Humans live in a close symbiotic relationship with Streptococcus pneumoniae. There is no other recognized natural reservoir for this organism, and, at any given time, ≥30% of children and 5%-10% of adults carry the organism in their nasopharynx without signs of disease.9,29 Nevertheless, pneumococcus has the capacity to spread locally in the upper and lower airways and to invade lymphatics or the blood stream, causing a wide array of infectious diseases. Invasive pneumococcal disease (IPD) remains an important problem worldwide, with a reported incidence ranging from 7 to 97 per 100,000 adults per year and a mortality of 8%-40%.17,19,20,27 In this article we describe IPD in the United States during the first decade of the 21st century, based on our experience at a large tertiary care medical center.
Under protocols approved by the Institutional Review Board, Baylor College of Medicine, we have maintained a database of patients with pneumococcal infection at the Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (MEDVAMC) since 2000. The present study included all cases of IPD, defined as those in which S pneumoniae was isolated from a normally sterile body site, including blood, cerebrospinal fluid (CSF), pleural fluid, peritoneal fluid, joint fluid, or a closed abscess, during 9 years between January 2000 and December 2008.
Although much of the relevant information had already been entered into our database, for the purposes of the current study we re-reviewed complete electronic records of patients to verify clinical, microbiologic, and epidemiologic data.
Since 2003, we have stored all pneumococcal isolates from normally sterile body sites at −70°C in tryptic soy broth containing 15% glycerol. Upon recovery from the freezer, isolates were restudied to verify colonial morphology, alpha-hemolysis on sheep blood agar, and susceptibility to optochin and bile. Penicillin and cefotaxime susceptibility were tested by the Kirby-Bauer method and/or E-test strips (AB Biodisk, Solna, Sweden), using breakpoints that were redefined in 2009.2 Serotyping was performed with agglutination and Quellung reactions using pneumococcal antisera (Statens Serum Institute, Copenhagen, Denmark). Sequential Multiplex polymerase chain reaction (PCR) was performed to verify capsular serotypes,8,37 using primers obtained from Sigma Genosys (The Woodlands, TX).
Categorical variables were analyzed by the Fisher exact test. Results were considered significant when p value was < 0.05.
One hundred thirty-two patients had 136 episodes of IPD during the study period. In 4 patients who had 2 infections each, the time between infections was up to 8 years. Because the age, vaccine status, and even the comorbid conditions changed between the first and second infection, we elected to analyze each bout of infection as if it had occurred in a separate patient. Ninety of 136 cases (66.2%) of IPD occurred during 5 months, December through April (18.0 cases per mo), compared to 46 during the 7 months May through November (6.6 per mo). This distribution was not constant per month (p < 0.001) and appeared seasonal, with most cases clustered during the winter months (chi-square Goodness of Fit test, Figure 1). The average age of patients (63.0 yr; range, 28-92 yr) and the male predominance (97.8%) closely resembled the population served by MEDVAMC (Table 1). The racial distribution of IPD cases, however, differed. Whereas white patients comprise 64.1% of our population and African American patients 29.8%, among IPD cases, 52.9% of patients were white and 43.4% black. The number of cases per year did not change during the 9-year study, nor did the overall mortality at 30 days after hospitalization.
Of the 136 patients, 121 (88.9%) had ≥1 comorbid condition for which 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended, and an additional 8 lacked comorbid conditions but were aged ≥65 years old (Table 1); thus 94.9% of patients with IPD had at least 1 medical indication for receiving PPV23. Of these subjects only 74 (57.4%) had been vaccinated. This compares to an estimated compliance rate for PPV23 of about 82% at MEDVAMC.
One hundred forty-one sites of infection were identified (Table 2). Bacteremic pneumonia was the most common form of IPD, affecting 116 of 136 patients (85.3%). These patients were remarkably similar to those previously described from this medical center.30 Eleven of the 116 patients (9.5%) had a pleural effusion that was large enough to tap. Ten of these (8.6% of the 116) were exudative effusions,22 of which 3 (2.6% of the 116) had bacteria detected by gram stain and/or culture, thereby meeting criteria for empyema.23 All had received antibiotics before the pleural fluid was obtained, so it is possible that bacteria might have been found in the others had the pleural tap been done in a more timely fashion.
Seven of 136 patients (5.1%) had pneumococcal bacteremia of unknown source. None had respiratory symptoms, and chest X-rays in all cases were negative, as was computerized tomography of the chest in 1. These patients had major underlying diseases; 5 had either a hematologic malignancy or a metastatic solid organ tumor, although none was neutropenic. Two had alcoholic cirrhosis with ascites, but a peritoneal tap with culture was not done to exclude spontaneous bacterial peritonitis as a possible source for the bacteremia. The only cases of polymicrobial bacteremia in this series occurred in patients with no apparent source: 1 with concurrent Escherichia coli and 1 with Neisseria meningitidis.
Five of the 136 patients (3.7%) had pneumococcal meningitis; the presenting symptoms suggested the diagnosis in all cases. All 5 patients had altered mental status and fever. Four had a stiff neck; the fifth patient had a supple neck on repeated examination despite a CSF white blood cell count of 15,000/mm3 and a glucose level of 6 mg/dL. Two of these had clinical findings consistent with otitis media, and a third had chronic otitis with fluid detected in the middle ear at the time of admission.
Septic arthritis involved the knee in all 3 of the 136 patients (2.2%) who had this condition; 1 had infection of both knees. Two patients (1.5%) had endocarditis; 1 of these also had vertebral osteomyelitis and spinal epidural abscess. In only 3 cases of IPD were blood cultures negative (2 spontaneous bacterial peritonitis and 1 septic arthritis); in 1 additional case of septic arthritis, blood culture was not done. In 1 patient, the source of IPD was a dental root abscess.
Of 136 patients, 49 (36.0%) were treated with a beta-lactam together with a macrolide. Twenty-one (15.4%) received beta-lactam with a quinolone and 5 (3.7%) received a beta-lactam, a macrolide, and a quinolone. Sixteen patients (11.8%) were treated with a quinolone alone, and 36 (26.5%) with a beta-lactam alone. Nine patients (6.6%) received other antibiotics. There appeared to be no differences in survival based on any of these regimens.
Eight of 136 patients (5.9%) died within 72 hours, 15 (11.0%) within 7 days, and 22 (16.2%) within 30 days after the first culture that yielded S pneumoniae was obtained. Eleven of 116 patients (9.5%) with pneumonia died within 7 days, compared with 4 of the 12 (33.3%) who had primary bacteremia or spontaneous bacterial peritonitis (p = 0.03).
Eighty pneumococci from 2003 to 2008 were available for serotyping. Except for 7 isolates of type 6A, the predominant serotypes, comprising 57.5% of all isolates, were included in PPV23, namely, types 3, 19A, 22F, 7F, 11A, and 12F; none of these is a constituent of the 7-valent pediatric pneumococcal conjugate vaccine (PCV7). Type 7F appeared only in the final year of the study. Although classical serotyping techniques identified most serotypes, 5 isolates that could not be typed with antiserum pools were identified as type 6A/B by PCR. After this, the isolates were retested with specific antisera and were finally identified as 6A.
Of the 136 patients, 52 (38.2%) had received PPV23 within the last 5 years, and 23 (16.9%) at some time before that. Similar proportions of vaccine serotypes infected previously vaccinated and nonvaccinated patients (63.8% vs. 72.7%, respectively; p = 0.5).
Using currently accepted breakpoints,2 130 of 132 isolates were fully susceptible to penicillin and cefotaxime. One CSF isolate was resistant to penicillin (minimum inhibitory concentration [MIC] 1.5 μg/mL) but susceptible to cefotaxime, and 1 blood isolate was resistant to cefotaxime (MIC 4.0 μg/mL) but susceptible to penicillin.
In an age of continuing evolution of some infectious diseases, the manifestations of IPD have remained relatively constant. The distribution of cases during the first 9 years of the present century is similar to what was seen in the United States and Europe in the pre-antibiotic era,15 and in Brooklyn, New York 1952-1962,4 Sweden 1964-1980,7 Huntington, Virginia 1978-1981,28 and Israel 1993-1995,39 as well as in the Netherlands and the United States in the past decade1,17,43 (Table 3). The 43.4% prevalence of African Americans among patients with IPD when compared to the 29.8% background in the population served by our medical center is consistent with the observation14 that, in the American population, African American patients are at higher risk for IPD than white patients. In the modern era, IPD does not often occur in generally healthy young adults; 121 of the 136 patients (88.9%) in the current study had 1 or more comorbid conditions associated with susceptibility to pneumococcal infection, and another 8 were aged ≥65 years old. Thus, only 7 of 136 patients (5.1%) were apparently free of conditions known to predispose to pneumococcal disease.
Pneumonia is, by far, the most common IPD syndrome in adults, accounting for 85.3% of cases, followed distantly by bacteremia with no recognized focus (primary bacteremia), meningitis, spontaneous bacterial peritonitis, septic arthritis, endocarditis, and individual cases with other foci of infection. Studies from this medical center30 have previously confirmed earlier work36 showing that lobar is more likely than subsegmental pneumonia to cause bacteremia, and the majority of patients in the present series had lobar pneumonia.
In the current study, 11 of the 116 pneumonia patients had a pleural effusion that was deemed large enough to tap; 3 of these 11 (27.3%) met criteria for empyema,23 and it is likely that others would also have met these criteria had pleural effusions been obtained in a more timely fashion. After nearly a century of speculation, it is still uncertain whether empyema results from migration of pneumococci through visceral pleural lymphatics or by hematogenous seeding of a sympathetic pleural effusion.29 Empyema is generally seen when lobar pneumonia abuts the pleura, although, on occasion, a central pneumonia is responsible. In the pre-antibiotic era, this complication occurred less frequently with type 2 pneumococcal pneumonia than with pneumonia due to other types despite the high frequency of bacteremia in type 2 disease,15 supporting the concept that local rather than bacteremic spread to the pleura is the more likely pathogenesis.
It is noteworthy that even with the best modern techniques, no focus of infection could be identified in 7 of 136 patients (5.1%), slightly lower than the 7%-17% of patients with no recognized source for IPD that has been reported previously.7,17,39 This observation helps to explain the pathogenesis of syndromes such as septic arthritis without recognized bacteremia, in which hematogenous spread of organisms is clearly responsible despite the absence of pneumonia or recognition of positive blood cultures.42 Two of these 7 patients may have had spontaneous bacterial peritonitis, but appropriate microbiologic studies were not done to evaluate the possibility.
The pathogenesis of meningitis, which occurred in 5 of 136 patients (3.7%), is also complex.29 This condition is generally thought to arise from hematogenous seeding of the choroid plexus. Recent work points to an interaction between pneumococcal surface proteins and vascular endothelial cell receptors such as laminin or platelet activating factor, perhaps facilitated by cytokine-mediated upregulation.21,35,38 However, direct epithelial invasion with retrograde spread from the nasopharynx, sinuses, or middle ear via lymphatics may also be responsible. Three of our patients had clinical findings consistent with otitis immediately preceding the onset of meningitis. Other complications of IPD, such as endocarditis, osteomyelitis, and abscesses have always been rare and were found in individual cases in our series.
The 7-day mortality from bacteremic pneumococcal pneumonia was 11 of 116 (9.5%), perhaps lower, although not significantly so, than 10 of 52 (19.2%) reported from this same medical center between 1996 and 1999 (p = 0.13) or the 10%-20% mortality in series from other centers.4,11,24 It is noteworthy that, even if mortality appears to be somewhat reduced, it remains high despite earlier initiation of antibiotic therapy in accord with guidelines,25 greater availability of intensive care for persons who are severely ill, or a higher rate of vaccination (55% of our patients had previously received PPV23 compared to only 17% in our earlier report30 and 0% in the cases reported by Austrian and Gold4). In the current study, 72-hour mortality was 5.9%, identical to that in the Austrian and Gold study (although they included only patients with bacteremic pneumonia), and slightly lower than the 10.9% recorded by Yu et al.44
Although literature from the 1990s emphasized resistance of S pneumoniae to beta-lactam and other antibiotics, problems with then-accepted definitions of susceptibility or resistance31 led to a redefinition based on achievable antibiotic levels at the site of infection (specifically, systemic vs. central nervous system infection).2 With the use of these new definitions, 130 of 132 isolates (98.5%) were fully susceptible to penicillin and cefotaxime. Eighty-two percent of patients in the current study received a beta-lactam as a part of their therapeutic regimen.
Capsular typing of S pneumoniae by agglutination or the quellung technique has been in use for more than a century;15 our results suggest, however, that as many as 6.3% of types cannot be clearly identified by these techniques and that more reliance should probably be placed on PCR. Especially in the case of type 6A, we were readily able to serotype isolates by screening with PCR followed by the use of individual antisera for final identification.
The majority of patients (57.4%) in this series for whom PPV23 was indicated had received this vaccine, compared to approximately 82% in the population served by MEDVAMC. This finding is consistent with some protective effect by pneumococcal polysaccharide vaccine.10,26 Recent studies (Musher et al33 and Musher et al, unpublished data) have shown that low levels of antibody persist for at least 5-10 years, albeit at low levels. It is noteworthy that the infecting serotypes were similar in vaccinated and nonvaccinated patients. Although the numbers are small, there was no apparent difference in the 7-day mortality among vaccinated (6/75, 8.0%) versus nonvaccinated patients (9/61, 14.8%; p = 0.27). Persons with comorbid conditions that predispose to pneumococcal disease are likely to make lower levels of antibody after vaccination,32,40 and the antibody produced has lower biological activity than antibody that appears in otherwise healthy subjects.41 Further, 30% of patients with pneumococcal pneumonia have apparently ample levels of antibody against their own infecting serotype at the time of hospitalization as measured by enzyme-linked immunosorbent assay (ELISA), but this antibody does not opsonize the infecting organism well for phagocytosis and does not protect mice against experimental challenge.34 Thus, although PPV23 stimulates antibody production and reduces the incidence of pneumococcal pneumonia by 30%-60%,10,26 such protection is clearly far from uniform.
PCV7, introduced to widespread use in 2000, not only prevents disease caused by the 7 serotypes that it includes,5 but also reduces colonization.18 As colonization and disease due to PCV7 strains have decreased, new strains, called replacement strains, have emerged to fill the ecological niche that the original, highly prevalent strains once occupied; among the most widely recognized replacement strains are serotypes 19A and 7F,6,16 which were also prominent in our series. In other locales these types have exhibited varying degrees of reduced susceptibility to beta-lactam antibiotics,3 although we did not observe this phenomenon in the current study.
Limitations of the present study include the fact that all patients who might have invasive pneumococcal disease did not have blood cultures, so the true number of cases of IPD at our medical center may have been higher than our data reflect. In addition, our retrieval of cases in the first 2 years of the study was not as complete as in the final 7 years. Finally, we did not store isolates in 2000-2002, so serotype data are not available for those years.
In conclusion, S pneumoniae maintains its capacity to cause a wide array of syndromes of invasive disease, especially in persons who, because of comorbid conditions or advanced age, are at increased risk for such infection. Mortality is substantial despite the susceptibility of the causative organism to available antibiotics, and even prior administration of PPV23 is not fully protective. Alternative strategies for prevention, for example the use of broader-spectrum conjugate pneumococcal vaccines13 or non-capsule-based vaccines,12 need to be sought to prevent pneumococcal disease in populations at high risk for pneumococcal infection.
The authors are indebted to Dr. Laura Ann Peterson for unpublished data on the demographics of patients seen at the Michael E. DeBakey Veterans Administration Medical Center, Houston, and to Dr. Thomas Giordano for statistical advice.
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