Comparing single versus multiple virus detection in pediatric acute gastroenteritis postimplementation of routine multiplex RT-PCR diagnostic testing.

Utilizing multiplex real time polymerase chain reaction (RT-PCR) for rapid diagnosis of gastroenteritis, enables simultaneous detection of multiple pathogens. A comparative analysis of disease characteristics was conducted between cases with single and multiple viruses. Rotavirus vaccine was introduced in 2010, reaching a 70% coverage in 2 years. All rectal swabs collected from diarrheic children (<5 years) between December 2017 and March 2022 were included. Detection of the same viruses within 2 months was considered a single episode. Episodes with positive stool bacterial PCR were excluded. A total of 5879 samples were collected, revealing 86.9% (1509) with single virus detection and 13.1% (227) with multiple viruses. The most frequent combination was rotavirus and norovirus (27.8%), these infections followed a winter-spring seasonality akin to rotavirus. Children with multivirus infections exhibited higher immunodeficiency (OR 2.06) rates, but lower food allergy (OR 0.45) and prematurity rates (OR 0.55) compared to single infections. Greater disease severity, evaluated by the Vesikari score, was observed in multivirus episodes (p < 0.001, OR 1.12). Multivirus infections accounted for 13.1% of symptomatic cases in hospitalized young children. Despite vaccination efforts, rotavirus remained prominent, frequently in co-infections with norovirus. Overall, multivirus infections were linked to more severe diseases than single virus cases.

Candida lusitaniae Fungemia in Children: A multicenter case series of emerging pathogen.

Candida lusitaniae fungemia is a serious infection that is rarely reported in children. The aim of this study is to describe a case series of C. lusitaniae fungemia and review previous publications regarding this rare pathogen. This is a multicenter case series of children diagnosed with C. lusitaniae fungemia. A total of 18 cases that occurred over a 15-year period in five tertiary hospitals were included. Additionally, a review of the literature regarding C. lusitaniae fungemia in children was performed. A total of 18 cases were enrolled; 11/18 (61%) were males, with a mean age of 2.3 years. All patients had severe underlying diseases and risk factors for opportunistic infection, most commonly prematurity and malignancies. More than one-third of cases occurred during the last 2 years of the study period. All isolates were susceptible to all tested antifungals. The survival rate following the acute infection was 94%, whereas the survival rate of 14 previously published cases was 71%, with the most common underlying diseases being CGD and malignancies. Candida lusitaniae fungemia is not a common event in the pediatric population, occurring exclusively in children with severe underlying diseases and significant risk factors. This cohort revealed better clinical outcomes than previously reported. All tested isolates were susceptible to all antifungal agents; variability in susceptibility as previously reported was not found in this study. The allegedly higher rate of infection in recent years is in need of further investigation in larger prospective studies in order to conclude if a real trend is at play.

Candida lusitaniae fungemia is a serious infection rarely reported in children. This cohort revealed better clinical outcomes than previously reported. All tested isolates were susceptible to all antifungal agents. The higher rate of infection in recent years is in need of further investigation.

Viral load in hospitalized infants with respiratory syncytial virus bronchiolitis: a three-way comparative analysis.

Viral load measurement of Respiratory syncytial virus (RSV) in acute bronchiolitis depends on specimen collection, viral load quantification, and transport media. The aim of this study was to investigate viral load in three-way-comparative analyses; nasal swab versus nasal wash, quantitative real-time polymerase chain reaction (RT-PCR) versus cell tissue culture, and various transport media. A prospective cohort study of infants aged < 12 months, admitted to the Soroka Medical Center, due to acute bronchiolitis, was conducted. Two nasal swabs and two nasal wash samples (in UTM and VCM) were collected from each infant upon admission and after 48 h. Samples were immediately stored at -80 °C and tested at Viroclinics DDL (Rotterdam, Netherlands). Quantitative RT-PCR and quantitative virus culture were performed using tissue culture infective dose (TCID50). Spearman's correlation coefficient test assessed the correlation between the different methods, viral load, and clinical severity score. One hundred samples were collected from 13 infants (mean age 5.7 ± 3.8 months, 46% males). Twelve patients were RSV-A positive, and one was RSV-B positive. A high correlation was found between transport media- UTM and VCM (0.92, P < 0.001) and between nasal swabs and nasal wash samples (0.62, P = 0.02). RSV signals were higher in nasal wash than in swabs. PCR signals were lower in the second collection compared to the first. No correlation was found between viral load and clinical severity.    Conclusion: RSV viral load is comparable across nasal wash, nasal swabs, and various transport media. However, it did not correlate with clinical severity, probably due to the limited sample size. Broader analyses are warranted. What is Known: • Viral load measurement in Respiratory Syncytial Virus (RSV) bronchiolitis depends on specimen collection, viral load quantification, and transport media. • The COVID-19 pandemic underscored the paramount significance of proper specimen collection, notably through nasal swabs. What is New: • RSV viral load was investigated in three-way-comparative analyses. • RSV viral load correlated well across PCR and tissue culture, nasal wash and swabs, and various transport media. RSV viral load did not correlate with clinical severity.

Infant Botulism, Israel, 2007-2021.

Infant botulism (IB) is an intestinal toxemia that manifests as descending paralysis, constipation, and, in some cases, respiratory failure. Laboratory-confirmed IB cases are rare, and recent data in Israel are lacking. We conducted a national multicenter retrospective study of laboratory-confirmed IB cases reported in Israel during 2007-2021. A total of 8 cases were reported during the study period. During 2019-2021, incidence may have increased because of a cluster of 5 cases. Infant median age for diagnosis was 6.5 months, older than previously reported (3 months). Most cases occurred during March-July. Honey consumption was reported in 1 case, and possible environmental risk factors (living nearby rural or construction areas, dust exposure, and having a father who works as a farmer) were reported in 6 cases. Although IB is rare, its incidence in Israel may have increased over recent years, and its epidemiology and risk factors differ from cases reported previously in Israel.

Dynamics of Pediatric Antibiotic Use Differ between High- and Low-Prescribing Clinics after Pneumococcal Conjugate Vaccines.

OBJECTIVE: To compare dispensed oral antibiotic prescription rates (DAPRs) after implementation of pneumococcal conjugate vaccine (PCV) in high antibiotic-prescribing clinics (HPC) with low antibiotic-prescribing clinics (LPC) in 2 distinct ethnic groups of children (Jewish and Bedouin children) <5 years of age. METHODS: Clinics with ≥50 insured children, active both pre-PCV (2005-2009) and post-PCV (2010-2018) implementation, were included. HPC and LPC were defined by DAPRs above or below the median in each age and ethnic group. Monthly dispensed antibiotic prescription rate (DAPR) trends (adjusted for age and ethnicity) were calculated using interrupted time series. Mean yearly incidence rate-ratios (late PCV13 vs pre-PCV) were calculated. RESULTS: Bedouin HPC had the highest pre-PCV overall-DAPR per 1000 child-years ± SD (2520.4 ± 121.2), followed by Jewish HPC (1885.5 ± 47.6), Bedouin LPC (1314.8 ± 81.6), and Jewish LPC (996.0 ± 19.6). Shortly after PCV implementation, all DAPRs and amoxicillin/amoxicillin-clavulanate DAPRs declined in all groups except Jewish LPC, stabilizing within 4-5 years post-PCV. The rates and magnitudes of declines were directly proportional to the pre-PCV DAPR magnitudes, achieving near-complete closure of the pre-PCV DAPR gaps between the 4 groups (rates during late-PCV13 ranging from 1649.4 ± 23.5 [Bedouin HPC] to 1200.3 ± 72.4 [Jewish LPC]). CONCLUSIONS: PCVs are a powerful tool in reducing outpatient antibiotic consumption among young children, especially in HPC, resulting in partial closure of DAPR gap between HPC and LPC. The higher impact on HPC suggests that PCV-associated declines of respiratory disease may strongly contribute to a judicious antibiotic approach in clinics with high antibiotic consumption.

Effectiveness of BNT162b2 Vaccination During Pregnancy in Preventing Hospitalization for Severe Acute Respiratory Syndrome Coronavirus 2 in Infants.

OBJECTIVE: To assess the clinical effectiveness of the BNT162b2 vaccine during pregnancy in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospitalizations of infants. STUDY DESIGN: A retrospective, multicenter, 1:3 case-control (test-negative) study. Symptomatic hospitalized infants less than 6 months of age, with a positive SARS-CoV-2 polymerase chain reaction test between January 3, 2021, and March 11, 2021, were matched by age and time to negative controls, hospitalized with symptoms compatible with SARS-CoV-2 infection. Mothers were defined as fully vaccinated who received 2 doses of BNT162b2 with the second given 2 weeks to 6 months before delivery; or partially vaccinated, if they received only 1 dose or 2 doses with the second given more than 6 months or less than 2 weeks before delivery. Severe SARS-CoV-2 was defined as a need for assisted ventilation. RESULTS: We matched 116 SARS-CoV-2 positive infants with 348 negative controls with symptoms compatible with SARS-CoV-2 infection. The effectiveness of fully vaccinated mothers was 61.6% (95% CI, 31.9-78.4) and the effectiveness of partially vaccinated mothers was not significant. Effectiveness was higher in infants 0-2 vs 3-6 months of age. The effectiveness (57.1%; 95% CI, 22.8-76.4) was similar when excluding mothers who were infected with SARS-CoV-2 during pregnancy. The OR of severe infection in infants born to unvaccinated vs fully vaccinated mothers was 5.8. CONCLUSIONS: At least 2 doses of BNT162b2 vaccine administered during the second or third trimester of pregnancy had an effectiveness of 61.6% in decreasing hospitalization for SARS-CoV-2 infection in infants less than 6 months of age.

Comparison Between Peripheral and Central Blood Cultures in Pediatric Oncology Patients With Blood Stream Infections.

BACKGROUND: Current guidelines for fever in children with cancer recommend obtaining blood cultures from all lumens of the central venous catheter (CVC) and to consider a concurrent peripheral blood culture. We assessed the characteristics of blood stream infections (BSI) in oncology children and compared central and peripheral pathogen growth. METHODS: A prospective, computerized surveillance of BSI in children treated at the oncology unit between May 2014 and July 2020. The growth of the same organism within a month was considered a single episode, ≥2 organisms in the same culture were defined as different episodes. Only children with concomitant cultures, drawn at presentation before initiation of antibiotics were included in the comparison between CVC and peripheral cultures. RESULTS: A total of 139 episodes in 81 children (with implanted Port-A-catheters) were considered true BSI. Of the 94/139 (67.6%) cases where a central and peripheral culture were concomitantly obtained, 52/94 (55.3%) had positive central/peripheral cultures that grew the same organism, 31/94 (33.0%) had positive central cultures only, and 11/94 (11.7%) had positive peripheral cultures only. In 3/94 cases, the organisms that grew from the CVC were not identical to those from the peripheral site. Four of 52 (7.7%) of the same positive central/peripheral pathogens had different susceptibility testing results. Higher CVC removal rates were observed when both peripheral and CVC cultures were positive ( P =0.044). CONCLUSIONS: Overall, 11.7% of BSI episodes were identified only by peripheral culture and 7.7% of paired organisms did not share the same susceptibility test results which emphasizes the importance of a peripheral culture in managing fever in oncology children.

Implementing a screening algorithm for early recognition of sepsis in hospitalized children: a quality improvement project.

Sepsis is a leading cause of mortality in children. Utilizing a screening tool for early recognition of sepsis is recommended. Our centre had no screening tool for sepsis nor a standardized protocol for sepsis management. In December 2020, a screening algorithm for sepsis was implemented. The algorithm consisted of vital signs measurements in children with an abnormal body temperature, a pop-up alert, nurse's and physician's evaluation, and activation of a workup protocol. The project's primary aim was to increase vital signs measurement rates in hospitalized children with abnormal body temperature from 40% to >90% within 6 months, by 1 June 2021, and sustain until 31 December 2021. Adherence to the algorithm and performance were monitored during 2021, and the outcomes were compared to the preceding 5 years and a control ward. The alert identified 324 children and 596 febrile episodes. Vital signs measurement adherence increased from 42.7% to >90% in 2 months. A nurse evaluated 86.4% of episodes, and a physician evaluated 83.0% of these. Paediatric intensive care unit (PICU) admission rates were lower in the intervention period vs. the pre-intervention period vs. the control ward (4.6% vs. 5.6% vs. 6.0%, respectively); the median PICU length of stay was shorter in the intervention vs. the control ward [2.0 (IQR 1, 4) vs. 5.5 (IQR 2, 7), respectively]. These differences were not statistically significant. During the intervention period, the adherence to vital signs measurements reached the goal of >90%. The alert system prompted an evaluation by caregivers and management according to the protocol. Further monitoring is needed to improve outcomes.

Decline in Pneumococcal Disease in Young Children During the Coronavirus Disease 2019 (COVID-19) Pandemic in Israel Associated With Suppression of Seasonal Respiratory Viruses, Despite Persistent Pneumococcal Carriage: A Prospective Cohort Study.

BACKGROUND: The incidence of invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from nonpharmaceutical interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis. METHODS: The first SARS-CoV-2 cases were detected in February 2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory infections necessitating chest X-rays (NA-LRIs), nasopharyngeal pneumococcal carriage in nonrespiratory visits, nasopharyngeal respiratory virus detection (by polymerase chain reaction), and nationwide IPD. Monthly rates (January 2020 through February 2021 vs mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity were compared. RESULTS: CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios [IRRs]: .07 and .19, respectively); NA-LRIs and nonpneumonia IPD were also reduced by a lesser magnitude (IRRs: .46 and .42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced, and density of colonization and pneumococcal serotype distributions were similar to previous years. The decline in pneumococcus-associated disease was temporally associated with a full suppression of respiratory syncytial virus, influenza viruses, and human metapneumovirus, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. CONCLUSIONS: Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic in Israel were not predominantly related to reduced pneumococcal carriage and density but were strongly associated with the disappearance of specific respiratory viruses.

Disproportionate reduction in respiratory vs. non-respiratory outpatient clinic visits and antibiotic use in children during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic led to improved hygiene and reduced social encounters. Near elimination of the activity of respiratory syncytial virus and influenza viruses were observed, worldwide. Therefore, we assessed the rates of pediatric outpatient clinic visits and medications prescribed at those visits during the coronavirus disease 2019 (COVID-19) pandemic and pre-COVID-19 period (2016-2019). METHODS: Monthly and annual incidence rates for respiratory and non-respiratory diagnoses and dispensed prescription rates were calculated. Acute gastroenteritis (AGE) visits were analyzed separately since the mode of transmission is influenced by hygiene and social distancing. RESULTS: Overall, 5,588,702 visits were recorded. Respiratory and AGE visits declined by 49.9% and 47.3% comparing the COVID-19 and pre-COVID-19 periods. The respective rate reductions for urinary tract infections, trauma, and skin and soft tissue infections were 18.2%, 19.9%, and 21.8%. Epilepsy visits increased by 8.2%. Overall visits rates declined by 21.6%. Dispensed prescription rates of antibiotics and non-antibiotics respiratory medications declined by 49.3% and 44.4%, respectively. The respective declines for non-respiratory antibiotics and non-antibiotics were 15.1% and 0.2%. Clinic visits and prescription rates reductions were highest in April-May, following the first lockdown in Israel. CONCLUSIONS: COVID-19 pandemic resulted in a substantial reduction in respiratory outpatient clinic visits and dispensed respiratory drugs, with only a mild reduction seen for non-respiratory visits. These trends were probably driven by COVID-19 mitigation measures and by the profound disruption to non-SARS COV-2 respiratory virus activity.

Unraveling the Impact of Pneumococcal Conjugate Vaccines on Ambulatory Antibiotic Drug Consumption in Young Children: An Interrupted Time-Series Analysis.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) reduce respiratory infections in young children, the main antibiotic consumers. Following PCV implementation, dispensed antibiotic prescription (DAP) rates in young children were expected to decline. METHODS: Computerized data on DAP for children <5 years were examined during a 13-year period (including 4 pre-PCV years). All DAPs from clinics with ≥50 insured children, active both pre- and post-PCV implementation were included. Interrupted time-series with segmented regression was applied to analyze monthly DAP rate trends, adjusted for age, ethnicity, and season. Incidence rate ratios (IRRs) of DAPs during the late PCV13 period versus 4 years pre-PCV were calculated both as absolute rate ratios (aIRRs) and relative to expected rates (rIRRs). RESULTS: Of 1 090 870 DAPs, 57% were in children <2 years. All-DAP rates peaked in the cold season. Post-PCV7/PCV13 implementation, all DAP rates abruptly and significantly declined, reaching a plateau within 5 years. This was largely driven by amoxicillin/amoxicillin-clavulanate (75% of DAPs). Age <2 years and Bedouin ethnicity were significantly associated with higher pre-PCV DAP rates but with faster and greater decline post-PCV, achieving near elimination of gaps between ages and ethnic groups. Overall reduction (95% CIs) in DAP rates per 1000 was estimated between aIRR (344.7 [370.9-358.4]) and rIRR (110.4 [96.9-123.7]) values. CONCLUSIONS: Shortly following PCV implementation, overall DAP rates showed an abrupt, steep decline, stabilizing within 5 years, in parallel to post-PCV respiratory infection trends previously described in this population, suggesting causality. The variable patterns of certain drug categories suggest additional influences beyond PCV.

Understanding the Evolution of Antibiotic-nonsusceptible Pneumococcal Nasopharyngeal Colonization Following Pneumococcal Conjugate Vaccine Implementation in Young Children.

BACKGROUND: Four main processes determine pneumococcal conjugate vaccine (PCV) antibiotic-nonsusceptible Streptococcus pneumoniae (ANSP) carriage: reduction of PCV serotypes, increase of non-PCV serotypes, potential overall reduction in carriage, and within-serotype nonsusceptibility resulting from continuous antibiotic pressure. The post-PCV implementation dynamics of these components were examined in young children from 2 distinct ethnic populations: Jewish and Bedouin. METHODS: We performed ongoing, prospective, population-based, active surveillance initiated at the time of 7- and 13-valent PCVs (PCV7; PCV13) implementation. Nasopharyngeal cultures for S. pneumoniae were obtained daily from children aged <5 years who visited the only pediatric emergency room in the district during a 6-year period (2009 to 2015). RESULTS: Of 8446 nasopharyngeal samples, 48.3% were positive (42.0% and 52.8% for Jewish and Bedouin children, respectively; P < .001). Nonsusceptibility was significantly more frequent among PCV serotypes than among non-PCV serotypes and among Bedouin children than among Jewish children. PCV serotype carriage declined by 80%, while that of non-PCV serotypes increased by 140%. The overall (all serotypes) pneumococcal carriage significantly declined (33% and 11% in Bedouin and Jewish children, respectively). Among non-PCV isolates, the proportion of ANSP significantly increased with time in both populations. As a summation of all 4 processes, ANSP carriage significantly decreased among both Bedouin and Jewish children. CONCLUSIONS: PCV impact on ANSP nasopharyngeal carriage is a dynamic, multicomponent process, highly dependent on antibiotic consumption in the community, which may result in a continuous increase in antibiotic resistance in the replacing serotypes.

Hodgkin's lymphoma, nephrotic syndrome, and echinococcosis cysts: an unusual association and literature review.

We present a 5-year-old female with minimal change nephrotic syndrome (MCNS). Within several months, she became steroid-dependent with progression of edema and ascites. Imaging studies revealed abnormal solid mass and liver cysts and she was diagnosed with both abdominal Hodgkin's lymphoma (cHD) and large hepatic cystic echinococcosis (CE). Association between MCNS and cHL or with CE has been described in the literature in adults and rarely in the pediatric population. We report, for the first time, a simultaneous occurrence of all three: MCNS, cHL, and CE. Literature review and suggested pathophysiologic mechanisms underlying this phenomenon are presented.

Mechanism of Hyponatremia in Community-Acquired Pneumonia: Does B-type Natriuretic Peptide Play a Causative Role?

OBJECTIVE: Hyponatremia is a well-known sequela of community-acquired pneumonia (CAP). B-type natriuretic peptide (BNP) has a natriuretic effect and was found to be elevated in patients with CAP. We investigated whether BNP has a role in the pathophysiology of hyponatremia in pediatric CAP. METHODS: Serum and urine electrolytes and osmolality, as well as NT-pro-BNP (N-BNP), were obtained in 49 hospitalized pediatric patients with CAP (29 with hyponatremia, 20 with normal sodium levels. RESULTS: Urine sodium levels were lower in the hyponatremic group compared with the normonatremic group (24.3 meq/L vs 66.7 meq/L, P = 0.006). No difference in N-BNP levels was found between groups (median, 103.8 vs 100.1; P = 0.06; interquartile range, 63.7-263.3 pg/mL vs 47.4-146.4 pg/mL). N-BNP was not associated with serum or urinary sodium levels. CONCLUSIONS: These results indicate that BNP is unlikely to play a causative role in the mechanism of hyponatremia in CAP.

Severe Allergic Contact Dermatitis From Temporary "Black Henna" Coloring of the Hair During Religious Cultural Celebrations: Three Different Cases, Same History.

Contact dermatitis after the application of temporary, paint-on, henna tattoos represents a well-known, potentially serious problem of active sensitization. We describe 3 cases involving 3 children of the same age who developed a severe contact dermatitis with massive face and neck swelling after application of black henna to their hair during "Purim" celebrations. All 3 cases had a history of having applied henna tattoos in the previous year with mild local reactions. Their reactions are presumed to be due to sensitization to para-phenylenediamine. Although reactions to henna are being increasingly reported, reactions of this severity seem to be rare and could lead to permanent skin changes.

Does extreme leukocytosis predict serious bacterial infections in infants in the post-pneumococcal vaccine era? The experience of a large, tertiary care pediatric hospital.

BACKGROUND: Extreme leukocytosis, defined as a peripheral white blood cell count greater than 25,000/mm, may alarm clinicians and prompt extensive evaluation in infants with fever, especially in the pediatric emergency department. METHODS: We reviewed data from children aged 3 to 36 months with extreme leukocytosis, fever and the risk of serious bacterial infections (SBI) at our institution from July 2010 to December 2012, a period after the universal introduction of pneumococcal vaccine. RESULTS: Serious bacterial infection was recorded in 57 (39%) of the 147 infants. The most common SBI were segmental or lobar pneumonia, in 28 (19%) patients, and urinary tract infection in 16 (10.9%) patients. Three patients had positive blood cultures, corresponding to a bacteremia rate of 2%. C-reactive protein was significantly higher in the SBI group than in the non-SBI group. CONCLUSIONS: All well-looking febrile infants with white blood cell greater than 25,000/mm should undergo a chest radiograph unless there are clear physical findings that indicate a different etiology. Urine culture should be considered in women. C-reactive protein can have an added value in the differential diagnosis.

Seizures caused by ingestion of Atropa belladonna in a homeopathic medicine in a previously well infant: case report and review of the literature.

Atropa belladonna is a poisonous plant that can cause anticholinergic effects when ingested. Roots, leaves, and fruits of the plant contain the alkaloids atropine, hyoscyamine, and scopolamine, which can lead to an anticholinergic toxidrome; however, not all characteristics of the toxidrome are necessarily present in each case of poisoning. We present an infant who suffered serious seizures after ingestion of a homeopathic agent containing A. belladonna. The 20-day-old infant arrived at the emergency department with fever and generalized seizures for 30 minutes, 2 hours after ingesting the correct dose of a homeopathic medication agent used for infantile colic. The patient was treated with intravenous benzodiazepines and antibiotics after a full sepsis work up; all the laboratory results were normal and the fever resolved after several hours. The infant recovered fully with normal neurological function and a normal electroencephalogram. This infant probably manifested what is known as the central anticholinergic syndrome. We discuss his presentation and review of the literature on this topic.

Diurnal rhythms in varicella vaccine effectiveness.

BACKGROUNDImmune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time of day and vaccine effectiveness.METHODSA national cohort, children younger than 6 years, were enrolled between January 2002 and December 2023. We compared children vaccinated during morning (7:00-10:59), late morning to afternoon (11:00-15:59), or evening hours (16:00-19:59). A Cox proportional hazards regression model was used to adjust for ethnicity, sex, and comorbidities. The first varicella infection occurring at least 14 days after vaccination and a second dose administration were treated as terminal events.RESULTSOf 251,141 vaccinated children, 4,501 (1.8%) experienced breakthrough infections. Infection rates differed based on vaccination time, with the lowest rates associated with late morning to afternoon (11:00-15:59), HR 0.88, 95% CI 0.82-0.95, P < 0.001, and the highest rates with evening vaccination (16:00-19:59), HR 1.41, 95% CI 1.32-1.52, P < 0.001. Vaccination timing remained significant after adjustment for ethnicity, sex, and comorbidities. The association between immunization time and infection risk followed a sinusoidal pattern, consistent with a diurnal rhythm in vaccine effectiveness.CONCLUSIONWe report a significant association between the time of varicella vaccination and its clinical effectiveness. Similar association was observed with the COVID-19 vaccine, providing proof of concept consistent with a diurnal rhythm in vaccine effectiveness.