% vs. 10%,p = 0.003) and leukopenia (67% vs. 7%,p = 0.002). Cutaneous atrophy and hyperpigmentation occurred in 83% of patients. CONCLUSIONS: Panniculitis is a rare skin manifestation of cSLE occurring in the first three years of disease with considerable sequelae. The majority of patients have concomitant mild lupus manifestations.

Epidemiology and management practices for childhood-onset systemic lupus erythematosus patients: a survey in Latin America.

To assess epidemiology and management practices of Latin America Pediatric Rheumatologists (LAPR) about childhood-onset systemic lupus erythematosus (cSLE). A cross-sectional study was performed in 288 LAPR PANLAR members based on online survey about cSLE practices. The response rate of web-based survey by LAPR was 170/288(59%) and the majority worked in university hospitals (63%). The ACR and/or SLICC classification criteria (99%) and disease activity tools (97%) were almost universally used by LAPR, whereas damage index (70%) and CHAQ (58%) instruments were less frequently used. Laboratory exams, diagnostic imaging, and biopsies were generally available (> 75%), however low availability for densitometry (66%). Drug access was excellent for the most common prescribed medications (> 75%), except for belimumab (11%). Emerging mosquito-borne diseases were also reported: dengue (20%), chikungunya (11%), and Zika (8%). Groups were further divided in two, according to the median number of cSLE patients followed by LAPR in the last year: groups A and B (≥ 25 and < 25, respectively). Frequencies of condom in combination with other contraceptive methods were significantly higher in group A than B (p = 0.01). The frequencies of reported pregnancy (p < 0.001) and non-adherence to therapy were significantly higher in group A (p = 0.023). Alcohol intake (p = 0.004) and illicit drug use (p = 0.007) were also reported more frequently by LAPR of group A in at least one cSLE patient. This first large web-based survey demonstrated an overall excellent access for diagnosis and therapy by LAPR, probably related to their high rate of practices in tertiary care of university hospitals. Adherence to therapy, pregnancy, and substance abuse was identified as major challenges in this population, particularly in larger centers.

Autoimmune hepatitis in 847 childhood-onset systemic lupus erythematosus population: a multicentric cohort study.

OBJECTIVE: To evaluate autoimmune hepatitis (AIH) in a multicenter cohort of childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: This retrospective multicenter study included 847 patients with cSLE, performed in 10 Pediatric Rheumatology services of São Paulo state, Brazil. AIH was defined according to the International Autoimmune Hepatitis Group criteria (IAHGC). The statistical analysis was performed using the Bonferroni's correction (p < 0.0033). RESULTS: AIH in cSLE patients confirmed by biopsy was observed in 7/847 (0.8%) and all were diagnosed during adolescence. The majority occurred before or at cSLE diagnosis [5/7 (71%)]. Antinuclear antibodies were a universal finding, 43% had concomitantly anti-smooth muscle antibodies and all were seronegative for anti-liver kidney microsomal antibodies. All patients with follow-up ≥18 months (4/7) had complete response to therapy according to IAHGC. None had severe hepatic manifestations such as hepatic failure, portal hypertension and cirrhosis at presentation or follow-up. Further comparison of 7 cSLE patients with AIH and 28 without this complication with same disease duration [0 (0-8.5) vs. 0.12 (0-8.5) years, p = 0.06] revealed that the frequency of hepatomegaly was significantly higher in cSLE patients in the former group (71% vs. 11%, p = 0.003) with a similar median SLEDAI-2 K score [6 (0-26) vs. 7 (0-41), p = 0.755]. No differences were evidenced regarding constitutional involvement, splenomegaly, serositis, musculoskeletal, neuropsychiatric and renal involvements, and treatments in cSLE patients with and without AIH (p > 0.0033). CONCLUSIONS: Overlap of AIH and cSLE was rarely observed in this large multicenter study and hepatomegaly was the distinctive clinical feature of these patients. AIH occurred during adolescence, mainly at the first years of lupus and it was associated with mild liver manifestations.