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Since the widespread introduction of highly active antiretroviral therapy (HAART), decreasing rates of invasive pneumococcal disease (IPD) in HIV-infected patients [1–7] have been reported. Despite these data, the incidence of IPD in persons with HIV infection remains significantly higher than in similarly aged non-HIV-infected adults [1,2,5]. Advanced immunodeficiency and the association with other comorbidities appear to be the main risk factors for IPD [6–11], but a high incidence of IPD has also been reported, even in HIV-infected patients with CD4 counts >200 cells/μL .
Studies assessing the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV) in preventing pneumococcal pneumonia and IPD in HIV-infected adults have yielded controversial results. Several cohort and case–control studies have found that the vaccine produces a beneficial effect by decreasing the incidence of IPD, particularly in patients receiving HAART and with higher CD4 counts but also in patients with CD4 counts below 200 cells/μL [4,6,7,12–14]. In contrast, other studies, including the only published randomized double-blind placebo-controlled study, have not found a clear benefit of the 23-valent PPV in preventing IPD in HIV-infected patients [10,15–18]. In any case, because the impact of pneumococcal infections on morbidity and mortality remains high, vaccination with 23-valent PPV is currently recommended in HIV-infected patients, particularly in those with CD4 counts >200 cells/μL [19,20].
Recent studies in hospitalized patients with community-acquired pneumonia (CAP) have found a lower risk of bacteraemia and better clinical outcomes, including a faster resolution of pneumonia symptoms, a shorter length of hospital stay and a lower mortality rate, in patients who had previously received the 23-valent PPV compared with unvaccinated individuals [21–23]. Furthermore, among patients with documented pneumococcal pneumonia and patients with major risk factors for pneumococcal pneumonia (i.e. older patients and nursing home residents) the association of prior vaccination with 23-valent PPV and better clinical outcomes appeared to be more significant . To our knowledge there are no published data about these additional effects of 23-valent PPV in HIV-infected patients. The aim of the present study was to assess the influence of prior 23-valent PPV on clinical outcomes in HIV-infected adults hospitalized with IPD.
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A total of 162 episodes of IPD were studied. The mean age of patients was 38.5 years, and 126 (77.8%) episodes occurred in men and 36 (22.2%) in women. In 23 episodes (14.2%), the patient had previously received the 23-valent PPV, and in seven episodes the vaccine was administered more than 5 years before the episode of IPD.
Baseline characteristics of the patients stratified by 23-valent PPV vaccination status are shown in Table 1. There were some differences between vaccinated and unvaccinated patients at baseline. There was only one patient (4.3%) with chronic liver disease among the vaccinated patients, in comparison with 27 (19.4%) of 139 unvaccinated patients, although the difference was not significant. Prior vaccine recipients had significantly higher CD4 counts at the time of pneumococcal infection (325 cells/μL in vaccinated patients vs. 209 cells/μL in unvaccinated patients; P=0.014) and were more likely to be on HAART (59.1%vs. 34.5%; P=0.034).
Table 1. Baseline characteristics of patients according to pneumococcal vaccination status
| ||Vaccinated patients (n=23)||Unvaccinated patients (n=139)||P|
|Age (years) [mean (SD)]||38.5 (9.1)||38.5 (8.6)||0.993|
|Sex [n (%)]|
| Male||20/23 (87)||106/139 (76.3)||0.416|
| Female||3/23 (13)||33/139 (23.7)|| |
|Tobacco use [n (%)]||17/23 (73.9)||90/138 (65.2)||0.482|
|Alcohol abuse [n (%)]||4/23 (17.4)||31/138 (22.5)||0.786|
|Chronic liver disease [n (%)]||1/23 (4.3)||27/139 (19.4)||0.132|
|COPD [n (%)]||2/23 (8.7)||9/139 (6.5)||0.657|
|Haematological malignancy and/or splenectomy [n (%)]||4/23 (17.4)||4/139 (2.9)||0.015|
|Solid neoplasm [n (%)]||0/23||2/139 (1.4)||1|
|Prior hospitalization* [n (%)]||4/23 (17.4)||40/138 (29)||0.318|
|Current or previous injecting drug use [n (%)]||13/23 (56.5)||103/139 (74.1)||0.132|
|CD4 lymphocyte count [mean (SD)]||325 (244.2)||209 (192.1)||0.014|
|CD4 ≥200 cells/μL [n (%)]||15/21 (71.4)||61/138 (44.2)||0.033|
|HIV-1 viral load <50 copies/mL [n (%)]||5/20 (25)||13/113 (11.5)||0.148|
|HAART use [n (%)]||13/22 (59.1)||48/139 (34.5)||0.034|
|Prophylactic TMP-SMZ [n (%)]||5/22 (22.7)||40/138 (29)||0.619|
|Previous AIDS-defining illness [n (%)]||9/23 (39.1)||58/138 (42)||0.824|
The most common clinical presentation of IPD was bacteraemic pneumonia in both groups of patients and, interestingly, none of the patients who had received the 23-valent PPV had meningitis (Table 2). We could determine pneumococcal serotype in 101 cases. In 84 of them (83.2%) the serotype of the pneumococcal strain was included in the 23-valent PPV without significant differences between vaccinated and unvaccinated patients (76.9%vs. 84.1%).
Table 2. Clinical and microbiological characteristics according to pneumococcal vaccination status
| ||All patients (n=162; 100%)||Vaccinated patients (n=23; 14.4%)||Unvaccinated patients (n=139; 85.6%)||P|
|Bacteraemic pneumonia||134/162 (82.7%)||21/23 (91.3%)||113/139 (81.3%)||0.376|
|Primary bacteraemia||8/162 (4.9%)||2/23 (8.7%)||6/139 (4.3%)||0.317|
|Meningitis||10/162 (6.2%)||0/23||10/139 (7.2%)||0.360|
|Peritonitis||10/162 (6.2%)||0/23||10/139 (7.2%)||0.360|
|23-valent PPV included serotype*||84/101 (83.2%)||10/13 (76.9%)||74/88 (84.1%)||0.455|
|Penicillin nonsusceptible strain*||60/157 (38.2%)||5/23 (21.7%)||58/139 (41.7%)||0.104|
|Cefotaxime nonsusceptible strain*||22/128 (17.2%)||1/20 (5%)||21/108 (19.4%)||0.194|
|Cotrimoxazole nonsusceptible strain*||68/153 (44.4%)||5/20 (25%)||63/133 (47.4%)||0.090|
In Table 3 we show the outcome variables related to pneumococcal infection according to prior pneumococcal vaccination. Overall, in 21 episodes (13%) patients required ICU admission, 25 patients (15.4%) died during their hospital stay, and in 34 episodes (21%) patients reached the composite outcome of death and/or admission to the ICU. In none of the 23 episodes that occurred in patients who had previously received the 23-valent PPV was the composite outcome of death and/or admission to the ICU reached, in comparison with 34 episodes (24.5%) that occurred in unvaccinated patients (P=0.004). None of the vaccinated patients died or required ICU admission, in contrast with 25 (P=0.026) and 21 (P=0.046) of the unvaccinated patients, respectively. Moreover, the mean length of hospital stay was significantly shorter in vaccinated patients (8.48 vs. 13.27 days; P=0.011). When we examined the subgroup of patients with bacteraemic pneumonia, we found that those who had received the 23-valent PPV were less likely to have severe pneumonia at clinical presentation (PSI class IV or V) than unvaccinated patients (16.7 and 37.4%, respectively) and none of the vaccinated patients developed empyema compared with 9.3% of the unvaccinated patients, although these differences were not significant.
Table 3. Outcome variables related to invasive pneumococcal disease according to prior vaccination status; on the right side of the table, patients with chronic liver disease have been excluded
|(n=162)||All patients (n=162)||All patients included||Patients with chronic liver disease excluded*|
|Vaccinated (n=23)||Unvaccinated (n=139)||P||Vaccinated (n=22)||Unvaccinated (n=112)||P|
|Death and/or ICU admission||34/162 (21)||0/23||34/139 (24.5)||0.004||0/22||25/112 (22.3)||0.013|
|In-hospital mortality||25/162 (15.4)||0/23||25/139 (18)||0.026||0/22||16/112 (14.3)||0.073|
|ICU admission||21/162 (13)||0/23||21/139 (15.1)||0.046||0/22||19/112 (17)||0.042|
|Orotracheal intubation||15/162 (9.3)||0/23||15/139 (10.8)||0.132||0/22||13/112 (11.6)||0.126|
|Shock||17/135 (12.6)||1/21 (4.8)||16/114 (14)||0.471||1/20 (5)||14/96 (14.6)||0.463|
|Empyema||10/129 (7.8)||0/21||10/108 (9.3)||0.365||0/20||10/95 (10.5)||0.206|
|PSI high risk classes†||43/125 (34.4)||3/18 (16.7)||40/107 (37.4)||0.111||2/17 (11.8)||29/95 (30.5)||0.146|
|Days of hospital stay [mean (SD)]||12.62 (13.87)||8.48 (6.14)||13.27 (14.62)||0.011||8.5 (6.29)||14.29 (15.88)||0.007|
|Days to defervescence [mean (SD)]||3.11 (4.09)||2.55 (2.72)||3.21 (4.28)||0.484||2.62 (2.76)||3.17 (3.52)||0.497|
Only one of the 24 patients with chronic liver disease had received 23-valent PPV. As chronic liver disease has been described as a risk factor for pneumococcal infection and this condition could influence the results, favouring a worse prognosis in unvaccinated patients, we attempted to avoid a possible selection bias by performing a new analysis excluding all patients with chronic liver disease (Table 3). In this subgroup of patients the difference between vaccinated and unvaccinated patients remained significant when the composite outcome of death or admission to the ICU was measured. None of the previously vaccinated patients reached this composite outcome, in contrast with 22.3% of the unvaccinated patients (P=0.013). The proportion of unvaccinated patients who died during their hospital stay (14.3%) or required ICU admission (17%) remained higher than that for vaccinated patients, where there were no deaths or ICU admissions, although differences in mortality rates were not statistically significant. The length of hospital stay was also significantly shorter for previously vaccinated patients than for unvaccinated patients (8.5 vs. 14.29 days; P=0.007).
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Recently, some authors have suggested that prior pneumococcal vaccination is associated with improved outcomes in vaccinated patients who develop CAP [22–24]. Our findings in HIV-infected patients are consistent with those previously published in non-HIV-infected patients. The composite outcome of death or admission to the ICU was significantly lower in previously vaccinated patients compared with unvaccinated patients. In fact, none of the vaccinated patients died or required admission to the ICU during their hospital stay for IPD. These data suggest that, despite the failure to prevent pneumococcal infection, prior PPV administration has a favourable impact in HIV-infected patients who develop IPD by improving clinical outcomes. The length of hospital stay was also significantly shorter in vaccinated patients. Regarding the presence of shock and also the severity in terms of clinical presentation and the development of empyema, among patients with bacteraemic pneumonia, the differences did not reach statistical significance but appeared to be clinically relevant.
In previous studies in non-HIV-infected patients, similar results were obtained. In a cohort of 554 adults hospitalized with community-acquired pneumococcal pneumonia (CAP), Mykietiuk et al.  reported a lower risk of bacteraemia and also better clinical outcomes, including a faster resolution of pneumonia symptoms, a lower rate of mortality and a shorter length of hospital stay, in prior PPV recipients compared with unvaccinated patients. Fisman et al.  studied a large cohort of 62,918 adults hospitalized with CAP and found that the prior receipt of pneumococcal vaccine was associated with decreased length of hospital stay and lower rates of severe complications and death during hospitalization. More recently, Johnstone et al.  analysed prospectively a cohort of 3415 adults hospitalized with CAP and found that prior 23-valent PPV vaccination was associated with a reduction in the rate of death or ICU admission in hospitalized adults with CAP. In this last study, a pre-specified sensitivity analysis restricted to patients who presented with bacteraemic pneumococcal pneumonia was conducted. Among 95 patients with bacteraemic pneumococcal pneumonia, none of the 10 previously vaccinated patients died or was admitted to the ICU, in comparison with 27 (32%) of 85 patients who had not received pneumococcal vaccine (P=0.06).
To our knowledge, these additional effects of the 23-valent PPV in patients who develop IPD have not previously been studied in HIV-infected patients. Our study focused on a cohort of HIV-infected patients with IPD in whom this effect of PPV might be expected to be particularly beneficial because of the high risk of complications related to IPD in this population.
In HIV-infected patients, as in the general population, the most common pneumococcal serotypes involved in IPD are those included in the 23-valent PPV [3,26]. In this study, it is worth noting that, in both the vaccinated and the unvaccinated groups, the most common causal serotypes were those included in the 23-valent PPV. This finding demonstrates that the vaccine failed to prevent pneumococcal infection in some prior vaccinated patients. However, the better clinical outcomes found in patients who had received the 23-valent PPV suggest that pneumococcal vaccination in HIV-infected patients could have significant clinical benefits, despite not conferring protection against IPD. It has been shown in animal models that a vaccine-generated immune response may facilitate opsonization, activate complement and promote bacterial phagocytosis. Therefore, it has been suggested that, although the antibody response following vaccination may not be sufficient to prevent pneumococcal infection and pneumonia, the partial immune response generated could attenuate the early inflammatory response and prevent early mortality and complications of pneumococcal infection [27,28]. In seven patients the 23-valent PPV was administered more than 5 years before the episode of IPD. None of these seven patients died or was admitted to the ICU, suggesting that the 23-valent PPV could retain this additional effect for a longer time.
Clinical guidelines recommend that re-immunization should be considered 5 years after the first dose of 23-valent PPV, specifically if the initial vaccination was given when the CD4 count was <200 cells/μL , although there are no available data supporting the clinical efficacy of revaccination. Moreover, some studies in patients with CD4 counts above 200 cells/μL and patients receiving HAART showed that revaccination did not improve the immune response over that achieved after the initial vaccination [29,30].
As a nonrandomized study, this observational study carries the limitations related to possible selection bias and confounding factors. The patients' records from 1996 to 1999 were reviewed retrospectively, and from 2000 onwards all data were collected prospectively. All 47 cases (29%) included in the period from 1996 to 1999 were studied retrospectively but clinical charts were carefully reviewed and the protocol was exactly the same throughout the study period, so we feel that the results have not been influenced by this fact. One problem for the analysis was the presence of recurrent episodes in some patients, which could influence the results. Three of these patients were vaccinated after the first episode of IPD, so the same patient could be counted as unvaccinated in one episode and as vaccinated in another. Because the different vaccination status of the same patient in different episodes of IPD could influence the outcomes, we decided to analyse each episode of IPD separately. In any case, in order to assess a possible selection bias related to the inclusion of patients with recurrent episodes, we carried out a new analysis after excluding all patients with repeated episodes of IPD (127 episodes in 127 patients) and the results did not change significantly (data not shown).
We found that patients who received PPV had higher CD4 cell counts and were more likely to be receiving HAART. The effectiveness of PPV in severely immunosuppressed patients has been broadly questioned and pneumococcal vaccination in HIV-infected patients is recommended in current guidelines, particularly in those with CD4 counts above 200 cells/μL. Although we only recorded the CD4 cell count at IPD presentation, it is possible that patients with severe immunosuppression were less likely to have received PPV. Nevertheless, we did not find significant differences in the proportion of patients with undetectable viral load. A decreased incidence of IPD associated with the use of HAART and immunological improvement has been reported [1–7]. In contrast, some studies showed that clinical presentation, severity of illness and mortality related to IPD were not associated with CD4 cell count or the use of HAART . Thus, we believe that the beneficial effect of prior pneumococcal vaccination may not be attributable to a different severity of pneumococcal infection in patients with higher CD4 lymphocyte counts or those using HAART.
Among patients who had received PPV, there was only one patient with chronic liver disease. Chronic liver disease has been described as a risk factor for both IPD and a low response to PPV , so it could influence the clinical outcomes of IPD and the differences found could be overestimated. Because none of the previously vaccinated patients died or required ICU admission, we could not perform a multivariate analysis, so we attempted to avoid this possible selection bias by performing a new analysis excluding all patients with chronic liver disease. The differences between vaccinated and unvaccinated patients according to the composite outcome of death or admission to the ICU, admission to the ICU and length of hospital stay remained significant. Regarding the other clinical outcomes measured, the differences did not reach statistical significance, which could be explained by the reduction in the size of the sample. However, these differences appear to be clinically relevant.
Another difference between vaccinated and unvaccinated patients is that those who received the pneumococcal vaccine were less likely to be current or previous injecting drug users. Injecting drug use has been associated with a higher risk of IPD, and these findings, although they did not reach statistical significance, suggest that efforts should be made to increase vaccination rates in HIV-infected patients with other underlying high-risk conditions such as injecting drug use or chronic liver disease.
In summary, this study suggests that, as has been shown in non-HIV-infected patients, prior vaccination with PPV may provide some beneficial effects in HIV-infected patients by improving clinical outcomes in those who eventually develop IPD. Although 23-valent PPV fails to prevent IPD in some HIV-infected patients, previously vaccinated patients may have less severe illness, a lower risk of ICU admission, reduced in-hospital mortality and a shorter length of stay in hospital. We believe that these results support the current guidelines that recommend pneumococcal vaccination of HIV-infected adults, and emphasize the importance of this recommendation in order to decrease the morbidity and mortality related to pneumococcal infections in the HIV-infected population.