key: cord-265366-vmuqbpkk
authors: Leibowitz, Jill; Krief, William; Barone, Stephen; Williamson, Kristy A.; Goenka, Pratichi K.; Rai, Shipra; Moriarty, Shannon; Baodhankar, Prachi; Rubin, Lorry G.
title: Comparison of Clinical and Epidemiologic Characteristics of Young Febrile Infants with and without SARS-CoV-2 Infection
date: 2020-10-09
journal: J Pediatr
DOI: 10.1016/j.jpeds.2020.10.002
sha: 
doc_id: 265366
cord_uid: vmuqbpkk

OBJECTIVE: To determine features that distinguish febrile young infants with SARS-CoV-2 infection. STUDY DESIGN: Retrospective single-center study included febrile infants <57 days evaluated in the Emergency Department of Cohen Children’s Medical Center of Northwell Health, New Hyde Park, New York during March 1-April 30 of 2018, 2019, and 2020. Sociodemographic and clinical features were compared between those seen during the 2020 COVID-19 pandemic and previous years, as well as between SARS-CoV-2 infected infants and SARS-CoV-2 uninfected infants (SARS-CoV-2 negative or evaluated during 2018 and 2019). RESULTS: In all, 124 febrile infants <57 days of age were identified; 38 during the 2-month study period in 2018, 33 in 2019, and 53 in 2020. During 2020, fewer febrile infants had a serious bacterial infection (SBI) or a positive respiratory viral panel (RVP) than in prior years (6% versus 21%, P = .02; 15% versus 53%, p<.001, respectively). SARS-CoV-2 was the most frequent pathogen detected in 2020; of 30 infants tested, 20 tested positive. Infants with SARS-CoV-2 were more likely to identify as Hispanic (p=.004), have public insurance or were uninsured (p=.01), exhibited lethargy (p=.02), had feeding difficulties (p=.002), and had lower white blood cell (p=.001), neutrophil (p<.001), and lymphocyte counts (p=.005) than the 81 infants without SARS-CoV-2 infection. None of the infants with SARS-CoV-2 had concurrent SBI or detection of another virus. Overall, disease in infants with SARS-CoV-2 was mild. CONCLUSIONS: During the peak of the pandemic, SARS-CoV-2 was the predominant pathogen among febrile infants. Socioeconomic, historical, and laboratory features differed significantly between SARS-CoV-2 infected and uninfected infants. None of the 20 infants with SARS-CoV-2 infection had an identified co-viral or serious bacterial infection.

Based on data from the Centers for Disease Control and Prevention through July 2020, infants < 3 months of age accounted for 18.8% of hospitalized pediatric COVID-19 patients in the US, and children younger than one year of age accounted for 10% of fatalities associated with SARS-CoV-2 in US children, however, the proportion of children younger than 2-3 months of age was not specified. 4, 5 Although an early study from Wuhan, China reported 10.6% of COVID-19 cases in children less than one

year of age to be critical or severe, of these cases, not all were laboratory confirmed SARS-CoV-2 infection and other viral etiologies of illness were not excluded. 6 Since then, a number of case reports and small series describing infants less than 2 months of age have been published, most reporting mild disease, with many infants coming to medical attention due to fever, lethargy and poor feeding, but without respiratory manifestations as seen in adult patients. 7, 8, 9, 10, 11, 12, 13 The largest case series to date describes 18 infants younger than 90 days of age who tested positive for SARS-CoV-2, 14 of whom were febrile. 9 The objective of this study was to compare the clinical and demographic characteristics and hospital course of febrile infants who presented to Cohen Children's Medical Center (CCMC) during March and April of 2020, the time period of peak COVID-19 incidence in our region, to febrile infants treated in CCMC during March and April of previous years. 14 Particular emphasis was placed on infants in whom SARS-CoV-2 was detected in order to provide relevant clinical data for clinicians evaluating infants with fever during the pandemic.

We conducted a single centered, retrospective study of febrile infants evaluated in the York, which was the epicenter of COVID-19 in the US during the study period. The investigation included both infants who were evaluated and discharged from the CCMC ED and those admitted to an inpatient unit. Per institutional policy, all febrile infants < 28 days are hospitalized, but for infants 29-56 days of age a decision to hospitalize is based on clinical criteria. For infants with an ED revisit or readmission to CCMC within 7 days, only the first visit was included in the study.

Patients were classified as having SARS-CoV-2 when a nasopharyngeal or combined nasopharyngeal/oropharyngeal swab tested positive by one of several nucleic acid amplification (NAA) assays for SARS-CoV-2 in Northwell Health Laboratories. As of March 24, 2020 all infants admitted to CCMC underwent SARS-CoV-2 testing but prior to March 24, testing for SARS-CoV-2 was not universal because of limited testing capacity. During the study period SARS-CoV-2 testing of febrile infants who were discharged from the emergency department was not universally applied.

Cases were ascertained through review of ICD-10 billing codes and discharge diagnosis in the electronic medical record. Clinical, laboratory and sociodemographic data were abstracted from the electronic health record and managed with the use of a REDCap electronic database. 15 Collected data included age, sex, ethnicity, race, primary language, insurance, length of hospital stay, history of sick contacts or known COVID-19 exposure, history of prematurity or underlying medical condition, disposition from the ED (discharged home versus hospital admission), and need for admission to the pediatric intensive care unit (PICU). The presence or absence of symptoms such as fever, cough, rhinorrhea, feeding difficulties (defined as decreased oral intake), emesis, diarrhea, irritability, lethargy and rash, and vital signs and ascultatory lung examination were also recorded. Laboratory results included SARS-CoV-2 NAA assays test results, complete blood count (CBC) and white blood cell differential, urinalysis, hepatic assays, cerebrospinal fluid parameters, bacterial cultures (urine, blood, cerebrospinal fluid), respiratory viral panel (RVP); GenMark Diagnostics, Carlsbad, CA), erythrocyte sedimentation rate and C-reactive protein, stool assays (stool culture, rotavirus antigen, multiple pathogen gastrointestinal panel by NAA (GI NAA) assay, and herpes simplex virus (HSV) testing (NAA testing of cerebrospinal fluid, whole blood, surface specimens and vesicles). Days of antimicrobial therapy, measured from date of first to last dose, and type and duration of respiratory support (e.g., supplemental oxygen, non-invasive ventilation or mechanical ventilation), measured from date of initiation to discontinuation, were recorded. Neutropenia was defined as an absolute neutrophil count (ANC) of < 1000 cells/µL, lymphopenia was defined as an absolute lymphocyte count (ALC) of < 3000 J o u r n a l P r e -p r o o f blood, urine, or cerebrospinal fluid that was deemed pathogenic. 18, 19 Febrile infants were classified based on the year of presentation (eg, 2018, 2019, 2020). Febrile infants were also categorized based on their SARS-CoV-2 status: (1) infants who were SARS-CoV-2 test positive during March-April 2020 were classified as SARS-CoV-2 infected; (2) infants who were treated between March and April 2020 but were not tested for SARS-CoV- Sixteen of the SARS-CoV-2 infected infants were reported in previous studies. 13, 14 This study was approved by the Northwell Health Institutional Review Board.

We categorized and analyzed the data according to the patients' SARS-CoV-2 status (infected or uninfected) and year of presentation. For purposes of analysis, we combined the 2018 and 2019 cohorts as a single cohort. We performed descriptive and bivariable analyses using Fisher exact test for categorical data, Student t test for continuous variables, and the Wilcoxon rank-sum test J o u r n a l P r e -p r o o f for ordinal data. All tests of significance were 2-sided with an α value of 0.05. Statistical analysis was performed by using SPSS 25 (IBM Corp, Armonk, NY). Overall, the age distribution was as follows: 12 (10%) were 0-14 days, 29 (23%) were 15-28 days, and 83 (67%) were 29-56 days; 69 (56%) were male; 80(65%) were admitted to general inpatient unit, 2 (2%) to the PICU, and 42 (34%) were discharged home from the ED. Patient demographics are summarized in Table I .

Compared with febrile infants presenting in 2018 and 2019, febrile infants in 2020 were similar in age and by sex, but were more likely to identify as Hispanic (p=.04) ( Table 1 ). In 2020, there were significantly fewer infants with a SBI, as SBI was detected in three of 53 (6%) infants in 

Demographic and clinical variables of 20 SARS-CoV-2 positive infants were compared with 81 uninfected infants (71 seen 2018 and 2019 and the 10 SARS-CoV-2 negative infants seen in 2020) ( Table 2 and Table 3) . A significantly higher proportion of infants in the COVID-19 group had public insurance or were uninsured and identified as Hispanic (p=.01 and p=.004, respectively). The racial distribution of the groups differed significantly with a higher proportion of patients identified as "multiracial/other" and a smaller proportion identified as Asian or Black in the SARS-CoV-2 group (p=.04). Infants with COVID-19 were significantly younger (p=.03), had a higher proportion with reported feeding difficulty (p=.002) and had a higher proportion with reported lethargy (p=.02) than the SARS-CoV-2 negative group. Infants 

The key findings of our study are that during the peak of the COVID-19 pandemic in New York, SARS-CoV-2 was the predominant pathogen identified among febrile infants younger than 57 days of age, and the disease was self-limited in all infants with COVID-19. None of the infants infected with SARS-CoV-2 had an additional pathogen identified. Febrile young infants with SARS-CoV-2 infection differ from other febrile infants in that they are younger, are more likely to be lethargic or exhibit feeding difficulties, have lower mean WBC, ANC, and ALC and have a higher likelihood of neutropenia and lymphopenia Despite performing SARS-CoV-2 testing on only 57% of the 2020 cohort of febrile infants due to limitations on availability of testing during this time, SARS-CoV-2 was detected in 38% of the entire cohort and 67% of those tested. In contrast, although the entire 2020 cohort was tested for other respiratory viruses, a virus was detected in only 15% of febrile infants, similar to a study that demonstrated a decrease in influenza rates while COVID-19 was prevalent and while local school closures and stay-at-home orders were in place. 20 The majority of febrile infants with COVID-19 had a relatively mild infections, with only 2 of 20 infants requiring supplemental oxygen, one of whom also required high flow nasal cannula, findings similar to those described in other case reports and small case series. 8, 9, 10, 11, 12 However, severe disease with respiratory failure has been reported in a 4-weekold infant with COVID-19 who was born after a 33-week gestation and in previously healthy infants with COVID-19 who developed pneumonia and evidence of myocardial involvement. 21, 22, 23 The significantly higher proportion of infants with SARS-CoV-2 infection of Hispanic ethnicity and with public health insurance compared with SARS-CoV-2 uninfected infants may reflect the more pronounced impact of COVID-19 in Hispanic persons than those of other ethnicities and in persons from lower socioeconomic groups that has been observed in adults. 24, 25 The SARS-CoV-2 infected infants were younger than the SARS-CoV-2 uninfected infants, and were also younger than the subgroup with other respiratory viral infections. This may in part be an artifact of our practice of admitting infants younger than 29 days of age hospital and preferential testing of admitted patients over ambulatory patients. This finding also could reflect the high prevalence of SARS-CoV-2 among women presenting in labor during this pandemic with transmission from the infant's mother or another household member. 26 Infants with COVID-19 presented with lethargy and feeding difficulty more with SARS-CoV-2 infection among infants younger than 90 days of age. 9, 12 The uncommon occurrence of SBI or a second viral pathogen strongly support the assertion that SARS-CoV-2 infection is the cause of the febrile illness in most or all of these infants rather than that detection reflects an asymptomatic infection.

There were several limitations to this study. This was a single center study and findings may not be generalizable. Additionally, as the initial phase of the COVID-19 pandemic in the United States took place in March and April of 2020, we compared febrile infants seen during this time period with febrile infants evaluated in the ED during corresponding months of 2018 and 2019 so generalizability to other time periods is not possible. Lastly, due to variable testing for SARS-CoV-2 at the initial stages of the pandemic, 23 of 53 infants evaluated in the ED because of fever were not tested; therefore we may have underestimated the prevalence of COVID-19 in this patient population during this time period.

SARS-CoV-2 should be considered as a cause of fever in young infants, particularly when the infant has poor feeding and/or lethargy and when leukopenia, lymphopenia, or neutropenia is present. The infection generally is self-limited and has a relatively rapid clinical resolution.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f .14 J o u r n a l P r e -p r o o f .09

Mean WBC x 5 Defined as presence of any of the following: abnormal lung exam (crackles, rhonchi or wheeze), hypoxia, parenchymal infiltrate on chest X-ray 6 Defined as an ANC of < 1.0x10/ 9 L 7 Defined as an ALC of < 3.0x10/ 9 L J o u r n a l P r e -p r o o f 

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