key: cord-1046757-gkidz745 authors: Mark, Elyse G.; Golden, W. Christopher; Gilmore, Maureen M.; Sick-Samuels, Anna; Curless, Melanie S.; Nogee, Lawrence M.; Milstone, Aaron M.; Johnson, Julia title: Community-Onset SARS-CoV-2 Infection in Young Infants: A Systematic Review date: 2020-09-08 journal: J Pediatr DOI: 10.1016/j.jpeds.2020.09.008 sha: bd2691656fc0b01775ed0a3b47a2dc9d713b97e1 doc_id: 1046757 cord_uid: gkidz745 OBJECTIVE: To summarize and evaluate current reports on community-onset severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young infants. STUDY DESIGN: We performed a systematic review to identify reports published from November 1, 2019, until June 15, 2020, on laboratory-confirmed community-onset SARS-CoV-2 infection in infants less than 3 months of age. We excluded studies reporting neonates with perinatal COVID exposure and diagnosis prior to hospital discharge and hospital-onset disease, as well as clinically diagnosed cases without confirmation. Two independent reviewers performed study screening, data abstraction, and risk of bias assessment. Variables of interest included patient age, exposure to COVID-19, past medical history, clinical symptoms, SARS-CoV-2 testing, laboratory findings, clinical course, and disposition. RESULTS: 38 publications met inclusion criteria, including 23 single case reports, 14 case series, and 1 cohort study, describing 63 infants under 3 months of age with laboratory confirmed SARS-CoV-2 infection. Most cases were mild to moderate. Fever, respiratory, gastrointestinal, cardiac, and neurologic findings were reported. Laboratory abnormalities included neutropenia, lymphopenia, and elevated serum levels of inflammatory markers and aminotransferases. Fifty-eight (92%) infants were hospitalized, 13 (21%) were admitted to the intensive care unit (ICU), and 2 (3%) required mechanical ventilation. No death was reported. CONCLUSIONS: Among young infants with laboratory-confirmed SARS-CoV-2 infection, most cases were mild to moderate and improved with supportive care. Our results demonstrate a need for a high index of suspicion for SARS-CoV-2 infection in young infants presenting with generalized symptoms such as fever or decreased feeding, even in the absence of respiratory symptoms. infants less than 3 months of age. We excluded studies reporting neonates with perinatal COVID exposure and diagnosis prior to hospital discharge and hospital-onset disease, as well as clinically diagnosed cases without confirmation. Two independent reviewers performed study screening, data abstraction, and risk of bias assessment. Variables of interest included patient age, exposure to COVID-19, past medical history, clinical symptoms, SARS-CoV-2 testing, laboratory findings, clinical course, and disposition. Results: 38 publications met inclusion criteria, including 23 single case reports, 14 case series, and 1 cohort study, describing 63 infants under 3 months of age with laboratory confirmed SARS-CoV-2 infection. Most cases were mild to moderate. Fever, respiratory, gastrointestinal, cardiac, and neurologic findings were reported. Laboratory abnormalities included neutropenia, lymphopenia, and elevated serum levels of inflammatory markers and aminotransferases. Fiftyeight (92%) infants were hospitalized, 13 (21%) were admitted to the intensive care unit (ICU), and 2 (3%) required mechanical ventilation. No death was reported. Conclusions: Among young infants with laboratory-confirmed SARS-CoV-2 infection, most cases were mild to moderate and improved with supportive care. Our results demonstrate a need for a high index of suspicion for SARS-CoV-2 infection in young infants presenting with generalized symptoms such as fever or decreased feeding, even in the absence of respiratory symptoms. Since its identification in December 2019, severe acute respiratory coronavirus 2 (SARS-CoV-2) has proven highly contagious and globally devastating, causing 728,013 fatalities as of August SARS-CoV-2 spreads primarily through droplet and contact transmission, with a high incidence of familial clustering and significant proportion of asymptomatic infection. (8) Infants may be at higher risk of exposure to SARS-CoV-2 infection due to frequent contact with healthcare workers in the first few weeks of life, dependency on caretakers, and necessity for close contact during feeding and care that may increase exposure to respiratory secretions of infected persons. At present, studies of community-onset SARS-CoV-2 infection in young infants are primarily limited to case reports and small case series. This systematic review aims to consolidate reports of laboratory-confirmed, community-onset cases in infants less than 3 months of age. We conducted a systematic review to identify studies published from November 1, 2019, until June 15, 2020, on laboratory-confirmed community-onset SARS-CoV-2 infection in infants less than 3 months of age. We searched PubMed and Embase and only included peer-reviewed publications for which full text articles could be retrieved (search strategy, Table I [available at www.jpeds.com]). Additional articles were identified via snowball search. Inclusion criteria were infant age less than 3 months, community onset of illness, and laboratory-based confirmation by at least one positive SARS-CoV-2 polymerase chain reaction (PCR) test. Exclusion criteria were perinatal COVID-19 exposure with positive PCR testing in infants prior to hospital discharge, nosocomial infection, and presentation of aggregate pediatric data that included age groups greater than 3 months. Two independent reviewers performed screening of articles in Covidence Among included studies, 23 were single case reports, 14 were case series, and 1 was a cohort study, with the majority of publications from the United States (n=11), China (n=10), and Italy (n=7) ( Table 2) . Infant ages ranged from 5 days to less than 3 months (Table 3) . Among 59 infants with reported sex, 41 (69%) were male. Six (16%) infants with known gestational age were premature. Eight infants were reported as having a significant prior medical history, including extreme prematurity (n=1), congenital heart disease (n=3), cystic fibrosis (n=1), and renal anomalies (n=3). One neonate had a genetic syndrome associated with multiple congenital anomalies. Among the cases with a known contact history, 41 infants (69%) were exposed to a symptomatic or COVID-positive person. Among 62 infants with specified test site for SARS-CoV-2 PCR testing, 60 (97%) had at least one positive respiratory specimen ( Table 2) . Two infants tested positive only from an anal swab.(12) All infected infants who had nasopharyngeal (NP) testing (n=48) had a positive test, as did 12 (83%) infants who had an oropharyngeal (OP) sample tested. PCR testing of cerebrospinal fluid (CSF), blood, and urine was infrequently performed and was positive in 1/6 (17%), 1/3 (33%), and 1/2 (50%) samples, respectively. Eight (80%) of 10 infants tested had a positive PCR result from stool or an anal swab, with persistent viral shedding in stool reported in J o u r n a l P r e -p r o o f several infants. Han et al reported serial quantitative PCR testing in an infant and her mother who was also hospitalized with COVID-19.(13) The infant had positive PCR testing from NP, OP, saliva, blood, urine, and stool samples, with gradual decline in viral load over a three-week hospital admission. Her mother had detectable virus in NP/OP, sputum, and stool samples; testing of blood and urine samples was negative. Fever was the most common symptom reported among infants (n=46, 73%), followed by respiratory symptoms (rhinitis, cough, or respiratory distress) (n=40, 66%) ( Table 3) . Reported gastrointestinal symptoms included diarrhea (n=9) and emesis (n=9). Two infants (3%) presented with seizures. Three infants (5%) were asymptomatic, including one infant with cystic fibrosis who had been tested due to known exposure to a family member with COVID-19. (14) Laboratory tests were performed and reported in up to two-thirds of cases. Reported hematologic abnormalities included neutropenia (n=22/39, 56%), lymphopenia (n=7/45, 16%), and thrombocytopenia (n=2/27, 7%). Median C-reactive protein (CRP) was 2.1 mg/L (interquartile range (IQR) 0.9-4.5; range, below limit of detection to172); 5 (19%) infants had an elevated CRP Although the spectrum of clinical disease of community-onset SARS-CoV-2 infection among young infants ranges from asymptomatic to critical illness, most identified infants appear to have mild to moderate illness and recover quickly with supportive treatment alone. We were unable to draw conclusions regarding prevalence of infant disease given the preponderance of case reports among publications to date. Larger pediatric studies have reported epidemiologic data of interest; however, aggregate reporting of data in broader age groups (i.e., children <12 months of age or children <5 years) prohibits commentary on prevalence among young infants. There was a notable male predominance among reported infants, mirroring observations in other groups. (28, J o u r n a l P r e -p r o o f 29) It is unclear whether male sex could predispose infants to infection or to more significant clinical symptomatology, increasing likelihood of seeking care and of SARS-CoV-2 testing. Clinical presentation in infants largely was non-specific with predominance of fever and respiratory symptoms among ill infants. Laboratory abnormalities such as neutropenia, leukopenia, and elevated inflammatory markers seen in these cases also can be observed in a included. a Two infants were described as thrombocytopenic without reported platelet count. b Values reported in one study were excluded as they represented significant outliers, with concern for possible incorrect reporting of units. Study authors were contacted for clarification with no response. c One infant was reported to have significant aminotransferase elevation with an AST >500 U/L. Precise value was not provided and therefore not included in statistical analysis. d One infant did not require admission on initial presentation but was admitted after blood culture was positive, ultimately determined to be a contaminant. Infant not included in n of infants requiring hospitalization. J o u r n a l P r e -p r o o f Were patient's demographic characteristics clearly described? Was the patient's history clearly described and presented as a timeline? Q3 Was the current clinical condition of the patient on presentation clearly described? Were diagnostic tests or assessment methods and the results clearly described? Was the intervention(s) or treatment procedure(s) clearly described? Was the post-intervention clinical condition clearly described? Were adverse events (harms) or unanticipated events identified and described? Does the case report provide takeaway lessons? Were the two groups similar and recruited from the same population? Q2 Were the exposures measured similarly to assign people to both exposed and unexposed groups? Q3 Was the exposure measured in a valid and reliable way? Q4 Were confounding factors identified? Were strategies to deal with confounding factors stated? Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)? Were the outcomes measured in a valid and reliable way? Was the follow up time reported and sufficient to be long enough for outcomes to occur? Was follow up complete, and, if not, were the reasons to loss to follow up described and explored? Q10 Were strategies to address incomplete follow up utilized? Q11 Was appropriate statistical analysis used? J o u r n a l P r e -p r o o f World Health Organization. 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abnormal, n/n obtained (%) 9/9 (100) Blood culture, n positive/n obtained (%) 3/37 (8) Urine culture, n positive/n obtained (%) 3/28 (11) CSF culture, n positive/n obtained (%) 0/26