Changes in Hospital Admissions Pattern in Patients with Human Immunodeficiency Virus Infection in the Era of Pneumocystis carinii Prophylaxis

Changes in Hospital Admissions Pattern in Patients with Human Immunodeficiency Virus Infection in the Era of Pneumocystis carinii Prophylaxis* Sin-Ming Chien, M.D., Ph.D.;t Mustafa Rawji; Sheldon Mintz, M.D., F.C.C.P.; Anita Rachlis, M.D.; and Charles K. Chan, M.D., F.C.C.P. Background: Pneumocystis carinii pneumonia (PCP) was the leading cause of hospital admissions in patients with human immunode6ciency virus (HIV) infection before the widespread use of PCP prophylaxis. We studied retrospectively the changes in annual hospital admission patterns after the start of a population-based PCP prophylaxis program in Toronto. The purpose of the study was to identify the cogent diseases requiring hospitalization of HIV patients in the current era of PCP prophylaxis. This information is important for the allocation of health care resources in the future as well as for targeting research in the prevention of speci6c HIV-related diseases. Methods: The annual HIV-related hospital admissions before and after the start of the Toronto aerosol pentamidine program (May 1989) were studied. All admission records due to AIDS-de6ning illnesses or occurring in patients with ImOWD HIV status in three major referral centers were reviewed. The two periods for comparison were May 1988 through April 1989 and May 1989 through April 1990. The data obtained were strati6ed according to the following: (1) cause of the illness prompting hospital admission; (2) PCP admissions; and (3) admissions according to the major organ

system involved. These categoric data were compared by nonparametric Xl tests. Results and Conclusions: Population-based prophylaxis of PCP with aerosol pentamidine resulted in a signi6cant reduction in the total number of PCP hospital admissions. Infection remains the principal cause of hospital admission in HIV patients after the start of the PCP prophylaxis program. However, there was an increase in the proportion of hospital admissions due to nonrespiratory-related infections. There was also a modest increase in admissions due to neurologic and gastrointestinal diseases. Central nervous system lymphoma and cytomegalovirus retinitis accounted for the majority of the rise in the nervous system. These data suggest there is a changing pattern of the diseases leading to the hospitalization of patients with HIV infection in the era of PCP prophylaxis. (Chest 1992; 102:1035-39)

pneumocystis carinii pneumonia (PCP) is the most

Furthermore, PCP has a high recurrence rate, approximately 50 percent within the nine months following the first episode. 6 Aerosol pentamidine (AP) has been shown to be an effective secondary prophylactic agent for preventing PCP relapses;7.8 it can reduce the recurrence rate at nine months from 50 percent to 15 percent.6-8 In Toronto, since May 1, 1989, there has been a centralized, community-based facility for the administration of AP to HIV patients for the prophylaxis of PCE funded by the Ministry of Health of Ontario. AP is provided free to all individuals in the city fulfilling the Centers for Disease Control (CDC) criteria for either primary or secondary prophylaxis of PCE9 Prior to the widespread use of AP in Toronto, PCP was the number one cause of HIV-related hospitalization. The purpose of this retrospective study is to investigate the changes in hospital admission patterns of HIV patients after the start of a widespread PCP prophylaxis program in Toronto. We elected to study hospital admission patterns, because the bulk ofhealth care resources is spent in the treatment ofhospitalized patients. The goals of the study are as follows: (1) to

common pulmonary infection in patients infected with the human immunodeficiency virus (HIV).· It is the index disease for diagnosing acquired immunodeficiency syndrome (AIDS) in 60 percent of the reported cases, and without prophylaxis, approximately 80 percent of individuals with AIDS will have PCP some time during the course of their illness. 2-3 In the United States alone, 100,000 cases of PCP were expected in 1991. 4 The cost of treating PCP is substantial. There is a strong correlation between the incidence of PCP and the number of helper T cells (CD 4 ) in the peripheral blood of individuals infected with HIV 5 *From the Departments of Medicine, The \Vellesley, \Vomen's College, and Sunnybrook Hospitals, University of Toronto, Toronto, Canada. Presented in part as a poster at the 57th Annual Scientific Assembly, American Colle~e of Chest Physicians, San Francisco, November 4-8, 1991. Sup~rted in part by program fundings from the Ministry of Health of Ontario. tFellow, Medical Research Council of Canada. Manuscript received November 25; revision accepted February 11. Reprint requests: Dr. Chan, 160 Wellesley Street East, 242 ]ones Bldg, Toronto, Ontario, Canada M4Y 1J3

=

= =

AP aerosol pentamidine; CDC Centers for Disease Control; CMV cytomegalovirus; ICD International Classification of Diseases; PCP = Pneumocy.tis carinii pneumonia; TMPSMX trimethoprim-sulfamethoxazole

= =

CHEST I 102 I 4 I OCTOBER, 1992

1035

identify the diseases requiring hospitalization in AIDS patients in the era of PCP prophylaxis; (2) to provide preliminary information for future planning in the allocation of health care resources; and (3) to identify cogent areas for future research in the prevention of HIV-related illnesses. To the best of our knowledge, there is no literature on hospital admission patterns in this situation. METHODS

Pentamidine was aerosolized using an ultrasonic nebulizer (Fisoneb, Fisons, Rochester, NY) as validated in the Canadian Cooperative Study."·IO The prophylactic regimen for both primary and secondary prophylaxis consisted of five loading doses of 60 mg on alternate days, followed by a maintenance dose of 60 mg every two weeks!~·IO Individuals with a CD. count <300 x 1()fi!L or who had survived a previous episode of PCP were eligible for the program. At the time of reporting, approximately 1,200 individuals have been enrolled, and 776 persons were in the program during the first year. The annual admission records of all HIV-related cases before and after the start of the PCP prophylaxis program were compared retrospectively. The two secular periods for comparison were May 1988 through April 1989 as the preaerosol pentamidine (pre-AP) period and May 1989 through April 1990 as the post-aerosol pentamidine (post-AP) period. All three hospitals involved in the study are affiliated with the University of Toronto and are among the major referral centers for HIV patients in the city. Data Collection All HIV-related hospital admissions in the three hospitals were coded according to the International Classification of Diseases (ICD). We selected all admissions due to AIDS-defining illnesses according to the CDC guidelines lJ as well as admissions due to other (non-AIDS-defining) illnesses in patients known to be infected with HI~ All admissions under these special codings during the period from May 1988 to April 1990 were obtained from the Medical Records Departments of the three hospitals and were reviewed systematically. A data collection form was designed for recording pertinent information from each hospital admission record. These data included age, gender, risk behavior associated with the HIV infection, presenting illness for the admission, and duration of the hospitalization. The admitting diagnosis was always cross-referenced with the discharge diagnosis for any discrepancy. In cases with PCP as the admitting diagnosis, information was obtained on the method of diagnosis (to confirm the diagnosis), and whether this was a first or a repeated episode of PCE Admissions due to illnesses other than PCP were classified according to both cause and the major organ involved. For patients with multiple hospital admissions, each admission was treated as a separate data entry point. Only the presenting illness leading to the admission was registered as the principal cause of hospitalization. For instance, for a HIV patient with Kaposi sarcoma who presented with a recurrent episode of PC~ that hospitalization would be attributed to PCP and not Kaposi sarcoma. Data Analysis The data during the pre-AP period (May 1988 through April 1989) was compared with the post-AP period (May 1989 through April 1990). The data from both periods were stratified and compared according to three categories; (1) cause of the illness leading to admission; (2) PCP admissions; and (3) admissions according to the major organ system involved. These categoric data were compared by nonparametric x2 tests. A p value <0.05 was considered statistically significant.

1036

RESULTS

There were a total of 642 admissions in the three hospitals during the two-year period. Male patients accounted for 98.5 percent of the admissions. The annual number of admissions was 294 in the pre-AP period and 348 in the post-AP period respectively (a rise of 18.3 percent). The Olean length of stay per admission was comparable between the two periods (16 days per admission vs 14 days per admission). The annual hospital admission patterns of the preAP and post-AP periods were analyzed according to the principal illness responsible for the admission. As shown in Table 1, there \vas no change in the percentage ofannual admissions due to infectious or neoplastic causes during the two periods. Infection remained the number one cause of HIV-related admissions and accounted for close to 69 percent of the total number of admissions during the two periods. Admissions due to neoplastic causes are also stable (11 percent and 12 percent) over the two periods. Despite the stability in the percentage of total infection-related admissions during the two periods, there was a significant reduction in the number of PCP admissions (Table 1). The total number of PCP admissions declined from 95 to 69 cases (p
Etiology Infections PCP Non-PCP Respiratory Nonrespiratory Respiratory (Non-PCP) Neoplasms Others Total

Pre-AP May 88-April 89

Post-AP May 89-April 90

(%)

(%)

P Value

235 (67.5) 69 (29) 166 (71) 132 (56) 103 (44) 63 (27)

NS <0.001 <0.01 NS <0.05 NS

200 95 105 135 65 40

(68) (48) (52) (68) (32) (20)

32 (11) 62 (21) 294

42 71 348

(12) (20)

NS NS

*HIV = human immunodeficiency virus; AP = aerosol pentamidine; PCP = Pneumocystis carinii pneumonia. Changes in Hospital Admissions Pattern in HIV and PCP (Chien et 81)

arated into first and repeated episodes. There was a marked decline in the number of admissions (from 37 to 18 cases) and the percentage oftotal PCP admissions (from 39 percent to 28 percent) due to recurrent episodes during the post-AP period. However, a relative increase in the percentage of admissions due to a first episode of PCP (from 61 percent to 72 percent) was observed during the post-AP period. Several reasons may be responsible for the persistently high incidence of first episode PCP during the postAP period in this study, including lack of prophylaxis due to delay in diagnosing asymptomatic HIV infection, noncompliance with prophylaxis, as well as breakthrough episode while receiving prophylaxis. Due to the nature of this retrospective study, the extent ofpentamidine prophylaxis among patients with a first episode of PCP in our study population could not be determined because of incomplete data. Only one case of disseminated P carinii was documented during the two-year period. The true total of disseminated cases would probably be higher than the observed number, if a diligent search for dissemination (involving invasive procedures, including biopsy specimens from liver, bone marro~ or lymph node) has been carried out. For obvious ethical reasons, these procedures were not performed unless patients became symptomatic. The reported case of extrapulmonary pneumocystosis was identified when the patients presented with a right ear ache; biopsy specimen of a nodular lesion in the external auditory canal showed an inflammatory reaction with abundance of P carinii organisms. Annual HIV-related hospital admissions were also stratified according to the major organ system involved. As shown in Table 2, the respiratory system was the most common cause for HIV-related admission, followed by the nervous and gastrointestinal systems. Comparing the pre-AP and post-AP periods, there was a significant decline in the percentage of admissions due to illness of the respiratory system in the post-AP period (p
*AP = aerosol pentamidine.

Pre-AP (%) 148 59 39 246 48

(50) (20) (13) (84) (16)

Post-AP (%) 143 75 50 268 80

(41) (22) (14) (77) (23)

p Value

<0.05 NS NS

number one cause of HIV-related admissions in the post-AP era. An increase in the number of hospital admissions due to illnesses of the nervous and gastrointestinal systems was observed during the post-AP period. However, the numbers were too small to be of statistical significance at the present time. It will be of interest to observe whether this trend continues after PCP prophylaxis has been utilized for a longer duration. The specific diagnoses for illnesses of the three major organ systems are presented in Table 3. In contrast to the pattern of PCP admissions, there was an increase in the number of admissions due to bacterial pneumonia during the post-AP period, from 38 to 61 cases (from 26 percent to 45 percent of admissions due to the respiratory system). Hemophilus influenzae (46 percent) and Streptococcus pneumonia (17 percent) were the major pathogens among cases with bacterial identification. No significant change was observed in the other categories of respiratory illness. Fungal pneumonia was uncommon in this cohort. It Table 3-Annual HIV-Helated Hospital Admissions According to Specific Diagnosis* No. of Admissions Periods Respiratory system PCP Bacterial pneumonia Fungal pneumonia Kaposi sarcoma Mycobacterial Others Gastrointestinal system Neoplasm Kaposi sarcoma Lymphoma Infection Others Nervous system Neoplastic CNS lymphoma Infection Toxoplasmosis Meningitis Encephalitis CMV retinitis PML Seizure disorder AIDS dementia Neurolmyopathy others

Pre-AP

Post-AP

95

38

69 61

1 10 1 3 (148)

6 2 2 (140)

1 3

3 4 22 10 (39)

19 (50)

7

15

9 6

7 4

28

3

3

9 2 2 8 4 9 (59)

18 3 6 9 0 10 (75)

*AIDS = acquired immunodeficiency syndrome; AP = aerosol pen-

tamidine; CMV = cytomegalovirus; HIV = human immunodeficiency virus; PCP = Pneumocystis carinii pneumonia; PML = progressive multifocalleukoencephalopathy. CHEST I 102 I 4 I OCTOBER, 1992

1037

should be mentioned that only cases severe enough to require hospitalization were included in this study. This may explain the relatively low incidence of mycobacterial infection being recorded in this study, as most of the infection can be managed in an ambulatory setting. The previously noted increasing trend of post-AP admissions due to diseases of the gastrointestinal and nervous systems is apparent in Table 3. Lymphoma of the central nervous system and cytomegalovirus (CMV) retinitis accounted for the majority of the increases due to the nervous system. There was no significant change in the number of admissions due to other disorders of the nervous system. The "others" category includes the following diseases: suicide, personality disorder, organic brain syndrome, and substance abuse. No change was seen in the pattern of gastrointestinal system admissions during the two periods. Infectious causes included CMV esophagitis and colitis, Candida esophagitis, cryptosporidiosis, herpes simplex anal ulcer, and viral hepatitis. The "others" category includes peptic ulcer disease, appendicitis, cholecystitis, pancreatitis, anal warts and fistulas, and diverticulitis. DISCUSSION

The association of PCP with AIDS was first reported in 1981.12 Over the last decade, HIV has become the number one cause of morbidity and mortality in people between ages 20 and 40 years, most of these individuals dying of either opportunistic infection (usually PCP pneumonia) or atypical malignant neoplasms. Effective therapy and prophylactic agents have since been developed for the treatment and prevention of PCE 13 Toronto is the first center in Canada to have a government-sponsored, population-based centralized facility for administering one such prophylactic agent (AP) for the prevention of PCE AP is provided free to all individuals in the city fulfilling the CDC criteria for either primary or secondary prophylaxis; thus, it is available to most HIV-positive patients who require it. In fact, it is the principal method of prophylaxis against PCP during the study period. This provides a unique opportunity to study the early effects of widespread PCP prophylaxis on the hospital admissions pattern in AIDS patients. In this study, the annual hospital admissions patterns at the three major referral centers in Toronto during the pre-AP and post-AP periods were analyzed. During the pre-AP period, 68 percent of the admissions resulted from infection, and, as expected, PCP was the major opportunistic infection. However, during the post-AP period, there was a significant decrease in the number of PCP admissions, especially from recurrent PCE This suggests that the large-scale, population-based PCP prophylaxis program has 1038

achieved its objective. It is possible that factors other than AP may also have contributed to the reduction of PCP admissions during the post-AP period. These factors include the use of zidovudine, an antiviral agent and trimethoprim-sulfamethoxazole (TMP-SMX), an alternative form of PCP prophylaxis. However, they are likely to have only a minor role in the drastic reduction in the recurrence of PCP between the pre-AP and post-AP period observed in this study. Zidovudine has been widely available to all HIV patients in Toronto since 1987, a year prior to the initiation of the AP program in the city. Furthermore, it is well known that zidovudine is not effective in preventing episodes of PCE Thus, it is unlikely to be a major factor leading to the drastic reduction of PCP admissions between the preAP and post-AP periods. Trimethoprim-sulfamethoxazole (TMP-SMX) is another means of prophylaxis against pcr However, at the recommended dosage during the study period (two double-strength tablets per day), it was associated with significant side effects, and was much less popular than AE In Toronto, AP was the preferred method for prophylaxis against PCP during 1989 to 1990. Only a very small proportion of HIV patients used TMPSMX. Thus, TMP-SMX would not have been an important factor in the reduction of PCP hospital admissions during the two study periods. In this study, the reduction of pneumonia due to P carinii was accompanied by an increase in bacterial pneumonia during the post-AP period. H infiuenzae and S pneumoniae were the major pathogens identified. This observation suggests that primary prophylaxis against these common pathogens for communityacquired pneumonia by vaccination may have a role in the treatment of HIV patients during the era of PCP prophylaxis. The results of this study also point toward an increase in hospital admission due to neurologic and gastrointestinal diseases. Central nervous system (CNS) lymphoma and CMV retinitis account for the majority of the rise in the nervous systems. At present, there is no effective treatment for the former disease, and the latter requires long-term maintenance therapy with gancyclovir. These are potential areas where therapeutic and preventive research efforts should be concentrated. Several conclusions can be drawn from this retrospective analysis of the changing pattern of HIVrelated hospital admissions in the era of PCP prophylaxis. First, AP results in significant reduction in the number of admissions due to pcr Second, infection remains the number one cause of admissions. However, there is a significant increase in the number of admissions due to infections in nonrespiratory systems. Third, there is a trend for increase in the Changes in Hospital Admissions Pattern in HIV and PCP (Chien et 81)

number of admissions due to diseases of the nervous and gastrointestinal systems; CNS lymphoma and CMV retinitis account for the majority of the increase in the nervous system. This study reflected only the changes in the hospital admission pattern after one year of a population-based pentamidine prophylaxis program in our city. As we enter the 1990s with widespread use of effective PCP prophylaxis, and as the survival of HIV patients improves, diseases ofmore chronic nature or neoplastic disorders that have a longer incubation period may become the predominant reasons for hospitalization. For instance, in this study, although overall hospital admissions due to neoplastic disorders remained stable during the two study periods, admissions due to CNS lymphoma have doubled after the first year of AP prophylaxis. Thus, it would be of interest to observe the changes in hospital admissions pattern in HIV patients after PCP prophylaxis has been administered for a much longer duration. During the preparation of this article, Peters et al 14 reported a retrospective study on the disease pattern of AIDS patients at a referral center in Britain. From 1984 to 1989, there was a decline in the number of admissions for PCP and Kaposi sarcoma at their center, and increased mortality due to CNS lymphoma and Kaposi sarcoma. AIDS and its associated opportunistic infections and atypical malignancies will remain the major challenge for the medical professions in the next decade. Studies of the disease and hospital admission patterns will allow us to concentrate our research and health care resources in the appropriate areas. REFERENCES 1 Glatt AE, Chirgwin K, Landesman SHe Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988; 318:1439-48 2 Murray JF, Felton CE Garay SM, Gottlieb MS, Hopewell PC,

Stover DE, et al. Pulmonary complications of the acquired immunodeficiency syndrome: report of a National Heart, Lung, and Blood Institute Workshop. N Engl J Med 1984; 310: 1682-

88

3 Murray JF, Garay SM, Hopewell PC, Mills J, Snider GL, Stover DE. Pulmonary complications of the acquired immunodeficiency syndrome: an update report of the Second National Heart, Lung and Blood Institute Workshop. Am Rev Respir Dis 1987; 135:504-09 4 Centers for Disease Control. Update, acquired immunodeficiency syndrome-United States. MMWR 1986; 35:17 5 Polk BF, Fox R, Brookmeyer R, Kanchanaraksa S, Kaslow R, Visscher B, et a1. Predictors of acquired immunodeficiency syndrome developing in a cohort of seropositive homosexual man. N Eng) J Med 1987; 316:61-6 6 Glatt AE, Chirgwin K, Landesman SHe Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988; 318:1439-48 7 Leoung GS, Feigal D~ Montgomery AB, Corkery K, Wardlaw L, Adams M, et a1. Aerosolized pentamidine for prophylaxis against Pneumoncystis carinii pneumonia: the San Francisco community prophylaxis trial. N Eng) J Med 1990; 323:769-75 8 Montaner JSG, Lawson L, Gervais A, Hyland RH, Chan CK, Falutz JM, et a1. Aerosol pentamidine in the secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia: a randomized placebo-controlled study. Ann Intern Med 1991; 114:948-53 9 Centers for Disease Control. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989; 38:1-9 10 Toronto Aerosolized Pentamidine Study (TAPS) Group. Acute pulmonary effects of aerosolized pentamidine, a randomized controlled study. Chest 1990; 98:907-10 11 Centers for Disease Control. Update: acquired immunodeficiency syndrome- United States. MMWR 1986; 35:757-60, 76566 12 Centers for Disease Control. Kaposi's sarcoma and Pneumocystis carinii pneumonia among homosexual men - New York City and California. MMWR 1981; 30:305 13 Levine SJ, White D. Pulmonary effects of AIDS: Pneumocystis carinii. Clin Chest Med 1988; 9:395-423 14 Peters BS, Beck EJ, Coleman DG, Wadsworth MJH, McGuinness 0, Harris J~ et a1. Changing disease patterns in patients with AIDS in a referral cantre in the United Kingdom: the changing face of AIDS. BMJ 1991; 302:203-07

CHEST I 102 I 4 I OCTOBER, 1992

1039