Invasive Pneumococcal Disease After 2 Decades of Pneumococcal Conjugate Vaccine Use.

OBJECTIVES: We sought to describe the evolving epidemiology of invasive pneumococcal disease (IPD) among children in Massachusetts, United States, over the last 2 decades during which sequential 7-valent pneumococcal conjugate vaccines (PCV7) and 13-valent PCVs (PCV13) were implemented. METHODS: Cases of IPD in children aged <18 years were detected between 2002 and 2021 through an enhanced population-based, statewide surveillance system. Streptococcus pneumoniae isolates from normally sterile sites were serotyped and evaluated for antimicrobial susceptibility. IPD incidence rates and rate ratios with 95% confidence intervals (CIs) were calculated. RESULTS: We identified 1347 IPD cases. Incidence of IPD in children aged <18 years declined 72% over 2 decades between 2002 and 2021 (incidence rate ratios 0.28, 95% CI 0.18-0.45). IPD rates continued to decline after replacement of PCV7 with PCV13 (incidence rate ratios 0.25, 95% CI 0.16-0.39, late PCV7 era [2010] versus late PCV13 era [2021]). During the coronavirus disease 2019 pandemic years, 2020 to 2021, the rate of IPD among children aged <18 years reached 1.6 per 100 000, the lowest incidence observed over the 20 years. In PCV13 era, approximately one-third of the IPD cases in children aged >5 years had at least 1 underlying condition (98, 30.3%). Serotypes 19A and 7F contributed 342 (48.9%) of all cases before implementation of PCV13 (2002-2010). Serotype 3 (31, 8.6%), and non-PCV13 serotypes 15B/C (39, 10.8%), 33F (29, 8.0%), 23B (21, 0.8%), and 35B (17, 4.7%) were responsible for 37.8% of cases in PCV13 era (2011-2021). Penicillin nonsusceptibility continued to decline (9.8% vs 5.3% in pre-/late PCV13 era, P = .003), however has become more common among non-PCV13 serotypes compared with vaccine serotypes (14.8% vs 1.4%, P < .001). CONCLUSIONS: Robust ongoing surveillance networks are critical for identifying emerging serotypes and development of next-generation vaccine formulations.

Analysis of nasopharyngeal microbiome patterns in Zambian infants with fatal acute febrile illness.

Introduction: Associative connections have previously been identified between nasopharyngeal infections and infant mortality. The nasopharyngeal microbiome may potentially influence the severity of these infections. Methods: We conducted an analysis of a longitudinal prospective cohort study of 1,981 infants who underwent nasopharyngeal sampling from 1 week through 14 weeks of age at 2-3-week intervals. In all, 27 microbiome samples from 9 of the infants in the cohort who developed fatal acute febrile illness (fAFI) were analyzed in pooled comparisons with 69 samples from 10 healthy comparator infants. We completed 16S rRNA amplicon gene sequencing all infant NP samples and characterized the maturation of the infant NP microbiome among the fAFI(+) and fAFI(-) infant cohorts. Results: Beta diversity measures of fAFI(-) infants were markedly higher than those of fAFI(+) infants. The fAFI(+) infant NP microbiome was marked by higher abundances of Escherichia, Pseudomonas, Leuconostoc, and Weissella, with low relative presence of Alkalibacterium, Dolosigranulum, Moraxella, and Streptococcus. Conclusions: Our results suggest that nasopharyngeal microbiome dysbiosis precedes fAFI in young infants. Early dysbiosis, involving microbes such as Escherichia, may play a role in the causal pathway leading to fAFI or could be a marker of other pathogenic forces that directly lead to fAFI.

Postmortem Nasopharyngeal Microbiome Analysis of Zambian Infants With and Without Respiratory Syncytial Virus Disease: A Nested Case Control Study.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and lower respiratory tract infections in children in their first year of life, disproportionately affecting infants in developing countries. Previous studies have found that the nasopharyngeal (NP) microbiome of infants with RSV infection has specific characteristics that correlate with disease severity, including lower biodiversity, perturbations of the microbiota and differences in relative abundance. These studies have focused on infants seen in clinical or hospital settings, predominantly in developed countries. METHODS: We conducted a nested case control study within a random sample of 50 deceased RSV+ infants with age at death ranging from 4 days to 6 months and 50 matched deceased RSV- infants who were all previously enrolled in the Zambia Pertussis and RSV Infant Mortality Estimation (ZPRIME) study. All infants died within the community or within 48 hours of facility admittance. As part of the ZPRIME study procedures, all decedents underwent one-time, postmortem NP sampling. The current analysis explored the differences between the NP microbiome profiles of RSV+ and RSV- decedents using the 16S ribosomal DNA sequencing. RESULTS: We found that Moraxella was more abundant in the NP microbiome of RSV+ decedents than in the RSV- decedents. Additionally, Gemella and Staphylococcus were less abundant in RSV+ decedents than in the RSV- decedents. CONCLUSIONS: These results support previously reported findings of the association between the NP microbiome and RSV and suggest that changes in the abundance of these microbes are likely specific to RSV and may correlate with mortality associated with the disease.

Infant deaths from respiratory syncytial virus in Lusaka, Zambia from the ZPRIME study: a 3-year, systematic, post-mortem surveillance project.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and a key driver of childhood mortality. Previous RSV burden of disease estimates used hospital-based surveillance data and modelled, rather than directly measured, community deaths. Given this uncertainty, we conducted a 3-year post-mortem prevalence study among young infants at a busy morgue in Lusaka, Zambia-the Zambia Pertussis RSV Infant Mortality Estimation (ZPRIME) study. METHODS: Infants were eligible for inclusion if they were aged between 4 days and less than 6 months and were enrolled within 48 h of death. Enrolment occurred mainly at the University Teaching Hospital of the University of Zambia Medical School (Lusaka, Zambia), the largest teaching hospital in Zambia. We extracted demographic and clinical data from medical charts and official death certificates, and we conducted verbal autopsies with the guardian or next of kin. RSV was identified using reverse transcriptase quantitative PCR and stratified by age, time of year, and setting (community vs facility deaths). By combining the PCR prevalence data with syndromic presentation, we estimated the proportion of all infant deaths that were due to RSV. FINDINGS: The ZPRIME study ran from Aug 31, 2017, to Aug 31, 2020, except for from April 1 to May 6, 2020, during which data were not collected due to restrictions on human research at this time (linked to COVID-19). We enrolled 2286 deceased infants, representing 79% of total infant deaths in Lusaka. RSV was detected in 162 (7%) of 2286 deceased infants. RSV was detected in 102 (9%) of 1176 community deaths, compared with 10 (4%) of 236 early facility deaths (<48 h from admission) and 36 (5%) of 737 late facility deaths (≥48 h from admission). RSV deaths were concentrated in infants younger than 3 months (116 [72%] of 162 infants), and were clustered in the first half of each year and in the poorest and most densely populated Lusaka townships. RSV caused at least 2·8% (95% CI 1·0-4·6) of all infant deaths and 4·7% (1·3-8·1) of community deaths. INTERPRETATION: RSV was a major seasonal cause of overall infant mortality, particularly among infants younger than 3 months of age. Because most RSV deaths occurred in the community and would have been missed through hospital-based surveillance, the global burden of fatal RSV has probably been underestimated. FUNDING: Bill & Melinda Gates Foundation.

What is the prevalence of COVID-19 detection by PCR among deceased individuals in Lusaka, Zambia? A postmortem surveillance study.

OBJECTIVES: To determine the prevalence of COVID-19 postmortem setting in Lusaka, Zambia. DESIGN: A systematic, postmortem prevalence study. SETTING: A busy, inner-city morgue in Lusaka. PARTICIPANTS: We sampled a random subset of all decedents who transited the University Teaching Hospital morgue. We sampled the posterior nasopharynx of decedents using quantitative PCR. Prevalence was weighted to account for age-specific enrolment strategies. INTERVENTIONS: Not applicable-this was an observational study. PRIMARY OUTCOMES: Prevalence of COVID-19 detections by PCR. Results were stratified by setting (facility vs community deaths), age, demographics and geography and time. SECONDARY OUTCOMES: Shifts in viral variants; causal inferences based on cycle threshold values and other features; antemortem testing rates. RESULTS: From 1118 decedents enrolled between January and June 2021, COVID-19 was detected among 32.0% (358/1116). Roughly four COVID-19+ community deaths occurred for every facility death. Antemortem testing occurred for 52.6% (302/574) of facility deaths but only 1.8% (10/544) of community deaths and overall, only ~10% of COVID-19+ deaths were identified in life. During peak transmission periods, COVID-19 was detected in ~90% of all deaths. We observed three waves of transmission that peaked in July 2020, January 2021 and ~June 2021: the AE.1 lineage and the Beta and Delta variants, respectively. PCR signals were strongest among those whose deaths were deemed 'probably due to COVID-19', and weakest among children, with an age-dependent increase in PCR signal intensity. CONCLUSIONS: COVID-19 was common among deceased individuals in Lusaka. Antemortem testing was rarely done, and almost never for community deaths. Suspicion that COVID-19 was the cause of deaths was highest for those with a respiratory syndrome and lowest for individuals <19 years.

Community-acquired pneumonia in infants: Not simply an acute event with complete recovery.

BACKGROUND: Pneumonia in infancy has been linked to long-term consequences for the rapidly developing lung. We examined the impact of hospitalized community-acquired pneumonia (CAP) on subsequent respiratory health. METHODS: We conducted a retrospective matched-cohort study using the Optum® de-identified Electronic Health Record Dataset (2009-2018). Study population comprised healthy infants hospitalized for CAP ("CAP patients"), and matched comparators without pneumonia ("comparison patients"), before age 2 years. Study outcomes included any chronic respiratory disorder, reactive airway disease (asthma, hyperactive airway disease, recurrent wheezing), and CAP hospitalization occurring between age 2-5 years, and were evaluated overall as well as by age and etiology at first CAP hospitalization. RESULTS: Study population totaled 1,343 CAP patients and 6,715 comparison patients. Rates per 100 patient-years and relative rates (RR) of study outcomes from age 2-5 years for CAP patients versus comparison patients were: any chronic respiratory disorder, 11.6 vs. 4.9 (RR = 2.4 [95% CI: 2.1-2.6]); reactive airway disease, 6.1 vs 1.9 (RR = 3.2 [2.6-3.8]); and CAP hospitalization, 1.0 vs 0.2 (RR = 6.3 [3.6-10.9]). Rates of study outcomes were highest among CAP patients who had their initial hospitalization in the second year of life. CONCLUSIONS: Infant CAP foreshadows an increased risk of subsequent chronic respiratory disorders, which may be elevated when CAP occurs closer to pre-school age (i.e., age 2-5 years). These findings are most consistent with the hypothesis that inflammation persists beyond the acute stage of pneumonia and plays a role in the development of chronic respiratory sequelae.

Histopathological Evaluation of Deceased Persons in Lusaka, Zambia With or Without Coronavirus Disease 2019 (COVID-19) Infection: Results Obtained From Minimally Invasive Tissue Sampling.

BACKGROUND: Although much has been learned about the pathophysiology of coronavirus disease 2019 (COVID-19) infections, pathology data from patients who have died of COVID-19 in low- and middle-income country settings remain sparse. We integrated minimally invasive tissue sampling (MITS) into an ongoing postmortem surveillance study of COVID-19 in deceased individuals of all ages in Lusaka, Zambia. METHODS: We enrolled deceased subjects from the University Teaching Hospital Morgue in Lusaka, Zambia within 48 hours of death. We collected clinical and demographic information, a nasopharyngeal swab, and core tissue biopsies from the lung, liver, and kidneys for pathologic analysis. Individuals were considered eligible for MITS if they had a respiratory syndrome prior to death or a COVID-19+ polymerase chain reaction (PCR) nasopharyngeal swab specimen. Samples were retested using quantitative reverse transcriptase PCR. RESULTS: From June to September 2020 we performed MITS on 29 deceased individuals. PCR results were available for 28/29 (96.5%) cases. Three had a COVID-19+ diagnosis antemortem, and 5 more were identified postmortem using the recommended cycle threshold cut-point <40. When expanding the PCR threshold to 40 ≤ cycle threshold (Ct) ≤ 45, we identified 1 additional case. Most cases were male and occurred in the community The median age at death was 47 years (range 40-64). Human immunodeficiency virus (HIV)/AIDS, tuberculosis, and diabetes were more common among the COVID-19+ cases. Diffuse alveolar damage and interstitial pneumonitis were common among COVID-19+ cases; nonspecific findings of hepatic steatosis and acute kidney injury were also prevalent in the COVID-19+ group. Vascular thrombi were rarely detected. CONCLUSIONS: Lung abnormalities typical of viral pneumonias were common among deceased COVID-19+ individuals, as were nonspecific findings in the liver and kidneys. Pulmonary vascular thrombi were rarely detected, which could be a limitation of the MITS technique. Nonetheless, MITS offers a valuable alternative to open autopsy for understanding pathological changes due to COVID-19.

Twenty-Year Public Health Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines in US Children.

Pneumococcal conjugate vaccines (PCVs) have been used in the United States since 2000. To assess the cumulative 20-year effect of PCVs on invasive pneumococcal disease (IPD) incidence among children <5 years of age, we analyzed Active Bacterial Core Surveillance data, conducted a literature review, and modeled expected and observed disease. We found that PCVs have averted >282,000 cases of IPD, including ≈16,000 meningitis, ≈172,000 bacteremia, and ≈55,000 bacteremic pneumonia cases. In addition, vaccination has prevented 97 million healthcare visits for otitis media, 438,914-706,345 hospitalizations for pneumonia, and 2,780 total deaths. IPD cases declined 91%, from 15,707 in 1997 to 1,382 in 2019. Average annual visits for otitis media declined 41%, from 78 visits/100 children before PCV introduction to 46 visits/100 children after PCV13 introduction. Annual pneumonia hospitalizations declined 66%-79%, from 110,000-175,000 in 1997 to 37,000 in 2019. These findings confirm the substantial benefits of PCVs for preventing IPD in children.

Verbal Autopsies for Out-of-Hospital Infant Deaths in Zambia.

OBJECTIVES: In Zambia, a significant number of infants die in the community. It is hypothesized that delays in care contribute to many of these so-called "brought in dead" infants. METHODS: We analyzed free-text narratives from verbal autopsies, in which families narrate the final series of events leading to each infant's death. Using the 3-delays model framework and working iteratively to achieve consensus, we coded each narrative using NVivo software to identify, characterize, and quantify the contribution of delays and other factors to the fatal outcome. RESULTS: Verbal autopsies were collected from 230 families of brought in dead infants younger than 6 months of age. As many as 82.8% of infants had 1 or more delays in care. The most-common delay was in the family's decision to seek care (54.8%), even as severe symptoms were frequently described. Similarly, 27.8% of infants died en route to a health care facility. Delays in receiving adequate care, including infants dying while waiting in line at a clinic or during referral from a clinic to a hospital, occurred in 24.7% of infants. A third of infants had been previously evaluated by a clinician in the days before their death. CONCLUSIONS: Delays in care were the rule rather than the exception in this population of Zambian infants. Accessing care requires families to navigate significant logistic barriers, and balance complex forces in deciding to seek care. Strategies to avoid such delays could save many infants lives.

Covid-19 deaths in Africa: prospective systematic postmortem surveillance study.

OBJECTIVE: To directly measure the fatal impact of coronavirus disease 2019 (covid-19) in an urban African population. DESIGN: Prospective systematic postmortem surveillance study. SETTING: Zambia's largest tertiary care referral hospital. PARTICIPANTS: Deceased people of all ages at the University Teaching Hospital morgue in Lusaka, Zambia, enrolled within 48 hours of death. MAIN OUTCOME MEASURE: Postmortem nasopharyngeal swabs were tested via reverse transcriptase quantitative polymerase chain reaction (PCR) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Deaths were stratified by covis-19 status, location, age, sex, and underlying risk factors. RESULTS: 372 participants were enrolled between June and September 2020; PCR results were available for 364 (97.8%). SARS-CoV-2 was detected in 58/364 (15.9%) according to the recommended cycle threshold value of <40 and in 70/364 (19.2%) when expanded to any level of PCR detection. The median age at death among people with a positive test for SARS-CoV-2 was 48 (interquartile range 36-72) years, and 69% (n=48) were male. Most deaths in people with covid-19 (51/70; 73%) occurred in the community; none had been tested for SARS-CoV-2 before death. Among the 19/70 people who died in hospital, six were tested before death. Among the 52/70 people with data on symptoms, 44/52 had typical symptoms of covid-19 (cough, fever, shortness of breath), of whom only five were tested before death. Covid-19 was identified in seven children, only one of whom had been tested before death. The proportion of deaths with covid-19 increased with age, but 76% (n=53) of people who died were aged under 60 years. The five most common comorbidities among people who died with covid-19 were tuberculosis (22; 31%), hypertension (19; 27%), HIV/AIDS (16; 23%), alcohol misuse (12; 17%), and diabetes (9; 13%). CONCLUSIONS: Contrary to expectations, deaths with covid-19 were common in Lusaka. Most occurred in the community, where testing capacity is lacking. However, few people who died at facilities were tested, despite presenting with typical symptoms of covid-19. Therefore, cases of covid-19 were under-reported because testing was rarely done not because covid-19 was rare. If these data are generalizable, the impact of covid-19 in Africa has been vastly underestimated.

A systematic review of the burden and risk factors of sudden infant death syndrome (SIDS) in Africa.

BACKGROUND: While sudden infant death syndrome (SIDS) has long been recognized as a leading preventable cause of infant mortality in high-income countries, little is known about the burden of SIDS in Africa. To address this knowledge gap, we conducted the first systematic review of SIDS-related publications in Africa. Our objective was to assess the prevalence of SIDS and its risk factors in Africa. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane, and Google Scholar to identify studies published until December 26, 2020. Review authors screened titles and abstracts, and selected articles independently for full-text review. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) or a modification. Data on the proportion of infants who died of SIDS and reported prevalence of any risk factors were extracted using customized data extraction forms in Covidence. RESULTS: Our analysis rested on 32 peer-reviewed articles. Nine studies presented prevalence estimates on bedsharing and prone sleeping, suggesting near-universal bedsharing of infants with parents (range, 60 to 91.8%) and frequent use of the prone sleeping position (range, 26.7 to 63.8%). Eleven studies reported on the prevalence of SIDS, suggesting high rates of SIDS in Africa. The prevalence of SIDS ranged from 3.7 per 1000 live births in South Africa, 2.5 per 1000 live births in Niger, and 0.2 per 1000 live births in Zimbabwe. SIDS and other sudden infant deaths accounted for between 2.5 to 21% of infant deaths in South Africa and 11.3% in Zambia. CONCLUSIONS: Africa may have the highest global rate of SIDS with a high burden of associated risk factors. However, majority of the studies were from South Africa which limits generalizability of our findings to the entire continent. There is an urgent need for higher quality studies outside of South Africa to fill this knowledge gap. PROTOCOL REGISTRATION: Prospero Registration Number: CRD42021257261.

Characteristics of Serotype 3 Invasive Pneumococcal Disease before and after Universal Childhood Immunization with PCV13 in Massachusetts.

BACKGROUND: Although a substantial decline in vaccine-serotype invasive pneumococcal disease (IPD) incidence was observed following the introduction of pneumococcal conjugate vaccines (PCV), the estimated range of thirteen-valent conjugate vaccine (PCV13) effectiveness for serotype 3 disease is wide and includes zero. We assessed the impact of PCV13 on serotype 3 IPD incidence and disease characteristics in Massachusetts' children. METHODS: Serotype 3 IPD cases in children <18 years old were identified via enhanced passive surveillance system in Massachusetts. We compared incidence rates and characteristics of IPD cases before and after PCV13. RESULTS: A total of 47 serotype 3 IPD cases were identified from 2002 to 2017; incidence of serotype 3 IPD in the years following PCV13 was 0.19 per 100,000 children compared to 0.21 before PCV 13, incidence rate ratio (IRR) = 0.86 (95% CI 0.47-1.57). The majority (78%) of post-PCV13 serotype 3 IPD cases occurred among fully vaccinated children. Age distribution, clinical syndrome and presence of comorbidities among serotype 3 IPD cases were similar before and after PCV13 introduction. There was no association between the date of the last PCV13 dose and time to IPD to suggest waning of immunity. CONCLUSIONS: seven years following PCV 13 we found no significant changes in serotype 3 IPD incidence or disease characteristics in children in Massachusetts.

Hepatic Legionella pneumophila Infection in an Infant With Severe Combined Immunodeficiency.

Rare cases of extrapulmonary involvement in Legionella spp. infections have been described, mostly in immunocompromised adults. We report a case of a 2-month old male with reticular dysgenesis variant of severe combined immune deficiency with multiple liver lesions. Core-needle biopsies of one liver lesion demonstrated Gram-negative bacilli and a broad-spectrum polymerase chain reaction assay detected Legionella pneumophila.

The Pertussis resurgence: putting together the pieces of the puzzle.

Pertussis incidence is rising in almost every country where acellular pertussis (aP) vaccines have been introduced, and is occurring across all age groups from infancy to adulthood. The key question is why? While several known factors such as waning of immunity, detection bias due to more sensitive tests and higher awareness of the disease among practitioners, and evolutionary shifts among B. pertussis all likely contribute, collectively, these do not adequately explain the existing epidemiologic data, suggesting that additional factors also contribute. Key amongst these is recent data indicating that the immune responses induced by aP vaccines differ fundamentally from those induced by the whole cell pertussis (wP) vaccines, and do not lead to mucosal immunity. If so, it appears likely that differences in how the two categories of vaccines work, may be pivotal to our overall understanding of the pertussis resurgence.