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Pneumococcal Disease among Human Immunodeficiency Virus-Infected Persons: Incidence, Risk Factors, and Impact of Vaccination

  1. Mark S. Dworkin1,a,
  2. John W. Ward1,3,
  3. Debra L. Hanson1,
  4. Jeffrey L. Jones1,2,
  5. Jonathan E. Kaplan1,2, and
  6. the Adult and Adolescent Spectrum of HIV Disease Projectb
  1. 1 Division of HIV/AIDS Prevention-Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention, Atlanta
  2. 2 National Center for Infectious Diseases, Atlanta
  3. 3 Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta
  1. Reprints: National Center for HIV, STD, and TB Prevention, Office of Communications, Centers for Disease Control and Prevention, Mail Stop E-06, Atlanta, GA 30333. Correspondence: Dr. Mark S. Dworkin, State Epidemiologist, Illinois Department of Public Health, 160 N. LaSalle St., #7 South, Chicago, IL 60601 (mdworkin{at}idph.state.il.us).

  • ↵a Present affiliation: Illinois Department of Public Health, Chicago.

 
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Abstract

To determine the factors associated with pneumococcal disease (pneumococcal pneumonia or invasive disease) and the impact of pneumococcal vaccine in HIV-infected persons, we analyzed patient data collected by the Adult and Adolescent Spectrum of HIV Disease Project for person-time between January 1990 and December 1998. Among 39,086 persons with 71,116 person-years (py) of observation, 585 episodes of pneumococcal disease were diagnosed (incidence, 8.2 episodes per 1000 py). Factors associated with an increased risk for pneumococcal disease (P < .05) included injection drug use (adjusted relative risk [RR], 1.5) and blood transfusion (RR, 2.0) as the mode of HIV transmission (referent, male-male sex); black race/ethnicity (RR, 1.5; referent, white race); history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic illness (RR, 2.1); a CD4+ cell count of 200–499 cells/µL (RR, 2.5) or <200 cells/µL (RR, 3.7; referent, CD4+ cell count of ⩾500 cells/µL); and alcoholism (RR, 2.0). Factors associated with a decreased risk included prescription of antiretroviral therapy (RR for monotherapy, 0.6; for dual therapy, 0.7; for triple therapy, 0.5) and pneumococcal vaccination (RR for persons vaccinated at a CD4+ cell count of ⩾500 cells/µL, 0.5). We recommend that pneumococcal vaccine be given to HIV-infected persons before profound immunosuppression has occurred.

Infection with Streptococcus pneumoniae is the most common cause of bacterial pneumonia among HIV-infected persons in the United States [1]. It has been estimated to occur 100 times more frequently among such persons than among the general population [2]. Recurrence is relatively common (13% of cases recur within 6 months), and the reported mortality rate among HIV-infected persons with bacteremic pneumococcal pneumonia is 5%–11% [3].

Immunization with a single dose of 23-valent polysaccharide pneumococcal vaccine is recommended for HIV-infected adolescents and adults who have a CD4+ T lymphocyte count of ⩾200 cells/µL; it is optional for persons who have a CD4+ cell count of <200 cells/µL [4]. These recommendations were based on the results of 2 studies that predated the use of highly active antiretroviral therapy and virus load monitoring [5, 6]. Clinical trial data that demonstrate the efficacy of pneumococcal vaccine among HIV-infected persons are scarce. To describe the incidence and risk factors of pneumococcal disease and the impact of pneumococcal vaccine, we analyzed data collected throughout the 1990s by the Adult and Adolescent Spectrum of HIV Disease Project (ASD), a large, diverse cohort of HIV-infected persons in the United States. Our results reinforce the importance of administration of pneumococcal vaccine to HIV-infected persons early during the course of the infection.

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Methods

The methods used by the ASD, a national surveillance project of the Centers for Disease Control and Prevention in collaboration with 11 state and local health departments, have been reported elsewhere [7, 8]. The staff of the ASD abstracts data from the medical records of HIV-infected patients at selected health care facilities. Initial abstraction of data from these records involves collection of information on demographics, the mode of exposure to HIV, previous occurrences of conditions listed in the surveillance case definition of AIDS [9] and of other conditions, types of medications prescribed, and CD4+ cell counts recorded during the year before patient selection. The initial data abstraction is followed by abstractions that are performed every 6 months until the patient either dies or is lost to follow-up. ASD staff members began abstracting data from medical records at project sites in 1990 (Atlanta, Dallas, Houston, San Antonio, Denver, Detroit, Los Angeles, New Orleans, and Seattle), 1991 (New York City), and 1992 (Bayamon, Puerto Rico). Participating facilities include hospitals, outpatient offices, and emergency departments.

Data were collected through April 1999 and reflect follow-up observations that occurred from January 1990 through December 1998. The cumulative duration of follow-up for the population was used to calculate person-time (expressed as “person-years” [py] of follow-up). The data set was restricted to 6-month follow-up intervals, during which time either a health care visit occurred (e.g., for an outpatient visit, hospitalization, or phlebotomy) or the patient died. Pneumococcal disease was defined as physician-diagnosed pneumonia, meningitis, bacteremia, sepsis, endocarditis, pleural effusion, or joint infection for which S. pneumoniae was identified as the etiologic agent. The specific method used to identify S. pneumoniae was not recorded. Diagnosis of pneumococcal otitis media or externa, pharyngitis, bronchitis, or unspecified upper respiratory tract infection did not define a case in the analysis, because these clinical conditions may be less severe and because their primary etiologic agent may be viral in patients with pneumococcal carriage. Invasive conditions included bacteremia with and without pneumonia, meningitis, sepsis, endocarditis, pleural effusion, and joint infection.

Poisson multiple regression with robust variance estimates [10] was used to determine the independent factors associated with all episodes of pneumococcal disease. Factors that were examined for a possible association with pneumococcal disease included alcoholism documented during the previous or concurrent 6-month interval; hospitalization that occurred during the previous 6-month interval; current age; the CD4+ cell count (<200 cells/µL, 200–499 cells/µL, or ⩾500 cells/µL) measured within 5 months prior to, or at the time of, observation; history of an AIDS-defining opportunistic illness (other than recurrent bacterial pneumonia); mode of HIV transmission; sex; race/ethnicity; prescription of trimethoprim-sulfamethoxazole (TMP-SMZ) and Mycobacterium avium complex (MAC) prophylaxis (with rifabutin, clarithromycin, or azithromycin [the antimicrobial spectrum of all 3 includes S. pneumoniae]) during the previous and current 6-month intervals; prescription of antiretroviral therapy (e.g., monotherapy, dual therapy, or triple-drug therapy) during the previous 6-month interval; diagnosis of pneumococcal disease during the 12 months prior to enrollment in the ASD; and administration of pneumococcal vaccine at varying CD4+ cell count levels. To determine whether the risk for pneumococcal disease associated with pneumococcal vaccine status was constant for all subpopulations, we examined models stratified according to race/ethnicity, mode of HIV transmission, sex, antiretroviral therapy, and CD4+ cell count.

Follow-up intervals that included a diagnosis of pneumonia caused by a pathogen other than S. pneumoniae or an unspecified pathogen were excluded from the risk-factor analysis, since S. pneumoniae could have been the cause of some of these pneumonias but may not have been detected or recorded in the medical records. Intervals that included a diagnosis of noninvasive pneumococcal disease (e.g., sinusitis, otitis, or other upper respiratory tract infection) were also excluded for the same reasons. If patients were vaccinated with pneumococcal vaccine more than once, the interval after the second vaccination was excluded. Incidence density rates were computed as the number of cases per 1000 py of follow-up.

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Results

During 71,116 py of observation, there were 585 episodes of pneumococcal disease (incidence rate, 8.2 episodes per 1000 py). Among these episodes, there were 474 episodes of pneumonia (with or without bacteremia; 81.0%), 110 episodes of bacteremia (18.8%), 11 episodes of meningitis (1.9%), 4 episodes of pleural effusion (0.7%), 3 episodes of joint infection (0.5%), and 2 episodes of endocarditis (0.3%). These diagnoses were not mutually exclusive. Among persons who were not vaccinated with pneumococcal vaccine, the rate of incidence of pneumococcal disease, as stratified according to recent CD4+ cell counts, increased in relation to decreases in the CD4+ cell count (incidence among patients with a CD4+ cell count of <200 cells/µL, 12.7 episodes per 1000 py; 200–499 cells/µL, 5.9 episodes per 1000 py; and ⩾500 cells/µL, 1.9 episodes per 1000 py).

Characteristics of the cases, persons, and person-years included in the analysis, as well as incidence rates and results of risk-factor analysis, are summarized in table 1. The risk factors that were significantly associated with an increased risk of pneumococcal disease included injection drug use or blood transfusion as the mode of HIV transmission, black race/ethnicity, history of AIDS-related opportunistic illness, CD4+ cell count of <500 cells/µL, alcoholism, recent hospitalization, and history of pneumococcal disease.

Table 1Table 1
View larger version:
Table 1

Characteristics, incidence, and results of multivariate Poisson regression analysis done to determine the independent risk factors associated with pneumococcal disease among HIV-infected persons.

A decreased risk for pneumococcal disease was demonstrated in association with prescription of antiretroviral therapy (e.g., monotherapy, dual therapy, or triple therapy) and administration of pneumococcal vaccine when the CD4+ cell count was ⩾500 cells/µL. The risk for pneumococcal disease was not affected by the prescription of prophylaxis with TMP-SMZ for Pneumocystis carinii pneumonia or prophylaxis against MAC (table 1). There were no significant effects of interaction between vaccine status and other covariates included in the model.

Additional multivariate analyses were performed to examine the impact of pneumococcal vaccination on the incidence of noninvasive pneumococcal pneumonia and invasive pneumococcal disease. For noninvasive pneumococcal pneumonia (368 episodes), the incidence decreased in relation to increasing CD4+ cell counts at the time of vaccination (incidence among patients with a CD4+ cell count of <200 cells/µL, 6.7 episodes per 1000 py; 200–499 cells/µL, 3.3 episodes per 1000 py; and ⩾500 cells/µL, 1.8 episodes per 1000 py; in comparison, the incidence among patients who were not vaccinated was 5.8 episodes per 1000 py). For invasive pneumococcal disease (238 episodes), a similar decrease in incidence was observed to occur in relation to an increase in the CD4+ cell count at the time of vaccination (incidence among patients with a CD4+ cell count of <200 cells/µL, 3.7 episodes per 1000 py; 200–499 cells/µL, 2.7 episodes per 1000 py; and ⩾500 cells/µL, 0.8 episodes per 1000 py; in comparison, the incidence among patients who were not vaccinated was 3.8 episodes per 1000 py). However, among the additional multiple regression analyses, only the analysis of invasive disease demonstrated a statistically significant finding. Those persons who had a CD4+ cell count of ⩾500 cells/µL at the time of vaccination had a reduced risk for invasive pneumococcal disease (P = .05).

Of all 39,086 persons, 14,696 (37.6%) had documentation of pneumococcal vaccination in their medical records; 5144 (35%) of the 14,696 had received the vaccination within 6 months of follow-up after enrollment. No temporal trend in vaccination rates was demonstrated for these persons. Among persons in the analysis with subsequent follow-up and a known CD4+ cell count at vaccination, 20.4% had been vaccinated at a CD4+ cell count of ⩾500 cells/µL. The median CD4+ cell count at vaccination was 257 cells/µL (25th percentile, 82 cells/µL; 75th percentile, 452 cells/µL). Missed opportunities to vaccinate were demonstrated by the fact that only 40.2% of person-time at a CD4+ cell count of ⩾500 cells/µL (3951 persons/9821.5 py) occurred among persons who had received the vaccine.

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Discussion

Our study demonstrated several risk factors associated with pneumococcal disease. Among these factors was black race, since an increased risk for pneumococcal disease was found among black patients. This finding is similar to that in a nested case-control study of 85 case patients and 85 control subjects described by Gebo et al. [6], who found an increased risk of pneumococcal disease among black patients. Other investigators have also reported similar findings in studies of the general population [11–13]. Whether this increased risk is based on genetic susceptibility, socioeconomic status, or some other factor remains to be determined.

We also found that injection drug use, blood transfusion, alcoholism, recent hospitalization, and a history of pneumococcal disease within 1 year of enrollment in the ASD were associated with an increased risk for pneumococcal disease. Injection drug use has been reported to be a risk factor for bacterial pneumonia [14–18]. However, blood transfusion has not been previously reported as a mode of HIV transmission associated with an increased risk for pneumococcal disease.

Other analyses of pneumococcal disease have not assessed blood transfusion as a risk factor for disease, since too few patients with this mode of HIV transmission have been included in the study populations. However, blood transfusion is a plausible risk factor, because persons who underwent blood transfusions may have had predisposing risk factors for pneumococcal infection (e.g., renal failure or malignancy) at the time that they received HIV-infected blood [19, 20]. Previous hospitalization is probably associated with pneumococcal infection, because diseases that are recognized as risk factors for pneumococcal disease in the general population are often reasons for hospitalization [21]. Alcoholism was reported to be associated with pneumococcal infection prior to the beginning of the recognition of the HIV epidemic in the early 1980s [19, 22, 23], although it has not been consistently demonstrated to increase either the risk for pneumococcal infection [19] or the risk for bacterial pneumonia in HIV-infected persons [14]. Our study documents an increased risk for pneumococcal disease in association with the aforementioned factors in an HIV-infected population.

In our study, the incidence of pneumococcal disease decreased in association with administration of antiretroviral therapy. Gebo et al. [6] found a decreased risk for pneumococcal disease among persons who were prescribed zidovudine. These findings suggest that the effects of antiretroviral therapy are associated with a decreased risk for pneumococcal disease as well as improved AIDS-related morbidity and mortality rates [24–26].

Our study did not demonstrate a decreased risk for pneumococcal disease in patients who were prescribed TMP-SMZ. Similar findings have been reported elsewhere [6, 16]. In one study, TMP-SMZ prophylaxis was reported to decrease the risk of confirmed cases of bacterial pneumonia by 67%; however, S. pneumoniae was identified in less than one-fifth of these cases of pneumonia [14]. On the basis of the results of these studies, we suspect that TMP-SMZ may prevent some episodes of bacterial pneumonia but that it is not effective for prevention of pneumococcal disease [27].

Studies of bacterial pneumonia in HIV-infected persons demonstrate that although S. pneumoniae is the most common cause, it is found in fewer than 20% of patients, and a pathogen is not generally identified as the cause [14, 16]. Antimicrobial resistance and lack of information on the dosage of TMP-SMZ necessary to prevent pneumococcal disease have been cited as possibly being related to the failure of TMP-SMZ to prevent pneumococcal disease [6]. In the United States, the prevalence of resistance of S. pneumoniae to TMP-SMZ has been reported to vary from 18% to 60% and to have increased during the past 2 decades [28–30].

We did not find a decreased risk for pneumococcal disease in association with the prescription of prophylaxis against MAC. Other studies have reported that regimens that include azithromycin and that are prescribed as prophylaxis against MAC have reduced the frequency of non-MAC bacterial infections [31, 32]. Emerging resistance to macrolides may have an impact on this benefit, especially in persons infected with penicillin-resistant organisms, since such strains have a higher prevalence of resistance to macrolides [28].

Our study demonstrated that pneumococcal vaccines that were administered when the CD4+ cell count was ⩾500 cells/µL produced a significantly decreased risk for pneumococcal disease among HIV-infected persons. This finding supports the recommendation to vaccinate when the patient's CD4+ cell count is in this range [4]. On the basis of our study, the language in the US Public Health Service/Infectious Diseases Society of America guidelines for the prevention of opportunistic infections in persons infected with HIV could be changed to indicate that persons with a CD4+ cell count of ⩾500 cells/µL should “always,” rather than “generally,” be offered pneumococcal vaccination. This effect was not demonstrated for persons with CD4+ cell counts of 200–499 cells/µL; however, the incidences of pneumococcal disease, noninvasive pneumococcal pneumonia, and invasive pneumococcal disease were lower for persons with a CD4+ cell count in this range who were vaccinated, compared with those who were not vaccinated. Therefore, we suspect that vaccination may benefit some persons who have a CD4+ cell count in this middle range and that it should be considered.

Administration of pneumococcal vaccine to HIV-infected persons is supported by the following factors: it is inexpensive and cost-effective [33], and it covers the majority of pneumococcal serogroups that cause pneumococcal bacteremia [34]. It is of increased importance to vaccinate HIV-infected persons, given the reported increases in antibiotic-resistant S. pneumoniae [4]. In addition, HIV-infected persons have many of the risk factors for acquisition of drug-resistant S. pneumoniae infections, including infection with HIV, recent antimicrobial therapy, coexisting illness or underlying disease, immunodeficiency, and recent or current hospitalization [28].

We found that rates of vaccination were very low and had not increased during the study period. A low level of pneumococcal vaccination among the general US population has also been reported [35]. We hypothesize that this is due to several factors, including the reimbursement practices of some insurance payers, the lack of significant advertising or public health campaigns that advocated pneumococcal vaccination in the 1990s, the absence of a controlled clinical trial that demonstrates the efficacy of the vaccine in HIV-infected persons, and concern about vaccine-associated adverse reactions that occur after revaccination as well as observations of increased virus load [3, 35–39].

However, pneumococcal vaccine has not been demonstrated to cause long-lasting changes in virus load [40, 41]. In our study, the median CD4+ cell count at the time of pneumococcal vaccination was 276 cells/µL. Therefore, many patients who receive the vaccine are undergoing vaccination when the immune system has impaired antibody responses [3, 42, 43]. Our study supports vaccination that is done early during the course of HIV infection, and it underscores the need to identify HIV-infected persons as early as possible and to provide them with care.

Among the limitations of our study is the fact that the ASD does not involve population-based surveillance. As a result, the findings of our study might not be generalizable to all HIV-infected adults and adolescents who receive care in the United States. However, the ASD is large and diverse, and it has enrolled thousands of HIV-infected persons since its inception. Because the ASD is a surveillance study that involves the abstraction of data from medical records, it relies on documentation by health care providers and their staff for completeness of information. We cannot be certain that pneumococcal vaccination is routinely recorded in the medical records, and our rates of vaccination thus may be lower than the true rates.

The initial data abstraction in the ASD is a 12-month retrospective review of the medical records for most conditions, and it includes review of pneumococcal vaccination. Some patients could have been vaccinated prior to this 12-month period. However, many patients enrolled in the ASD are beginning to receive care for HIV disease and are unlikely to have received pneumococcal vaccine in the past. The rate of vaccination found in our study was similar to the low rates described in other populations [35].

Our study did not address patient adherence to medications, such as prophylaxis or antiretroviral agents, nor did it collect exact dates or reasons why medications were chosen. The ASD is able to monitor only prescription of medications. Finally, these data were derived from an observational database and not from a prospective clinical trial. Although our findings may not carry the same weight as the results of a clinical trial of pneumococcal vaccine in HIV-infected persons, there are no data from US clinical trials that are available for comparison.

In conclusion, we emphasize heightened awareness of the potential value of pneumococcal vaccine, and we recommend that it be administered to HIV-infected persons early in the course of HIV infection, before profound immunosuppression has occurred. It remains to be determined whether pneumococcal vaccine should be withheld from HIV-infected antiretroviral-naive persons with a CD4+ cell count of <500 cells/µL until antiretroviral therapy has been administered and the CD4+ cell count has been boosted.

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Acknowledgments

We gratefully acknowledge the administrative assistance of Scott B. McCombs, the database management performed by Pei-Chun T. Wan and Michael Adams (for the ASD), and the review of the manuscript by Anne Schuchat.

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Footnotes

  • Received May 12, 2000.
  • Revision received July 14, 2000.
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Appendix

ASD investigators (locations): Melanie Thompson and Julia Gable (AIDS Research Consortium of Atlanta); Sylvia Odem and Dr. Sharon Melville (Texas Department of Health, Austin); Drs. Arthur Davidson, David L. Cohn, and Cornelius Rietmeijer (Denver Department of Health and Hospitals); Dr. Linda L. Wotring and Eve D. Mokotoff (Michigan Department of Community Health, Detroit); Wes McNeely and Kaye Reynolds (Houston Department of Health and Human Services); Dr. Frank Sorvillo, Jane Turner, and Dorothy Masters (Los Angeles County Department of Health Services); Stephanie Broyles and Anne Morse (Louisiana Office of Public Health, New Orleans); Dr. Judy Sackoff (The City of New York Department of Health); Jose Otero, and Drs. Robert Hunter and Maria de los Angeles Gomez (University Central del Caribe, Bayamon, Puerto Rico); Sandra Miranda (Puerto Rico Department of Health, San Juan); and Beth Sohlberg, and Drs. Susan Buskin and Sharon G. Hopkins (Seattle-King County Department of Public Health).

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  1. Clin Infect Dis. (2001) 32 (5): 794-800. doi: 10.1086/319218
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