Distinguishing features of long COVID identified through immune profiling.

Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.

Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity.

The emergence of SARS-CoV-2 variants with mutations in major neutralizing antibody-binding sites can affect humoral immunity induced by infection or vaccination1-6. Here we analysed the development of anti-SARS-CoV-2 antibody and T cell responses in individuals who were previously infected (recovered) or uninfected (naive) and received mRNA vaccines to SARS-CoV-2. While individuals who were previously infected sustained higher antibody titres than individuals who were uninfected post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (for example, B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (for example, B.1.617.2). While both groups retained neutralization capacity against all variants, plasma from individuals who were previously infected and vaccinated displayed overall better neutralization capacity than plasma from individuals who were uninfected and also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the effect of emerging variants on antibody neutralizing activity.

Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age.

BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination.

The impact of Coronavirus Disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated 2 of the most widely propagated claims to determine (1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities; and (2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from these murine pregnancies vaccinated prior to the formation of the definitive placenta exhibit high circulating levels of anti-spike and anti-receptor-binding domain (anti-RBD) antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) consistent with maternal antibody status, indicating transplacental transfer in the later stages of pregnancy after early immunization. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.

Lack of association between pandemic chilblains and SARS-CoV-2 infection.

An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.

Safety and Immunogenicity of a Delayed Heterologous Avian Influenza A(H7N9) Vaccine Boost Following Different Priming Regimens: A Randomized Clinical Trial.

BACKGROUND: Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown. METHODS: We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 × 2 group), MIV with AS03 (AS03 × 2 group), unadjuvanted MIV (No Adj group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 group), and A/H7-naive (unprimed group). Participants were randomized to receive 1 dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing antibody assays. RESULTS: We enrolled 304 participants: 153 received the adjuvanted boost and 151 received the unadjuvanted boost. At 21 days postvaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of ≥40 in the adjuvanted and unadjuvanted arms, respectively, were 88% and 49% in MF59 × 2 group, 89% and 75% in AS03 × 2 group, 59% and 20% in No Adj group, 94% and 55% in Adjx1group, and 9% and 11% in unprimed group. CONCLUSIONS: Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens. CLINICAL TRIALS REGISTRATION: NCT03738241.

A Phase 1, Double-blinded, Placebo-Controlled Clinical Trial to Evaluate the Safety and Immunogenicity of HEV-239 (Hecolin®) Vaccine in Healthy US Adults.

INTRODUCTION: Establishing the safety and immunogenicity of a hepatitis E virus vaccine in multiple populations could facilitate broader access and prevent maternal and infant mortality. METHODS: We conducted a phase 1, randomized, double-blinded, placebo-controlled (4:1 vaccine: placebo) trial of 30 µg HEV-239 (Hecolin®, Xiamen Innovax Biotech Company Limited, China) administered intramuscularly in healthy US adults aged 18-45 years. Participants were vaccinated on days 1, 29, and 180. Participants reported solicited local and systemic reactions for 7 days following vaccination and were followed through 12 months after enrollment for safety and immunogenicity (IgG, IgM). RESULTS: Solicited local and systemic reactions between treatment and placebo group were similar and overall mild. No participants experienced serious adverse events related to HEV-239. All participants receiving HEV-239 seroconverted at one month following the first dose and remained seropositive throughout the study. HEV-239 elicited a robust hepatitis E IgG response that peaked one month following the second dose (Geometric Mean Concentration (GMC) 6.16; 95% CI 4.40-8.63), was boosted with the third dose (GMC 11.50; 95% CI 7.90-16.75) and persisted through 6 months. CONCLUSIONS: HEV-239 is safe and elicits a durable immune response through at least 6 months after the third dose in healthy US adults. CLINICAL TRIALS REGISTRATION: NCT03827395. Safety Study of Hepatitis E Vaccine (HEV239) - Full Text View - ClinicalTrials.gov.

Influenza Vaccine Effectiveness Pre-pandemic Among Adults Hospitalized With Congestive Heart Failure or Chronic Obstructive Pulmonary Disease and Older Adults.

BACKGROUND: Data are limited on influenza vaccine effectiveness (VE) in the prevention of influenza-related hospitalizations in older adults and those with underlying high-risk comorbidities. METHODS: We conducted a prospective, test-negative, case-control study at 2 US hospitals from October 2018-March 2020 among adults aged ≥50 years hospitalized with acute respiratory illnesses (ARIs) and adults ≥18 years admitted with congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) exacerbations. Adults were eligible if they resided in 1 of 8 counties in metropolitan Atlanta, Georgia. Nasopharyngeal and oropharyngeal swabs were tested using BioFire FilmArray (bioMérieux, Inc.) respiratory panel, and standard-of-care molecular results were included when available. Influenza vaccination history was determined from the Georgia vaccine registry and medical records. We used multivariable logistic regression to control for potential confounders and to determine 95% confidence intervals (CIs). RESULTS: Among 3090 eligible adults, 1562 (50.6%) were enrolled. Of the 1515 with influenza vaccination history available, 701 (46.2%) had received vaccination during that season. Influenza was identified in 37 (5.3%) vaccinated versus 78 (9.6%) unvaccinated participants. After adjustment for age, race/ethnicity, immunosuppression, month, and season, pooled VE for any influenza-related hospitalization in the eligible study population was 63.1% (95% CI, 43.8-75.8%). Adjusted VE against influenza-related hospitalization for ARI in adults ≥50 years was 55.9% (29.9-72.3%) and adjusted VE against influenza-related CHF/COPD exacerbation in adults ≥18 years was 80.3% (36.3-93.9%). CONCLUSIONS: Influenza vaccination was effective in preventing influenza-related hospitalizations in adults aged ≥50 years and those with CHF/COPD exacerbations during the 2018-2020 seasons.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

BK polyomavirus DNAemia, allograft rejection, and de novo donor-specific antibodies after lowering target tacrolimus levels in pediatric kidney transplant recipients.

BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.

Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight-based dosed valganciclovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality in solid organ transplant recipients (SOTR). Valganciclovir (VGC) is extensively used for prophylaxis. Optimal dosing in children, risk factors for failure, and the impact of dose adjustments on CMV DNAemia is not well established. METHODS: This retrospective cohort study of pediatric SOTR transplanted between 2010-2018 evaluated the epidemiology of CMV DNAemia and used Cox-regression to assess the risk factors for CMV DNAemia within one-year following SOTR. RESULTS: In 393 pediatric SOTR (heart [96, 24.4%], kidney [180, 45.6%], liver [117, 29.8%]; median age 9.5 ± 0.3 years), overall CMV DNAemia incidence was 6.6/10 000 days (95%CI 5.1/10 000-7.9/10 000) and varied by organ groups: heart 8.2/10 000 days (95%CI 4.9/10 000-11.4/10 000), kidney 5.8/10 000 days (95%CI 3.9/10 000-7.8/10 000), liver 6.2/10 000 days (95%CI 3.7/10 000-8.7/10 000). CMV DNAemia was detected in 75 of 275 (27.2%) patients who received prophylaxis (40 cases occurred during prophylaxis and 35 occurred after completion of prophylaxis). The median VGC dose given according to institutional weight-based algorithm was approximately 1.5-fold lower than the manufacturer-recommended dose. This discordance was more prominent at younger age groups (3.2-fold lower in <2-year-old [100 mg versus 325 mg], 2.5-fold lower in <6-year-old [200 mg versus 447 mg]). Dose reduction due to adverse events was an independent risk factor for breakthrough CMV DNAemia (hazard ratio 2.2, 95%CI 1.2-3.8) among patients with similar age, CMV risk stratification, starting VGC dose, immunosuppressive therapy, and organ group. CONCLUSION: CMV events occurred while on VGC prophylaxis. Weight-based VGC may prevent supratherapeutic VGC exposure especially in younger children. Dose reduction of VGC prophylaxis for adverse event management places patients at an increased risk for CMV DNAemia suggesting other agents with fewer adverse effects should be considered and need to be studied in children.

Vaccination in pediatric solid organ transplant: A primer for the immunizing clinician.

Pediatric solid organ transplant (SOT) recipients are at a uniquely elevated risk for vaccine preventable illness (VPI) secondary to a multitude of factors including incomplete immunization at the time of transplant, inadequate response to vaccines with immunosuppression, waning antibody titers observed post-SOT, and uncertainty among providers on the correct immunization schedule to utilize post-SOT. Multiple guidelines are in existence from the Infectious Diseases Society of America and the American Society of Transplantation, which require use in adjunct with additional published references. We summarize the present state of SOT vaccine recommendations from relevant resources in tandem with the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices guidance utilizing both routine and rapid catch-up schedules. The purpose of this all-inclusive review is to provide improved clarity on the most optimal pre- and post-transplant vaccine management within a one-stop-shop for the immunizing clinician.

Risk of Disseminated Gonococcal Infections With Terminal Complement Blockade.

Paroxysmal nocturnal hemoglobinuria is a clonal hematopoietic stem cell disorder resulting in complement-mediated hemolysis. Eculizumab, a monoclonal antibody against complement protein C5, has been shown to reduce both intravascular hemolysis and risk for thrombosis, and thereby improve the quality of life in these patients. While the infection risk from Neisseria meningitidis due to terminal complement blockade can be mitigated with appropriate immunizations and prophylactic antibiotics, these patients remain vulnerable to infections from Neisseria gonorrhoeae. Physicians and families should be aware of disseminated and severe gonococcal infections in patients receiving complement blockade, especially in this era of emerging cephalosporin and azithromycin resistance.

Prevalence of Chronic Diseases, Depression, and Stress Among US Childcare Professionals During the COVID-19 Pandemic.

INTRODUCTION: Given their central role in supporting children's development, childcare professionals' overall physical and mental health is important. We evaluated the prevalence of chronic diseases, depression, and stress levels during the COVID-19 pandemic among US childcare professionals. METHODS: Data were obtained from US childcare professionals (N = 81,682) through an online survey from May 22, 2020, through June 8, 2020. We used multivariable logistic and linear regression models to assess the association of sociodemographic characteristics with 4 physical health conditions (asthma, heart disease, diabetes, and obesity), depression, and stress weighted to national representativeness. RESULTS: For physical health conditions, 14.3% (n = 11,717) reported moderate to severe asthma, 6.5% (n = 5,317) diabetes, 4.9% (n = 3,971) heart disease, and 19.8% (n = 16,207) obesity. For mental health, 45.7% (n = 37,376) screened positive for depression and 66.5% (n = 54,381) reported moderate to high stress levels. Race, ethnicity, and sex/gender disparities were found for physical health conditions but not mental health of childcare professionals during the COVID-19 pandemic. CONCLUSION: Our findings highlighted that childcare professionals' depression rates during the pandemic were higher than before the pandemic, and depression, stress, and asthma rates were higher than rates among US adults overall during the pandemic. Given the essential work childcare professionals provided during the pandemic, policy makers and public health officials should consider what can be done to support their physical and mental health.

Recognition and Outcomes of Pneumococcal Meningitis in 2 Tertiary Pediatric Hospitals Since the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine.

OBJECTIVES: The aims of the study were to analyze the demographics, presentation, laboratory findings, and complications of pediatric Streptococcus pneumoniae meningitis since the introduction of the 13-valent pneumococcal conjugate vaccine, to improve recognition, and to minimize patient morbidity and mortality. METHODS: This study used a retrospective analysis of pediatric pneumococcal meningitis cases at 2 tertiary healthcare systems in the Southeastern United States from 2010 to 2018. RESULTS: We describe 21 cases of pneumococcal meningitis. All patients presented with fever, 95% had altered mental status by history or examination, and 48% had meningeal signs. Forty-three percent had seen another provider within 48 hours of admission. Forty-eight percent had delay in lumbar puncture (LP) of more than 6 hours after antibiotic administration, decreasing rates of positive cerebrospinal fluid cultures from 100% to 40% (P < 0.001). Decision to delay LP was due to either low suspicion for meningitis (n = 4) or clinical instability (n = 6) and was associated with lower rates of meningeal signs (P = 0.014) and higher rates of altered mental status on examination (P = 0.031). Fourteen patients (67%) were up-to-date on pneumococcal immunization. Serotypes were determined in 16 cases, with 2 patients (13%) immunized against the strain that infected them. Primary outcomes included seizures (48%), hearing loss (48%), cranial nerve palsy (33%), and death (5%). Delay in LP with low suspicion for meningitis was associated with longer hospital length of stay approaching statistical significance (P = 0.053). CONCLUSIONS: Pneumococcal meningitis remains a relevant and potentially fatal disease despite widespread use of 13-valent pneumococcal conjugate vaccine. Its diagnosis is often delayed during interactions with physicians, which may put patients at increased risk for poor clinical outcomes.

Respiratory Syncytial Virus-Associated Mortality Among Young Infants in Karachi, Pakistan: A Prospective Postmortem Surveillance Study.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of infant morbidity and mortality and a potential target for maternal immunization strategies. However, data on the role of RSV in young infant deaths in developing countries are limited. METHODS: We conducted a community-based mortality surveillance from August 2018-March 2020 for infants ≤6 months in Karachi, Pakistan. We tested (reverse transcription-polymerase chain reaction) nasopharyngeal swabs from deceased infants for presence of RSV. We performed verbal autopsies and calculated odds of RSV-associated mortality with 95% CIs and used multivariable logistic regression to evaluate associations. RESULTS: We collected 490 nasopharyngeal specimens from 1280 eligible infant deaths. There were 377/490 (76.9%) live births and 14/377 (3.7%; 95% CI: 1.8-5.6) were RSV positive. Most deaths occurred in neonates (254/377; 67.4%), males (226/377; 59.9%), and respiratory illnesses (206/377; 54.6%). Postneonatal age (10/14, 71.4%; OR: 5.5; 95% CI: 1.7-18.0), respiratory symptoms (12/14, 85.7%; OR: 5.2; 1.2-23.7), and high RSV season (9/14, 64.3%; OR: 4.4; 1.4-13.3) were associated with RSV mortality. In multivariable logistic regression analysis, respiratory symptoms (OR: 6.6; 95% CI: 1.3-32.5), RSV seasonality (6.1; 1.8-20.4), and age (9.2; 2.6-33.1) were significant predictors of RSV-associated mortality. CONCLUSIONS: RSV has a significant mortality burden in early infancy in Karachi, Pakistan. Age, RSV seasonality, and respiratory symptoms were significant predictors of RSV-associated mortality. Our findings have implications for clinical management of young infants with cold-like symptoms, policy development, and research regarding maternal immunization against RSV during pregnancy, in resource-constrained, low-income, and vaccine-hesitant populations.

A Retrospective Test-Negative Case-Control Study to Evaluate Influenza Vaccine Effectiveness in Preventing Hospitalizations in Children.

BACKGROUND: Vaccination is the primary strategy to reduce influenza burden. Influenza vaccine effectiveness (VE) can vary annually depending on circulating strains. METHODS: We used a test-negative case-control study design to estimate influenza VE against laboratory-confirmed influenza-related hospitalizations among children (aged 6 months-17 years) across 5 influenza seasons in Atlanta, Georgia, from 2012-2013 to 2016-2017. Influenza-positive cases were randomly matched to test-negative controls based on age and influenza season in a 1:1 ratio. We used logistic regression models to compare odds ratios (ORs) of vaccination in cases to controls. We calculated VE as [100% × (1 - adjusted OR)] and computed 95% confidence intervals (CIs) around the estimates. RESULTS: We identified 14 596 hospitalizations of children who were tested for influenza using the multiplex respiratory molecular panel; influenza infection was detected in 1017 (7.0%). After exclusions, we included 512 influenza-positive cases and 512 influenza-negative controls. The median age was 5.9 years (interquartile range, 2.7-10.3), 497 (48.5%) were female, 567 (55.4%) were non-Hispanic Black, and 654 (63.9%) children were unvaccinated. Influenza A accounted for 370 (72.3%) of 512 cases and predominated during all 5 seasons. The adjusted VE against influenza-related hospitalizations during 2012-2013 to 2016-2017 was 51.3% (95% CI, 34.8% to 63.6%) and varied by season. Influenza VE was 54.7% (95% CI, 37.4% to 67.3%) for influenza A and 37.1% (95% CI, 2.3% to 59.5%) for influenza B. CONCLUSIONS: Influenza vaccination decreased the risk of influenza-related pediatric hospitalizations by >50% across 5 influenza seasons.

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Clinical Epidemiology and Outcomes of Pediatric Musculoskeletal Infections.

OBJECTIVES: To understand the epidemiology of acute hematogenous osteomyelitis and septic arthritis, including clinical and demographic features, microbiology, treatment approaches, treatment-associated complications, and outcomes. STUDY DESIGN: Retrospective cohort study of 453 children with acute hematogenous osteomyelitis and/or septic arthritis from 2009 to 2015. RESULTS: Among the 453 patients, 218 (48%) had acute hematogenous osteomyelitis, 132 (29%) had septic arthritis, and 103 (23%) had concurrent acute hematogenous osteomyelitis/septic arthritis. Treatment failure/recurrent infection occurred in 41 patients (9%). Patients with concurrent acute hematogenous osteomyelitis/septic arthritis had longer hospital stays, longer duration of antibiotic therapy, and were more likely to have prolonged bacteremia and require intensive care. Staphylococcus aureus was identified in 228 (51%) patients, of which 114 (50%) were methicillin-resistant S aureus. Compared with septic arthritis, acute hematogenous osteomyelitis and concurrent acute hematogenous osteomyelitis/septic arthritis were associated with higher odds of treatment failure (OR, 8.19; 95% CI, 2.02-33.21 [P = .003]; and OR, 14.43; 95% CI, 3.39-61.37 [P < .001], respectively). The need for more than 1 surgical procedure was also associated with higher odds of treatment failure (OR, 2.98; 95% CI, 1.18-7.52; P = .021). Early change to oral antibiotic therapy was not associated with treatment failure (OR, 0.64; 95% CI, 0.24-1.74; P = .386). Most (73%) medically attended treatment complications occurred while on parenteral therapy. CONCLUSIONS: Musculoskeletal infections are challenging pediatric infections. S aureus remains the most common pathogen, with methicillin-resistant S aureus accounting for 25% of all cases. Concurrent acute hematogenous osteomyelitis/septic arthritis is associated with more severe disease and worse outcomes. Fewer treatment-related complications occurred while on oral therapy. Early transition to oral therapy was not associated with treatment failure.

The burden of respiratory syncytial virus infections among children with sickle cell disease.

BACKGROUND: Although respiratory syncytial virus (RSV) is the leading cause of pediatric lower respiratory tract infections, the burden of RSV in children with sickle cell disease (SCD) is unknown. METHODS: We conducted a retrospective, nested, case-control study of children with SCD <18 years who had respiratory viral panels (RVPs) performed at Children's Healthcare of Atlanta from 2012 to 2019. We abstracted the medical records to describe the demographics, clinical features, and outcomes of children who tested positive for RSV (cases) versus children who tested negative (controls). We calculated the annual incidence of RSV and related hospitalization rates with 95% confidence intervals (CIs) and used multivariate logistic regression to evaluate associations. RESULTS: We identified 3676 RVP tests performed on 2636 patients over seven respiratory seasons resulting in 219/3676 (6.0%) RSV-positive tests among 160/2636 (6.1%) patients. The average annual incidence of laboratory-confirmed RSV infection among children with SCD was 34.3 (95% CI 18.7-49.8) and 3.8 (95% CI 0.5-7.0) cases per 1000 person-years for those <5 years and 5-18 years, respectively. The RSV-related hospitalization rate for children <5 years was 20.7 (95% CI 8.5-32.8) per 1000 person-years. RSV-positive cases were significantly younger than RSV-negative patients (3.8 years vs 7.6 years, P < .001). Of RSV-positive cases, 22 (13.8%) developed acute chest syndrome and nine (5.6%) required intensive care, which was not significantly different from RSV-negative children with SCD. CONCLUSION: RSV infections are common in children with SCD with higher burden in younger patients. RSV is associated with considerable morbidity, including higher rates of hospitalization compared to the general population.