Allergic fungal rhinosinusitis (AFRS) is a unique endotype of chronic rhinosinusitis with nasal polyps (CRSwNP). Despite high recurrence rates and often more severe presenting signs compared with other subtypes of CRSwNP, research dedicated to AFRS has been lacking. Diagnostic criteria are outdated, the mechanistic relationship of AFRS to other associated diseases is unclear, and the pathophysiology of disease and risk factors for recurrence have not been well studied. In December 2023, a multidisciplinary group of rhinologists, otolaryngologists, pulmonologists, allergists, immunologists, scientists, and infectious disease experts met at the National Institute of Health to discuss unmet needs for future AFRS research and care, including patient management, diagnostic criteria, severity, pathophysiology, and related conditions. A summary of these clinical and associated research discussions is included below.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonotic disease characterized by a high case fatality rate of ~30%. CCHF is endemic in Kyzylorda Oblast, Kazakhstan, which has a population of 800,000, with approximately 10 cases reported annually. In 2022, by end of July, 15 cases had been reported. We conducted an investigation to identify the risk factors associated with CCHF and to recommend preventive measures. METHODS: We conducted a case-control study. Case-patients were defined as individuals hospitalized between April and July 2022, showing signs consistent with CCHF and having a history of exposure-contact with ticks or animals and sudden onset of unexplained bleeding-within 2 weeks before the onset of illness. Confirmed case-patients additionally tested positive for CCHF-using both polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) for both immunoglobulin M (IgM) and immunoglobulin G (IgG) tests. For every case-patient, two people from neighboring households were selected as controls. We used logistic regression to assess the factors associated with CCHF. Ticks collected from animals residing on the case-patient's property were tested for CCHF. We also reviewed public environmental and livestock data. RESULTS: We studied 17 suspected, 7 probable, and 14 confirmed case-patients, along with 71 controls. Case-patients were predominantly male (74%), 47% were livestock workers and 37% were agricultural workers. Among the 14 confirmed CCHF case patients, 4 died from the illness (case fatality rate: 29%). Among the all case-patients, 100% reported weakness, 97% headaches, and 84% fevers. Over half (53%) of case-patients reported ticks on their bodies and clothing ≤2 weeks before the onset of the illness compared to 1% of controls (p < 0.001). Nearly half (47%) of the case-patients visited or lived in a high-risk area for tick bites ≤2 weeks before the onset of the illness compared to 6% of controls (p < 0.001). Livestock and agricultural workers had higher odds of CCHF compared to those not in these professions (odds ratios and 95% confidence interval [CI]: 3.0 [1.3-7.2] and 4.0 [1.5-10.5], respectively). Among the 55 control persons tested for CCHF, 1 (2%) tested IgG-positive. Of 163 ticks tested, 0.6% were PCR positive. In 2022, Kyzylorda had increased livestock numbers, above-average temperatures in February and March, and a delayed acaricidal treatment for livestock and pastures. CONCLUSION: We found a high occupational risk for CCHF. The prevalence of CCHF in ticks in our study was 0.6%, which is consistent with regional tick surveillance data. Increased tick control measures and personal protective measures for people with occupational exposure to ticks may help reduce cases.

Whilst a quarter of the world's population is estimated to be infected with Mycobacterium tuberculosis, it is unknown whether TB infection (TBI) increases the risk of severe COVID-19, which is relevant in TB-endemic settings, especially where HIV co-infection is also common. A convenience cohort of symptomatic and asymptomatic COVID-19 patients aged 8-80 years in western Kenya was followed daily for 14 days to assess disease progression using the validated inFLUenza-Patient-Reported-Outcome Plus signs and symptom tool. Nasal swabbing for SARS-CoV-2 was conducted to confirm the virus using polymerase chain reaction. QuantiFERON-TB Gold Plus was used to diagnose TBI. HIV status was based on self-reports. Between January 3, 2021, and January 20, 2022, 373 out of 387 participants had conclusive QuantiFERON results. At baseline, 5.9% (22/373) had self-reported severe COVID-19, 33.2% (124/373) had TBI, and 11.1% (38/341) reported being HIV-infected. Median follow-up of the cohort was 105 days (range 0-368). Self-reported severe COVID-19 was experienced by 10 of 124 (8.1%) participants compared with 12 of 249 (4.8%) without TBI (odds ratio [OR] 1.73, 95% CI 0.73-4.12, p = 0.21). HIV was not associated with self-reported severe COVID-19 (OR 3.13, 0.96-8.77, p = 0.039, adjusted OR 2.77, 95%CI 0.84-7.93, p = 0.070), but age ≥ 50 years was associated with self-reported severe COVID-19 (OR 3.73, 1.47-9.07, p = 0.004, adjusted OR 2.91, 95%CI 1.02-7.69, p = 0.035). One participant died of COVID-19 three days after diagnosis, and another participant developed active TB 128 days after his COVID-19 diagnosis and was successfully treated. Both were QuantiFERON positive. Self-reported severe COVID-19 was associated with older age and not TBI. Our finding that increased age was associated with self-reported severe COVID-19 is consistent with findings in multiple settings around the world.

BACKGROUND: Marburg virus disease (MVD) is a severe viral infection caused by the Marburg marburgvirus species. In February 2023, Equatorial Guinea declared its first outbreak. This case series describes the natural history of MVD in five laboratory confirmed patients. METHODS: Patients with confirmed MVD admitted to the national treatment center in Bata, Equatorial Guinea, were monitored for vital signs and symptoms. Comprehensive clinical data was collected to understand the progression and outcome of the disease. RESULTS: Five patients were confirmed to have MVD. Three male healthcare workers were diagnosed early in their disease and subsequently survived. The other two patients, both females, were admitted later in their disease progression and died within 24 hours of admission. Four patients received remdesivir under a protocol for the Monitored Emergency Use of Unregistered and Experimental Interventions. The early symptoms were non-specific, with rapid progression to more severe conditions in the later stages of the disease. Early treatment with remdesivir showed the drug to be well tolerated. CONCLUSIONS: Contrary to some reports and the recommended case definition for MVD, our patients presented with a rash but did not exhibit vomiting or diarrhea. Hemorrhagic signs were solely observed in the terminal stage, preceding demise. Despite the limited sample size, these findings emphasize the importance of tailoring the case definition to the specific outbreak. Further evidence on the efficacy and safety of therapeutics for MVD, including remdesivir, should be gathered through well-designed trials during future epidemic responses.

BACKGROUND: Surveillance of traumatic brain injury (TBI) in the USA has historically relied on healthcare administrative datasets, but these methods likely undercount the true burden of TBI. Self-report measures may help obtain more comprehensive estimates. A fundamental question is whether TBI prevalence estimated through self-report varies by whether and how TBI signs and symptoms are ascertained in the survey question(s). METHODS: Self-report data were collected from 4303 adults in the summer wave of Porter Novelli's 2023 ConsumerStyles survey. Respondents were randomised to receive a question about their 12-month experience of head injury and a grouped list of TBI signs/symptoms or a question about their 12-month experience of head injury and an option to select individual TBI signs and symptoms that resulted from the head injury. All respondents who indicated they experienced a head injury received a set of follow-up questions. RESULTS: A significantly higher percentage of people who received the 'individual signs/symptoms' question self-reported a TBI (8.3%) than those who received the 'grouped signs/symptoms' question (4.3%) χ(2)=19.6, p<0.0001. Among TBI cases identified, there were no statistical differences between question type in relation to whether the respondent reported being evaluated for or diagnosed with a TBI, nor any demographic differences. CONCLUSIONS: These results demonstrate that how TBI is ascertained in a survey can meaningfully impact reporting of TBI prevalence and provides evidence that question wording and structure affect estimates on national surveys.

The TS POC test, Taenia solium point-of-care test, is a two-strip lateral flow assay using the recombinant antigen rES33 on the TS POC T test strip, and rT24H on the TS POC CC test strip, to detect antibodies against T. solium taeniosis and cysticercosis, respectively. The objective of this study was to assess the diagnostic performance of the TS POC test for the detection of T. solium taeniosis and cysticercosis in individuals attending district hospitals in Tanzania. In this prospective two-phase diagnostic accuracy study, we recruited participants aged 10 and above, excluding pregnant women and those with acute severe illness. Participants were consecutively recruited in three cohorts according to their signs/symptoms: compatible with neurocysticercosis (cohort 1), intestinal worm infections (cohort 2), and other signs/symptoms (cohort 3). Lacking a gold standard test for both infections, diagnostic accuracy was evaluated using results of two coprological and two serological tests for taeniosis, and three serological tests for cysticercosis, in a Bayesian Latent Class Model approach. The TS POC test was conducted on 601 participants in cohort 1, 1661 participants in cohort 2, and 662 participants in cohort 3. Most individuals tested negative on both TS POC test strips, with proportions of 83% (n = 496), 97% (n = 1613) and 97% (n = 641) in cohorts 1, 2 and 3, respectively. Complete case data were available for 120, 114, and 53 participants for taeniosis, and 126, 122, and 55 participants for cysticercosis. Sensitivity values for the TS POC T test strip were 50.2% [95% credible interval 4.9 - 96.4], 40.8% [2.2 - 95.2], and 40.4% [2.3 - 95.0], while specificity values were 98.6% [97.1 - 99.6], 99.3% [98.7 - 99.7] and 99.4% [98.5 - 99.9], respectively. For the TS POC CC test strip, the sensitivity was 77.5% [37.8 - 99.2], 24.9% [95% CI 6.4 - 52.7] and 44.2% [6.6 - 91.5], and the specificity 92.3% [86.5 - 98.8], 99.1% [97.8 - 100], and 98.1% [96.1 - 99.7] across the respective cohorts. Although the TS POC test has a low sensitivity, it demonstrates a high specificity, which may have clinical utility to guide treatment and diagnostic decisions, or in epidemiological studies. An important strength of this study lies in its assessment of the TS POC test under real-world conditions, revealing divergent estimates across distinct cohorts. The study underscores the suboptimal performance of existing tests under field conditions, emphasizing the need to enhance and validate these tests for better performance in practical real-world settings. Registration number: PACTR201712002788898.

BACKGROUND: Persistent trachoma is increasingly recognized as a serious concern for the global trachoma program. Persistent trachoma is defined as those districts that have had two or more trachoma impact surveys in which the trachomatous inflammation-follicular (TF) prevalence has never been <5%, the elimination threshold for TF. Enhanced tools such as infection and serological monitoring elucidate long-term transmission patterns within persistent districts. This study aimed to clarify trachoma intensity via both traditional indicators and Chlamydia trachomatis (Ct) infection and serologic markers in four districts experiencing persistent trachoma with >10 years of interventions. METHODOLOGY: Population-based surveys were conducted in 2019 in four trachoma persistent districts. Children ages 1-9 years were examined for trachoma clinical signs and children 1-5 years were swabbed for Ct infection. Antibodies to the trachoma antigens Pgp3 and CT694 were measured for all individuals ≥1 year, assessed by multiplex bead assay. Seroconversion rates (SCRs) to both antigens were estimated for children and for individuals of all ages. RESULTS: One district, Ebinat, remained highly endemic, with a TF prevalence and infection prevalence (ages 1-5 years) of 42.5% and 7.1% respectively. Indicators were lower in the other three districts ranging from 10.7%-17.9% TF and 0%-1.7% infection. The Pgp3 SCR among children ages 1-9 years was considerably higher in Ebinat with 10.8 seroconversions per 100 child-years, (95% Confidence Interval [CI]: 8.2, 14.4) compared to the other three districts (SCR range: 0.9-3.9). All-age Pgp3 SCR estimates detected a significant decline in seroprevalence in Machakel district at approximately 12 years prior to 2019. CONCLUSIONS: Infection and serology may be useful tools for clarifying transmission, particularly among persistent districts, and ongoing interventions likely helped push these hyperendemic districts towards the elimination threshold. However, districts such as Ebinat may require more intense interventions to reach elimination within acceptable timelines.

OBJECTIVES: After respiratory syncytial virus (RSV), human metapneumovirus (hMPV) was the second-ranked pathogen attributed to severe pneumonia in the PERCH study. We sought to characterize hMPV-positive cases in high-burden settings, which have limited data, by comparing with RSV-positive and other cases. METHODS: Children aged 1-59 months hospitalized with suspected severe pneumonia and age/season-matched community controls in seven African and Asian countries had nasopharyngeal/oropharyngeal swabs tested by multiplex PCR for 32 respiratory pathogens, among other clinical and lab assessments at admission. Odds ratios adjusted for age and site (adjusted OR [aOR]) were calculated using logistic regression. Aetiologic probability was estimated using Bayesian nested partial latent class analysis. Latent class analysis identified syndromic constellations of clinical characteristics. RESULTS: hMPV was detected more frequently among cases (267/3887, 6.9%) than controls (115/4976, 2.3%), among cases with pneumonia chest X-ray findings (8.5%) than without (5.5%), and among controls with respiratory tract illness (3.8%) than without (1.8%; all p ≤ 0.001). HMPV-positive cases were negatively associated with the detection of other viruses (aOR, 0.18), especially RSV (aOR, 0.11; all p < 0.0001), and positively associated with the detection of bacteria (aORs, 1.77; p 0.03). No single clinical syndrome distinguished hMPV-positive from other cases. Among hMPV-positive cases, 65.2% were aged <1 year and 27.5% had pneumonia danger signs; positive predictive value for hMPV aetiology was 74.5%; mortality was 3.9%, similar to RSV-positive (2.4%) and lower than that among other cases (9.6%). DISCUSSION: HMPV-associated severe paediatric pneumonia in high-burden settings was predominantly in young infants and clinically indistinguishable from RSV. HMPV-positives had low case fatality, similar to that in RSV-positives.

In late January 2025, CDC received anecdotal reports of children with influenza-associated acute necrotizing encephalopathy (ANE), a severe form of influenza-associated encephalopathy or encephalitis (IAE), including several fatal cases. In response, CDC examined trends in the proportions of cases with IAE among influenza-associated pediatric deaths reported during the 2010-11 through 2024-25 influenza seasons, including demographic and clinical characteristics of identified cases. CDC contacted state health departments to ascertain whether any pediatric influenza-associated deaths with IAE reported this season also had a diagnosis of ANE. Among 1,840 pediatric influenza-associated deaths during the 2010-11 through 2024-25 influenza seasons, 166 (9%) had IAE, ranging from 0% (2020-21 season) to 14% (2011-12 season); preliminary data for the 2024-25 season (through February 8, 2025) indicate that nine of 68 (13%) had IAE. Across seasons, the median age of patients with fatal IAE was 6 years; 54% had no underlying medical conditions, and only 20% had received influenza vaccination. Because no dedicated national surveillance for IAE or ANE exists, it is unknown if the numbers of cases this season vary from expected numbers. Health care providers should consider IAE in children with acute febrile illness and neurologic signs or symptoms lasting >24 hours. Evaluation should include testing for influenza and other viruses and neuroimaging; clinical management should include early antiviral treatment for suspected or confirmed influenza and supportive critical care management as needed. Influenza vaccination is recommended for all eligible persons aged ≥6 months as long as influenza viruses are circulating.

OBJECTIVES: Direct electronic access to multiple electronic health record (EHR) systems through patient portals offers a novel avenue for decentralized research. Given the critical value of patient characterization, we sought to compare computable evaluation of health conditions from patient-portal EHR against the traditional self-report. MATERIALS AND METHODS: In the nationwide Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) study, which linked self-reported questionnaires with multiplatform patient-portal EHR data, we compared self-reported health conditions across different clinical domains against computable definitions based on diagnosis codes, medications, vital signs, and laboratory testing. We assessed their concordance using Cohen's Kappa and the prognostic significance of differentially captured features as predictors of 1-year all-cause hospitalization risk. RESULTS: Among 1683 participants (mean age 41 ± 15 years, 67% female, 63% non-Hispanic Whites), the prevalence of conditions varied substantially between EHR and self-report (-13.2% to +11.6% across definitions). Compared with comprehensive EHR phenotypes, self-report under-captured all conditions, including hypertension (27.9% vs 16.2%), diabetes (10.1% vs 6.2%), and heart disease (8.5% vs 4.3%). However, diagnosis codes alone were insufficient. The risk for 1-year hospitalization was better defined by the same features from patient-portal EHR (area under the receiver operating curve [AUROC] 0.79) than from self-report (AUROC 0.68). DISCUSSION: EHR-derived computable phenotypes identified a higher prevalence of comorbidities than self-report, with prognostic value of additionally identified features. However, definitions based solely on diagnosis codes often undercaptured self-reported conditions, suggesting a role of broader EHR elements. CONCLUSION: In this nationwide study, patient-portal-derived EHR data enabled extensive capture of patient characteristics across multiple EHR platforms, allowing better disease phenotyping compared with self-report.

Highly pathogenic avian influenza (HPAI) A(H5N1) virus, clade 2.3.4.4b, genotype B3.13 infection has been documented in cats on U.S. dairy cattle farms. In May 2024, the detection of HPAI A(H5N1) virus infection in two cats that were reported to be exclusively indoor, and that had respiratory and neurologic illness in different households, prompted an investigation by the Michigan Department of Health and Human Services and Mid-Michigan District Health Department (MDHHS/MMDHD). The cats' owners and household members were interviewed and offered testing for influenza A(H5) virus. The owner of one cat worked on a dairy farm but declined A(H5) testing; three other household members received negative A(H5) test results. The owner of the other cat lived alone and worked on multiple dairy farms transporting unpasteurized milk; this worker also reported getting splashed in the face and eyes by unpasteurized milk but declined A(H5) testing. Both workers were employed in a county known by MDHHS/MMDHD to have HPAI A(H5N1) virus, clade 2.3.4.4b, genotype B3.13-positive dairy cattle. In states with confirmed HPAI A(H5N1) in livestock, veterinary care can be aided if veterinarians obtain household members' occupational information, especially when evaluating cats with signs of respiratory or neurologic illness. If occupational exposure to HPAI A(H5N1)-infected livestock is identified among cat owners, and their companion cats are suspected to have HPAI A(H5N1) virus infection, it is important that veterinarians contact state and federal public health and animal health officials to collaborate on joint One Health investigations and testing to protect human and animal health.

Investigating acute respiratory illnesses (ARIs) is difficult due to non-specific symptoms, varied health-seeking behaviors, and resource limitations; yet early detection is critical to global health security. Kenya's Ministry of Health (MOH) uses the Integrated Disease Surveillance strategy for public health surveillance, incorporating event-based surveillance (EBS) and indicator-based surveillance (IBS) for early warning system. MOH, supported by the US-CDC, established Influenza Sentinel Surveillance (ISS) in 2006 and later launched community EBS (CEBS) and health facility EBS (HEBS) pilots to enhance surveillance for COVID-19. On March 2, 2021, the CEBS system detected a signal of "Two or more people presenting with similar signs and symptoms in a community within a week" in a county. Investigations launched on March 4, 2021, investigations revealed unreported ARI cases which had been missed by both the ISS and IBS. A total of 176 ARI cases were line-listed with 91/176 (51.7%) aged <5-years and 46/176 (26.1%) hospitalized. RT-PCR tests confirmed 34/79 (43.0%) SARS-CoV-2 and 1/7 (14.3%) A/H3N2 cases. Of the CEBS, HEBS, IBS, and ISS systems deployed by the county to strengthen the early warning for respiratory diseases, CEBS detected a signal of unreported ARIs that facilitated further investigations and response.

Background: The World Health Organization (WHO) has developed guidance for community health workers (CHWs) in identifying sick young infants based on clinical signs. We conducted a prospective, observational cohort study to characterise mortality risk of young infants based on their clinical signs. Methods: We conducted a population-based, prospective observational cohort study at five sites in Bangladesh (Sylhet, November 01, 2011–December 31, 2013), India (Vellore and Odisha, September 01, 2013–February 28, 2015), and Pakistan (Karachi, January 01, 2012–December 31, 2013; Matiari, March 01, 2012–December 31, 2013) to identify newborn infants who were followed-up by CHWs through 10 scheduled home visits over the first 60 completed days after birth to identify signs of possible serious bacterial infection (PSBI). We determined the frequency of signs and conducted Cox regression to investigate the association of signs with mortality risk within 7 days of identification of the signs. Findings: CHWs made 522,309 visits to assess 63,017 young infants and found ≥1 sign(s) of PSBI at 14,245 visits (2.7%), including 5.8% (5568 of 96,390) and 1.8% (6635 of 365,769) of visits of infants 0–<3 and 7–<60 days of age, respectively. Each of the seven signs of PSBI when found alone was associated with significantly (p < 0.0001) increased risk for mortality, which increased further if any other additional sign of PSBI was found concurrently. Over the young infant period (days 0–<60) CHW identification of no movement or movement only on stimulation was associated with the highest risk for mortality [adjusted hazard ratio (aHR) 73.0, 95% confidence interval (CI) 44.4–119.9] followed by poor feeding (aHR 31.9, 95% CI 24.1–42.3) and hypothermia (<35.5 °C) (aHR 31.4, 95% CI 23.5–41.9). Hypothermia had particularly high risk for mortality during days 7–<60 (HR 45.1, 95% CI 27.6–73.4). Interpretation: WHO reconsideration of hypothermia as a sign of critical illness is warranted. Implementation research is urgently needed to reduce infant mortality by ensuring immediate referrals and interventions for children identified early by CHWs with no movement or movement only on stimulation, hypothermia, or poor feeding, especially in resource-poor settings. Funding: Bill and Melinda Gates Foundation, New Venture Fund for Global Policy and Advocacy. © 2025 The Author(s)

IMPORTANCE: Multisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory illness that occurs 2 to 6 weeks after SARS-CoV-2 infection. Presentation overlaps with other conditions, and risk factors for severity differ by patient. Characterizing patterns of MIS-C presentation can guide efforts to reduce misclassification, categorize phenotypes, and identify patients at risk for severe outcomes. OBJECTIVE: To characterize phenotypic clusters of MIS-C and identify clusters with increased clinical severity. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, MIS-C phenotypic clusters were inferred using latent class analysis applied to the largest cohort to date of cases from US national surveillance data from 55 US public health jurisdictions. Cases reported to the Centers for Disease Control and Prevention MIS-C national surveillance program as of April 4, 2023, with symptom onset on or before December 31, 2022, were retrospectively analyzed. Twenty-nine clinical signs and symptoms were selected for clustering after excluding variables with 20% or more missingness and 10% or less or 90% or more prevalence. A total of 389 cases missing 10 or more variables were excluded, and multiple imputation was conducted on the remaining cases. MAIN OUTCOMES AND MEASURES: Differences by cluster in prevalence of each clinical sign and symptom, percentage of patients admitted to the intensive care unit (ICU), length of hospital and ICU stay, mortality, and relative frequency over time. RESULTS: Among 8944 included MIS-C cases (median [IQR] patient age, 8.7 [5.0-12.5] years; 5407 [60.5%] male), latent class analysis identified 3 clusters characterized by (1) frequent respiratory findings primarily affecting older children (respiratory cluster; 713 cases [8.0%]; median [IQR] age, 12.7 [6.3-16.5] years), (2) frequent shock and/or cardiac complications (shock and cardiac cluster; 3359 cases [37.6%]; median [IQR] age, 10.8 [7.7-14.0] years), and (3) remaining cases (undifferentiated cluster; 4872 cases [54.5%]; median [IQR] age, 6.8 [3.6-10.3] years). The percentage of patients with MIS-C admitted to the ICU was highest for the shock and cardiac cluster (82.3% [2765/3359]) followed by the respiratory (49.5% [353/713]) and undifferentiated clusters (33.0% [1609/4872]). Among patients with data on length of stay available, 129 of 632 hospitalizations (20.4%) and 54 of 281 ICU stays (19.2%) in the respiratory cluster lasted 10 or more days compared with 708 of 3085 (22.9%) and 157 of 2052 (7.7%), respectively, in the shock and cardiac cluster and 293 of 4467 (6.6%) and 19 of 1220 (1.6%), respectively, in the undifferentiated cluster. The proportion of cases in both the respiratory cluster and the shock and cardiac cluster decreased after emergence of the Omicron variant in the US. CONCLUSIONS AND RELEVANCE: In this cohort study, MIS-C cases clustered into 3 subgroups with distinct clinical phenotypes, severity, and distribution over time. Use of clusters in future studies may support efforts to evaluate surveillance case definitions and identify groups at highest risk for severe outcomes.

National case-based surveillance data show that reported neurologic manifestations of syphilis increased during 2019-2022 among persons with early and late-stage syphilis. Neurologic manifestations occurred across demographic groups and among those with and without HIV, highlighting the importance of evaluating for neurologic signs and symptoms in all persons with syphilis.

Due to its natural influenza susceptibility, clinical signs, transmission, and similar sialic acid residue distribution, the ferret is the primary animal model for human influenza research. Antibodies generated following infection of ferrets with human influenza viruses are used in surveillance to detect antigenic drift and cross-reactivity with vaccine viruses and circulating strains. Inoculation of ferrets, with over 1,500 human clinical influenza isolates (1998-2019) resulted in lower antibody responses (HI <1:160) to 86% (387 out of 448) influenza B viruses (IBVs) compared to 2.7% (30 out of 1,094) influenza A viruses (IAVs). Here, we show that the immune responses in ferrets inoculated with IBV were delayed and reduced compared to IAV. Innate gene expression in the upper respiratory tract and blood indicated that IAV generated a strong inflammatory response, including an early activation of the interferon (IFN), whereas IBV elicited a delayed and reduced response. Serum levels of cytokines and IFNs were all much higher following IAV infection than IBV infection. Pro-inflammatory, IFN, TH1/TH2, and T-effector proteins were significantly higher in sera of IAV-infected than IBV-infected ferrets over 28 days following the challenge. Serum levels of Type-I/II/III IFNs were detected following IAV infection throughout this period, whereas Type-III IFN was only late for IBV. An early increase in IFN-lambda corresponded to gene expression following IAV infection. Reduced innate immune responses following IBV infection reflected the subsequent delayed and reduced serum antibodies. These findings may help in understanding the antibody responses in humans following influenza vaccination or infection and consideration of potential addition of innate immunomodulators to overcome low responses. IMPORTANCE: The ferret is the primary animal model for human influenza research. Using a ferret model, we studied the differences in both innate and adaptive immune responses following infection with influenza A and B viruses (IAV and IBV). Antibodies generated following infection of ferrets is used for surveillance assays to detect antigenic drift and cross-reactivity with vaccine viruses and circulating influenza strains. IAV infection of ferrets to generate these reagents resulted in a strong antibody response, but IBV infection generated weak antibody responses. In this study using influenza-infected ferrets, we found that IAV resulted in an early activation of the interferon (IFN) and pro-inflammatory response, whereas IBV showed a delay and reduction in these responses. Serum levels of IFNs and other cytokines or chemokines were much higher in ferrets following IAV infection. These reduced innate responses were reflected the subsequent delayed and reduced antibody responses to IBV in the sera. These findings may help in understanding low antibody responses in humans following influenza B vaccination and infection and may warrant the use of innate immunomodulators to overcome these weak responses.

Early-onset sepsis (EOS) is a significant cause of neonatal morbidity and mortality.1 EOS pathogenesis typically involves ascending infection of the fetal compartment by maternal colonizing gastrointestinal and genitourinary microbial flora or exposure during labor and delivery with subsequent neonatal colonization and infection.2 Signs of neonatal EOS can be difficult to distinguish from clinical instability associated with prematurity and from newborn physiologic transition to extrauterine life.3 EOS is defined by the isolation of pathogenic microbial species from blood or spinal fluid culture in the first 3 days after birth, although definitions vary and may extend to the first week after birth. Sensitivity of neonatal cultures is high, but concerns persist about maternal antibiotic exposures and small blood volumes affecting results.4 Limitations of EOS risk assessment and diagnosis, in addition to substantial infection-attributable morbidity and mortality, have led to high rates of antibiotic use among newborns.5,6 | Several advancements have been made over the last decades in the prevention, diagnosis, and treatment of neonatal EOS.7 Prevention efforts have focused on detecting maternal vaginal-rectal colonization with group B Streptococcus (GBS) and administering intrapartum antibiotic prophylaxis (IAP). Targeted prevention strategies do not exist for other organisms, such as Escherichia coli. Automated culture technology has improved diagnostic yield, though limitations remain for the newborn population. Treatment primarily consists of antimicrobials and supportive (often intensive) care. Increases in drug-resistant infections have led to debate about the risks and benefits of broad versus narrow empiric antibiotic regimens for suspected EOS. | Here, we review the contemporary epidemiology and microbiology of neonatal EOS in the United States and highlight differences between term and preterm newborns and across international settings. We explore 4 current controversies in neonatal EOS: (1) the pros and cons of IAP, (2) options for the current plateau in EOS prevention, (3) optimal empiric treatment regimen, and (4) ongoing disparities in EOS.

Zanzibar, a low-resource semiautonomous region of Tanzania, has an estimated prevalence of hepatitis B virus (HBV) infections of 3.6%. To assess the feasibility of care and treatment, a 5-year hepatitis B demonstration project was implemented in Zanzibar during January 2017-December 2021, following the 2015 WHO HBV care and treatment guidelines. Participants included adults (aged ≥ 18 years) who tested positive for HBV surface antigen and tested negative for HIV and hepatitis C antibody. Participants were examined for clinical signs of liver disease and testing was conducted at baseline to assess treatment eligibility and every 6-12 months thereafter. Tenofovir disoproxil fumarate (TDF) was provided at no cost to treatment-eligible participants. Clinical and laboratory data were analysed to assess improvement in proximal disease outcomes. Among 596 participants enrolled, the median age was 32 years (IQR 26-39) and 365 (61%) were male. Of those enrolled, 268 (45%) returned for ≥ 1 follow-up visit, with a median of 511 days of follow-up. Overall, 58 patients initiated treatment: 15 met treatment criteria based on liver cirrhosis alone; 13 by APRI > 1.5; among those with HBV DNA results, six met criteria based on HBV DNA levels and ALT activity; 24 met ≥ 2 criteria. Significant decreases in ALT activities, APRI scores and HBV DNA levels were observed among those treated. This hepatitis B care and treatment programme was demonstrated to be feasible in a low-resource setting. Despite challenges, testing and linkage to care is critical to decrease the global burden of hepatitis B.

BACKGROUND: Traumatic brain injury (TBI) is a common injury in children. Though research on youth TBI has largely focused on high school students, this study describes selected school outcomes after TBI in the past 12 months among children aged 5-17 years. METHODS: Data from parent-proxy respondents from the pilot administration of the National Concussion Surveillance System (a random-digit-dial telephone survey with over 10,000 adult respondents) were examined. Descriptive statistics of demographic and injury characteristics of children who sustained a TBI were calculated. The association between TBI signs/symptoms and selected school outcomes were determined by multinomial logistic regressions. RESULTS: Among the 3557 children sampled via parent-proxy-reporting, 9.9% sustained a TBI in the past year. Changes in sleep or being more tired than usual, trouble concentrating, sensitivity to light or noise, and difficulty learning or remembering new things were associated with a greater risk of worse school outcomes following a TBI. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: To promote a positive return to learn (RTL) experience among children following TBI, school districts may prioritize accommodations (e.g., breaks in learning, extra time for assignments) and implement existing ascending levels of academic support where warranted. CONCLUSION: These findings may inform stakeholders seeking to enhance RTL and provide needed support or services for school-aged children who sustain a TBI.

Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4'-fluorouridine (4'-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4'-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4'-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4'-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4'-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4'-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.

Background: Cardiomyopathy (CM) and other cardiovascular conditions (OCVs) are among the most frequent causes of pregnancy-related death in the United States. Objectives: The purpose of this paper was to report demographic and clinical characteristics, preventability, contributing factors, and Maternal Mortality Review Committee (MMRC) recommendations among pregnancy-related deaths with underlying causes of CM, OCVs, and the 2 combined (cardiovascular conditions, CV). Methods: We analyzed pregnancy-related death data from MMRCs in 32 states, occurring during 2017 to 2019, with MMRC-determined underlying causes of CVs. We describe distributions of demographic characteristics, present the most frequent contributing factor classes, and provide example MMRC prevention recommendations. Results: Among 210 pregnancy-related deaths due to CVs, 84 (40%) were due to CM and 126 (60%) to OCVs. More than half (51.2%) of CM deaths were among non-Hispanic Black persons. Two-thirds (66%) of all CV deaths occurred among people <35 years old. Approximately 53% of CM deaths and 31% of OCV deaths occurred 43 to 365 days postpartum. Over 75% of pregnancy-related deaths due to CVs were determined by MMRCs to be preventable. The 5 most frequent contributing factor classes accounted for 50% of the total MMRC-identified contributing factors. MMRC prevention recommendations occur at multiple levels. Conclusions: Most pregnancy-related deaths due to CM and OCV are preventable. Example MMRC recommendations provided in this report illustrate prevention opportunities that address contributing factors, including broader awareness of urgent warning signs, improved handoffs for care coordination and continuity, and expanded accessibility of community-based comprehensive and integrated care services. © 2024 The Authors

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder that classically presents with symptoms associated with myotonia, early onset cataracts, and muscular weakness, although the presentation and pattern of disease progression is quite varied. Presenting symptoms are well documented among adults with DM1. However, less is known about the co-occurrence of symptoms over time. We aimed to use factor analysis to explore the correlation pattern of signs and symptoms (S/S) that emerged during the clinical course. RESULTS: Clinical records of 228 individuals with adult onset DM1 were abstracted using the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from a six-site cohort in the United States during an eight-year study period. Factor analysis was used to group the correlated S/S into latent factors. Three factors were identified. Group 1: 'Facial Weakness/Myotonia' includes the two most common S/S, as indicated by its name. Group 2: 'Skeletal Muscle Weakness' includes eight muscular S/S and is more frequently reported by males and those with older age at onset. Group 3: 'Gastrointestinal distress/Sleepiness' includes four non-muscular S/S and hand stiffness. The abstracted medical records reported that over 63% of individuals had S/S from all three groups. Associations of covariates with factor scores were also examined using linear regression. CTG repeat length was significantly positively associated with higher factor scores for all three factors. CONCLUSIONS: This study identified three latent factors of S/S which accumulated during the clinical course of adult onset DM1.

BACKGROUND: Limited research exists on suicide among children aged 5 to 9 years. The objective of this study was to examine characteristics of suicide in children younger than 10 years. METHODS: Data are from the National Fatality Review-Case Reporting System (NFR-CRS) for years 2006 through 2021 for children aged 6 to 9 years who died by suicide. No suicide deaths were reported in NFR-CRS for children aged ≤ 5 years. Descriptive analyses by demographics and circumstances were conducted. A thematic analysis of prevention recommendations made by child death review teams was performed. RESULTS: From 2006 to 2021, NFR-CRS identified 78 suicide decedents aged 6 to 9 years. The largest share were aged 9 years (72%), male (74%), non-Hispanic Black (42%), and died by hanging (86%) at home (91%). School-related problems (39%), history of child maltreatment (36%), history of mental health services (30%), argument with parents (23%), and familial discord (19%) were common circumstances. Key suicide prevention themes included education for caregivers and school staff, improved behavioral health services, and implementation of school policies and programs. CONCLUSIONS: Results provide a more complete picture of suicide among younger children, improving understanding of their unique characteristics. It is recommended that program planners consider both age-appropriateness and the impacts of social (eg, racism) and structural inequities in their approaches to prevention, encompassing both community and school-based strategies. For pediatricians, results emphasize the importance of lethal means counseling, safety planning, and educating parents and caregivers on the distinct warning signs of suicide for younger children.

BACKGROUND: Experimental studies have shown associations between gestational phthalate exposure and behavioral problems among offspring; however, epidemiological evidence is still mixed. This study aims to investigate whether gestational phthalate exposure is associated with behavioral problems in preschool-aged children. METHODS: Participants include 178 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with high familial likelihood of autism spectrum disorder (ASD). We quantified 14 phthalate metabolites in multiple maternal urine samples collected during the 2nd and 3rd trimesters. Preschool behavior problems were assessed using the Child Behavioral Checklist (CBCL), a standardized instrument for evaluating behavior problems of children aged 1.5-5 years. To examine associations of CBCL scores with both individual phthalate biomarker concentrations and their mixture, we used negative binomial regression and weighted quantile sum regression. RESULTS: Overall, maternal phthalate biomarker concentrations were not associated with child behavior problems. Monoisobutyl phthalate (MiBP) concentrations were inversely associated with child anxious/depressed symptoms and somatic complaints. Mono-hydroxy-isobutyl phthalate (MHiBP) and monobenzyl phthalate (MBzP) were also inversely associated with somatic complaints. When assessing trimester-specific associations, more behavior problems were associated with the 2nd trimester biomarker concentrations: mono(3-carboxypropyl) phthalate (MCPP) and monocarboxyisononyl phthalate (MCNP) were positively associated with somatic complaints. All associations became non-significant after false discovery rate correction. No association between a mixture of phthalates and CBCL scores was found. CONCLUSIONS: Our study observed no clear evidence of gestational phthalate exposure on child behavior problems. However, our findings based on the biomonitoring assessment of multiple samples per participant could improve our understanding of gestational phthalate exposure in association with behavior problems in preschool-aged children.

PROBLEM/CONDITION: Seasonal influenza accounts for 9.3 million-41 million illnesses, 100,000-710,000 hospitalizations, and 4,900-51,000 deaths annually in the United States. Since 2003, the Influenza Hospitalization Surveillance Network (FluSurv-NET) has been conducting population-based surveillance for laboratory-confirmed influenza-associated hospitalizations in the United States, including weekly rate estimations and descriptions of clinical characteristics and outcomes for hospitalized patients. However, a comprehensive summary of trends in hospitalization rates and clinical data collected from the surveillance platform has not been available. REPORTING PERIOD: 2010-11 through 2022-23 influenza seasons. DESCRIPTION OF SYSTEM: FluSurv-NET conducts population-based surveillance for laboratory-confirmed influenza-associated hospitalizations among children and adults. During the reporting period, the surveillance network included 13-16 participating sites each influenza season, with prespecified geographic catchment areas that covered 27 million-29 million persons and included an estimated 8.8%-9.5% of the U.S. population. A case was defined as a person residing in the catchment area within one of the participating states who had a positive influenza laboratory test result within 14 days before or at any time during their hospitalization. Each site abstracted case data from hospital medical records into a standardized case report form, with selected variables submitted to CDC on a weekly basis for rate estimations. Weekly and cumulative laboratory-confirmed influenza-associated hospitalization rates per 100,000 population were calculated for each season from 2010-11 through 2022-23 and stratified by patient age (0-4 years, 5-17 years, 18-49 years, 50-64 years, and ≥65 years), sex, race and ethnicity, influenza type, and influenza A subtype. During the 2020-21 season, only the overall influenza hospitalization rate was reported because case counts were insufficient to estimate stratified rates. RESULTS: During the 2010-11 to 2022-23 influenza seasons, laboratory-confirmed influenza-associated hospitalization rates varied significantly across seasons. Before the COVID-19 pandemic, hospitalization rates per 100,000 population ranged from 8.7 (2011-12) to 102.9 (2017-18) and had consistent seasonality. After SARS-CoV-2 emerged, the hospitalization rate for 2020-21 was 0.8, and the rate did not return to recent prepandemic levels until 2022-23. Inconsistent seasonality also was observed during 2020-21 through 2022-23, with influenza activity being very low during 2020-21, extending later than usual during 2021-22, and occurring early during 2022-23. Molecular assays, particularly multiplex standard molecular assays, were the most common influenza test type in recent seasons, increasing from 12% during 2017-18 for both pediatric and adult cases to 43% and 55% during 2022-23 for pediatric and adult cases, respectively. During each season, adults aged ≥65 years consistently had the highest influenza-associated hospitalization rate across all age groups, followed in most seasons by children aged 0-4 years. Black or African American and American Indian or Alaska Native persons had the highest age-adjusted influenza-associated hospitalization rates across these seasons. Among patients hospitalized with influenza, the prevalence of at least one underlying medical condition increased with increasing age, ranging from 36.9% among children aged 0-4 years to 95.4% among adults aged ≥65 years. Consistently across each season, the most common underlying medical conditions among children and adolescents were asthma, neurologic disorders, and obesity. The most common underlying medical conditions among adults were hypertension, obesity, chronic metabolic disease, chronic lung disease, and cardiovascular disease. The proportion of FluSurv-NET patients with acute respiratory signs and symptoms at hospital admission decreased from 90.6% during 2018-19 to 83.2% during 2022-23. Although influenza antiviral use increased during the 2010-11 through the 2017-18 influenza seasons, it decreased from 90.2% during 2018-19 to 79.1% during 2022-23, particularly among children and adolescents. Admission to the intensive care unit, need for invasive mechanical ventilation, and in-hospital death ranged from 14.1% to 22.3%, 4.9% to 11.1%, and 2.2% to 3.5% of patients hospitalized with influenza, respectively, during the reported surveillance period. INTERPRETATIONS: Influenza continues to cause severe morbidity and mortality, particularly in older adults, and disparities have persisted in racial and ethnic minority groups. Persons with underlying medical conditions represented a large proportion of patients hospitalized with influenza. Increased use of multiplex tests and other potential changes in facility-level influenza testing practices (e.g., influenza screening at all hospital admissions) could have implications for the detection of influenza infections among hospitalized patients. Antiviral use decreased in recent seasons, and explanations for the decrease should be further evaluated. PUBLIC HEALTH ACTION: Continued robust influenza surveillance is critical to monitor progress in efforts to encourage antiviral treatment and improve clinical outcomes for persons hospitalized with influenza. In addition, robust influenza surveillance can potentially reduce disparities by informing efforts to increase access to preventive measures for influenza and monitoring any subsequent changes in hospitalization rates.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), and Neisseria meningitidis (N. meningitidis) are leading causes of childhood bacterial meningitis and preventable by vaccines. The aim of this hospital-based sentinel surveillance is to describe the epidemiological characteristics of pneumococcal meningitis, including disease burden, and to provide baseline data on pneumococcal serotype distribution to support decision making for pneumococcal conjugate vaccine (PCV) introduction in Vietnam. METHODS: Surveillance for probable bacterial meningitis in children 1-59 months of age is conducted in three tertiary level pediatric hospitals: one in Hanoi and two in Ho Chi Minh City. Cerebrospinal fluid (CSF) specimens were collected via lumbar puncture from children with suspected meningitis. Specimens were transferred immediately to the laboratory department of the respective hospital for cytology, biochemistry, and microbiology testing, including culture. PCR testing was conducted on CSF specimens for bacterial detection (S. pneumoniae, H. influenzae, and N. meningitidis) and pneumococcal serotyping. RESULTS: During 2015-2018, a total of 1,803 children with probable bacterial meningitis were detected; 1,780 had CSF specimens available for testing. Of 245 laboratory-confirmed positive cases, the majority were caused by S. pneumoniae (229,93.5%). Of those with S. pneumoniae detected, over 70% were caused by serotypes included in currently available PCV products; serotypes 6 A/6B (27.1%), 14 (19.7%), and 23 F (16.2%) were the most common serotypes. Children with laboratory-confirmed pneumococcal meningitis were more likely to live in Hanoi (p < 0.0001) and children 12-23 months of age were at greater odds (OR = 1.65, 95% CI: 1.11, 2.43; p = 0.006) of having confirmed pneumococcal meningitis compared to children < 12 months of age when compared to those without laboratory-confirmed bacterial meningitis. Additionally, children with confirmed pneumococcal meningitis were more likely to exhibit signs and symptoms consistent with clinical meningitis compared to negative laboratory-confirmed meningitis cases (p < 0.0001) and had a greater odds of death (OR = 6.18, 95% CI: 2.98, 12.86; p < 0.0001). CONCLUSIONS: Pneumococcal meningitis contributes to a large burden of bacterial meningitis in Vietnamese children. A large proportion are caused by serotypes covered by PCVs currently available. Introduction of PCV into the routine immunization program could reduce the burden of pneumococcal meningitis in Viet Nam.

On September 28, 2023, a kitten aged approximately 6 weeks found in Omaha, Nebraska, had test results positive for rabies at the Nebraska Veterinary Diagnostic Center (NVDC) after dying with neurologic signs and having bitten and scratched its caretakers. Preliminary investigation identified 10 exposed persons for whom postexposure prophylaxis (PEP)(†) was recommended. Subsequent variant-typing by NVDC yielded a presumptive positive result for the Eastern raccoon rabies virus variant (RRVV), which CDC confirmed on October 6.

BACKGROUND: Clostridioides difficile infection (CDI) may be misdiagnosed if testing is performed in the absence of signs or symptoms of disease. This study sought to support appropriate testing by estimating the impact of signs, symptoms, and healthcare exposures on pre-test likelihood of CDI. METHODS: A panel of fifteen experts in infectious diseases participated in a modified UCLA/RAND Delphi study to estimate likelihood of CDI. Consensus, defined as agreement by >70% of panelists, was assessed via a REDCap survey. Items without consensus were discussed in a virtual meeting followed by a second survey. RESULTS: All fifteen panelists completed both surveys (100% response rate). In the initial survey, consensus was present on 6 of 15 (40%) items related to risk of CDI. After panel discussion and clarification of questions, consensus (>70% agreement) was reached on all remaining items in the second survey. Antibiotics were identified as the primary risk factor for CDI and grouped into three categories: high-risk (likelihood ratio [LR] 7, 93% agreement among panelists in first survey), low-risk (LR 3, 87% agreement in first survey), and minimal-risk (LR 1, 71% agreement in first survey). Other major factors included new or unexplained severe diarrhea (e.g., ≥ 10 liquid bowel movements per day; LR 5, 100% agreement in second survey) and severe immunosuppression (LR 5, 87% agreement in second survey). CONCLUSION: Infectious disease experts concurred on the importance of signs, symptoms, and healthcare exposures for diagnosing CDI. The resulting risk estimates can be used by clinicians to optimize CDI testing and treatment.

BACKGROUND: Previous investigations into clinical signs and symptoms associated with influenza types and subtypes have not definitively established differences in the clinical presentation or severity of influenza disease. METHODS: The study population included children 0 through 17 years old enrolled at 8 New Vaccine Surveillance Network sites between 2015 and 2020 who tested positive for influenza virus by molecular testing. Demographic and clinical data were collected for study participants via parent/guardian interview and medical chart review. Descriptive statistics were used to summarize demographic and clinical characteristics by influenza subtype. Multivariable logistic regression and Cox proportional hazard models were used to assess effects of age, sex, influenza subtype, and history of asthma on severity, including hospital admission, need for supplemental oxygen, and length of stay. RESULTS: Retractions, cyanosis, and need for supplemental oxygen were more frequently observed among patients with influenza A(H1N1)pdm09. Headaches and sore throat were more commonly reported among patients with influenza B. Children with influenza A(H1N1)pdm09 and children with asthma had significantly increased odds of hospital admission (adjusted odds ratio (AOR): 1.39, 95% CI: 1.14-1.69 and AOR: 2.14, 95% CI: 1.72-2.67, respectively). During admission, children with influenza A(H1N1)pdm09 had significantly increased use of supplemental oxygen compared to children with A(H3N2) (AOR: 0.60, 95% CI: 0.44-0.82) or B (AOR: 0.56, 95% CI: 0.41-0.76). CONCLUSIONS: Among children presenting to the emergency department and admitted to the hospital, influenza A(H1N1)pdm09 caused more severe disease compared to influenza A(H3N2) and influenza B. Asthma also contributed to severe influenza disease regardless of subtype.