Anti-SARS-CoV-2 Antibody Levels Associated with COVID-19 Protection in Outpatients Tested for SARS-CoV-2, US Flu VE Network, October 2021-June 2022.

BACKGROUND: We assessed associations between binding antibody (bAb) concentration <5 days of symptom onset and testing positive for COVID-19 among patients in a test-negative study. METHODS: From October 2021─June 2022, study sites in seven states enrolled patients aged ≥6 months presenting with acute respiratory illness. Respiratory specimens were tested for SARS-CoV-2. In blood specimens, we measured concentrations of anti-SARS-CoV-2 antibodies against the ancestral strain spike protein receptor binding domain (RBD) and nucleocapsid (N) antigens in standardized binding antibody units (BAU/mL). Percent change in odds of COVID-19 by increasing anti-RBD bAb was estimated using logistic regression as (1-adjusted odds ratio of COVID-19)x100, adjusting for COVID-19 mRNA vaccine doses, age, site, and high-risk exposure. RESULTS: Out of 2,018 symptomatic patients, 662 (33%) tested positive for acute SARS-CoV-2 infection. Geometric mean RBD bAb were lower among COVID-19 cases than SARS-CoV-2 test-negative patients during both the Delta-predominant (112 vs. 498 BAU/mL) and Omicron-predominant (823 vs. 1,189 BAU/mL) periods. Acute phase ancestral spike RBD bAb associated with 50% lower odds of COVID-19 were 1,968 BAU/mL against Delta and 3,375 BAU/mL against Omicron; thresholds may differ in other laboratories. CONCLUSION: During acute illness, antibody concentrations against ancestral spike RBD were associated with protection against COVID-19.

Avian influenza A(H5) virus circulation in live bird markets in Vietnam, 2017-2022.

BACKGROUND: Highly pathogenic avian influenza A(H5) human infections are a global concern, with many A(H5) human cases detected in Vietnam, including a case in October 2022. Using avian influenza virus surveillance from March 2017-September 2022, we described the percent of pooled samples that were positive for avian influenza A, A(H5), A(H5N1), A(H5N6), and A(H5N8) viruses in live bird markets (LBMs) in Vietnam. METHODS: Monthly at each LBM, 30 poultry oropharyngeal swab specimens and five environmental samples were collected. Samples were pooled in groups of five and tested for influenza A, A(H5), A(H5N1), A(H5N6), and A(H5N8) viruses by real-time reverse-transcription polymerase chain reaction. Trends in the percent of pooled samples that were positive for avian influenza were summarized by LBM characteristics and time and compared with the number of passively detected avian influenza outbreaks using Spearman's rank correlation. RESULTS: A total of 25,774 pooled samples were collected through active surveillance at 167 LBMs in 24 provinces; 36.9% of pooled samples were positive for influenza A, 3.6% A(H5), 1.9% A(H5N1), 1.1% A(H5N6), and 0.2% A(H5N8). Influenza A(H5) viruses were identified January-December and at least once in 91.7% of sampled provinces. In 246 A(H5) outbreaks in poultry; 20.3% were influenza A(H5N1), 60.2% A(H5N6), and 19.5% A(H5N8); outbreaks did not correlate with active surveillance. CONCLUSIONS: In Vietnam, influenza A(H5) viruses were detected by active surveillance in LBMs year-round and in most provinces sampled. In addition to outbreak reporting, active surveillance for A(H5) viruses in settings with high potential for animal-to-human spillover can provide situational awareness.

Anti-SARS-CoV-2 Antibody Levels Associated with COVID-19 Protection in Outpatients Tested for SARS-CoV-2, US Flu VE Network, October 2021-June 2022.

Background: We assessed the association between antibody concentration ≤5 days of symptom onset and COVID-19 illness among patients enrolled in a test-negative study. Methods: From October 2021-June 2022, study sites in seven states enrolled and tested respiratory specimens from patients of all ages presenting with acute respiratory illness for SARS-CoV-2 infection using rRT-PCR. In blood specimens, we measured concentration of anti-SARS-CoV-2 antibodies against the ancestral strain spike protein receptor binding domain (RBD) and nucleocapsid (N) antigens in standardized binding antibody units (BAU/mL). Percent reduction in odds of symptomatic COVID-19 by anti-RBD antibody was estimated using logistic regression modeled as (1-adjusted odds ratio of COVID-19)×100, adjusting for COVID-19 vaccination status, age, site, and high-risk exposure. Results: A total of 662 (33%) of 2,018 symptomatic patients tested positive for acute SARS-CoV-2 infection. During the Omicron-predominant period, geometric mean anti-RBD binding antibody concentrations measured 823 BAU/mL (95%CI:690-981) among COVID-19 case-patients versus 1,189 BAU/mL (95%CI:1,050-1,347) among SARS-CoV-2 test-negative patients. In the adjusted logistic regression, increasing levels of anti-RBD antibodies were associated with reduced odds of COVID-19 for both Delta and Omicron infections. Conclusion: Higher anti-RBD antibodies in patients were associated with protection against symptomatic COVID-19 during emergence of SARS-CoV-2 Delta and Omicron variants.

Severity of influenza-associated hospitalisations by influenza virus type and subtype in the USA, 2010-19: a repeated cross-sectional study.

BACKGROUND: Influenza burden varies across seasons, partly due to differences in circulating influenza virus types or subtypes. Using data from the US population-based surveillance system, Influenza Hospitalization Surveillance Network (FluSurv-NET), we aimed to assess the severity of influenza-associated outcomes in individuals hospitalised with laboratory-confirmed influenza virus infections during the 2010-11 to 2018-19 influenza seasons. METHODS: To evaluate the association between influenza virus type or subtype causing the infection (influenza A H3N2, A H1N1pdm09, and B viruses) and in-hospital severity outcomes (intensive care unit [ICU] admission, use of mechanical ventilation or extracorporeal membrane oxygenation [ECMO], and death), we used FluSurv-NET to capture data for laboratory-confirmed influenza-associated hospitalisations from the 2010-11 to 2018-19 influenza seasons for individuals of all ages living in select counties in 13 US states. All individuals had to have an influenza virus test within 14 days before or during their hospital stay and an admission date between Oct 1 and April 30 of an influenza season. Exclusion criteria were individuals who did not have a complete chart review; cases from sites that contributed data for three or fewer seasons; hospital-onset cases; cases with unidentified influenza type; cases of multiple influenza virus type or subtype co-infection; or individuals younger than 6 months and ineligible for the influenza vaccine. Logistic regression models adjusted for influenza season, influenza vaccination status, age, and FluSurv-NET site compared odds of in-hospital severity by virus type or subtype. When missing, influenza A subtypes were imputed using chained equations of known subtypes by season. FINDINGS: Data for 122 941 individuals hospitalised with influenza were captured in FluSurv-NET from the 2010-11 to 2018-19 seasons; after exclusions were applied, 107 941 individuals remained and underwent influenza A virus imputation when missing A subtype (43·4%). After imputation, data for 104 969 remained and were included in the final analytic sample. Averaging across imputed datasets, 57·7% (weighted percentage) had influenza A H3N2, 24·6% had influenza A H1N1pdm09, and 17·7% had influenza B virus infections; 16·7% required ICU admission, 6·5% received mechanical ventilation or ECMO, and 3·0% died (95% CIs had a range of less than 0·1% and are not displayed). Individuals with A H1N1pdm09 had higher odds of in-hospital severe outcomes than those with A H3N2: adjusted odds ratios (ORs) for A H1N1pdm09 versus A H3N2 were 1·42 (95% CI 1·32-1·52) for ICU admission; 1·79 (1·60-2·00) for mechanical ventilation or ECMO use; and 1·25 (1·07-1·46) for death. The adjusted ORs for individuals infected with influenza B versus influenza A H3N2 were 1·06 (95% CI 1·01-1·12) for ICU admission, 1·14 (1·05-1·24) for mechanical ventilation or ECMO use, and 1·18 (1·07-1·31) for death. INTERPRETATION: Despite a higher burden of hospitalisations with influenza A H3N2, we found an increased likelihood of in-hospital severe outcomes in individuals hospitalised with influenza A H1N1pdm09 or influenza B virus. Thus, it is important for individuals to receive an annual influenza vaccine and for health-care providers to provide early antiviral treatment for patients with suspected influenza who are at increased risk of severe outcomes, not only when there is high influenza A H3N2 virus circulation but also when influenza A H1N1pdm09 and influenza B viruses are circulating. FUNDING: The US Centers for Disease Control and Prevention.

Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p = 0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p = 0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p = 0.022) epitope types. The association of symptomatic malaria with reduced hazard of homologous reinfection was strongest for rare epitope types. Symptomatic malaria provides more durable protection against reinfection with parasites bearing homologous epitope types. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.

Knowledge, attitudes, and practices associated with frequent influenza vaccination among healthcare personnel in Peru, 2016─2018.

Introduction: Despite a government-subsidized vaccination program, healthcare personnel (HCP) influenza vaccination uptake remains low in Peru. Using three years of cross-sectional surveys and an additional five years of prior vaccination history of HCP in Peru, we explored HCP knowledge, attitudes, and practices (KAP) of influenza illness and its impact on vaccination frequency. Methods: In 2016, the Estudio Vacuna de Influenza Peru (VIP) cohort was initiated in Lima, Peru, which collected information about HCP KAP and influenza vaccination history from 2011─2018. HCP were classified by their 8-year influenza vaccination history as never (0 years), infrequently (1─4 years), or frequently (5─8 years) vaccinated. Logistic regression models were used to describe KAP associated with frequent compared to infrequent influenza vaccination, adjusted for each HCP's healthcare workplace, age, sex, preexisting medical conditions, occupation, and length of time providing direct patient care. Results: From 2016─2018, 5131 HCP were recruited and 3120 fully enrolled in VIP; 2782 consistently reported influenza vaccination status and became our analytic sample. From 2011─2018, 14.3% of HCP never, 61.4% infrequently, and 24.4% frequently received influenza vaccines. Compared to HCP who were infrequently vaccinated, frequently vaccinated HCP were more likely to believe they were susceptible to influenza (adjusted odds ratio [aOR]:1.49, 95% confidence interval [CI]:1.22─1.82), perceived vaccination to be effective (aOR:1.92, 95%CI:1.59─2.32), were knowledgeable about influenza and vaccination (aOR:1.37, 95%CI:1.06─1.77), and believed vaccination had emotional benefits like reduced regret or anger if they became ill with influenza (aOR:1.96, 95%CI:1.60─2.42). HCP who reported vaccination barriers like not having time or a convenient place to receive vaccines had reduced odds of frequent vaccination (aOR:0.74, 95%CI:0.61─0.89) compared to those without reported barriers. Conclusion: Few HCP frequently received influenza vaccines during an eight-year period. To increase HCP influenza vaccination in middle-income settings like Peru, campaigns could strengthen influenza risk perception, vaccine knowledge, and accessibility.

Risk factors for infection with influenza A(H3N2) virus on a US university campus, October-November 2021.

BACKGROUND: Knowledge of the specific dynamics of influenza introduction and spread in university settings is limited. METHODS: Persons with acute respiratory illness symptoms received influenza testing by molecular assay during October 6-November 23, 2022. Viral sequencing and phylogenetic analysis were conducted on nasal swab samples from case-patients. Case-control analysis of a voluntary survey of persons tested was used to identify factors associated with influenza; logistic regression was conducted to calculate odds ratios and 95% CIs. A subset of case-patients tested during the first month of the outbreak was interviewed to identify sources of introduction and early spread. RESULTS: Among 3268 persons tested, 788 (24.1%) tested positive for influenza; 744 (22.8%) were included in the survey analysis. All 380 sequenced specimens were influenza A (H3N2) virus clade 3C.2a1b.2a.2, suggesting rapid transmission. Influenza (OR [95% CI]) was associated with indoor congregate dining (1.43 [1.002-2.03]), attending large gatherings indoors (1.83 [1.26-2.66]) or outdoors (2.33 [1.64-3.31]), and varied by residence type (apartment with ≥1 roommate: 2.93 [1.21-7.11], residence hall room alone: 4.18 [1.31-13.31], or with roommate: 6.09 [2.46-15.06], or fraternity/sorority house: 15.13 [4.30-53.21], all compared with single-dwelling apartment). Odds of influenza were lower among persons who left campus for ≥1 day during the week before their influenza test (0.49 [0.32-0.75]). Almost all early cases reported attending large events. CONCLUSIONS: Congregate living and activity settings on university campuses can lead to rapid spread of influenza following introduction. Isolating following a positive influenza test or administering antiviral medications to exposed persons may help mitigate outbreaks.

Risk for Infection in Humans after Exposure to Birds Infected with Highly Pathogenic Avian Influenza A(H5N1) Virus, United States, 2022.

During February 7─September 3, 2022, a total of 39 US states experienced outbreaks of highly pathogenic avian influenza A(H5N1) virus in birds from commercial poultry farms and backyard flocks. Among persons exposed to infected birds, highly pathogenic avian influenza A(H5) viral RNA was detected in 1 respiratory specimen from 1 person.

Early and Increased Influenza Activity Among Children - Tennessee, 2022-23 Influenza Season.

Influenza seasons typically begin in October and peak between December and February (1); however, the 2022-23 influenza season in Tennessee began in late September and was characterized by high pediatric hospitalization rates during November. This report describes a field investigation conducted in Tennessee during November 2022, following reports of increasing influenza hospitalizations. Data from surveillance networks, patient surveys, and whole genome sequencing of influenza virus specimens were analyzed to assess influenza activity and secondary illness risk. Influenza activity increased earlier than usual among all age groups, and rates of influenza-associated hospitalization among children were high in November, reaching 12.6 per 100,000 in children aged <5 years, comparable to peak levels typically seen in high-severity seasons. Circulating influenza viruses were genetically similar to vaccine components. Among persons who received testing for influenza at outpatient clinics, children were twice as likely to receive a positive influenza test result as were adults. Among household contacts exposed to someone with influenza, children were more than twice as likely to become ill compared with adults. As the influenza season continues, it is important for all persons, especially those at higher risk for severe disease, to protect themselves from influenza. To prevent influenza and severe influenza complications, all persons aged ≥6 months should get vaccinated, avoid contact with ill persons, and take influenza antivirals if recommended and prescribed.

Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum . We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with a reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p=0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p=0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p=0.022) epitope types. The association of symptomatic malaria with reduced risk of homologous reinfection was strongest for rare epitope types. Symptomatic malaria more effectively promotes functional immune responses. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.

Plasmodium falciparum Genetic Diversity in Coincident Human and Mosquito Hosts.

Population genetic diversity of Plasmodium falciparum antigenic loci is high despite large bottlenecks in population size during the parasite life cycle. The prevalence of genetically distinct haplotypes at these loci, while well characterized in humans, has not been thoroughly compared between human and mosquito hosts. We assessed parasite haplotype prevalence, diversity, and evenness using human and mosquito P. falciparum infections collected from the same households during a 14-month longitudinal cohort study using amplicon deep sequencing of two antigenic gene fragments (ama1 and csp). To a prior set of infected humans (n = 1,175/2,813; 86.2% sequencing success) and mosquito abdomens (n = 199/1,448; 95.5% sequencing success), we added sequences from infected mosquito heads (n = 134/1,448; 98.5% sequencing success). The overall and sample-level parasite populations were more diverse in mosquitoes than in humans. Additionally, haplotype prevalences were more even in the P. falciparum human population than in the mosquito population, consistent with balancing selection occurring at these loci in humans. In contrast, we observed that infections in humans were more likely to harbor a dominant haplotype than infections in mosquitoes, potentially due to removal of unfit strains by the human immune system. Finally, within a given mosquito, there was little overlap in genetic composition of abdomen and head infections, suggesting that infections may be cleared from the abdomen during a mosquito's lifespan. Taken together, our observations provide evidence for the mosquito vector acting as a reservoir of sequence diversity in malaria parasite populations. IMPORTANCE Plasmodium falciparum is the deadliest human malaria parasite, and infections consisting of concurrent, multiple strains are common in regions of high endemicity. During transitions within and between the parasite's mosquito and human hosts, these strains are subject to population bottlenecks, and distinct parasite strains may have differential fitness in the various environments encountered. These bottlenecks and fitness differences may lead to differences in strain prevalence and diversity between hosts. We investigated differences in genetic diversity and evenness between P. falciparum parasites in human and mosquito hosts collected from the same households during a 14-month longitudinal study in Kenya. Compared to human parasite populations and infections, P. falciparum parasites observed in mosquito populations and infections were more diverse by multiple population genetic metrics. This suggests that the mosquito vector acts as a reservoir of sequence diversity in malaria parasite populations.

Impact of Age and Symptom Development on SARS-CoV-2 Transmission in Households With Children-Maryland, New York, and Utah, August 2020-October 2021.

Background: Households are common places for spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated factors associated with household transmission and acquisition of SARS-CoV-2. Methods: Households with children age <18 years were enrolled into prospective, longitudinal cohorts and followed from August 2020 to August 2021 in Utah, September 2020 to August 2021 in New York City, and November 2020 to October 2021 in Maryland. Participants self-collected nasal swabs weekly and with onset of acute illness. Swabs were tested for SARS-CoV-2 using reverse transcription polymerase chain reaction. We assessed factors associated with SARS-CoV-2 acquisition using a multilevel logistic regression adjusted for household size and clustering and SARS-CoV-2 transmission using a logistic regression adjusted for household size. Results: Among 2053 people (513 households) enrolled, 180 people (8.8%; in 76 households) tested positive for SARS-CoV-2. Compared with children age <12 years, the odds of acquiring infection were lower for adults age ≥18 years (adjusted odds ratio [aOR], 0.34; 95% CI, 0.14-0.87); however, this may reflect vaccination status, which protected against SARS-CoV-2 acquisition (aOR, 0.17; 95% CI, 0.03-0.91). The odds of onward transmission were similar between symptomatic and asymptomatic primary cases (aOR, 1.00; 95% CI, 0.35-2.93) and did not differ by age (12-17 years vs <12 years: aOR, 1.08; 95% CI, 0.20-5.62; ≥18 years vs <12 years: aOR, 1.70; 95% CI, 0.52-5.83). Conclusions: Adults had lower odds of acquiring SARS-CoV-2 compared with children, but this association might be influenced by coronavirus disease 2019 (COVID-19) vaccination, which was primarily available for adults and protective against infection. In contrast, all ages, regardless of symptoms and COVID-19 vaccination, had similar odds of transmitting SARS-CoV-2. Our findings underscore the importance of SARS-CoV-2 mitigation measures for persons of all ages.

Public Health Actions to Control Measles Among Afghan Evacuees During Operation Allies Welcome - United States, September-November 2021.

On August 29, 2021, the United States government oversaw the emergent establishment of Operation Allies Welcome (OAW), led by the U.S. Department of Homeland Security (DHS) and implemented by the U.S. Department of Defense (DoD) and U.S. Department of State (DoS), to safely resettle U.S. citizens and Afghan nationals from Afghanistan to the United States. Evacuees were temporarily housed at several overseas locations in Europe and Asia* before being transported via military and charter flights through two U.S. international airports, and onward to eight U.S. military bases,† with hotel A used for isolation and quarantine of persons with or exposed to certain infectious diseases.§ On August 30, CDC issued an Epi-X notice encouraging public health officials to maintain vigilance for measles among Afghan evacuees because of an ongoing measles outbreak in Afghanistan (25,988 clinical cases reported nationwide during January-November 2021) (1) and low routine measles vaccination coverage (66% and 43% for the first and second doses, respectively, in 2020) (2).

Effect of three years' seasonal malaria chemoprevention on molecular markers of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine and amodiaquine in Ouelessebougou, Mali.

BACKGROUND: In 2012, seasonal malaria chemoprevention (SMC) was recommended as policy for malaria control by the World Health Organization (WHO) in areas of highly seasonal malaria transmission across the Sahel sub-region in Africa along with monitoring of drug resistance. We assessed the long-term impact of SMC on Plasmodium falciparum resistance to sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) over a 3-year period of SMC implementation in the health district of Ouelessebougou, Mali. METHODS: In 8 randomly selected sub-districts of Ouelessebougou, Mali, children aged 0-5 years were randomly selected during cross-sectional surveys at baseline (August 2014) and 1, 2 and 3 years post-SMC, at the beginning and end of the malaria transmission season. Blood smears and blood spots on filter paper were obtained and frequencies of mutation in P. falciparum genes related to resistance to SP and AQ (Pfdhfr, Pfdhps, Pfmdr1, and Pfcrt) were assessed by PCR amplification on individual samples and PCR amplification followed by deep sequencing on pooled (by site and year) samples. RESULTS: At each survey, approximately 50-100 individual samples were analysed by PCR amplification and a total of 1,164 samples were analysed by deep sequencing with an average read depth of 18,018-36,918 after pooling by site and year. Most molecular markers of resistance did not increase in frequency over the period of study (2014-2016). After 3 years of SMC, the frequencies of Pfdhps 540E, Pfdhps 437G and Pfcrt K76T remained similar compared to baseline (4.0 vs 1.4%, p = 0.41; 74.5 vs 64.6%, p = 0.22; 71.3 vs 67.4%, p = 0.69). Nearly all samples tested carried Pfdhfr 59R, and this proportion remained similar 3 years after SMC implementation (98.8 vs 100%, p = 1). The frequency of Pfmdr1 N86Y increased significantly over time from 5.6% at baseline to 18.6% after 3 years of SMC (p = 0.016). Results of pooled analysis using deep sequencing were consistent with those by individual analysis with standard PCR, but also indicated for the first time the presence of mutations at the Pfdhps A581G allele at a frequency of 11.7% after 2 years of SMC, as well as the Pfdhps I431V allele at frequencies of 1.6-9.3% following 1 and 2 years of SMC, respectively. CONCLUSION: Two and 3 years of SMC implementation were associated with increased frequency of the Pfmdr1 N86Y mutation but not Pfdhps 540E, Pfdhps 437G and Pfcrt K76T. The first-time detection of the Pfdhps haplotype bearing the I431V and A581G mutations in Mali, even at low frequency, warrants further long-term surveillance.

Plasmodium falciparum importation does not sustain malaria transmission in a semi-arid region of Kenya.

Human movement impacts the spread and transmission of infectious diseases. Recently, a large reservoir of Plasmodium falciparum malaria was identified in a semi-arid region of northwestern Kenya historically considered unsuitable for malaria transmission. Understanding the sources and patterns of transmission attributable to human movement would aid in designing and targeting interventions to decrease the unexpectedly high malaria burden in the region. Toward this goal, polymorphic parasite genes (ama1, csp) in residents and passengers traveling to Central Turkana were genotyped by amplicon deep sequencing. Genotyping and epidemiological data were combined to assess parasite importation. The contribution of travel to malaria transmission was estimated by modelling case reproductive numbers inclusive and exclusive of travelers. P. falciparum was detected in 6.7% (127/1891) of inbound passengers, including new haplotypes which were later detected in locally-transmitted infections. Case reproductive numbers approximated 1 and did not change when travelers were removed from transmission networks, suggesting that transmission is not fueled by travel to the region but locally endemic. Thus, malaria is not only prevalent in Central Turkana but also sustained by local transmission. As such, interrupting importation is unlikely to be an effective malaria control strategy on its own, but targeting interventions locally has the potential to drive down transmission.

Development and evaluation of standardized pregnancy identification and trimester distribution algorithms in U.S. IBM MarketScan® Commercial and Medicaid data.

OBJECTIVES: Creation of new algorithms to identify pregnancies in automated health care claims databases is of public health importance, as it allows us to learn more about medication use and safety in a vulnerable population. Previous algorithms were largely created using international classification of disease codes, but despite the U.S. code transition in 2015, few algorithms are available with the latest ICD-10-CM codes. METHODS: Using U.S. IBM MarketScan® Commercial Claims and Encounters and Multi-State Medicaid databases for women aged 10-64 years during 2014 and 2016, two pregnancy algorithms (ICD-9-CM and ICD-10-CM) were created using expert clinical review. The algorithms were evaluated by assessing the distribution of pregnancy outcomes (live birth and pregnancy losses) within each time-based cohort and the ability of the algorithms to identify select medication use during pregnancy. Medication exposure, demographics, comorbidities, and pregnancy outcomes were compared to published literature estimates for the two time periods. RESULTS: For the IBM MarketScan® Commercial database, the algorithms identified 687,228 pregnancies in 2014 and 444,293 in 2016. In the IBM MarketScan® Medicaid database, 389,132 pregnancies in 2014 and 406,418 in 2016 were identified. Percentages of most pregnancy outcomes identified using the algorithms were similar to national data sources; however, percentages of preterm births and pregnancy losses were not comparable. Most medication use estimates from the algorithms were similar to or higher than published estimates. CONCLUSIONS: By incorporating the latest ICD-10-CM codes, the new algorithms provide more complete estimates of medication use during pregnancy than algorithms using the outdated codes.

Impact of asymptomatic Plasmodium falciparum infection on the risk of subsequent symptomatic malaria in a longitudinal cohort in Kenya.

Background: Asymptomatic Plasmodium falciparum infections are common in sub-Saharan Africa, but their effect on subsequent symptomaticity is incompletely understood. Methods: In a 29-month cohort of 268 people in Western Kenya, we investigated the association between asymptomatic P. falciparum and subsequent symptomatic malaria with frailty Cox models. Results: Compared to being uninfected, asymptomatic infections were associated with an increased 1 month likelihood of symptomatic malaria (adjusted hazard ratio [aHR]: 2.61, 95% CI: 2.05 to 3.33), and this association was modified by sex, with females (aHR: 3.71, 95% CI: 2.62 to 5.24) at higher risk for symptomaticity than males (aHR: 1.76, 95% CI: 1.24 to 2.50). This increased symptomatic malaria risk was observed for asymptomatic infections of all densities and in people of all ages. Long-term risk was attenuated but still present in children under age 5 (29-month aHR: 1.38, 95% CI: 1.05 to 1.81). Conclusions: In this high-transmission setting, asymptomatic P. falciparum can be quickly followed by symptoms and may be targeted to reduce the incidence of symptomatic illness. Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (R21AI126024 to WPO, R01AI146849 to WPO and SMT).

Exposure to Diverse Plasmodium falciparum Genotypes Shapes the Risk of Symptomatic Malaria in Incident and Persistent Infections: A Longitudinal Molecular Epidemiologic Study in Kenya.

BACKGROUND: Repeated exposure to malaria infections could protect against symptomatic progression as people develop adaptive immunity to infections acquired over time. METHODS: We investigated how new, recurrent, and persistent Plasmodium falciparum infections were associated with the odds of developing symptomatic compared with asymptomatic malaria. Using a 14-month longitudinal cohort in Western Kenya, we used amplicon deep sequencing of 2 polymorphic genes (pfama1 and pfcsp) to assess overlap of parasite genotypes (represented by haplotypes) acquired within an individual's successive infections. We hypothesized infections with novel haplotypes would increase the odds of symptomatic malaria. RESULTS: After excluding initial infections, we observed 534 asymptomatic and 88 symptomatic infections across 186 people. We detected 109 pfcsp haplotypes, and each infection was classified as harboring novel, recurrent, or persistent haplotypes. Incident infections with only new haplotypes had higher odds of symptomatic malaria when compared with infections with only recurrent haplotypes [odds ratio (OR): 3.24; 95% confidence interval (CI), 1.20-8.78], but infections with both new and recurrent haplotypes (OR: 0.64; 95% CI: 0.15-2.65) did not. Assessing persistent infections, those with mixed (persistent with new or recurrent) haplotypes (OR: 0.77; 95% CI: 0.21-2.75) had no association with symptomatic malaria compared with infections with only persistent haplotypes. Results were similar for pfama1. CONCLUSIONS: These results confirm that incident infections with only novel haplotypes were associated with increased odds of symptomatic malaria compared with infections with only recurrent haplotypes but this relationship was not seen when haplotypes persisted over time in consecutive infections.

Genotyping cognate Plasmodium falciparum in humans and mosquitoes to estimate onward transmission of asymptomatic infections.

Malaria control may be enhanced by targeting reservoirs of Plasmodium falciparum transmission. One putative reservoir is asymptomatic malaria infections and the scale of their contribution to transmission in natural settings is not known. We assess the contribution of asymptomatic malaria to onward transmission using a 14-month longitudinal cohort of 239 participants in a high transmission site in Western Kenya. We identify P. falciparum in asymptomatically- and symptomatically-infected participants and naturally-fed mosquitoes from their households, genotype all parasites using deep sequencing of the parasite genes pfama1 and pfcsp, and use haplotypes to infer participant-to-mosquito transmission through a probabilistic model. In 1,242 infections (1,039 in people and 203 in mosquitoes), we observe 229 (pfcsp) and 348 (pfama1) unique parasite haplotypes. Using these to link human and mosquito infections, compared with symptomatic infections, asymptomatic infections more than double the odds of transmission to a mosquito among people with both infection types (Odds Ratio: 2.56; 95% Confidence Interval (CI): 1.36-4.81) and among all participants (OR 2.66; 95% CI: 2.05-3.47). Overall, 94.6% (95% CI: 93.1-95.8%) of mosquito infections likely resulted from asymptomatic infections. In high transmission areas, asymptomatic infections are the major contributor to mosquito infections and may be targeted as a component of transmission reduction.

A model for human and animal data integration: Weight of evidence strategy.

BACKGROUND: Integration of animal and human data to assess potential risks of the use of medications in pregnancy is important. A qualitative weight of evidence process enables all available evidence to be considered in a consistent, systematic manner. METHODS: We aim to describe the weight of evidence methodology utilized by the authors, a summary of which was presented at the 59th Annual Meeting of the Teratology Society entitled "Integration of Human and Animal Data to Inform Medication Use in Pregnant Women." The qualitative weight of evidence process evaluates data that inform on a potential relationship between an adverse pregnancy outcome and a medication exposure. An interdisciplinary panel evaluates all available human and animal data related to the question of interest. Study quality assessments of both human and animal data are incorporated. The evaluation assesses gaps in the data from the following areas: (a) strength, (b) specificity, (c) consistency, (d) dose response relationship, (e) methodological considerations, and (f) biological plausibility for the potential association of interest. RESULTS: The panel integrates all the information to arrive at an assessment of the evidence and provides recommendations, which may include obtaining more specific information. We provide examples of how the authors apply this process at a pharmaceutical company for evaluation of potential postmarketing safety issues regarding medications and pregnancy outcomes. CONCLUSIONS: This weight of evidence method improves the ability to integrate published literature and other data sources to assess the potential risks of medication use in pregnant women and inform future drug safety studies.