Vaccine-Preventable Disease Incidence Based on Clinically, Radiologically, and Etiologically Confirmed Outcomes: Systematic Literature Review and Re-analysis of Pneumococcal Conjugate Vaccine Efficacy Trials.

BACKGROUND: Vaccine regulatory decision making is based on vaccine efficacy against etiologically confirmed outcomes, which may underestimate the preventable disease burden. To quantify this underestimation, we compared vaccine-preventable disease incidence (VPDI) of clinically defined outcomes with radiologically/etiologically confirmed outcomes. METHODS: We performed a systematic review of efficacy trials for several vaccines (1997-2019) and report results for pneumococcal conjugate vaccines. Data were extracted for outcomes within a clinical syndrome, organized from most sensitive to most specific. VPDI was determined for each outcome, and VPDI ratios were calculated, with a clinically defined outcome (numerator) and a radiologically/etiologically confirmed outcome (denominator). RESULTS: Among 9 studies, we calculated 27 VPDI ratios; 24 had a value >1. Among children, VPDI ratios for clinically defined versus vaccine serotype otitis media were 0.6 (95% CI not calculable), 2.1 (1.5-3.0), and 3.7 (1.0-10.2); the VPDI ratios comparing clinically defined with radiologically confirmed pneumonia ranged from not calculable to 2.7 (1.2-10.4); the VPDI ratio comparing clinically suspected invasive pneumococcal disease (IPD) with laboratory-confirmed IPD was 3.8 (95% CI not calculable). Among adults, the ratio comparing clinically defined with radiologically confirmed pneumonia was 1.9 (-6.0 to 9.1) and with vaccine serotype-confirmed pneumonia was 2.9 (.5-7.8). CONCLUSIONS: While there is substantial uncertainty around individual point estimates, there is a consistent trend in VPDI ratios, most commonly showing under-ascertainment of 1.5- to 4-fold, indicating that use of clinically defined outcomes is likely to provide a more accurate estimate of a pneumococcal conjugate vaccine's public health value.

Hospital discharge diagnosis position: impact on adult pneumonia burden estimates.

OBJECTIVES: Pneumonia hospitalization studies using administrative claims rely on pneumonia coded in the first discharge diagnosis field over pneumonia in any coded field, and few have evaluated disposition following discharge. This study reports the total disease burden and discharge disposition among patients with pneumonia coded in any diagnosis field. STUDY DESIGN: Retrospective database review. METHODS: Data from the 2014 National Inpatient Sample of the Healthcare Cost and Utilization Project, a population-weighted, 20% sample of all US community hospitalizations, were analyzed for all pneumonia hospitalizations in adults aged 18 to 64 years and 65 years or older. Number of hospitalizations, hospital stay length, direct medical costs, in-hospital mortality, patient discharge disposition, illness severity, and likelihood of dying were evaluated based on the diagnosis field of pneumonia as a discharge diagnosis (eg, first, second, third, or further). RESULTS: In 2014, an estimated 2.4 million US adult hospitalizations were associated with pneumonia in any of the discharge diagnosis positions (33%-35% in first, 33%-36% in second, and 29%-34% in further positions). When estimates were based only on hospitalizations with pneumonia in the first diagnosis field, approximately 66% of hospitalizations, 78% of hospital days, 87% of in-hospital deaths, 76% and 73% of transfers to short-term hospitals and skilled nursing facilities, 68% of discharges with home health care services, and 82% of direct medical costs were excluded. CONCLUSIONS: Pneumonia hospitalizations were associated with substantial health care resource utilization and in-hospital mortality. Relying only on pneumonia in the first hospital diagnosis field may potentially underestimate the burden associated with pneumonia hospitalizations.

Invasive pneumococcal disease in Canada 2010-2017: The role of current and next-generation higher-valent pneumococcal conjugate vaccines.

BACKGROUND: In 2010-2011, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7- or 10-valent vaccine (PCV7 and PCV10, respectively) in pediatric immunization programs across Canada. For adults aged ≥65 years, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been publicly funded for several decades; PCV13 funding was not recommended in this population, partly due to expected ongoing vaccine-serotype disease decline stemming from herd effects of the pediatric program. Higher-valent PCVs (ie, 15- and 20-valent PCVs [PCV15 and PCV20, respectively]) currently in development may become available in Canada in the coming years. METHODS: Using the National Microbiology Laboratory surveillance reports, annual case counts and serotype distribution of invasive pneumococcal disease (IPD) from 2010 to 2017 in Canada were examined to assess the impact of existing programs on PCV13-serotype IPD and determine the proportion of IPD that can potentially be prevented by current and forthcoming higher-valent PCVs. RESULTS: The percentages of PCV13-serotype IPD decreased from 55% [1492/2708] in 2010 to 30% [902/3006] in 2017 in all age groups combined, including a decline from 67% [221/331] to 18% [40/219] in children aged <5 years and from 50% [487/967] to 23% [287/1238] in adults aged ≥65 years. Overall, IPD cases declined mainly before 2014 and have plateaued since then. In 2017, PCV15- and PCV20-serotypes (inclusive of PCV13 serotypes) accounted for 42% and 58% of IPD cases, respectively, in all ages. CONCLUSIONS: In Canada, publicly funded pediatric PCV13 use was associated with large declines in IPD due to vaccine serotypes. Substantial residual PCV13-serotype IPD proportions observed among all ages imply limits to indirect protection afforded by the pediatric PCV13 program at the current uptake level and suggest the adult PPSV23 program alone is insufficient. Higher-valent PCVs have the potential to address a substantial proportion of remaining IPD cases among all age groups.

One-Year Quality of Life Post-Pneumonia Diagnosis in Japanese Adults.

BACKGROUND: Pneumonia is a common, serious illness in the elderly, with a poorly characterized long-term impact on health-related quality of life (HRQoL). The Japanese Goto Epidemiology Study is a prospective, active, population-based surveillance study of adults with X-ray/CT scan-confirmed community-onset pneumonia, assessing the HRQoL outcome quality-adjusted life-years (QALYs). We report QALY scores and losses among a subset of participants in this study. METHODS: QALYs were derived from responses to the Japanese version of the EuroQol-5D-5L health-state classification instrument at days 0, 7, 15, 30, 90, 180, and 365 after pneumonia diagnosis from participants enrolled from June 2017 to May 2018. We used patients as their own controls, calculating comparison QALYs by extrapolating EuroQol-5D-5L scores for day -30, accounting for mortality and changes in scores with age. RESULTS: Of 405 participants, 85% were aged ≥65 years, 58% were male, and 69% were hospitalized for clinically and radiologically confirmed pneumonia. Compliance with interviews by patients or proxies was 100%. Adjusted EuroQol-5D-5L scores were 0.759, 0.561, 0.702, and 0.689 at days -30, 0 (diagnosis), 180, and 365, respectively. Average scores at all time points remained below the average day -30 scores (P ≤ .001). Pneumonia resulted in a 1-year adjusted loss of 0.13 QALYs (~47.5 quality-adjusted days) (P < .001). CONCLUSIONS: Substantial QALY losses were observed among Japanese adults following pneumonia diagnosis, and scores had not returned to prediagnosis levels at 1 year postdiagnosis. QALY scores and cumulative losses were comparable to those in US adults with chronic heart failure, stroke, or renal failure.

Streptococcus pneumoniae serotype distribution and antimicrobial nonsusceptibility trends among adults with pneumonia in the United States, 2009‒2017.

Background In the United States, the 13-valent pneumococcal conjugate vaccine has been recommended for children since 2010 and for adults aged ≥65 years since 2014. We assessed S. pneumoniae antimicrobial nonsusceptibility among adults with suspected pneumonia from hospital settings. Methods Isolates were collected from 105 US sites between 2009 and 2017 in the SENTRY Antimicrobial Surveillance Program. Clinical and Laboratory Standards Institute methods were used for susceptibility testing. Serotypes were determined by cpsB sequence obtained by PCR or whole genome sequencing, plus multiplex PCR and/or Neufeld Quellung reactions as needed. Findings Of 7254 S. pneumoniae isolates analyzed, 63.6% and 36.4% were from patients aged 18‒64 and ≥65 years, respectively. Among all isolates, penicillin and ceftriaxone nonsusceptibility declined by 72.3% and 73.8%, respectively, with smaller changes observed for other antibiotics. Nonsusceptibility patterns were serotype-specific; for example, nonsusceptibility was relatively stable for serotype 19A but declined for 19F. Simultaneously, the percentage of serotype 19A isolates decreased from 17.4% to 3.9%, whereas for serotype 19F this percentage increased from 2.8% to 5.0%. The percentage of serotype 3 isolates that were nonsusceptible increased for select antibiotic classes, and the percentage of serotype 3 among all isolates increased minimally from 10.2% to 11.8%. Interpretation Overall pneumococcal nonsusceptibility patterns were influenced by distinct patterns within serotypes, indicating the likelihood of serotype-specific resistance mechanisms. Serotype 19A observations were consistent with vaccine-induced reductions in circulation with no change in the organism susceptibility, whereas the nonsusceptibility increases for serotypes 3 and 19F may indicate circulation of more antibiotic-resistant clones.

Diabetes mellitus as a vaccine-effect modifier: a review.

INTRODUCTION: Diabetes mellitus (DM) is a highly prevalent, chronic condition in adults worldwide. Little is known about the potential role of diabetes as an effect modifier of vaccine protective responses. AREAS COVERED: We conducted a literature review of the immunogenicity, efficacy and effectiveness of immunization in individuals, in studies that compared subjects with DM (DM+) and without DM (DM-). We found few published studies, which were only for vaccines against hepatitis B, influenza, pneumococcal disease, or varicela zoster. Except for a consistent attenuation of the immune response to hepatitis B vaccine among DM+ individuals, we found little other consistent evidence for DM as an effect modifier of vaccine responses. EXPERT OPINION: There are substantial gaps in our knowledge of the impact of DM on the immune response to immunization or effect of vaccination.

Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Disease Caused by Serotype 3 in Children: A Systematic Review and Meta-analysis of Observational Studies.

The 13-valent pneumococcal conjugate vaccine (PCV13) is the only licensed PCV with serotype 3 polysaccharide in its formulation. Postlicensure PCV13 effectiveness studies against serotype 3 invasive pneumococcal disease (IPD) in children have shown inconsistent results.  We performed a systematic review and meta-analysis of observational studies to assess PCV13 vaccine effectiveness (VE) for serotype 3 IPD in children. We systematically searched PubMed, Embase, and the Cochrane library for studies published before 14 August 2017. We identified 4 published studies and 2 conference posters that provided PCV13 VE estimates stratified by serotype. The pooled PCV13 VE against serotype 3 IPD from the random-effects meta-analysis was 63.5% (95% confidence interval [CI], 37.3%-89.7%). A sensitivity analysis including conference posters gave a pooled VE estimate of 72.4% (95% CI, 56.7%-88.0%). The pooled data from case-control studies with similar methodologies and high quality support direct PCV13 protection against serotype 3 IPD in children.

Acute otitis media, antimicrobial prescriptions, and medical expenses among children in the United States during 2011-2016.

INTRODUCTION: We analyzed outpatient visits, incidence, antimicrobial prescriptions, and medical expenditures for acute otitis media (AOM) in the United States during 2011-2016. METHODS: Data sources included the National Disease and Therapeutic Index (NDTI™) projections by IQVIA (for AOM cases), The Medical Expenditure Panel Survey (for medical expenditures) and the US Census (for population estimates). Analyses focused on children aged ≤9 years between 2011 and 2016. We used the 2014 medical expenditure estimate per otitis media episode ($520) as proxy for all years. RESULTS: In 2011, there were an estimated 11.5 million AOM episodes in children aged 0-9 years in the US with AOM incidence rates (IR) of 476, 204, and 284 episodes per 1000 children aged 0-2, 3-9, and 0-9 years, respectively. All subsequent years had lower IRs, and by 2016, IR was 25.1% lower than in 2011 in children 0-9 years. In addition, there were estimates of 10.8 million and 9.2 million fewer cumulative AOM episodes and antimicrobial prescriptions for AOM nationwide between 2012 and 2016, compared to annual 2011 estimates, representing a ∼$5.6 billion decrease in direct medical expenditures. The average number of antibiotic prescriptions per AOM visit remained stable with 0.89 and 0.86 prescriptions per visit in 2011 and 2016, respectively. CONCLUSIONS: AOM incidence, antimicrobial prescriptions, and associated medical expenses decreased substantially between 2011 and 2016 in the United States. Antimicrobial prescribing practices remain unchanged. Additional studies are warranted to assess causality.

Post hoc analysis of the efficacy of the 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia in at-risk older adults.

BACKGROUND: Individuals with certain chronic medical conditions are at higher risk of developing pneumonia and pneumococcal disease than those without. Using data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), this post hoc analysis assessed the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥65 years with at-risk conditions. METHODS: The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was a double-blind, parallel-group, randomized, placebo-controlled study in the Netherlands in which adults aged ≥65 years received either PCV13 or placebo. Outcomes of interest were identified using prespecified clinical criteria, radiographic confirmation, routine microbiologic testing, and a serotype-specific urinary antigen detection assay. In this post hoc analysis, participants were classified by at-risk status based on self-reporting of any of the following chronic medical conditions: heart disease, lung disease, asthma, diabetes, liver disease, and smoking. The objective of this analysis was to assess PCV13 vaccine efficacy (VE) against a first episode of vaccine-serotype community-acquired pneumonia (VT-CAP) in at-risk participants. RESULTS: Of the 84,496 adults enrolled in the study, 41,385 (49.2%) were considered at risk owing to chronic medical conditions. Of the 139 VT-CAP cases, 115 (82.7%) occurred in these participants. VE of PCV13 against a first episode of VT-CAP among participants with at-risk conditions was 40.3% (95.2% CI: 11.4%, 60.2%). Average duration of follow-up since vaccination was 3.95 years for at-risk participants; protection did not wane over the study period. CONCLUSIONS: This post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed significant and persistent efficacy of PCV13 against VT-CAP in at-risk older adults. ClinicalTrials.gov identifier: NCT00744263.

Cost of Herpes Zoster in Patients With Selected Immune-Compromised Conditions in the United States.

Background. This retrospective study investigates the healthcare costs of herpes zoster (HZ) in patients with selected immune-compromised (IC) conditions in the United States (US). Methods. Patients with incident HZ diagnosis (index date) were selected from nationwide administrative claims databases from 2005 to 2009. Baseline IC groups, analyzed separately, included adults aged 18-64 years with the following: human immunodeficiency virus infection (HIV), solid organ transplant (SOT), bone marrow or stem cell transplant (BMSCT), or cancer; and older adults (aged ≥65 years) with cancer. Herpes zoster patients (n = 2020, n = 1053, n = 286, n = 13 178, and n = 9089, respectively) were 1-to-1 matched to controls without HZ (with randomly selected index date) in the same baseline group. The healthcare resource utilization and costs (2014 US dollars) during the first 2 postindex quarters were compared between matched cohorts with continuous enrollment during the quarter. Results. Herpes zoster patients generally had greater use of inpatient, emergency room and outpatient services, and pain medications than matched controls (P < .05). The incremental costs of HZ during the first postindex quarter were $3056, $2649, $13 332, $2549, and $3108 for HIV, SOT, BMSCT, cancer in adults aged 18-64 years, and cancer in older adults, respectively (each P < .05). The incremental costs of HZ during the second quarter were only significant for adults aged 18-64 years with cancer ($1748, P < .05). The national incremental costs of HZ were projected to be $298 million annually across the 5 IC groups. Conclusions. The healthcare cost associated with HZ among patients with studied IC conditions was sizable and occurred mainly during the first 90 days after diagnosis.