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Hospitalization for Pneumonia among Individuals With and Without HIV Infection, 1995–2007: A Danish Population-Based, Nationwide Cohort Study

  1. Ole S. Sogaard1,
  2. Nicolai Lohse2,
  3. Jan Gerstoft3,
  4. Gitte Kronborg4,
  5. Lars Ostergaard1,
  6. Court Pedersen5,
  7. Gitte Pedersen6,
  8. Henrik Toft Sørensen2, and
  9. Niels Obel3
  1. 1Department of Infectious Diseases, Aarhus University Hospital, Skejby
  2. 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus
  3. 3Department of Infectious Diseases, Rigshospitalet, Copenhagen
  4. 4Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre
  5. 5Department of Infectious Diseases, Odense University Hospital, Odense
  6. 6Department of Infectious Diseases, Aarhus University Hospital, Aalborg, Denmark
  1. Reprints or correspondence: Reprints or correspondence: Dr. Ole S. Sogaard, Dept. of Infectious Diseases, Aarhus University Hospital–Skejby, Brendstrupgaardvej 100, 8200 Aarhus N, Denmark (OKS{at}sks.aaa.dk).
 
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Abstract

Background. Human immunodeficiency virus (HIV)-infected individuals with high CD4+ cell counts may have increased susceptibility to other infections. We compared incidence rates of pneumonia among individuals with and without HIV infection and explored risk factors for pneumonia in the HIV-infected population.

Methods. This was an observational cohort study conducted during 1995–2007. Each member of a Danish population-based nationwide cohort of HIV-infected individuals was matched with up to 99 control individuals from the general population. Data on age, mortality, emigration, and hospital discharge diagnoses from 1977 onward were obtained from nationwide administrative databases. Individuals without previous hospitalization for pneumonia were observed from the date of HIV diagnosis until the first hospitalization to treat pneumonia (excluding pneumonia attributable to Pneumocystis jiroveci). Risk factors were assessed by Poisson regression.

Results. The study included 3516 persons with HIV infection and 328,738 persons without HIV infection, which provided 23,677 person-years and 2,944,760 person-years of observation, respectively. Incidence rates of pneumonia in HIV-infected individuals decreased from 50.6 hospitalizations per 1000 person-years (95% confidence interval [CI], 42.9–59.7 hospitalizations per 1000 person-years) during 1995–1996 to 19.7 hospitalizations per 1000 person-years (95% CI, 16.2–23.8 hospitalizations per 1000 person-years) during 2005–2007. Compared with control individuals, incidence rate ratios were 34.6 (95% CI, 28.4–41.8) during 1995–1996; 6.3 (95% CI, 5.1–7.7) during 2005–2007; and 5.9 (95% CI, 4.2–7.6) during 2005–2007 for the subgroup with a CD4+ cell count >500 cells/µL. Injection drug use, low current CD4+ cell count, nadir CD4+ cell count, increasing age, and no current receipt of highly active antiretroviral therapy increased the risk of pneumonia.

Conclusions. The risk of pneumonia in persons with HIV infection has decreased substantially since the introduction of highly active antiretroviral therapy, but HIV infection remains a strong risk factor for the need for hospitalization to treat pneumonia, even in persons with high CD4+ cell counts.

HAART has markedly reduced the incidence of AIDS and death among HIV-infected persons [1–3], but morbidity and mortality remain high, compared with those for persons without HIV infection [1]. Contributing factors are low CD4+ cell counts attributable to nonadherence to treatment, drug resistance, delayed HIV diagnosis [4], adverse effects of antiretroviral drugs [5], coexisting chronic infections (e.g., hepatitis B and/or C virus infection) [6, 7], or lifestyle-associated factors, such as injection drug use (IDU) and smoking [8]. Compared with the general population, persons with HIV infection have increased rates of non–AIDS-defining malignancies [9] and cardiovascular [10, 11], liver [12], and renal diseases [13], even among patients with full virological suppression and high CD4+ cell counts.

Bacterial pneumonia (first incidence or recurring) is a common hospital diagnosis among persons with HIV infection, including those receiving HAART [14, 15], and respiratory failure is the leading cause of intensive care unit admissions among HIV-infected patients [16]. A number of studies have reported increased rates of pneumonia among persons with HIV infection, compared with rates in the general population [17–20], but the impact of HAART and CD4+ cell count on risk of pneumonia in HIV-infected patients is still controversial.

We aimed to compare population-based incidence rates (IRs) of first-time hospitalizations for pneumonia among persons with and without HIV infection in Denmark, to estimate changes in IRs and IR ratios (IRRs) over time and according to age in the 2 populations, to estimate the influence of immunocompetence defined by CD4+ cell count, and to explore potential risk factors for non–AIDS-defining pneumonia among HIV-infected individuals.

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Patients and Methods

Study design and setting. We conducted a nationwide population-based cohort study among persons with and without HIV infection in Denmark during 1995–2007. The estimated prevalence of HIV infection in the adult population of Denmark, with a population of 5.4 million, is 0.07% [21]. Treatment for HIV infection occurs in only 8 specialized health care centers. The Danish health care system provides free, tax-supported medical care for all residents, including antiretroviral treatment of HIV infection.

Study Population

Inclusion criteria. We included persons who were ⩾16 years of age and had no recorded hospitalization for pneumonia before study inclusion.

Persons with HIV infection. The Danish HIV Cohort Study is a prospective, open, nationwide, population-based cohort of all HIV-infected individuals seen in Danish HIV clinics since 1 January 1995. Study methods were described in detail elsewhere [21, 22]. The study is ongoing, with continual enrollment of both patients with new diagnoses and new immigrants to Denmark who have HIV infection. Use of the Danish 10-digit personal identification number prevents multiple registrations of the same patient and allows tracking of deaths and losses to follow-up because of emigration. Study data are updated annually, with information about antiretroviral treatment, development of opportunistic infections and other AIDS-defining illnesses, and laboratory values, including viral load and CD4+ cell count.

Population control individuals without HIV infection. The Danish Civil Registration System includes information about each individual's personal identification number, sex, date and place of birth, place of residence, citizenship status, and continually updated information on vital status [23]. For each person living in Denmark at the time of HIV diagnosis, we aimed to identify 99 population control individuals—matched on the basis of sex, age (month and year of birth), and municipality—as the corresponding patient on the day the patient received the diagnosis of HIV infection. Because of shortage of eligible control individuals in some municipalities, we identified an average of 94.8 population control individuals per HIV-infected patient.

Identification of patients hospitalized with pneumonia. The Danish National Hospital Registry contains information about all patients discharged from Danish hospitals since 1977. Its records for each hospitalization include personal identification number, hospital department involved, discharge diagnoses, and dates of admission and discharge. Diagnoses are coded by the treating physician according to the International Classification of Diseases, 8th Revision (ICD-8), through the end of 1993 and, likewise, to the 10th revision (ICD-10) thereafter. For persons with HIV infection and the general population control individuals, we used the National Hospital Registry to identify all hospital stays with a discharge diagnosis of pneumonia, through identification of ICD-8 codes 480.XX–486.XX, 073.XX, and 471.XX and ICD-10 codes J11.0 (influenza with pneumonia), J12.X–J18.X (pneumonia), A481.X, (ornithosis), or A709.X (legionellosis). Thus, both community-acquired and hospital-acquired incidences of pneumonia were included. Criteria for hospital admission of HIV-infected patients and the general population were unchanged during the study. The onset of pneumonia was defined as the date of hospital admission. Because HIV-infected patients have an increased risk of receiving a diagnosis of pneumonia while visiting HIV centers, outpatient visits were not included. Also, AIDS-defining Pneumocystis jiroveci pneumonia was not included as an episode of pneumonia. To limit the study to first-time hospitalizations to treat pneumonia, individuals with a recorded episode of pneumonia between 1977 and 1 January 1995 were excluded.

Validation of discharge diagnoses. For a sample of 77 HIV-infected patients with a discharge diagnosis of pneumonia, we validated pneumonia diagnoses identified in the National Hospital Registry by reviewing medical records. We confined the review to Aarhus County, because data quality in the National Hospital Registry is considered to be uniform throughout the country [24]. Pneumonia diagnoses recorded in the National Hospital Registry for patients without HIV infection were validated previously [25], and we used the same criteria for patients with HIV infection. A discharge diagnosis of pneumonia was considered to be confirmed if an infiltrate was documented in a chest radiograph and if ⩾1 of the following clinical or laboratory findings was present: body temperature ⩾37.5°C, cough, dyspnea, chest pain or rales coincident with the area of infiltrate, increased amount of sputum, purulent sputum, microorganism isolated from blood culture, leukocyte count ⩾12×109 cells/L, or C-reactive protein concentration >100 mg per dL. We computed the percentage of episodes recorded in the National Hospital Registry that fulfilled the aforementioned criteria.

Definitions. HAART was defined as either a 3-drug regimen that included a nonnucleoside reverse-transcriptase inhibitor, a protease inhibitor, and/or abacavir or a 2-drug regimen with a combination of a nonnucleoside reverse-transcriptase inhibitor and a boosted protease inhibitor.

CD4+ cell count and viral load were estimated by using the most recent measurement. Nadir CD4+ cell count was defined as the lowest CD4+ cell count ever previously measured for that patient.

Statistical Analyses

Variables. The following variables were used in our analyses: sex, ethnicity, most likely mode of HIV acquisition, AIDS status [26, 27], and the time-varying covariates (TVCs) of current CD4+ cell count, nadir CD4+ cell count (TVC), current viral load (TVC), receipt of HAART (yes vs. no; TVC), and age (15–39 years, 40–49 years, 50–59 years, and ⩾60 years; TVC). Median and interquartile ranges were determined for age and CD4+ cell count. For other variables, frequencies and percentages were computed.

Time at risk. Subjects were observed from 1 January 1995 or the date of HIV diagnosis, whichever was later. Population control individuals entered the study on the same day as their matched HIV-infected person. We computed time from the date of first observation until the date of first hospitalization for pneumonia, death, emigration, or 1 May 2007, whichever came first.

IR, IRR, and cumulative risk. IRs of pneumonia hospitalization were computed for HIV-infected patients and for control individuals in the 4 age strata and in 6 time periods (1995–1996, 1997–1998, 1999–2000, 2001–2002, 2003–2004, and 2005–1 May 2007). In an analysis restricted to HIV-infected patients with current CD4+ cell counts >500 and their respective uninfected control individuals, we compared IR in the last time period. We computed IRRs and 5- and 10-year cumulative risk of pneumonia after 1 January 1997.

Poisson regression analysis. We used a Poisson regression model to explore risk factors for first-time hospitalization for pneumonia for all individuals with HIV infection. Variables entered into the model were ethnicity (white vs. nonwhite), most likely mode of infection (IDU vs. non-IDU), sex, age, receipt of HAART (yes vs. no), and nadir and current CD4+ cell counts. Viral load values were log-transformed, and the effect of current viral load was examined in a separate model limited to HAART-naive subjects. The effect of nadir CD4+ cell count among individuals receiving HAART was estimated for subjects with current CD4+ cell counts >300 cells/µL. The effect of HAART was estimated in 5 strata of CD4+ cell counts. In addition, we conducted a sensitivity analysis that excluded individuals with IDU as their most likely mode of HIV transmission. We did not include AIDS in these analyses, because nadir CD4+ cell count and AIDS are dependent covariates, and adjustment for AIDS could cancel out the effect of nadir CD4+ cell count. We used Stata software, version 9.2 (StataCorp) for statistical analyses. The study was approved by the Danish Data Protection Agency.

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Results

Study population. There were 3944 HIV-infected individuals and 373,856 matched population control individuals initially eligible for the study. We excluded 428 HIV-infected patients and 5996 members of the general population who had been hospitalized for pneumonia before study entry. Exclusion of the 428 HIV-infected patients entailed exclusion of an additional 39,121 matched control individuals from the general population. A total of 3516 HIV-infected patients and 328,738 population control individuals were included in the analysis, contributing 23,767 and 2,944,760 person-years of follow-up, respectively. Characteristics of study populations are shown in table 1. One hundred forty HIV-infected individuals (4.0%) and 12,833 control individuals (3.9%) were lost to follow-up, primarily because of emigration (116 [3.3%] and 10,096 [3.1%], respectively). A first-time hospitalization for pneumonia was identified for 582 persons with HIV infection and for 7042 persons without HIV infection.

Validation of pneumonia diagnoses. Seventy-three (95%) of 77 patients with HIV infection (95% CI, 87%–98%) who were registered as having pneumonia in the National Hospital Registry had their diagnoses confirmed by data in their medical records. In an earlier validation of pneumonia diagnoses among 100 patients without HIV infection, the diagnosis was confirmed for 90 (90%; 95% CI, 82%–95%) on the basis of their medical records [25].

IR, IRR, and cumulative risk. The overall IRs of hospitalization with pneumonia among HIV-infected persons decreased from 50.6 hospitalizations per 1000 person-years (95% CI, 42.9–59.7 hospitalizations per 1000 person-years) during 1995–1996 to 18.3 hospitalizations per 1000 person-years (95% CI, 14.4–23.2 hospitalizations per 1000 person-years) during 1999–2000 (figure 1) and remained stable, with a rate of 19.7 hospitalizations per 1000 person-years (95% CI, 16.2–23.8 hospitalizations per 1000 person-years) during 2005–2007. The IR among persons without HIV infection during 1995–2007 was 2.4 hospitalizations per 1000 person-years (95% CI, 2.3–2.4 hospitalizations per 1000 person-years) and increased from 1.5 hospitalizations per 1000 person-years (95% CI, 1.3–1.6 hospitalizations per 1000 person-years) during 1995–1996 to 3.1 hospitalizations per 1000 person-years (95% CI, 3.0–3.3 hospitalizations per 1000 person-years) during 2005–2007. Figure 2 shows that the decrease over time occurred in all age groups. The 5-year risk of pneumonia after 1 January 1997 was 11.0% (95% CI, 9.5%–12.7%) for HIV-infected patients and 1.0% (95% CI, 1.0%–1.0%) for control individuals. The corresponding 10-year risk was 21.3% (95% CI, 19.4%–23.4%) for HIV-infected patients and 2.4% (95% CI, 2.3%–2.5%) for control individuals. The overall IRR for hospitalization to treat pneumonia among HIV-infected patients, compared with control individuals, decreased over time, from 34.6 (95% CI, 28.4–41.8) during 1995–1996 to 9.3 (95% CI, 7.2–12.0) during 1999–2000 and to 6.3 (95% CI, 5.1–7.7) during 2005–2007 (table 2). During 2005–2007, IRs of pneumonia for those with CD4+ cell counts >500 cells/µL and their corresponding control individuals were 16.1 hospitalizations per 1000 person-years (95% CI, 12.0–21.6 hospitalizations per 1000 person-years) and 2.8 hospitalizations per 1000 person-years (95% CI, 2.6–3.0 hospitalizations per 1000 person-years), respectively, resulting in an IRR of 5.9 hospitalizations per 1000 person-years (95% CI, 4.2–7.9 hospitalizations per 1000 person-years).

Figure 1
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Figure 1

Incidence of first-time hospitalization to treat pneumonia in Denmark among individuals with and without HIV infection, 1995–2007

Figure 2
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Figure 2

Incidence rates of first-time hospitalization to treat pneumonia by HIV infection status and age group, 1995–2007

Figure 3
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Figure 3

Relationship between use of HAART and risk of pneumonia, in comparison of HAART-naive and HAART-experienced individuals, by CD4+ cell count strata. Point estimates and 95% CIs are indicated by vertical and horizontal bars, respectively. Gray bars indicate crude estimates. Black bars indicate estimates adjusted for nadir CD4+ cell count, age, injection drug use as mode of HIV transmission, sex, and ethnicity. IRR, incidence rate ratio.

Table 1
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Table 1

Characteristics of the HIV-infected and control populations at study entry.

Table 2
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Table 2

Incidence rate ratios for HIV-infected individuals by time and age.

Risk factors for hospitalization with pneumonia among persons with HIV infection. table 3 shows IRs of a first pneumonia hospitalization for persons with HIV infection, by potential risk factors for pneumonia, as well as crude and adjusted IRRs. Factors associated with increased risk of pneumonia were low current CD4+ cell count, low nadir CD4+ cell count, IDU, and male sex, whereas current receipt of HAART was protective. Among HAART-naive individuals, high current viral load was associated with an increased risk of pneumonia in the adjusted estimates. A sensitivity analysis excluding individuals with IDU as their most likely mode of HIV transmission provided estimates very similar to those displayed in table 3. Among patients receiving HAART with current CD4+ cell counts >300 cells/µL, nadir CD4+ cell count was not associated with increased risk of pneumonia; adjusted IRRs were 1.1 (95% CI, 0.7–1.8), 1.1 (95% CI, 0.7–1.9), 0.8 (95% CI, 0.4–1.6), and 1.3 (95% CI, 0.8–2.3) for nadir CD4+ cell counts of 201–300, 101–200, 51–100, and ⩽50 cells/µL, respectively, compared with those whose CD4+ cell counts were never <300 cells/µL. figure 3 shows the CD4+ cell count-independent protective effect of HAART on crude and adjusted IRRs for the 5 levels of current CD4+ cell counts, comparing HAART-naive with HAART-experienced individuals.

Table 3
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Table 3

Incidence rates of a first hospitalization to treat pneumonia in persons with HIV infection, by potential risk factors for pneumonia and with crude and adjusted incidence rate ratios.

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Discussion

To our knowledge, this population-based study is the first to explore on a national level the relative risk of pneumonia among HIV-infected patients. We found that the risk of first-time hospitalization for pneumonia remained 6-fold higher for HIV-infected individuals than for the general population until 2007, despite a decrease in incidence of pneumonia among HIV-infected persons after the introduction of HAART. The increased risk was observed even in persons with nearly normal CD4+ cell counts. The strongest risk factors for pneumonia were low current CD4+ cell count, IDU as the mode of HIV transmission, and, among HAART-naive patients, a high current viral load. HAART was associated with a decreased risk of pneumonia, but the protective effect of HAART was observed only for patients with CD4+ counts ⩽200 cells/µL.

The strengths of our study include the use of population-based, nationwide cohorts; access to complete hospitalization data; minor loss to follow-up; and availability of electronically collected longitudinal data on viral load and CD4+ cell counts. This is one of the largest studies of the incidence of pneumonia among HIV-infected individuals, yielding estimates with high statistical precision. Because we considered only the first hospitalization for pneumonia, our estimates were not biased by multiple pneumonia episodes occurring in highly susceptible individuals.

Our study also had limitations. Data on specific pathogens and pneumococcal vaccination status were not available. Therefore, we do not know the percentage of pneumonia cases caused by bacteria and whether this percentage differed between persons with and without HIV infection. Previous studies have found identifiable bacterial pathogens in 24%–38% of HIV-infected patients with pneumonia [17, 28], which is comparable to findings in persons without HIV infection [29]. In Denmark, the 23-valent polysaccharide vaccine is not routinely administered to HIV-infected individuals or to elderly persons (age, ⩾65 years). Recruitment for a recent Danish trial showed that <10% of HIV-infected persons had been vaccinated within the previous 5 years (O.S.S., unpublished data). We therefore assume that pneumococcal vaccination had very little influence on our results.

Physicians may have a lower threshold for hospital admission of HIV-infected patients presenting with signs and symptoms of pneumonia than for a person without HIV infection. In that case, pneumonia would be diagnosed in hospitals more frequently among HIV-infected persons than among the general population, leading to an overestimation of the IRR. However, this information bias is unlikely to be the sole cause of the higher risks observed. First, validation of diagnosis of pneumonia among patients with and without HIV infection was found to be comparable. Second, the general improvement in the immunocompetence of the HIV-infected population during the study period has made their hospitalization pattern approach what is seen in control individuals (N.O., unpublished data).

Finally, we did not have data on smoking, a well-known risk factor for pneumonia that may be more common among HIV-infected individuals, particularly among injection drug users. A recent cohort study found that 40% of HIV-infected individuals were smokers [30], compared with 27% of the Danish population as a whole in 2006 [31]. This difference is small and could not have accounted for our findings.

Our data extend previous research. Grau et al. [18] reported a 3-fold decrease in the incidence of invasive pneumococcal disease in the HAART era (1997–2002), compared with the pre-HAART era (1986–1996), that was similar to the decrease we observed in incidence of pneumonia between 1995–1996 and 1999–2000. Although our overall IRR for pneumonia did decrease between 1999–2000 and 2005–2007, the IR of pneumonia among persons with HIV infection remained stable for each age stratum during the same period (figure 2). The 12-fold higher incidence among HIV-infected versus HIV-uninfected individuals that was determined in the HIV Epidemiologic Research study by Kohli et al. [17] of primarily female injection drug users was based on incidence data from 1993–2000; therefore, it did not fully capture the decrease in IRRs over time that we observed between the pre-HAART and the late-HAART era. Many studies based on data from the early-HAART and pre-HAART era would, therefore, produce higher IRs than we observed after 2000 [17–20]. Availability of less toxic antiretroviral drugs in recent years has increased drug adherence, leading to the improved immune status of many HIV-infected individuals [32]. IRs for pneumonia increased over time in the background population; this is in line with results from a recent study [25]. Most risk factors identified in our study corroborated the findings of other studies [17–20, 28]. However, the increased risk of pneumonia in individuals with a current CD4+ cell count as high as 301–400 cells/µL supports recommendations for HAART initiation for patients with higher CD4+ cell counts [33].

The increased incidence of pneumonia among persons with HIV infection, even among those with nearly normal CD4+ cell counts, indicates that HIV infection increases the susceptibility to pneumonia beyond what is indicated by CD4+ cell counts. Possible mechanisms could be loss of immunological and epithelial integrity [34, 35], fibrosis of lymphatic tissue [36], and loss of IL-17-expressing CD4+ T lymphocytes from the gastrointestinal tract, leading to microbial translocation and generalized immune activation [34, 37], as shown in patients who had effective treatment despite high CD4+ cell counts. In animal studies, HAART seems to reduce microbial translocation [34], which may explain why HAART was associated with a decreased risk of pneumonia in treatment-naive and treatment-experienced individuals in the same low CD4+ cell strata. In addition, some reports have shown that HIV-infected persons in the HAART era may have a high prevalence of other chronic conditions (e.g., heart disease and cirrhosis), which may be additional risk factors for pneumonia [10–12].

In conclusion, introduction of HAART has substantially decreased the risk of pneumonia in HIV-infected patients. Although a high CD4+ count protects against pneumonia, persons with HIV infection and high CD4+ cell counts still have increased risk of the need for hospitalization to treat pneumonia compared with persons without HIV infection.

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Acknowledgments

We thank the staff of our clinical departments for their continuous support and enthusiasm.

Financial support. The Danish AIDS Foundation, Rigshospitalet, Odense University Hospital, Preben and Anna Simonsen's Foundation, the Foundation of the Danish Association of Pharmacists, and the Clinical Institute at the University of Southern Denmark.

Potential conflict of interest. N.O. has received research funding from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, Janssen-Cilag, and Swedish Orphan. J.G. has received research funding from Abbott, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pharmasia, GlaxoSmithKline, Swedish Orphan, and Boehringer Ingelheim. All other authors: no conflicts.

  • Received April 17, 2008.
  • Accepted July 17, 2008.
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  1. Clin Infect Dis. (2008) 47 (10): 1345-1353. doi: 10.1086/592692
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