The early period of the COVID-19 pandemic limited access to HIV services for children and adolescents living with HIV (C/ALHIV). To determine progress in providing care and treatment services, we describe viral load coverage (VLC) and suppression (VLS) (<1000 copies/ mL) rates during the COVID-19 pandemic in 12 United States President's Emergency Plan for AIDS Relief (PEPFAR)-supported countries. Data for children (0-9 years) and adolescents (10-19 years) on VLC and VLS were analyzed for 12 sub-Saharan African (SSA) countries between 2019 (pre-COVID-19) and 2020 (during COVID-19). We report the number of viral load (VL) tests, and percent change in VLC and VLS for patients on ART. For 12 countries, 181,192 children had a VL test during the pre-COVID-19 period compared with 177,683 December 2020 during COVID-19. VLC decreased from 68.8% to 68.3% overall. However, 9 countries experienced an increase ranging from a 0.7%-point increase for Tanzania and Zimbabwe to a 15.3%-point increase for Nigeria. VLS increased for all countries from 71.2% to 77.7%. For adolescents the number with a VL test increased from 377,342 to 402,792. VLC decreased from 77.4% to 77.1%. However, 7 countries experienced an increase ranging from 1.8% for Mozambique to 13.8% for Cameroon. VLS increased for all countries from 76.8% to 83.8%. This analysis shows variation in HIV VLC across 12 SSA countries. VLS consistently improved across all countries demonstrating resilience of countries during 2020. Countries should continue to improve clinical outcomes from C/ALHIV despite service disruptions that may occur during pandemic response.

Olfactory and taste dysfunctions have emerged as symptoms of COVID-19. Among individuals with COVID-19 enrolled in a household study, loss of taste and/or smell was the fourth most commonly reported symptom (26/42; 62%), and among household contacts, it had the highest positive predictive value (83%; 95% CI: 55–95%) for COVID-19. These findings support consideration of loss of taste and/or smell in possible case identification and testing prioritization for COVID-19.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData presented in the current study may be available from the corresponding author on request.

Antibiotics are important for the treatment and prevention of invasive Haemophilus influenzae disease. Reduced susceptibility to clinically relevant drugs, except ampicillin, has been uncommon in the United States. Susceptibility of 700 invasive H. influenzae isolates, collected through population-based surveillance during 2016, was assessed for 15 antibiotics using broth microdilution, according to the CLSI guidelines; a subset of 104 isolates were also assessed for rifampin susceptibility using Etest. Genomes were sequenced to identify genes and mutations known to be associated with reduced susceptibility to clinically relevant drugs. A total of 508 (72.6%) had reduced susceptibility to at least one antibiotic and more than half of the isolates exhibited reduced susceptibility to only one (33.6%) or two (21.6%) antibiotic classes. All tested isolates were susceptible to rifampin, a chemoprophylaxis agent, and <1% (n=3) of isolates had reduced susceptibility to third generation cephalosporins, which are recommended for invasive disease treatment. In contrast, ampicillin resistance was more common (28.1%) and predominantly associated with the detection of a -lactamase gene; 26.2% of isolates in the collection contained either a TEM-1 or ROB-1 -lactamase gene, including 88.8% of ampicillin-resistant isolates. -lactamase negative ampicillin-resistant (BLNAR) isolates were less common and associated with ftsI mutations; resistance to amoxicillin-clavulanate was detected in <2% (n=13) of isolates. The proportion of reduced susceptibility observed was higher among nontypeable H. influenzae and serotype e than other serotypes. US invasive H. influenzae isolates remain predominantly susceptible to clinically relevant antibiotics except ampicillin, and BLNAR isolates remain uncommon. IMPORTANCE Antibiotics play an important role for the treatment and prevention of invasive Haemophilus influenzae disease. Antimicrobial resistance survey of invasive H. influenzae isolates collected in 2016 showed that the US H. influenzae population remained susceptible to clinically relevant antibiotics, except for ampicillin. Detection of approximately a quarter ampicillin-resistant and -lactamase containing strains demonstrates that resistance mechanisms can be acquired and sustained within the H. influenzae population, highlighting the continued importance of antimicrobial resistance surveillance for H. influenzae to monitor susceptibility trends and mechanisms of resistance.

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.

Transitions between services for continued antiretroviral treatment (ART) during and after pregnancy are a commonly overlooked aspect of the HIV care cascade, but ineffective transitions can lead to poor health outcomes for women and their children. In this qualitative study, we conducted interviews with 15 key stakeholders from Ministries of Health along with PEPFAR-supported and other in-country non-governmental organizations actively engaged in national programming for adult HIV care and prevention of mother-to-child-transmission of HIV (PMTCT) services in Côte d'Ivoire, Lesotho and Malawi. We aimed to understand perspectives regarding transitions into and out of PMTCT services for continued ART. Thematic analysis revealed that, although transitions of care are necessary and a potential point of loss from ART care in all three countries, there is a lack of clear guidance on transition approach and no formal way of monitoring transition between services. Several opportunities were identified to monitor and strengthen transitions of care for continued ART along the PMTCT cascade.

Point-of-care antigen tests are an important tool for SARS-CoV-2 detection. Antigen tests are less sensitive than real-time reverse-transcriptase PCR (rRT-PCR). Data on the performance of the BinaxNOW antigen test compared to rRT-PCR and viral culture by symptom and known exposure status, timing during disease or exposure period and demographic variables are limited. During November 3(rd)-17(th), 2020, we collected paired upper respiratory swab specimens to test for SARS-CoV-2 by rRT-PCR and Abbott BinaxNOW (BinaxNOW) antigen test at two community testing sites in Pima County, Arizona. We administered a questionnaire to capture symptoms, known exposure status and previous SARS-CoV-2 test results. Specimens positive by either test were analyzed by viral culture. Previously we showed overall BinaxNOW sensitivity was 52.5%. Here we showed BinaxNOW sensitivity increased to 65.7% among currently symptomatic individuals reporting a known exposure. BinaxNOW sensitivity was lower among participants with a known exposure and previously symptomatic (32.4%) or never symptomatic (47.1%) within 14 days of testing. Sensitivity was 71.1% in participants within a week of symptom onset. In participants with a known exposure, sensitivity was highest 8-10 days post-exposure (75%). The positive predictive value for recovery of virus in cell culture was 56.7% for BinaxNOW-positive and 35.4% for rRT-PCR-positive specimens. Result reporting time was 2.5 hours for BinaxNOW and 26 hours for rRT-PCR. Point-of-care antigen tests have a shorter turn-around time compared to laboratory-based nucleic acid amplification tests, which allows for more rapid identification of infected individuals. Antigen test sensitivity limitations are important to consider when developing a testing program.

Serologic assays developed for SARS-CoV-2 detect different antibody subtypes and are based on different target antigens. Comparison of the performance of a SARS-CoV-2 Spike-Protein ELISA and the nucleocapsid-based Abbott ArchitectTM SARS-CoV-2 IgG assay indicated that the assays had high concordance, with rare paired discordant tests results.

Rapid antigen tests, such as the Abbott BinaxNOW COVID-19 Ag Card (BinaxNOW), offer results more rapidly (approximately 15-30 minutes) and at a lower cost than do highly sensitive nucleic acid amplification tests (NAATs) (1). Rapid antigen tests have received Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for use in symptomatic persons (2), but data are lacking on test performance in asymptomatic persons to inform expanded screening testing to rapidly identify and isolate infected persons (3). To evaluate the performance of the BinaxNOW rapid antigen test, it was used along with real-time reverse transcription-polymerase chain reaction (RT-PCR) testing to analyze 3,419 paired specimens collected from persons aged ≥10 years at two community testing sites in Pima County, Arizona, during November 3-17, 2020. Viral culture was performed on 274 of 303 residual real-time RT-PCR specimens with positive results by either test (29 were not available for culture). Compared with real-time RT-PCR testing, the BinaxNOW antigen test had a sensitivity of 64.2% for specimens from symptomatic persons and 35.8% for specimens from asymptomatic persons, with near 100% specificity in specimens from both groups. Virus was cultured from 96 of 274 (35.0%) specimens, including 85 (57.8%) of 147 with concordant antigen and real-time RT-PCR positive results, 11 (8.9%) of 124 with false-negative antigen test results, and none of three with false-positive antigen test results. Among specimens positive for viral culture, sensitivity was 92.6% for symptomatic and 78.6% for asymptomatic individuals. When the pretest probability for receiving positive test results for SARS-CoV-2 is elevated (e.g., in symptomatic persons or in persons with a known COVID-19 exposure), a negative antigen test result should be confirmed by NAAT (1). Despite a lower sensitivity to detect infection, rapid antigen tests can be an important tool for screening because of their quick turnaround time, lower costs and resource needs, high specificity, and high positive predictive value (PPV) in settings of high pretest probability. The faster turnaround time of the antigen test can help limit transmission by more rapidly identifying infectious persons for isolation, particularly when used as a component of serial testing strategies.

INTRODUCTION: Voluntary medical male circumcision (VMMC), an effective HIV prevention programme for men, is implemented in East and Southern Africa. Approximately 50% of VMMC clients are aged below 15 years. More targeted interventions to reach older men and others at higher short-term HIV risk are needed. METHODS: We implemented a quality improvement project testing the effectiveness of an active referral-based VMMC recruitment approach, targeting men attending STI clinics and those escorting partners to antenatal care (ANC) clinics, at Bwaila Hospital in Lilongwe, Malawi. We compared the proportions aged older than 15 years among men who received VMMC following referral from STI and ANC clinics with those among men referred from standard community mobilisation. We also analysed referral cascades to VMMC. RESULTS: In total, 330 clients were circumcised after referral from STI (242) and ANC (88) clinics, as compared with 3839 other clients attributed to standard community mobilisation. All clients from ANC and STI clinics were aged over 15 years, as compared with 69% from standard community mobilisation. STI clinics had a higher conversion rate from counselling to VMMC than ANC (12% vs 9%) and a higher contribution to total circumcisions performed at the VMMC clinic (6% vs 2%). CONCLUSIONS: Integrating VMMC recruitment and follow-up in STI and ANC clinics co-located with VMMC services can augment demand creation and targeting of men at risk of HIV, based on age and STI history. This approach can be replicated at least in similar health facilities with ANC and STI services in close proximity to VMMC service delivery.

Background: Pellagra is caused by niacin (vitamin B3) deficiency and manifested by a distinctive dermatitis. Isoniazid is critical for treating tuberculosis globally and is a component of most regimens to prevent tuberculosis. Isoniazid may contribute to pellagra by disrupting intracellular niacin synthesis. In 2017, Malawian clinicians recognized a high incidence of pellagra-like rashes after scale-up of isoniazid preventive treatment (IPT) to people living with HIV (PLHIV). This increase in pellagra incidence among PLHIV coincided with a seasonal period of sustained food insecurity in the region, which obscured epidemiological interpretations. Although isoniazid has been implicated as a secondary cause of pellagra for decades, no hypothesis-driven epidemiological study has assessed this relationship in a population exposed to isoniazid. We developed this case-control protocol to assess the association between large-scale isoniazid distribution and pellagra in Malawi. Methods: We measure the relative odds of having pellagra among isoniazid-exposed people compared to those without exposure while controlling for other pellagra risk factors. Secondary aims include measuring time from isoniazid initiation to onset of dermatitis, comparing niacin metabolites 1-methylnicotinamide (1-MN), and l-methyl-2-pyridone-5-carboxamide (2-PYR) in urine as a proxy for total body niacin status among subpopulations, and describing clinical outcomes after 30-days multi-B vitamin (containing 300 mg nicotinamide daily) therapy and isoniazid cessation (if exposed). We aim to enroll 197 participants with pellagra and 788 age- and sex-matched controls (1:4 ratio) presenting at three dermatology clinics. Four randomly selected community clinics within 3-25 km of designated dermatology clinics will refer persons with pellagra-like symptoms to one of the study enrollment sites for diagnosis. Trained study dermatologists will conduct a detailed exposure questionnaire and perform anthropometric measurements. A subset of enrollees will provide a casual urine specimen for niacin metabolites quantification and/or point-of-care isoniazid detection to confirm whether participants recently ingested isoniazid. We will use conditional logistic regression, matching age and sex, to estimate odds ratios for the primary study aim. Discussion: The results of this study will inform the programmatic scale-up of isoniazid-containing regimens to prevent tuberculosis.

Effective laboratory-based surveillance and public health response to bacterial meningitis depends on timely characterization of bacterial meningitis pathogens. Traditionally, characterizing bacterial meningitis pathogens such as Neisseria meningitidis (Nm) and Haemophilus influenzae (Hi) required several biochemical and molecular tests. Whole genome sequencing (WGS) has enabled the development of pipelines capable of characterizing the given pathogen with equivalent results to many of the traditional tests. Here, we present the Bacterial Meningitis Genomic Analysis Platform (BMGAP): a secure, web-accessible informatics platform that facilitates automated analysis of WGS data in public health laboratories. BMGAP is a pipeline comprised of several components, including both widely used, open-source third-party software and customized analysis modules for the specific target pathogens. BMGAP performs de novo draft genome assembly and identifies the bacterial species by whole-genome comparisons against a curated reference collection of 17 focal species including Nm, Hi, and other closely related species. Genomes identified as Nm or Hi undergo multi-locus sequence typing (MLST) and capsule characterization. Further typing information is captured from Nm genomes, such as peptides for the vaccine antigens FHbp, NadA, and NhbA. Assembled genomes are retained in the BMGAP database, serving as a repository for genomic comparisons. BMGAP's species identification and capsule characterization modules were validated using PCR and slide agglutination from 446 bacterial invasive isolates (273 Nm from nine different serogroups, 150 Hi from seven different serotypes, and 23 from nine other species) collected from 2017 to 2019 through surveillance programs. Among the validation isolates, BMGAP correctly identified the species for all 440 isolates (100% sensitivity and specificity) and accurately characterized all Nm serogroups (99% sensitivity and 98% specificity) and Hi serotypes (100% sensitivity and specificity). BMGAP provides an automated, multi-species analysis pipeline that can be extended to include additional analysis modules as needed. This provides easy-to-interpret and validated Nm and Hi genome analysis capacity to public health laboratories and collaborators. As the BMGAP database accumulates more genomic data, it grows as a valuable resource for rapid comparative genomic analyses during outbreak investigations.

BACKGROUND: Although many viral respiratory illnesses are transmitted within households, the evidence base for SARS-CoV-2 is nascent. We sought to characterize SARS-CoV-2 transmission within US households and estimate the household secondary infection rate (SIR) to inform strategies to reduce transmission. METHODS: We recruited laboratory-confirmed COVID-19 patients and their household contacts in Utah and Wisconsin during March 22-April 25, 2020. We interviewed patients and all household contacts to obtain demographics and medical histories. At the initial household visit, 14 days later, and when a household contact became newly symptomatic, we collected respiratory swabs from patients and household contacts for testing by SARS-CoV-2 rRT-PCR and sera for SARS-CoV-2 antibodies testing by enzyme-linked immunosorbent assay (ELISA). We estimated SIR and odds ratios (OR) to assess risk factors for secondary infection, defined by a positive rRT-PCR or ELISA test. RESULTS: Thirty-two (55%) of 58 households had evidence of secondary infection among household contacts. The SIR was 29% (n = 55/188; 95% confidence interval [CI]: 23-36%) overall, 42% among children (<18 years) of the COVID-19 patient and 33% among spouses/partners. Household contacts to COVID-19 patients with immunocompromised conditions had increased odds of infection (OR: 15.9, 95% CI: 2.4-106.9). Household contacts who themselves had diabetes mellitus had increased odds of infection (OR: 7.1, 95% CI: 1.2-42.5). CONCLUSIONS: We found substantial evidence of secondary infections among household contacts. People with COVID-19, particularly those with immunocompromising conditions or those with household contacts with diabetes, should take care to promptly self-isolate to prevent household transmission.

BACKGROUND AND OBJECTIVES: Limited data exist on severe acute respiratory syndrome coronavirus 2 in children. We described infection rates and symptom profiles among pediatric household contacts of individuals with coronavirus disease 2019. METHODS: We enrolled individuals with coronavirus disease 2019 and their household contacts, assessed daily symptoms prospectively for 14 days, and obtained specimens for severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction and serology testing. Among pediatric contacts (<18 years), we described transmission, assessed the risk factors for infection, and calculated symptom positive and negative predictive values. We compared secondary infection rates and symptoms between pediatric and adult contacts using generalized estimating equations. RESULTS: Among 58 households, 188 contacts were enrolled (120 adults; 68 children). Secondary infection rates for adults (30%) and children (28%) were similar. Among households with potential for transmission from children, child-to-adult transmission may have occurred in 2 of 10 (20%), and child-to-child transmission may have occurred in 1 of 6 (17%). Pediatric case patients most commonly reported headache (79%), sore throat (68%), and rhinorrhea (68%); symptoms had low positive predictive values, except measured fever (100%; 95% confidence interval [CI]: 44% to 100%). Compared with symptomatic adults, children were less likely to report cough (odds ratio [OR]: 0.15; 95% CI: 0.04 to 0.57), loss of taste (OR: 0.21; 95% CI: 0.06 to 0.74), and loss of smell (OR: 0.29; 95% CI: 0.09 to 0.96) and more likely to report sore throat (OR: 3.4; 95% CI: 1.04 to 11.18). CONCLUSIONS: Children and adults had similar secondary infection rates, but children generally had less frequent and severe symptoms. In two states early in the pandemic, we observed possible transmission from children in approximately one-fifth of households with potential to observe such transmission patterns.

BACKGROUND: Detection of SARS-CoV-2 infection has principally been performed through the use of real-time reverse-transcription PCR (rRT-PCR) testing. Results of such tests can be reported as cycle threshold (Ct) values, which may provide semi-quantitative or indirect measurements of viral load. Previous reports have examined temporal trends in Ct values over the course of a SARS-CoV-2 infection. METHODS: Using testing data collected during a prospective household transmission investigation of outpatient and mild COVID-19 cases, we examined the relationship between Ct values of the viral RNA N1 target and demographic, clinical, and epidemiological characteristics collected through participant interviews and daily symptom diaries. RESULTS: We found Ct values are lowest (corresponding to higher viral RNA concentration) soon after symptom onset and are significantly correlated with time elapsed since onset (p<0.001); within 7 days after symptom onset, the median Ct value was 26.5 compared with a median Ct value of 35.0 occurring 21 days after onset. Ct values were significantly lower among participants under 18 years of age (p=0.01) and those reporting upper respiratory symptoms at the time of sample collection (p=0.001) and were higher among participants reporting no symptoms (p=0.05). CONCLUSIONS: These results emphasize the importance of early testing for SARS-CoV-2 among individuals with symptoms of respiratory illness and allows cases to be identified and isolated when their viral shedding may be highest.

BACKGROUND: Improved understanding of SARS-CoV-2 spectrum of disease is essential for clinical and public health interventions. There are limited data on mild or asymptomatic infections, but recognition of these individuals is key as they contribute to viral transmission. We describe the symptom profiles from individuals with mild or asymptomatic SARS-CoV-2 infection. METHODS: From March 22 to April 22, 2020 in Wisconsin and Utah, we enrolled and prospectively observed 198 household contacts exposed to SARS-CoV-2. We collected and tested nasopharyngeal (NP) specimens by RT-PCR two or more times during a 14-day period. Contacts completed daily symptom diaries. We characterized symptom profiles on the date of first positive RT-PCR test and described progression of symptoms over time. RESULTS: We identified 47 contacts, median age 24 (3-75) years, with detectable SARS-CoV-2 by RT-PCR. The most commonly reported symptoms on the day of first positive RT-PCR test were upper respiratory (n=32, 68%) and neurologic (n=30, 64%); fever was not commonly reported (n=9, 19%). Eight (17%) individuals were asymptomatic at the date of first positive RT-PCR collection; two (4%) had preceding symptoms that resolved and six (13%) subsequently developed symptoms. Children less frequently reported lower respiratory symptoms (age <18: 21%, age 18-49: 60%, age 50+ years: 69%; p=0.03). CONCLUSIONS: Household contacts with lab-confirmed SARS-CoV-2 infection reported mild symptoms. When assessed at a single time-point, several contacts appeared to have asymptomatic infection; however, over time all developed symptoms. These findings are important to inform infection control, contact tracing, and community mitigation strategies.

In a household study, loss of taste and/or smell was the fourth most reported symptom (26/42; 62%) among COVID-19 case-patients and had the highest positive predictive value (83%; 95% CI: 55-95%) among household contacts. Olfactory and taste dysfunctions should be considered for COVID-19 case identification and testing prioritization.