The response of the Military Health System (MHS) to the COVID-19 pandemic: a summary of findings from MHS reviews.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused major disruptions to the US Military Health System (MHS). In this study, we evaluated the MHS response to the pandemic to understand the impact of the pandemic response in a large, national, integrated healthcare system providing care for ~ 9 million beneficiaries. METHODS: We performed a narrative literature review of 16 internal Department of Defense (DoD) reports, including reviews mandated by the US Congress in response to the pandemic. We categorized the findings using the Doctrine, Organization, Training, Materiel, Leadership, Personnel, Facilities, and Policy (DOTMLPF-P) framework developed by the DoD to assess system efficiency and effectiveness. RESULTS: The majority of the findings were in the policy, organization, and personnel categories. Key findings showed that the MHS structure to address surge situations was beneficial during the pandemic response, and the rapid growth of telehealth created the potential impact for improved access to routine and specialized care. However, organizational transition contributed to miscommunication and uneven implementation of policies; disruptions affected clinical training, upskilling, and the supply chain; and staffing shortages contributed to burnout among healthcare workers. CONCLUSION: Given its highly integrated, vertical structure, the MHS was in a better position than many civilian healthcare networks to respond efficiently to the pandemic. However, similar to the US civilian sector, the MHS also experienced delays in care, staffing and materiel challenges, and a rapid switch to telehealth. Lessons regarding the importance of communication and preparation for future public health emergency responses are relevant to civilian healthcare systems responding to COVID-19 and other similar public health crises.

Filling the Gaps in the Pandemic Response: Impact of COVID-19 on Telehealth in the Military Health System.

Introduction: As a result of the COVID-19 pandemic, telehealth use became widespread, allowing for continued health care while minimizing COVID-19 transmission risk for patients and providers. This rapid scale-up highlighted shortcomings of the current telehealth infrastructure in many health systems. We aimed to identify and address gaps in the United States Military Health System (MHS) response to the COVID-19 pandemic related to the implementation and utilization of telehealth. Methods: We conducted semistructured key informant interviews of MHS stakeholders, including policymakers, program managers, and health care providers. We recruited respondents using purposive and snowball sampling until we reached thematic saturation. Interviews were conducted virtually from December 2022 to March 2023 and coded by deductive thematic analysis using NVivo. Results: We interviewed 28 key informants. Several themes emerged from the interviews and were categorized into four defined areas of obstacles to the effective utilization of telehealth: administrative, technical, organizational, and quality issues. While respondents had positive perceptions of telehealth, issues such as billing, licensure portability, network connectivity and technology, and ability to monitor health outcomes represent major barriers in the current system, preventing the potential for further expansion. Conclusions: While the shift to telehealth during the COVID-19 pandemic demonstrated robust potential within the MHS, it highlighted shortcomings that impair the utility and expansion of telehealth on a level comparable to that of other large health systems. Future focus should be directed toward generating and implementing actionable recommendations that target these identified challenges in the MHS.

Evaluating SARS-CoV-2 Saliva and Dried Blood Spot Surveillance Strategies in a Congregate Population.

The optimal approach to COVID-19 surveillance in congregate populations remains unclear. Our study at the US Naval Academy in Annapolis, Maryland, USA, assessed the concordance of antibody prevalence in longitudinally collected dried blood spots and saliva in a setting of frequent PCR-based testing. Our findings highlight the utility of salivary-based surveillance.

Comparison of A(H3N2) Neutralizing Antibody Responses Elicited by 2018-2019 Season Quadrivalent Influenza Vaccines Derived from Eggs, Cells, and Recombinant Hemagglutinin.

BACKGROUND: Low vaccine effectiveness against A(H3N2) influenza in seasons with little antigenic drift has been attributed to substitutions in hemagglutinin (HA) acquired during vaccine virus propagation in eggs. Clinical trials comparing recombinant HA vaccine (rHA) and cell-derived inactivated influenza vaccine (IIV) to egg-derived IIVs provide opportunities to assess how egg-adaptive substitutions influence HA immunogenicity. METHODS: Neutralization titers in pre- and postimmunization sera from 133 adults immunized with 1 of 3 types of influenza vaccines in a randomized, open-label trial during the 2018-2019 influenza season were measured against egg- and cell-derived A/Singapore/INFIMH-16-0019/2016-like and circulating A(H3N2) influenza viruses using HA pseudoviruses. RESULTS: All vaccines elicited neutralizing antibodies to all H3 vaccine antigens, but the rHA vaccine elicited the highest titers and seroconversion rates against all strains tested. Egg- and cell-derived IIVs elicited responses similar to each other. Preimmunization titers against H3 HA pseudoviruses containing egg-adaptive substitutions T160K and L194P were high, but lower against H3 HA pseudoviruses without those substitutions. All vaccines boosted neutralization titers against HA pseudoviruses with egg-adaptive substitutions, but poorly neutralized wild-type 2019-2020 A/Kansas/14/2017 (H3N2) HA pseudoviruses. CONCLUSION: Egg- and cell-derived 2018-2019 season influenza vaccines elicited similar neutralization titers and response rates, indicating that the cell-derived vaccine did not improve immunogenicity against the A(H3N2) viruses. The higher responses after rHA vaccination may be due to its higher HA content. All vaccines boosted titers to HA with egg-adaptive substitutions, suggesting boosting from past antigens or better exposure of HA epitopes. Studies comparing immunogenicity and effectiveness of different influenza vaccines across many seasons are needed.

Malaria exacerbates inflammation-associated elevation in ferritin and soluble transferrin receptor with only modest effects on iron deficiency and iron deficiency anaemia among rural Zambian children.

OBJECTIVE: In 4- to 8-year-old Zambian children (n = 744), we evaluated the effects of adjusting for inflammation (α1-acid glycoprotein >1 g/l), with or without additional adjustment for malaria, on prevalence estimates of iron deficiency (ID) and iron deficiency anaemia (IDA) during low malaria (LowM) and high malaria (HighM) transmission seasons. METHODS: To estimate adjustment factors, children were classified as: (i) reference (malaria negative without inflammation), (ii) inflammation without malaria (I), (iii) malaria without inflammation (M) and (iv) inflammation with malaria (IM). We estimated the unadjusted ID or IDA prevalence, and then adjusted for inflammation alone (IDI or IDAI ) or inflammation and malaria (IDIM or IDAIM ). RESULTS: Mean ferritin was 38 (reference), 45 (I), 43 (M) and 54 µg/l (IM) in LowM, increasing to 44, 56, 96 and 167 µg/l, respectively, in HighM. Corresponding mean sTfR was 6.4, 6.9, 7.9 and 8.4 mg/l in LowM, increasing to 8.2, 9.2. 8.7 and 9.7 mg/l in HighM. Ferritin-based ID, IDI and IDIM were 7.8%, 8.7% or 9.1%, respectively, in LowM and 4.6%, 10.0% or 11.7%, respectively, in HighM. Corresponding soluble transferrin receptor (sTfR)-based estimates were 27.0%, 24.1% and 19.1%, respectively, in LowM, increasing to 53.6%, 46.5% and 45.3%, respectively, in HighM. Additional adjustment for malaria resulted in a ~1- to 2-percentage point change in IDA, depending on biomarker and season. CONCLUSIONS: In this population, malaria substantially increased ferritin and sTfR concentrations, with modest effects on ID and IDA prevalence estimates.

High Iron Stores in the Low Malaria Season Increase Malaria Risk in the High Transmission Season in a Prospective Cohort of Rural Zambian Children.

Background: Higher iron stores, defined by serum ferritin (SF) concentration, may increase malaria risk.Objective: We evaluated the association between SF assessed during low malaria season and the risk of malaria during high malaria season, controlling for inflammation.Methods: Data for this prospective study were collected from children aged 4-8 y (n = 745) participating in a biofortified maize efficacy trial in rural Zambia. All malaria cases were treated at baseline (September 2012). We used baseline SF and malaria status indicated by positive microscopy at endline (March 2013) to define exposure and outcome, respectively. Iron status was defined as deficient (corrected or uncorrected SF <12 or <15 µg/L, depending on age <5 or ≥5 y, respectively), moderate (<75 µg/L, excluding deficient), or high (≥75 µg/L). We used a modified Poisson regression to model the risk of malaria in the high transmission seasons (endline) as a function of iron status assessed in the low malaria seasons (baseline).Results: We observed an age-dependent, positive dose-response association between ferritin in the low malaria season and malaria incidence during the high malaria season in younger children. In children aged <6 y (but not older children), we observed a relative increase in malaria risk in the moderate iron status [incidence rate ratio (IRR) with SF: 1.56; 95% CI: 0.64, 3.86; IRR with inflammation-corrected SF: 1.92; 95% CI: 0.75, 4.93] and high iron status (IRR with SF: 2.66; 95% CI: 1.10, 6.43; or IRR with corrected SF: 2.93; 95% CI: 1.17, 7.33) categories compared with the deficient iron status category. The relative increase in malaria risk for children with high iron status was statistically significant only among those with a concurrently normal serum soluble transferrin receptor concentration (<8.3 mg/L; IRR: 1.97; 95% CI: 1.20, 7.37).Conclusions: Iron adequacy in 4- to 8-y-old children in rural Zambia was associated with increased malaria risk. Our findings underscore the need to integrate iron interventions with malaria control programs. This trial was registered at clinicaltrials.gov as NCT01695148.

The association of medication use with clearance or persistence of oral HPV infection.

PURPOSE: Persistent oral human papillomavirus (HPV) infection increases risk for oropharyngeal carcinoma, and people living with HIV have higher rates of oral HPV infection and related cancers. Some prescription medications have immunomodulatory effects, but the impact of medication use on oral HPV natural history is unknown. METHODS: Scope® oral rinse-and-gargle samples were collected semi-annually from 1,666 participants and tested for 37 types of oral HPV DNA using PCR; 594 HPV-infected participants with 1,358 type-specific oral HPV infections were identified. Data were collected on recent (past 6 months) use of medications. The relationship between medication use and oral HPV clearance was evaluated using Wei-Lin-Weissfeld regression, adjusting for biologic sex, prevalent versus incident infection, age, HIV status and CD4+ T cell count. RESULTS: Out of 11 medications examined, oral HPV clearance was significantly reduced in participants reporting recent use of antipsychotics (HR 0.75, 95% CI 0.57-0.99), anxiolytics/sedatives (HR 0.78, 95% CI 0.63-0.96) and antidepressants (HR 0.82, 95% CI 0.67-0.999). Among antipsychotics users, effect modification by HIV status was observed, with reduced clearance in HIV-infected (HR 0.67, 95% CI 0.49-0.91), but not HIV-uninfected participants (p-interaction = 0.009). After adjusted analysis, antipsychotic use remained significantly associated with reduced oral HPV clearance overall (aHR 0.75, 95% CI 0.57-0.99), and when restricted to only HIV-infected participants (aHR 0.66, 95% CI 0.48-0.90). After adjustment, anxiolytic/sedative use and antidepressant use were no longer significantly associated with reduced oral HPV clearance. CONCLUSIONS: Some medications were associated with decreased oral HPV clearance, most notably antipsychotic medications. These medications are prescribed for conditions that may have immunomodulating effects, so characteristics of underlying illness may have partially contributed to reduced oral HPV clearance.

Association of serum cytokines with oral HPV clearance.

BACKGROUND: Initial studies suggest higher serum levels of some pro-inflammatory cytokines may be associated with decreased cervical human papillomavirus (HPV) clearance. However, the relationship of cytokines with oral HPV clearance has not been explored. METHODS: From 2010 to 2014, oral rinse and serum samples were collected semi-annually from 1601 adults. Oral rinse samples were tested for HPV DNA using PCR. Based on oral HPV results, 931 serum samples were selected for cytokine evaluation to include a roughly equal number of prevalent (n=307), incident (n=313), and no oral HPV infections (n=311). Electrochemiluminescence multiplex assays were used to determine the concentrations of IL-6, IL-8, TNF-α, IFN-γ, IL-1ß, IL-2, IL-4, IL-10, IL-12 and IL-13. The relationship between serum cytokine concentrations (categorized into quartiles) and oral HPV clearance was evaluated with Wei-Lin-Weissfeld regression models, adjusting for HPV infection type (prevalent vs. incident), age, HIV status, and CD4 T cell count. RESULTS: Higher TNF-α concentration was associated with decreased clearance in men (highest vs. lowest quartile, adjusted hazard ratio [aHR]=0.52, 95% CI=0.34-0.79) and women (aHR=0.76, 95% confidence interval [CI]=0.55-1.04), with stronger associations in men than women (p-interaction=0.049). Higher IL-2 concentration was associated with reduced clearance in men (aHR=0.69, 95% CI=0.50-0.95), but not women (p-interaction=0.058). Results were similar within CD4 T cell strata (CD4⩾500 or CD4<500 cells/µl) among HIV-infected participants. No other cytokines were associated with clearance. CONCLUSION: High serum TNF-α is associated with reduced clearance of oral HPV infection.

Mass distribution of azithromycin for trachoma control is associated with increased risk of azithromycin-resistant Streptococcus pneumoniae carriage in young children 6 months after treatment.

BACKGROUND: Emerging evidence suggests that the mass distribution of azithromycin for trachoma control (MDA) may increase circulation of macrolide resistance in bacteria associated with severe pediatric infections in treated communities. METHODS: We examined the effect of MDA on nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae among 1015 young children living in rural Tanzania. MDA with a single dose of oral azithromycin was provided in 4 of 8 communities where trachoma prevalence was ≥10%. Isolates were tested for susceptibility to azithromycin (AZM) and commonly used antibiotics by disk diffusion and Etest. We calculated the proportion of antibiotic-resistant S. pneumoniae carriage at baseline and again 1, 3, and 6 months after treatment, and at comparable intervals in the untreated villages. RESULTS: The proportion of AZM-resistant isolates was similar between groups at baseline (MDA: 35.8% vs non-MDA: 35.4%), however, this proportion was greater in the MDA group in all subsequent surveys. At 6 months, the percentage of AZM-resistant isolates was significantly higher in the MDA group (81.9% vs 46.9%, P < .001). The odds of AZM-resistant carriage was 5-fold greater in the MDA group (odds ratio, 4.95 [95% confidence interval, 3.23-7.61]). The proportion of isolates clinically resistant to AZM (minimum inhibitory concentration ≥16 µg/mL) was also significantly greater in the MDA group at 6 months (35.3% vs 12.4%, P < .006). CONCLUSIONS: Mass distribution of a single dose of oral azithromycin for trachoma was associated with increased circulation of macrolide-resistant S. pneumoniae carriage among young children in the 6 months following treatment. It is crucial that changes in antibiotic resistance patterns and their clinical significance in the treatment of severe pediatric infections be assessed in future MDA trials.

Disparities in the use of colorectal cancer screening in a universally insured population during the COVID-19 pandemic.

BACKGROUND: Despite the known efficacy of colorectal cancer (CRC) screening, the rates of individuals undergoing such testing have remained lower than target thresholds, even prior to the healthcare disruptions associated with the COVID-19 pandemic. We evaluated the impact of the COVID-19 pandemic on CRC screening within a nationally representative US population and assessed disparities in screening across racial/ethnic groups and socioeconomic (SES) strata. METHODS: We performed a retrospective cross-sectional study using all eligible TRICARE beneficiaries aged 45-64 years between FY 2018 and 2021. High-risk individuals, those with a previous or current CRC diagnosis, and/or a personal/family history of colonic polyps, were excluded. The pre-COVID-19 period (September 1, 2018-March 31, 2020) was compared to the COVID-19 period (April 1, 2020-September 30, 2021). Secondary analyses were performed, evaluating the interaction between the COVID-19 time period, race, and our proxy for socioeconomic status. RESULTS: During the study period, we identified 1,749,688 eligible individuals. Following the onset of the COVID-19 pandemic, CRC screening overall decreased from 34% in the pre-pandemic period to 30% following the onset of the pandemic (p < 0.001). This finding persisted even after adjusting for confounders in multivariable analysis (odds ratio [OR] for the pandemic timeframe: 0.79; 95% CI: 0.27, 0.31; p < 0.001). In the setting of SES, in the pandemic period, the odds of individuals from both Senior Enlisted (OR: 0.55; 95% CI: 0.54, 0.56) and Junior Enlisted sponsor ranks (OR: 0.27; 95% CI: 0.25, 0.30) were diminished as compared to Senior Officers. CONCLUSIONS AND RELEVANCE: We found a 21% reduction in the odds of CRC screening in the context of the COVID-19 pandemic. Reductions in colonoscopies and other types of screening tests were not offset by changes in the use of at-home tests such as Cologuard.

Trends in breast cancer screening during the COVID-19 pandemic within a universally insured health system in the United States, 2017-2022.

BACKGROUND: In the United States, breast cancer is the most commonly diagnosed cancer and second leading cause of cancer death in women. Early detection through mammogram screening is instrumental in reducing mortality and incidence of disease. The COVID-19 pandemic posed unprecedented challenges to the provision of care, including delays in preventive screenings. We examined trends in breast cancer screening during the COVID-19 pandemic in a universally insured national population and evaluated rates across racial groups and socioeconomic strata. METHODS: In this retrospective open cohort study, we used the Military Health System Data Repository to identify female TRICARE beneficiaries ages 40-64 at average risk for breast cancer between FY2018 and FY2022, broken down into prepandemic (September 1, 2018-February 28, 2020), early pandemic (March 1, 2020-September 30, 2020), and late pandemic periods (October 1, 2020-September 30, 2022). The primary outcome was receipt of breast cancer screening. RESULTS: Screening dropped 74% in the early pandemic period and 22% in the late pandemic period, compared with the prepandemic period. Compared with White women, Asian/Pacific Islander women were less likely to receive mammograms during the late pandemic period (0.92RR; 0.90-0.93 95%CI). American Indian/Alaska Native women remained less likely to receive screenings compared with White women during the early (0.87RR; 0.80-0.94 95% CI) and late pandemic (0.94RR, 0.91-0.98 95% CI). Black women had a higher likelihood of screenings during both the early pandemic (1.10RR; 1.08-1.12 95% CI) and late pandemic (1.12RR, 1.11-1.13 95% CI) periods compared with White women. During the early and late pandemic periods, disparities by rank persisted from prepandemic levels, with a decrease in likelihood of screenings across all sponsor ranks. CONCLUSION: Our results indicate the influence of race and socioeconomics on mammography screening during COVID-19. Targeted outreach and further evaluation of factors underpinning lower utilization in these populations are necessary to improve access to preventative services across the population.

Differential serum cytokine responses to inactivated and live attenuated seasonal influenza vaccines.

Despite vaccine efforts, influenza outbreaks pose a significant threat to global public health. There are two commercially available seasonal influenza vaccines in the United States: the trivalent inactivated vaccine (TIV), delivered parenterally, and the live attenuated influenza vaccine (LAIV), delivered intranasally. Although both vaccines are generally efficacious, the immunologic mechanisms which contribute to protective immunity are incompletely understood. Thus, we investigated the protracted effects of TIV and LAIV on serum cytokine profiles at 14 and 28 days post-vaccination (when antibody titers are peak) in healthy adults over two influenza seasons. Vaccination with TIV was associated with a small, yet significant, decrease in the levels of both IL-8 and TNF-α at 14 and 28 days post-vaccination. LAIV, however, had no impact on serum cytokine levels. Similarly, analysis of serum antibody titers indicated that TIV recipients had a significantly higher sero-response rate compared to LAIV recipients, as has been previously shown. Finally, we examined the relationship between baseline serum cytokine levels and antibody responses to TIV (LAIV recipients were excluded due to the poor sero-response rate). Interestingly, in TIV recipients pre-vaccination levels of IL-8 were higher in sero-responders compared to non-responders. Collectively, these data suggest that cytokines may influence vaccine outcomes and indicate that parenteral immunization with TIV induces a sustained, systemic cytokine response which lasts for weeks.

Pneumococcal carriage at age 2 months is associated with growth deficits at age 6 months among infants in South India.

Nasopharyngeal colonization is the first step in the pathway to Streptococcus pneumoniae (Spn) infection, a leading cause of childhood morbidity and mortality. We investigated the effect of Spn colonization at ages 2 and 4 mo on growth at age 6 mo among 389 infants living in rural South India by using data from an Spn carriage study nested within a randomized, double-blind, placebo-controlled community trial designed to evaluate the impact of newborn vitamin A supplementation on Spn carriage in the first 6 mo of life. Primary outcomes were weight, length, and anthropometric indices of nutritional status. Growth data at age 6 mo were available for 84% (389 of 464) of infants in the Spn carriage study. Carriage at age 2 mo was associated with increased odds of stunting [OR: 3.07 (95% CI: 1.29, 7.36) P = 0.012] and lower weight [ß: -266 g (95% CI: -527, -5) P = 0.045], length [ß: -1.31 cm (95% CI: -2.32, -0.31) P = 0.010], and length-for-age Z scores [ß: -0.59; (95% CI: -1.05, -0.13) P = 0.012] at age 6 mo. Spn carriage at age 4 mo did not affect growth. Carriage of invasive serotypes at age 2 mo was associated with decreases in mean weight [ß: -289 g; (95% CI: -491, -106) P = 0.002] and length [ß:-0.38 cm (95% CI: -1.49, -0.01) P = 0.047] at age 6 mo. Newborn vitamin A supplementation did not modify the association between Spn carriage and growth. Results suggest that pneumococcal carriage at age 2 mo is an independent risk factor for poor growth in young infants. Future studies need to clarify the role of Spn carriage on growth retardation in low-income countries.

Respiratory Infections Are More Common Than Healthcare Records Indicate: Results From an Anonymous Survey.

INTRODUCTION: Influenza-like illnesses (ILIs) are common in military populations and can impair mission-readiness, particularly in the current severe acute respiratory syndrome coronavirus 2 pandemic; therefore, it is important to identify potential risk factors for infection and better understand the burden of infection. MATERIALS AND METHODS: A survey was administered to military medical trainees living in a congregated setting on JBSA Fort Sam Houston, Texas, from January 2017 to February 2019. The survey included questions about ILI experience and potential ILI risk factors. RESULTS: 2,121 individuals completed the survey. Respondents had a median age of 21 years, 46% were female, 32.6% were Air Force, 33.6% were Army, and 33.8% were Navy/Marines. Among the 815 (38%) who reported an ILI during training, 40% sought health care. The primary reasons for seeking healthcare included illness severity, concern about transmission, and accessibility of healthcare. Over half (54%) of the trainees who reported an ILI said the ILI had an impact on their performance, including reduced study time, missed physical training, and missed class. Multivariate model results indicate that women and younger trainees (<30 years) were more likely to report having had an ILI (women: OR 1.58, (95% CI 1.30, 1.92); age <30 years: OR 1.58, (1.06, 2.36)). In a subset analysis, those who reported washing their hands 10+ times per day were less likely to report an ILI (OR 0.61 (0.42, 0.89)). CONCLUSIONS: ILIs are likely to be more common during training than healthcare records indicate and may result in decreased training effectiveness. Increasing access to handwashing facilities and education about the importance of handwashing to prevent the spread of disease will likely reduce the ILI burden in this population.

Breath Biomarkers of Influenza Infection.

Background: Volatile organic compounds (VOCs) are produced systemically due to varied physiological states such as oxidative stress and are excreted through the lungs. Benchtop and preliminary clinical data suggest that breath testing may be a useful diagnostic modality for viral respiratory tract infections. Methods: Patients with influenza-like illness (ILI) presenting to a single clinic in San Antonio, Texas, from 3/2017 to 3/2019 submitted a 2-minute breath sample in addition to a nasopharyngeal swab collected for polymerase chain reaction (PCR) assay for respiratory pathogens. VOCs were assayed with gas chromatography-mass spectrometry (GC-MS), and data were analyzed to identify breath VOC biomarkers that discriminated between ILI patients with and without a polymerase chain reaction (PCR) assay that was positive for influenza. Results: Demographic, clinical, PCR, and breath data were available for 237 episodes of ILI, among which 32 episodes (13.5%) were PCR positive for influenza. Twenty candidate VOCs identified patients with influenza with greater than random accuracy. A predictive algorithm using 4 candidate biomarkers identified this group with 78% accuracy (74% sensitivity, 70% specificity). Based on their mass spectra, most of these biomarkers were n-alkane derivatives, consistent with products of oxidative stress. Conclusions: A breath test for VOC biomarkers accurately identified ILI patients with PCR-proven influenza. These findings bolster those of others that a rapid, accurate, universal point-of-care influenza diagnostic test based on assay of exhaled-breath VOCs may be feasible. The next step will be a study of patients with ILI using a simplified method of breath collection that would facilitate translation for use in clinical practice.

Newborn vitamin A supplementation does not affect nasopharyngeal carriage of Streptococcus pneumoniae in Bangladeshi infants at age 3 months.

Nasopharyngeal (NP) carriage of S. pneumoniae (Spn) is a risk factor for pneumococcal disease and its transmission. We assessed the impact of vitamin A (VA) supplementation shortly after birth in reducing Spn colonization in early infancy in rural Bangladesh. We recruited 500 infants participating in a cluster-randomized trial that reported a 15% reduction in mortality following receipt of an oral dose of VA (52.25 µmol) compared to placebo. NP specimens were collected at the age of 3 mo to study the effect of VA on the prevalence of culture-confirmed Spn. Analyses were conducted by intention to treat. Spn carriage prevalence did not differ between VA and placebo recipients [OR = 0.83 (95% CI: 0.55-1.27); P = 0.390]. Spn carriage at the age of 3 mo was not lowered by VA given at birth. Results are similar to those from an Indian study in which impact on Spn carriage was assessed at the age of 4 mo [OR = 0.73 (95% CI: 0.48-1.10); P = 0.128]. The point estimate of the pooled effect size for the 2 studies is OR = 0.78 [(95% CI: 0.58-1.04); P = 0.095], which may imply a modest impact on carriage. If so, then the evidence thus far would suggest that Spn carriage reduction is unlikely to be a primary ancillary benefit of newborn VA supplementation.

Antigen-based multiplex strategies to discriminate SARS-CoV-2 natural and vaccine induced immunity from seasonal human coronavirus humoral responses.

Sensitive and specific SARS-CoV-2 antibody assays remain critical for community and hospital-based SARS-CoV-2 sero-surveillance. With the rollout of SARS-CoV-2 vaccines, such assays must be able to distinguish vaccine from natural immunity to SARS-CoV-2 and related human coronaviruses. Here, we developed and implemented multiplex microsphere-based immunoassay strategies for COVD-19 antibody studies that incorporates spike protein trimers of SARS-CoV-2 and the endemic seasonal human coronaviruses (HCoV), enabling high throughout measurement of pre-existing cross-reactive antibodies. We varied SARS-CoV-2 antigen compositions within the multiplex assay, allowing direct comparisons of the effects of spike protein, receptor-binding domain protein (RBD) and nucleocapsid protein (NP) based SARS-CoV-2 antibody detection. Multiplex immunoassay performance characteristics are antigen-dependent, and sensitivities and specificities range 92-99% and 94-100%, respectively, for human subject samples collected as early as 7-10 days from symptom onset. SARS-CoV-2 spike and RBD had a strong correlative relationship for the detection of IgG. Correlation between detectable IgG reactive with spike and NP also had strong relationship, however, several PCR-positive and spike IgG-positive serum samples were NP IgG-negative. This spike and NP multiplex immunoassay has the potential to be useful for differentiation between vaccination and natural infection induced antibody responses. We also assessed the induction of de novo SARS-CoV-2 IgG cross reactions with SARS-CoV and MERS-CoV spike proteins. Furthermore, multiplex immunoassays that incorporate spike proteins of SARS-CoV-2 and HCoVs will permit investigations into the influence of HCoV antibodies on COVID-19 clinical outcomes and SARS-CoV-2 antibody durability.

Higher hospital costs and lengths of stay associated with quinolone-resistant Salmonella enterica infections in Hong Kong.

OBJECTIVES: The study sought to determine the differences in lengths of stay and medical costs between patients admitted to hospital with non-typhoidal salmonellosis that were either quinolone resistant (QR) or quinolone susceptible (QS). DESIGN: We examined medical records of all patients 1 year of age or older admitted to a Hong Kong hospital between 2003 and 2008 with confirmed salmonellosis diagnosis. Data were collected on length of stay, age, sex, comorbidities, antibiotics and other medication use, diagnostic tests completed, serotype and susceptibility characteristics of isolated and the circumstances of discharge from hospital. We used Cox proportional regression to determine the differences in lengths of stay and quantile regression for differences in hospital costs. RESULTS: Median duration of hospitalization among QR salmonellosis patients was 1 day (33%; 95% CI: 13-47%) longer than those with QS salmonellosis, adjusting for confounders. Adjusted median costs were US $399 (35%) and 75th percentile costs were US $760 (43%) higher in the QR group than those in the QS group, indicating a greater difference among sicker patients. CONCLUSION: The finding of substantially longer stays and higher costs associated with QR indicates that interventions that decrease QR prevalence will lead to significant savings for the health system in the management of hospitalized salmonellosis cases.

Biannual Treatment of Preschool Children with Single Dose Azithromycin to Reduce Mortality: Impact on Azithromycin Resistance in the MORDOR Trial in Tanzania.

The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance study showed that administration of biannual, single-dose azithromycin to preschool children reduces mortality. We sought to evaluate its impact on azithromycin resistance. Thirty randomly selected communities in Kilosa district, Tanzania, were randomized to receive 6-monthly single-dose azithromycin (∼20 mg/kg) versus placebo treatment of children aged 1-59 months. From each community, 40 children (aged 1-59 months) were randomly selected at baseline, 12 and 24 months. Isolation and resistance testing of Streptococcus pneumoniae and Escherichia coli were evaluated using nasopharyngeal and rectal swabs, respectively. The carriage prevalence and the proportion of azithromycin-resistant isolates were determined using disk diffusion. At baseline, the characteristics of the randomly selected children were similar by treatment arms. Both at baseline and in annual cross-sectional surveys, rates of S. pneumoniae and E. coli isolation between treatment arms were similar. The proportions of azithromycin-resistant S. pneumoniae isolates in the children in communities treated with azithromycin versus placebo at baseline, 12 months, and 24 months were 26.5% (18.1%; P = 0.26), 26.8% (16.5%; P = 0.29), and 13.4% (17.0%; P = 0.57), respectively. The proportions of azithromycin-resistant E. coli isolates at baseline, 12 months, and 24 months in the azithromycin (versus placebo) arms were 14.9% (18.9%; P = 0.16), 21.5% (16.6%; P = 0.10), and 14.9% (14.7%; P = 0.95), respectively. Over the 24 months, the mean treatment coverage for the azithromycin and placebo was 76.9% and 74.8%, respectively (P = 0.49). Biannual administration of single-dose azithromycin to children did not appear to result in excess azithromycin resistance in S. pneumoniae and E. coli isolates over 24 months of follow-up.