Causes of Death in Persons With Human Immunodeficiency Virus Infection MICHAELSTEIN, M.D., PATRICIAO’SULLIVAN,Ed& TOM WACHTEL,M.D., ALVANFISHER,M.D., DENNISMIKOLICH, M.D., STEVENSEPE,M.D., GLENNFORT, M.D., CHARLESCARPENTER, M.D., GAILSKOWRON,M.D., KENNETHMAYER,M.D., Providence, Rhode/s/and

PURPOSE: Pneumocysti carinii pneumonia (PCP) was reported to be the predominant cause of human immunodeficiency virus (HIV)-related deaths prior to 1966, the year that effective prophylaxis against PCP entered routine use. Our study was performed to study the causes of HIVrelated death since January 1988 in a region where patient tracking is virtually complete. PATIENTS AND MErHoDs: We surveyed physicians associated with the Brown University Acquired Immunodeficiency Syndrome (AIDS) Program who cared for greater than 95% of known HIV-positive patients in Rhode Island. These physicians identified alI those HIV-infected persons who had died under their care between January 1963 and July 1990, and determined these patients’ causes of death by chart review. For comparison, death certificates of identified persons were also reviewed at the Rhode Island Department of Vital Statistics. RESULTS: Among 126 deaths since January 1988, bacterial infections were the most common cause of death (30%), whereas PCP was responsible for only 16% of deaths. Persons not receiving any form of PCP prophylaxis were more likely to die from PCP than were those who received prophylaxis (26% versus 11% [p = 0.041). Cause of death as recorded on actual death certificates was imprecise, although bacterial infections were again the most common cause indicated. Only one death occurred in a patient with a CD4 count greater than 200/n& and this was not EIIV-related. CONCLUSION: PCP has not been the leading cause of death in our region since January 1988. Bacterial infections contribute substantially to mortality, and this may influence future prophylactic regimens. HIV-related deaths in patients

From the Department of Medicine, Brown University, Providence, Rhode Island. Requests for reprints should be addressed to Michael D. Stein, M.D., Division of General Internal Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903. Manuscript submitted October 30,1991, and accepted in revised form April 6. 1992.

with CD4 counts greater ullusual.

than 2OO/mL are

ause of death statistics allow physicians and C health policy planners to understand how particular diseases are affecting specific populations. Within the epidemic of human immunodeficiency virus (HIV), cause of death analyses might also enable researchers to study changes in the natural history of a new and complex disease. From 1981 to 1990, 101,000 deaths among persons with the acquired immunodeficiency syndrome (AIDS) were reported to the Centers for Disease Control (CDC)

M.

Pneumocystis carinii pneumonia (PCP) was reported to be the predominant cause of AIDS-related deaths prior to 1988, the year that effective prophylaxis against PCP entered routine use [2]. Both necropsy and clinical studies identifying HIV-related disease report PCP as the predominant cause of death prior to 1988 [3,4]. In Rhode Island, 55% of all HIV-related deaths prior to 1988 were attributed to PCP (Department of Health, personal communication). There is, however, little information available about specific causes of death related to HIV infection since that time. Cause of death is usually ascertained from death certificates, which are universally used and uniform in format. However, death certificates are often imprecise or incorrect [5]. Direct questioning of physicians regarding cause of death has been shown to improve the quality of reporting [6]. Rhode Island, a small state with only 10 acute care hospitals and a limited number of physicians caring for HIV-infected persons, offers a unique opportunity to study causes of death in AIDS. The purpose of this study was twofold: to determine causes of death since 1988 in our state and to evaluate how accurately these causes are reflected on death certificates.

PATIENTSAND METHODS We surveyed all physicians associated with the Brown University AIDS Program who cared for patients at each of the state’s 10 acute care hospitals. October

1992

The American

Journal

of Medicine

Volume

93

387

TABLE I Study Population (n = 126)

TABLE II Causeof Death (n = 126)

Age (mean + SD) y&y

I

IVDU ;Gd Death at home (%) Autopsy (%) CD&defined AIDS diagnosis (%) CD4 count < 200/mm3 (%) Survival from notification of HIV positivity (mean + SD)

Physician Responses (%) Bacterial infections 0;;’ opportunistic infections

14 7

Wastinglencephalopathy Liver failure Unknown Lymphoma Non-HIV-related Kaposi’s sarcoma AIDS Cardiopulmonary arrest

El; 13.3 + 12.3 mo

IVDU = mtravenous drug user; CDC = Centers for Disease Control; AIDS = acquired immunodefl crency syndrome; HIV = human lmmunodeficiency virus.

These 15 physicians reviewed charts of all HIVinfected persons they had seen who died between January 1988 and July 1990. Rhode Island statutes mandate that all HIV-seropositive cases be reported to the Department of Health with appropriate demographic data, but without individual identifiers. Based on HIV/AIDS case reporting, these physicians cared for greater than 95% of known HIVpositive persons in Rhode Island. Our study sample included all HIV-positive persons identified by retrieval systems available to the 15 participating physicians. For hospital deaths, data on subjects were retrieved from hospital computer files. As part of the Brown AIDS Program, physicians maintained readily retrievable office files on patients seen. All subjects from these two retrieval systems composed the sample. A questionnaire for each subject was completed based on record review by the subject’s attending physician or one of the authors. We collected the following data: patient demographics, transmission risk, date of HIV seroposi tivity, date and place of death, AIDS-defining diagnosis, other AIDS diagnoses, use of zidovudine and PCP prophylaxis for at least the 2 months prior to death, last CD4 count prior to death, resuscitation preferences, and autopsy findings when available. A CD4 count cutoff of 200 cells/mm3 was used to identify persons with advanced HIV disease; at this level, patients are candidates for both PCP prophylaxis and antiretroviral therapy [7]. From chart review, the principal condition being treated at the time of death was specified as the immediate cause of death. For example, if a patient receiving long-term therapy for toxoplasmosis developed bacterial pneumonia and died despite the institution of antibiotic therapy, this death was classified as a bacterial death. The death certificates of the identified persons were then reviewed for cause of death at the Rhode Island Department of Vital Statistics. All causes of death listed on standard death certificates were recorded, including the “immediate” cause, conditions leading to the “im399

October 1992 The American Journal of Medicine

Total

;t 16 8

On Death Certificates 1%) 25 18 16 ;

; 2” 1

! 2: 11

100

100

;P = Pneumocystis canmi pneumonia; HIV = human lmmunodeficiencyvirus; AIDS = acquire, munodeficlency syndrome.

mediate” cause, and “other significant conditions” contributing to death. The CDC surveillance case definition for AIDS was used for diagnostic classification [a]. The only bacterial infections identified by participating physicians were pneumonia (presumed or microbiologitally documented), sepsis, and endocarditis.

RESULTS Surveyed physicians reported 126 deaths between January 1988 and July 1990 in known HIVseropositive persons (Table I). The mean age of the sample was 39.9 f 9.6 years; 71% were white; 86% were male; and 30% had used intravenous drugs. Although 87% had CDC-defined AIDS diagnosis, 98% had a CD4 count of less than 200 cells/mm3 prior to death. Fourteen percent of the patients died at home, the remainder in a hospital. Seven percent had autopsies. The mean survival from notification of HIV positivity was 13.3 f 12.3 months. The leading AIDS-defining diagnosis was PCP (36%). An opportunistic infection other than PCP was the AIDS-defining disease for 28%, Kaposi’s sarcoma for 15%, wasting or encephalopathy for 5%, and lymphoma for 3%. The remaining 13% of persons did not have CDC-defined AIDS at the time of death. Causes of death as reported by physicians and as recorded on death certificates are shown in Table II. Bacterial infections were the leading cause of death (30%) in both. The 29 patients with pneumonias represented 74% of all deaths due to bacterial infections; pathogens found in sputum or bronchoalveolar lavage cultures included Staphylococcus aureus (6) and Huemophilus influenzae (5), Streptococcus pneumoniae (4), Legionella species (2), and Pseudomonas aeroginosa (1). More than three

Volume 93

quarters (79%) of the patients with the cause of death listed as pneumonia had had bronchoscopy within 2 weeks of death without finding Pneumocystis on silver stain, thereby excluding PCP as the cause of death. Ten additional persons had sepsis or endocarditis (diagnosed by positive blood cultures), and the most common pathogen was again S. aureus. Of the 38 persona who died of bacterial infections, 32 (82%) had met the CDC surveillance AIDS definition. Twenty-five percent of patients died of other opportunistic infections, with PCP (diagnosed with bronchoalveolar lavage) the third leading cause of death (16%) according to physician responses. Along with bacterial infections, these were the most common immediate causes listed on death certificates as well. However, 33% of deaths on death certificates were ascribed to “AIDS” and “cardiopulmonary arrest,” which are nonspecific. No death certificates listed cause of death as “unknown,” although physicians listed 6% of deaths as unknown after chart review. Non-HIV-related causes of death included gastrointestinal bleeding and myocardial infarction. All persons who met the CDC AIDS definition had been reported to the State Health Department. Table III presents all causes of death listed on death certificates. Although 32 certificates (25%) listed bacterial infections as the immediate cause of death, bacterial infections were listed on 4 additional death certificates. PCP was the immediate cause of death on 20 certificates and was listed as an additional cause on 6 others. “AIDS” was listed alone as the immediate cause of death on 28 certificates. Seventy-two percent of persons had used zidovudine for at least 2 months prior to death. No patient had granulocytopenia (fewer than 1.0 X log cells/L) at the time of death. Sixty-one percent of patients used PCP prophylaxis for at least 2 months prior to death; 7% of these persons had used trimethoprimsulfamethoxazole (TMP/SMX) prophylaxis. Persons not receiving any form of PCP prophylaxis were more likely to die of PCP than were those who had received prophylaxis for at least 2 months prior to death (26% versus 11%; p = 0.04), based on physician review.

COMMENTS After 1987, PCP was not the leading cause of HIV-related death in our state. Earlier diagnosis, better treatment, and increased use of prophylaxis for PCP all probably influenced the decline of PCP as a cause of death. One previous report documents a similar decline in fatal PCP infections [3] but without specifically identifying how cause of death was defined. This decline in fatal episodes of PCP

TABLE III All Causesof Death on Death Certificates Cause Bacterial infections* Alone With opportunistic With PCP With AIDS With lymphoma 0t~he;~portunistic With With With With

No. 32 (total)* 16 infections ;

infections

23 (total) 13

bacterial infection opportunistic infections PCP AIDS

: i 20 (total) 13

PCP Alone With bacterial infection With opportunistic infections With Kaposi’s sarcoma With AIDS

! .: 3 (total) 2 1 3 (total) 2 1

Liver failure

With opportunistic With PCP

infections

Lvmphoma

1 (total)

Non-HIV-related

1 (total)

Kaposi’s sarcoma

1 (total)

AIDS

28 (total)

Cardiopulmonary arrest Alone With bacterial infection With PCP With lymphoma With AIDS

14 (total) z ! 5

F lbrevlatlonsas in Table II. *Totals represent number hstec as the rmmed~atecause of death.

points out that access to PCP prophylaxis needs to continue for all populations when clinically indicated [9]. Bacterial infections are emerging as an important cause of death in the AIDS epidemic. These infections are not included in the CDC AIDS surveillance definition but are a rising source of mortality in patients with advanced disease as indicated by CD4 counts lower than 200 cells/mm3. Bacterial infections were also commonly noted early in the course of HIV infection (often due to S. aureu.s and H. influenzae), and these infections were also noted here [lo]. Our data, from a predominantly male homosexual sample, confirm the effect of bacterial infections on mortality reported among intravenous drug users in New York City [ll]. Appropriate antibiotic treatment in patients with CD4 counts less than 200 cells/mm3 may prevent premature death. In cases of terminal HIV

October

1992

The American

Journal

of Medicine

Volume

93

389

CAUSES OF DEATH IN HIV INFECTION / STEIN ET AL

disease, treating bacterial processes may, of course, be futile; in this series, reporting physicians clearly believed that antibiotic therapy was indicated and had a reasonable chance of success as indicated by their responses to the cause of death query. Indeed, terminal bacterial infections may have been underreported given the probability that there were instances when cultures were not done and physicians decided treatment was not indicated. Only 7% of our sample used TMP/SMX prophylaxis for PCP, in part because of patient preference in our region for aerosol pentamidine. It is possible that with more widespread use of TMP/SMX, bacterial infections will be less common. Our data may provide an additional reason for choosing TMP/SMX as a first-line PCP prophylactic regimen [7]. Death certificates were incomplete in providing specific information on the development of infections and malignancies in persons with HIV. Indeed, in 33% of cases (42 persons), the recorded immediate cause of death (AIDS, cardiopulmonary arrest) was imprecise. On only 4 of these 42 death certificates were HIV-related diseases (for example, lymphoma or PCP) noted. Death certificates may have been completed by covering or resident physicians who did not know the patient as well as the deceased’s personal physician and, therefore, inexact mechanisms of death such as “cardiorespiratory arrest” may have been used rather than precise causes. Even careful surveillance cannot identify deaths in unrecognized cases of HIV infection or deaths in which physicians do not mention AIDS or HIV on death certificates. However, improved public health surveillance has identified deaths among persons diagnosed with HIV infection without AIDS since update of the ICD-9 classification scheme for HIV in 1987. Underdiagnosis and underreporting were expected to be less of a problem in Rhode Island, given the limited number of physicians and hospitals who care for virtually all persons with HIV infection. Notably, all persons in this series who met the CDC AIDS definition had been reported to the Health Department. A review of deaths in New York City noted that 9% of HIV-infected persons did not have illnesses meeting the AIDS case definition [12]; in our series, 13% did not have CDC-defined AIDS. Interestingly, if the CDC extended the AIDS definition to all per-

390

October 1992 The American Journal of Medicine

sons with a CD4 count of less than 200/mm3, all but one person in this series would have AIDS. Because only 7% of deaths were followed by autopsies, cause of death as described by physicians here remains inconclusive. Previous surveys have demonstrated that autopsies often reveal AIDS-related diseases that were not suspected clinically [4]. In the autopsies done in our series, however, no unsuspected diseases were discovered that would explain cause of death. In addition, it is possible that some pneumonia deaths classified as bacterial may have been due to PCP; however, the high rate of bronchoscopy close to the time of death makes this possibility less likely. Only a single person in our series with a CD4 count higher than 200 cells/mm3 died, and this death was not HIV-related. Due to improved diagnoses and treatments, including antiretroviral and PCP prophylaxis, deaths due to PCP, the most common opportunistic infection in the first years of the epidemic, are declining. Early HIV testing and entry into the health care system should permit persons with HIV infection to live longer.

REFERENCES 1. Centers for Disease Control. Mortality attributable to HIV infection/AIDSUnited States, 1981-1990. MMWR 1991; 40: 41-4. 2. Kovacs JA, Masur H. Prophylaxis of Pneumocysfis carinii pneumonia: an update. J Infect Dis 1989; 160: 882-6. 3. Peters ES. Beck EJ, Coleman DG. eta/. Changing disease patterns in patients with AIDS in a referral center in the United Kingdom: the changing face of AIDS. BMJ 1991; 302: 203-7. 4. Wickes MS, Fortin AH, Felix JC. et al. Value of necropsy in acquired immunodeficiency syndrome. Lancet 1988; 2: 85-8. 5. Rosenberg HM. Improving cause-of-death statistics. Am J Public Health 1989; 79: 563-4. 6. Hopkins DD, Grant-Worley JA, Bollinger TL. Survey of cause-of-death query criteria used by state vital statistics programs in the US and the efficacy of criteria used by the Oregon Vital Statistics Program. Am J Public Health 1989; 79: 57D-4. 7. Volberding PA. Recent advances in the medical management of early HIV disease. J Gen Intern Med 1991; 6 Suppl: S7-12. 6. Centers for Disease Control. Revision of the CDC case definition for acquired immunodeficiency syndrome. MMWR 1987; 36: lS-15s. 9. Piette J, Stein M. Mor V, et a/. Patterns of secondary prophylaxis with aerosol pentamidine among persons with AIDS. J AIDS 1991; 4: 826-8. 10. Polsky B, Gold JWM, Whimbey E, eta/. Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104: 38-41. 11. Stoneburner !?A, DeJarlais DC, Benezra D. Alarger spectrum of severe HIV-1 related disease in intravenous drug users in New York City. Science 1989; 242:

916-9. 12. Hindin RH, Thomas P, Nicholas A, et al. Evaluating completeness of New York City’s case registry. Presented at the Fifth International Conference on AIDS, Montreal,

Volume 93

June 4-9.

1989.

Causes of death in persons with human immunodeficiency virus infection.

Pneumocystis carinii pneumonia (PCP) was reported to be the predominant cause of human immunodeficiency virus (HIV)-related deaths prior to 1988, the ...
469KB Sizes 0 Downloads 0 Views