Journal of the Pediatric Infectious Diseases Society

ImportanceMultisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory illness occurring 2-6 weeks after SARS-CoV-2 infection. Presentation overlaps with other conditions, and risk factors for severe clinical outcomes differ by patient. Characterizing patterns of MIS-C presentation can guide efforts to reduce misclassification, categorize phenotypes, and identify patients at risk for severe outcomes. ObjectiveTo characterize phenotypic clusters of MIS-C and identify clusters with increased clinical severity. DesignWe describe MIS-C phenotypic clusters inferred using latent class analysis (LCA) applied to the largest cohort to date of cases from U.S. national surveillance. Illness onset ranged from February 2020 through December 2022. SettingNational surveillance comprising data from 55 U.S. public health jurisdictions. ParticipantsWe analyzed 9,333 MIS-C cases. Twenty-nine clinical signs and symptoms were selected for clustering after excluding variables with [≥]20% missingness and [≤]10% or [≥]90% prevalence. We excluded 389 cases missing [≥]10 variables and conducted multiple imputation on the remaining 8,944 (96%) cases. Main Outcomes and MeasuresDifferences by cluster in prevalence of each clinical sign and symptom, percentage of cases admitted to the intensive care unit (ICU), length of hospital and ICU stay, mortality, and relative frequency over time. ResultsLCA identified three clusters characterized by 1) frequent respiratory findings primarily affecting older children (n = 713; 8.0% of cases; median age: 12.7 years); 2) frequent cardiac complications and shock (n = 3,359; 37.6%; 10.8 years); and 3) remaining cases (n = 4,872; 54.5%; 6.8 years). Mean duration of hospitalization and proportion of cases resulting in ICU admission or death were higher in the respiratory (7.9 days; 49.5%; 4.6%; respectively) and shock/cardiac clusters (8.7 days; 82.3%; 1.0%; respectively) compared with other cases (5.3 days; 33.0%; 0.06%; respectively). The proportion of cases in the respiratory and shock/cardiac clusters decreased after emergence of the Omicron variant in the United States. Conclusions and RelevanceMIS-C cases clustered into three subgroups with distinct clinical phenotypes, illness severity, and distribution over time. Use of clusters in future studies may support efforts to evaluate surveillance case definitions and help identify groups at highest risk for severe outcomes. Key pointsO_ST_ABSQuestionC_ST_ABSCan phenotypic clusters of multisystem inflammatory syndrome in children (MIS-C) be identified, and are some clusters associated with increased severity? FindingsWe describe clusters inferred using latent class analysis (LCA) on 9,333 MIS-C cases from U.S. national surveillance 2020-2022. LCA identified three clusters characterized by frequent respiratory symptoms, frequent cardiac complications and shock, and remaining clinically milder cases. Mortality and ICU admission were highest in the respiratory and shock/cardiac clusters; prevalence of these two clusters decreased over time. MeaningMIS-C clusters had distinct presentation, illness severity, and distribution over time, highlighting the importance of recognizing the varied presentation of MIS-C.

Direct comparisons of pediatric hospitalizations for acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. While there were more hospitalizations and deaths from acute COVID-19 amongst Canadian children between March 2020-May 2021, MIS-C cases were more severe, requiring more intensive care and vasopressor support.

As the pandemic enters its fifth month, information regarding COVID-19 in children is rapidly evolving. Here, we explore clinical features and SARS-CoV-2 genetic variation in children presenting with COVID-19. We observed diverse clinical presentations and identified association between disease severity, viral load and age. SARS-CoV-2 genomes from the patients showed limited number of variations and an evolutionary rate comparable to other RNA viruses. We did not identify correlation between disease severity and viral genetic variations. Epidemiological investigation revealed multiple introductions of virus into Southern California.

BackgroundA cohort study was conducted to describe and compare the characteristics of SARS-CoV-2 infection in hospitalized children in three countries. MethodsThis was a retrospective cohort of consecutive children admitted to 15 hospitals (13 in Canada and one each in Iran and Costa Rica) up to November 16, 2020. Cases were included if they had SARS-CoV-2 infection or multi-system inflammatory syndrome in children (MIS-C) with molecular detection of SARS-CoV-2 or positive SARS-CoV-2 serology. ResultsOf 211 included cases (Canada N=95; Costa Rica N=84; Iran N=32), 103 (49%) had a presumptive diagnosis of COVID-19 or MIS-C at admission while 108 (51%) were admitted with other diagnoses. Twenty-one (10%) of 211 met criteria for MIS-C. Eighty-seven (41%) had comorbidities. Children admitted in Canada were older than those admitted to non-Canadian sites (median 4.1 versus 2.2 years; p<0.001) and less likely to require mechanical ventilation (3/95 [3%] versus 15/116 [13%]; p<0.05). Sixty-four of 211 (30%) required supplemental oxygen or intensive care unit (ICU) admission and 4 (1.9%) died. Age < 30 days, admission outside Canada, presence of at least one comorbidity and chest imaging compatible with COVID-19 predicted severe or critical COVID-19 (defined as death or need for supplemental oxygen or ICU admission). ConclusionsApproximately half of hospitalized children with confirmed SARS-CoV-2 infection or MIS-C were admitted with other suspected diagnoses. Disease severity was higher at non-Canadian sites. Neonates, children with comorbidities and those with chest radiographs compatible with COVID-19 were at increased risk for severe or critical COVID-19. Main pointsApproximately half of hospitalized children with laboratory confirmed MIS-C or SARS-CoV-2 infection were admitted with another primary diagnoses. The severity of disease was higher in the middle income countries (Costa Rica and Iran) than in Canada.

ObjectiveWe sought to characterize clinical presentation and healthcare utilization for pediatric COVID-19 in Western Pennsylvania (PA). MethodsWe established and analyzed a registry of pediatric COVID-19 in Western PA that includes cases in patients <22 years of age cared for by the pediatric quaternary medical center in the area and its associated pediatric primary care network from March 11 through August 20, 2020. ResultsOur cohort included 424 pediatric COVID-19 cases (mean age 12.5 years, 47.4% female); 65% reported exposure and 79% presented with symptoms. The most common initial healthcare contact was through telehealth (45%). Most cases were followed as outpatients, but twenty-two patients (4.5%) were hospitalized: 19 with acute COVID-19 disease, and three for multisystem inflammatory syndrome of children (MIS-C). Admitted patients were younger (p<0.001) and more likely to have pre-existing conditions (p<0.001). Black/Hispanic patients were 5.8 times more likely to be hospitalized than white patients (p=0.012). Five patients (1.2%) were admitted to the PICU, including all three MIS-C cases; two required BiPAP and one mechanical ventilation. All patients survived. ConclusionsWe provide a comprehensive snapshot of pediatric COVID-19 disease in an area with low to moderate incidence. In this cohort, COVID-19 was generally a mild disease; however, [~]5% of children were hospitalized. Pediatric patients can be critically ill with this infection, including those presenting with MIS-C.

BackgroundLittle is known regarding the full spectrum of illness among children with SARS-CoV-2 infection across ambulatory and inpatient settings. MethodsActive surveillance was performed for SARS-CoV-2 by polymerase chain reaction among asymptomatic and symptomatic individuals in a quaternary care academic hospital laboratory in Tennessee from March 12-July 17, 2020. For symptomatic patients [&le;]18 years of age, we performed phone follow-up and medical record review to obtain sociodemographic and clinical data on days 2, 7, and 30 after diagnosis and on day 30 for asymptomatic patients [&le;]18 years. Daily and 7-day average test positivity frequencies were calculated for children and adults beginning April 26, 2020. ResultsSARS-CoV-2 was detected in 531/10327 (5.1%) specimens from patients [&le;]18 years, including 46/5752 (0.8%) asymptomatic and 485/4575 (10.6%) specimens from 459 unique symptomatic children. Cough (51%), fever (42%), and headache (41%) were the most common symptoms associated with SARS-CoV-2 infection. SARS-CoV-2-related hospitalization was uncommon (18/459 children; 4%); no children with SARS-CoV-2 infection during the study period required intensive care unit admission. Symptom resolution occurred by follow-up day 2 in 192/459 (42%), by day 7 in 332/459 (72%), and by day 30 in 373/396 (94%). The number of cases and percent positivity rose in late June and July in all ages. ConclusionsIn an integrated healthcare network, most pediatric SARS-CoV-2 infections were mild, brief, and rarely required hospital admission, despite increasing cases as community response measures were relaxed. Key pointsIn an integrated healthcare network in the Southeastern United States, symptomatic SARS-CoV-2 infection in children was generally mild, resolved rapidly, and rarely required hospitalization. Cases increased in children and adults as community mitigation measures became less restrictive.

Infectious gastroenteritis (IGE) is a major cause of pediatric morbidity globally, with viral pathogens accounting for a substantial proportion of cases. While seasonal patterns of viral IGE are well recognized, the association between specific environmental exposures, such as ambient temperature, and viral IGE has not been fully quantified. First, we performed a secondary analysis of data from a prospective, multisite study of children presenting to emergency departments at five medical centers across the continental United States, linking individual level laboratory data to environmental exposures, including temperature, humidity, and air pollutants, measured during the 14 days preceding symptom onset. Mixed-effects logistic regression was applied to evaluate the association between viral IGE and environmental exposures, adjusting for site-level clustering and patient age. Among 868 children with IGE, higher ambient temperature was inversely associated with viral etiology (OR 0.50, 95% CI 0.36-0.68, p < 0.001). We did not find statistically significant associations between other environmental variables and viral IGE. Then, to contextualize these individual-level findings in children, we examined all-ages population-level surveillance data from GermWatch, a regional laboratory testing-based infectious disease surveillance system, which demonstrated concordant declines in viral pathogen detection with increasing temperature. These findings support the association of weather with viral transmission patterns. Incorporating environmental context into clinical decision-making may improve diagnostic stewardship and support more effective resource allocation during periods of increased viral IGE prevalence.

Generally, children and teenagers do not become seriously ill with COVID-19. However, in countries with high rates of coronavirus disease, children with the syndrome COVID-19 associated inflammation syndrome referred to as PIMS-TS have been reported. Similarities noted between SARS-CoV-2 Spike protein sequences and those of other super antigens has prompted the suggestion that this might be the mechanism by SARS-CoV-ST triggers PIMS-TS. It has also been suggested that the D614G variant found more commonly in the US and across European countries may explain why PIMS-TS appears to be common in these countries. Here we analysed viral sequences from 13 paediatric COVID-19 patients of whom five were diagnosed with PIMS-TS. This is the first characterisation of viruses from PIMS-TS patients. In contrast to what has been hypothesised, we found no evidence of unique sequences associated with the viruses from PIMS-TS patients.

We analyzed the antibody and cytokine responses of twenty-three patients with multisystem inflammatory syndrome of children (MIS-C) that appeared with a three-to-six-week delay following a mild or asymptomatic SARS-CoV-2 infection. These responses were compared to healthy convalescent pediatric COVID-19 patients approximately twenty-eight days after the onset of symptoms. Both groups had strong IgG responses to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, but the MIS-C patients had weaker antibody responses to certain epitopes in the SARS-CoV-2 S and N proteins and to the S and N proteins of endemic human coronaviruses (HCoV) compared to pediatric convalescent COVID patients. HCoV antibody reactivity was correlated with age. In contrast, MIS-C patients had elevated serum levels of several proinflammatory cytokines compared to convalescent COVID patients, including interleukins IL-6, IL-8, IL-18 and chemokines CCL2, CCL8, CXCL5, CXCL9 and CXCL10 as well as tumor necrosis factor alpha and interferon gamma. Moreover, many cytokine responses of MIS-C patients were positively correlated with antibody responses to the SARS-CoV-2 S, N, membrane and ORF3a proteins while pediatric convalescent COVID patient cytokine responses were more often negatively correlated with antibody responses to the S, N and ORF3a proteins of SARS-CoV-2.

A retrospective observational cohort study evaluated acute illness predictors of pediatric Long COVID in Jamaica. Poisson regression modeling associated acute univariate symptoms of vomiting, abdominal pain, ageusia, anosmia, fatigue, confusion, brain fog, and multisystem inflammatory syndrome in children (MIS-C); multivariable composite predictors of MIS-C, vomiting, and ageusia. A high incidence in our cohort supports needs for improvements applicable in resource-constrained settings.

Importance: Respiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season. Objectives: To describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups. Design, Setting, and Participants: Surveillance registry of children 8- <24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV). Exposure: Preexisting health conditions potentially increasing risk of severe RSV disease. Main Outcomes and Measures: Patients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared. Results: Among 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001). Conclusions and Relevance: Approximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.

ImportanceAntenatal care provides unique opportunities to assess SARS-CoV-2 seroprevalence and antibody response duration after natural infection detected during pregnancy; transplacental antibody transfer may inform peripartum and neonatal protection. ObjectiveEstimate seroprevalence and durability of antibodies from natural infection (anti-nucleocapsid (anti-N) IgG) among pregnant people, and evaluate transplacental transfer efficiency. DesignSeroprevalence study: cross-sectional SARS-CoV-2 antibody screening among pregnant people December 9, 2020-June 19, 2021. Cohort study: Pregnant people screened anti-N IgG+ by Abbott Architect chemiluminescent immunoassay in seroprevalence study or identified through medical records with RT-PCR+ or antigen positive results enrolled in a prospective cohort December 9, 2020-June 30, 2022 to longitudinally measure anti-N IgG responses. We collected cord blood and assessed transplacental transfer of maternally-derived anti-N antibodies. SettingThree hospitals and 14 affiliated clinics providing antenatal and delivery care, Seattle, Washington metropolitan area. ParticipantsSeroprevalence study: pregnant people were screened for SAR-CoV-2 anti-N IgG during routine care. Cohort study: Pregnant people with evidence of prior SARS-CoV-2 infection (screened anti-N IgG+ from seroprevalence study or identified with a RT-PCR+ or antigen positive result from medical records) were enrolled in a cohort study to longitudinally measure anti-N IgG responses. Exposure(s) (for observational studies)COVID-19 diagnosis, symptoms, and disease severity. Main Outcome(s) and Measure(s)Presence and durability of SARS-CoV-2 anti-N IgG, transplacental transfer of maternally-derived anti-N IgG. ResultsOf 1289 pregnant people screened in the seroprevalence study, 5% (65) tested SARS-CoV-2 anti-N IgG+, including 39 (60%) without prior RT-PCR+ or antigen positive results and 53 (82%) without symptoms. Among 89 participants enrolled in the cohort study, 73 (82%) had anti-N IgG+ results during pregnancy. Among 49 participants with delivery samples 33 (67%) were anti-N IgG negative by delivery. Of 24 remaining anti-N IgG+ at delivery with paired cord blood samples, 12 (50%) had efficient transplacental anti-N IgG antibody transfer. Median time from first anti-N IgG to below positive antibody threshold was 17 weeks and did not differ by prior RT-PCR+ or antigen positive status. Conclusions and RelevanceMaternally-derived SARS-CoV-2 antibodies to natural infection may wane before delivery. Vaccines are recommended for pregnant persons to reduce severe illness and confer protection to infants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits an antibody response that targets several viral proteins including spike (S) and nucleocapsid (N); S is the major target of neutralizing antibodies. Here, we assess levels of anti-N binding antibodies and anti-S neutralizing antibodies in unvaccinated children compared with unvaccinated older adults following infection. Specifically, we examine neutralization and anti-N binding by sera collected up to 52 weeks following SARS-CoV-2 infection in children and compare these to a cohort of adults, including older adults, most of whom had mild infections that did not require hospitalization. Neutralizing antibody titers were lower in children than adults early after infection, but by 6 months titers were similar between age groups. The neutralizing activity of the childrens sera decreased modestly from one to six months; a pattern that was not significantly different from that observed in adults. However, infection of children induced much lower levels of anti-N antibodies than in adults, and levels of these anti-N antibodies decreased more rapidly in children than in adults, including older adults. These results highlight age-related differences in the antibody responses to SARS-CoV-2 proteins and, as vaccines for children are introduced, may provide comparator data for the longevity of infection-elicited and vaccination-induced neutralizing antibody responses.

BackgroundDespite decades of study, the characteristics of infants with invasive group B streptococcus (GBS) late onset disease (LOD) (onset day 7 to 89 of life) and in particular very late onset disease (VLOD) (after day 89 of life) are not well described. Materials and MethodsThis was a retrospective cohort study of infants hospitalized in four Edmonton hospitals April 1, 1994 through June 30, 2022 with LOD or VLOD GBS invasive disease. Data were collected on demographics, date of onset of GBS infection, clinical manifestations and outcomes. ResultsThere were 115 episodes of LOD in 111 infants of which 49 (45%) were preterm. Onset was on median day 27 (IQR 19-40.5) of life. All but one infant was bacteremic while 38 (34%) had proven and 17 (15%) had possible GBS meningitis. Five (5%) died before hospital discharge with all deaths presumed to be due to GBS. There were 11 episodes of VLOD in 11 infants (7 [64%] preterm) presenting on median day 116 (IQR 103-138) (range 93-207) of life. Three (27%) had GBS meningitis. All survived to discharge. Infants with VLOD were less likely to be born vaginally and more likely to be mechanically ventilated during their birth hospitalization and have invasive disease with other pathogens than were infants with LOD. Serotype III accounted for 78% of LOD and 64% of VLOD cases. ConclusionGBS remains a significant cause of infant morbidity and mortality. There is increasing evidence that GBS may sometimes be an opportunistic pathogen in infants over 90 days of age.

The impact of post-acute sequelae of SARS-CoV-2 infection (PASC) in children is underrecognized. We developed an EHR-based algorithm across eight pediatric institutions to identify children with COVID-19 based on serology testing from 3/2020 through 4/2022 who had not been identified by PCR. Overall, serology tests were used 100-fold less than PCR. Seroprevalence of IgG anti-nucleocapsid antibodies remained stable, while rates of positive IgG anti-spike antibodies increased in teenagers after COVID-19 vaccine approval. Through data harmonization and after excluding 1,410 serology test results that may have been influenced by vaccines, we identified 2,714 children that were COVID-19 positive exclusively by serology. These patients were frequently tested as inpatients (24% vs. 2%), had chronic conditions more frequently (37% vs 24%), and a MIS-C diagnosis (23% vs. <1%) compared with PCR-positive children. Identification of children that could have been paucisymptomatic, not tested, or missed is critical to define the burden of PASC in children.

ImportanceThe effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated. ObjectiveTo assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women. DesignImmune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood. SettingJohns Hopkins Hospital (JHH) ParticipantsPregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study. ExposuresSARS-CoV-2 Main Outcomes and MeasuresParticipant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression. ResultsSARS-COV-2 positive pregnant women expressed more IL1{beta}, but not IL6, in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy. Conclusions and RelevanceSARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.

ObjectivesEnterovirus (EV) and parechovirus (PeV) meningitis are significant causes of illness in febrile infants. The clinical significance of detecting EV/PeV in the CSF, particularly in the absence of pleocytosis and neurological symptoms, remains uncertain in this age group. We aimed to characterise the relationship between clinical features, systemic neuroinflammatory and immune responses, and CSF pleocytosis in infants with EV/PeV meningitis. MethodsProspective multicentre observational cohort study of febrile infants <90 days old undergoing CSF testing for infection. Infants were recruited as part of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study from 35 Paediatric Emergency Research in the UK and Ireland (PERUKI) sites from 6th July 2022 to 31st August 2023 (NCT05259683). Plasma proteomic profiling of 724 inflammation and neurology-related proteins was performed using Olink technology and compared with clinical and laboratory data. Results603 febrile infants were included, with 21/603 (3{middle dot}5%) PeV, and 173/197 (28.7%) EV meningitis cases. Lymphopenia was significantly more common in infants without pleocytosis, 62/101 (63.9%), than those with pleocytosis 7/54 (16.7%). No significant differences in clinical symptoms or timing of presentation were observed with differing CSF WBC counts. Proteomic analysis (n=131) revealed that infants without pleocytosis exhibited elevated inflammatory cytokine responses and enrichment of pathways related to apoptosis and CNS involvement. In contrast, those with pleocytosis showed muted cytokine responses. ConclusionsThe absence of CSF pleocytosis in EV and PeV meningitis may result from systemic lymphocyte depletion, potentially mediated by cytokine-driven apoptosis. Our findings do not support the hypothesis that the lack of pleocytosis is primarily attributable to early presentation or to incidental detection of viral RNA due to viremia in infants.

BackgroundOver 10,000 rare diseases (RDs) affect more than 300 million people globally, yet their influence on COVID-19 severity, reinfection risk, and long COVID remains poorly understood. This study evaluates the impact of RDs on these outcomes and examines the effectiveness of vaccination and antiviral treatments among individuals with and without RDs. MethodsWe conducted a retrospective cohort study using harmonized electronic health records (EHRs) from the National COVID Cohort Collaborative (N3C), encompassing 21,704,702 individuals, including 4,825,605 with confirmed SARS-CoV-2 infection between Jan 1, 2020, and Jan 4, 2024. RDs were defined using 12,003 conditions curated from GARD and Orphanet, mapped to OMOP concepts, and classified into 18 RD classes based on medical specialty involvement. Primary outcomes included: (1) COVID-19 severity (hospitalization and life-threatening disease), (2) long COVID, and (3) SARS-CoV-2 reinfection. We applied multivariable logistic regression with inverse probability of treatment weighting and reported adjusted odds ratios with 95% confidence intervals and associated p-values. Models were controlled for demographics, comorbidities, and exposure to vaccination and antiviral treatments. FindingsOf 21,704,702 individuals, we identify 4,825,605 COVID-19 positive individuals, 6.36% had RDs, with markedly higher rates of rare disease (RD) patients that have life-threatening illness (16% vs. 6.1% without life-threatening illness) and that are hospitalized (13% vs. 6.0% without hospitalization). Otorhinolaryngologic diseases showed the highest risk of life-threatening outcomes (OR 4.51; 95% CI 3.81-5.33), followed by developmental defect during embryogenesis (OR 1.84; 95% CI 1.72-1.98) and cardiac conditions (OR 1.79; 95% CI 1.51-2.11). Hospitalization risk was highest for otorhinolaryngologic (OR 2.90; 95% CI 2.61-3.23), developmental defect during embryogenesis (OR 2.06; 95% CI 1.97-2.16), and hematologic and endocrine diseases (OR 1.81; 95% CI 1.75-1.87 and OR 1.81; 95% CI 1.64-1.99, respectively). In patients with RDs, vaccination alone or antiviral treatment alone was associated with reduced odds of life-threatening COVID-19 disease compared to non-vaccinated individuals (OR 0.71; 95% CI 0.66-0.77 and OR 0.33; 95% CI 0.26-0.42, respectively). The combination of both vaccination and antiviral treatment showed the greatest reduction in odds ratio (OR 0.24; 95% CI 0.20-0.27). Similar results were observed in patients without RDs. In contrast, vaccination or antiviral therapy alone, compared to no intervention, did not significantly reduce long COVID risk in RD patients, although these interventions alone did result in a lower odds ratio in patients without RD. However, their combination was protective in both groups. Vaccination alone, compared to no vaccination, also reduced the risk of reinfection across RD and non-RD populations. InterpretationRD patients face elevated risks of severe COVID-19 outcomes. While vaccination and antivirals significantly reduce the acute severity of illness, their impact on long COVID appears limited in this population. Notably, vaccination was protective against COVID-19 reinfection in both RD and non-RD populations. These findings highlight the need for targeted strategies to protect RD patients beyond current interventions, particularly in preventing long-term complications. FundingThis work was supported in part by the intramural and extramural programs at NCATS (ZIA ZICTR000410).

Respiratory syncytial virus (RSV) infections and hospitalizations surged sharply in 2022 among young children. To assess whether COVID-19 contributed to this surge, we leveraged a real-time nation-wide US database of electronic health records (EHRs) using time series analysis from January 1, 2010 through January 31, 2023, and propensity-score matched cohort comparisons for children aged 0-5 years with or without prior COVID-19 infection. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. The monthly incidence rate for first-time medically attended cases, most of which were severe RSV-associated diseases, reached a historical high rate of 2,182 cases per 1,0000,000 person-days in November 2022, corresponding to a related increase of 143% compared to expected peak rate (rate ratio: 2.43, 95% CI: 2.25-2.63). Among 228,940 children aged 0-5 years, the risk for first-time medically attended RSV during 10/2022-12/2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (risk ratio or RR: 1.40, 95% CI: 1.27-1.55); and among 99,105 children aged 0-1 year, the overall risk was 7.90% for those with prior COVID-19 infection, higher than 5.64% for matched children without (RR: 1.40, 95% CI: 1.21-1.62). These data provide evidence that COVID-19 contributed to the 2022 surge of severe pediatric RSV cases.

ObjectivesPeriodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common autoinflammatory disorder of childhood, characterized by recurrent febrile episodes driven by dysregulated innate immune activation. Although genetic susceptibility contributes to disease risk, environmental modifiers remain poorly defined. Vaccinations may induce long-lasting modulation of innate immune responses and influence PFAPA incidence. We aimed to assess whether childhood vaccinations, including Bacillus Calmette-Guerin (BCG), are associated with PFAPA risk in a large national cohort. MethodsWe conducted a matched case-control study using electronic health records from a national healthcare provider in Israel. Children diagnosed with PFAPA were matched to children without PFAPA by age, sex, socioeconomic status, ethnic sector, and enrolment year. Vaccination history was obtained from the electronic immunization registry. A systematic screen of associations was performed across all recorded childhood vaccines, followed by adjusted conditional logistic regression models. Prior laboratory test results were analysed to characterize the immune profile. ResultsThe study included 1,641 PFAPA cases and 32,820 matched controls. Among all vaccines examined, prior Bacillus Calmette-Guerin (BCG) vaccination, received by 401 children (3 cases, 398 controls), showed the strongest association with reduced PFAPA risk (adjusted odds ratio 0.15, 95% confidence interval [CI] 0.05-0.46, p=0.001). Associations with other vaccines were heterogeneous and of smaller magnitude. PFAPA cases demonstrated a myeloid-skewed inflammatory profile prior to diagnosis, including elevated C-reactive protein, neutrophilia, increased neutrophil-to-lymphocyte ratio, and relative lymphopenia. ConclusionsIn this nationwide study, prior BCG vaccination emerged from a systematic screen as strongly associated with reduced PFAPA risk, supporting a role for immune programming in susceptibility to childhood autoinflammatory disease.