(See the major article by Sherwin et al on pages 1813–20.) Nearly a century ago, Dochez and Avery [1] reported their studies of the pneumococcus, which not only set the stage for modern immunology and genetics but also demonstrated that specific pneumococcal substances could be found in the urine at the onset of pneumococcal pneumonia: “a specifically reacting substance of pneumococcus origin occurs in the … urine of patients during lobar pneumonia … which reacts specifically with antipneumococcus serum of the type corresponding to the organism with which the individual is infected.” Although these “substances” were delivered to the kidney from the blood, they were concentrated in the urine and thus more easily detected there than in serum [1]. Inspired by that discovery, the urine antigen detection (UAD) method, used in the study by Sherwin et al [2] reported in this issue of The Journal, uses monoclonal antibodies to detect 13 serotype-specific Streptococcus pneumoniae polysaccharides found in the urine of patients with pneumococcal disease; the UAD test has a reported sensitivity and specificity for bacteremic pneumococcal pneumonia of 97% and 100%, respectively [3]. Tillett et al [4] further reported in 1930 that the pneumococcal C-polysaccharide was a species-specific antigen common to all pneumococci. Toward the end of the 20th century, this observation was exploited commercially in the form of the BinaxNOW urine antigen test (Alere North America), which can be used to help diagnose pneumococcal pneumonia in adults but does not provide serotype information [5]. The package-insert reported sensitivity and specificity of the BinaxNOW test for bacteremic pneumococcal pneumonia is 90% and 71%–78%, respectively. One caveat about both the UAD and BinaxNOW tests is the lack of a reference standard with which to evaluate test characteristics against nonbacteremic pneumococcal pneumonia, the real target of most investigations. Routine vaccination of US infants with a 7-valent pneumococcal conjugate vaccine (PCV7) started in 2000. The impact of PCV7 vaccination program on invasive pneumococcal disease (IPD) has been monitored through population laboratory-based surveillance. This surveillance has shown that by 2007, PCV7 serotypes were rare causes of IPD in young children, and because nasopharyngeal carriage rates of these serotypes also declined substantially, vaccine-serotype IPD had declined by >85% in older children and adults, through indirect or “herd” protection [6]. However, assessing the impact on pneumonia, a much more common pneumococcal disease, is not as straightforward, because although 30%–60% of community-acquired pneumonia in all ages has historically been attributed to the pneumococcus, a definite pneumococcal diagnosis is often not established [7]. If the pneumococcus is responsible for a large proportion of all-cause pneumonia and a substantial proportion of pneumococcal pneumonias are due to vaccine serotypes, then the large database of US hospital discharges, the Nationwide Inpatient Sample (http://www.hcup-us.ahrq.gov/nisoverview.jsp), should be able to detect changes in pneumococcal pneumonia incidence using this sensitive but nonspecific outcome. By 2004, US pneumonia hospitalizations in children aged <2 years had declined by 39% (95% confidence interval [CI], 22%–52%) relative to pre-PCV7 rates, and a statistically significant decline in all-cause pneumonia discharges was also seen for adults aged 18–39 years, a subgroup who have close contact with vaccinated children [8]. These earlier declines have been sustained, and by 2009, all-cause pneumonia hospitalizations had declined 43% (95% CI, 35%–52%) in children aged <2 years and 11% (95% CI, 8%–13%) overall, with significant declines of 7%, 13%, and 23% in persons aged 65–74, 75–84, and ≥85 years. However, among adults aged 40–64 years, pneumonia hospitalizations had increased by 10% [9]. Trends in pneumonia hospitalizations thus suggest a substantial decline in pneumococcal pneumonia in the oldest age groups. The relative increase in pneumonia in adults aged 40–64 years is puzzling, but to some extent it parallels changes in IPD incidence. The overall decline in IPD, which takes into account the decline in vaccine serotypes and the increase in non–vaccine related disease, was only 18% in persons aged 50–64 years by 2007, compared with 37% in those aged ≥65 years and 40%–76% in younger age groups [6]. The study by Sherwin et al [2] was conducted in the United States in 2010–2011, right after the switch from PCV7 to 13-valent pneumococcal conjugate vaccine (PCV13) for childhood immunization in February 2010. The study used a UAD test, which was developed by Wyeth (now Pfizer) and includes the 13 pneumococcal serotypes included in Pfizer's pneumococcal conjugate vaccine (PCV13). The study evaluated the distribution of pneumococcal serotypes among patients with pneumonia and explored the residual fraction of pneumococcal pneumonia due to PCV7 serotypes a decade after PCV7 was introduced. The study included 710 patients aged ≥50 years (median age, 65 years) presenting with community-acquired (78%) or healthcare-associated (22%) pneumonia to study hospitals at 13 US sites. A combination of conventional techniques and the BinaxNOW and UAD tests demonstrated S. pneumoniae in 98 patients (13.8%). The UAD results were positive in 78 (11%) and, despite testing only 13 serotypes, the UAD test had a remarkably higher yield than the BinaxNOW test (4.8%) or blood cultures (2.0%). In fact, the BinaxNOW test detected only 15 (19%) of the 78 pneumonias due to the 13 vaccine serotypes that were detected with the UAD test. In addition, these 15 represented only 44% of detections with the BinaxNOW test, indicating that up to 56% of pneumonias detected with this test could have been due to serotypes not included in PCV13. Thus, the low sensitivity of the BinaxNOW test in this study suggests that as many as 25% of pneumonia cases requiring hospitalization could be pneumococcal in origin, rather than the 13.8% identified. The UAD test results were positive in 17%, 12%, and 10% of patients aged 50–64, 65–74, and ≥75 years, respectively. This could indicate a greater contribution of pneumococcal disease in the youngest age groups but could also result in part from the study's “convenience sampling” and apparent overrepresentation of patients with mild disease. Of the pneumonias identified with the UAD test, about 25% were associated with PCV7 serotypes, and 75% were due to the additional 6 serotypes in PCV13. Two other published studies have employed similar serotype-specific urinary antigen testing. A study of community-acquired pneumonia among adults in the Netherlands [10], performed 2–3 years after PCV7 introduction, used a diagnostic approach to pneumococcal detection almost identical to that used by Sherwin et al [2]. Pneumococcal pneumonia was diagnosed in 33%, and an estimated 70% of those cases were due to serotypes in PCV13; the distributions of PCV7 and the other 6 serotypes were 40% and 60%. A similar study of community-acquired pneumonia among adults in a single hospital in England 2–4 years after PCV7 introduction used conventional techniques plus the BinaxNOW and Bio-Plex urinary assays, which detected all PCV13 serotypes plus serotype 8 [11]. With use of these techniques, 40% of pneumonias were classified as pneumococcal, 57% of which were due to serotypes in PCV13; the distributions of PCV7 and the other 6 serotypes were 34% and 66%. The higher detection of pneumococcal disease in these populations as well as a higher representation of PCV7 serotypes could reflect the shorter use of PCV7 at the times of the studies but may also reflect differences in age, disease severity, and other characteristics of the study populations. The valuable data presented by Sherwin et al [2] call for additional studies to systematically ascertain the etiology of pneumonia and specifically the distribution of pneumococcal serotypes among pneumonia cases. This information will be useful to inform current US pneumococcal vaccination policies for adults. The 14- and then 23-valent pneumococcal polysaccharide vaccines have been recommended for persons at high risk for pneumococcal disease since the 1970s. Although the evidence for effectiveness against invasive disease is well established, there is still considerable controversy about the efficacy of polysaccharide vaccine in the prevention of noninvasive pneumococcal pneumonia and no conclusive evidence for efficacy against pneumonia in adults with chronic diseases [12]. With the changing epidemiology of pneumococcal diseases after routine vaccination of children with pneumococcal conjugate vaccines, the current polysaccharide vaccine will become much less cost-effective. On the other hand, the pneumococcal conjugate vaccines cover fewer serotypes, but indirect protection of adults derived from vaccination of infants with PCV7 is well recognized. Nevertheless, evidence of clinical efficacy from direct vaccination of adults with pneumococcal conjugate vaccines is currently limited to subjects with immunocompromising conditions [13]. The current study by Sherwin et al [2] indicates that, 10 years after PCV7 introduction, PCV7 vaccine serotypes that have declined substantially in both children and adults continue to cause a residual amount of pneumonia in adults. Interestingly, all 3 studies that used some variation of the new serotype-specific urinary antigen test suggest that the distribution of serotypes that cause pneumonia may differ somewhat from the distribution of those that cause invasive disease, an observation that requires further research. These studies also hold out realistic hope for a continued decline in pneumonias after the switch to the PCV13 vaccine in the United States, because these additional serotypes contribute a substantial burden of adult pneumonias. Whether PCV13 should be recommended for more adults awaits the results of the CAPITA trial [14], a placebo-controlled trial of PCV13 for pneumonia prevention in adults being conducted in the Netherlands as well as a careful evaluation of the indirect protection derived from routine vaccination of children with PCV13. The identification of specific serotypes responsible for noninvasive pneumococcal pneumonia, as performed by Sherwin et al [2], provides key information for the necessary evaluation of vaccine choices for adults. Because other organisms, both pneumococcal and nonpneumococcal, may “occupy the niche” of vaccine serotypes both in the respiratory tract and in clinical pneumonia, it will be important to continue to monitor the overall incidence and etiology of all-cause pneumonia. Financial support. M. R. G. and C. G. G. received grant support from the Centers for Disease Control and Prevention, the Thrasher Foundation, and Pfizer, and C. G. G. served as a consultant for GSK. M. R. G. is funded in part by the Mid-South Geriatric Research Education and Clinical Center, VA Tennessee Valley Health Care System. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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Griffin et al. (2013) studied this question.