Tuhercle and Lund Dwra.ve(1992) 73,77-X2 6 1992 Longman GroupUK
Ltd
I
I
Deaths in tuberculosis patients in British Columbia, 1980-1984 H. J. Xie, D. A. Em-son,?
C. W. Chao,* E. A. Allen,* S. Grzybowski*
Division of TB Control, Ministry of Health and Respiratory Division, University of British Columbia, Vancouver, British Columbia, Canada and the Department of Medicine, University of Alberta, Canada.
S UMMA R Y. Records of all 1884 newly notified tuberculosis cases, over the 5-year period 1980-1984 in British Columbia, Canada, were reviewed and 201 deaths were identified, including 48 diagnosed only after death, and 153 who died while on treatment; 56 of unrelated causes, 67 in whom tuberculosis was a contributing cause, and 30 in whom it was the principal cause. Significant predictors of death while on treatment (specific to tuberculosis) were the extent of disease, history of previous disease and sputum smearpositive for acid-fast organisms. Significant predictors of failure of diagnosis, in patients who died, were the presence of disseminated disease and the absence of a history of previous disease. The presenting features were not different in those dying, in whom the diagnosis was made before, as compared with after, death. The most frequent mode of death due to tuberculosis was respiratory failure, followed by multiple organ system failure and haemoptysis. The case fatality rate was low (1.6%) and did not change over 10 years. One-half of patients whose death was due to tuberculosis were diagnosed only after death and this had not changed over 10 years. We conclude that death due to tuberculosis is uncommon in patients while on treatment and that the main reason for death due to tuberculosis is that some patients are not diagnosed, and therefore not treated, before they die of the disease. Rf?S UMk. Les dossiers de l’ensemble des 1884 cas de tuberculose nouvellemment recenses ont Cte CtudiCs pendant 5 ans, 1980-1984 au Colombie britannique, Canada, et 201 d&es ont ete identifies, dont 48 diagnostiques seulement aprb de&s et 153 survenus au tours du traitement: 56 d&&s relevaient de causes independantes de la tuberculose. Pour 67 la tuberculose reprdsentait un facteur contributif et pour 30 d&&s elle Ctait le facteur dominant. Les facteurs predictifs significatifs de d&es pendant le traitement (pour tuberculose) Ctaient: l’etendue de la maladie, l’histoire anterieure de la maladie et l’existence de frottis-positif pour les organismes acido-resistants. Les causes significatives de faillite du diagnostic chez les d&d& Ctaient la presence d’une maladie disseminee et l’absence d’une histoire de maladie anterieure dans les ant&da&s. Le tableau symptomatique n’etait pas different dans les cas Cvoluant vet-s la mort compare a celui de sujets diagnostiques apt-es d&&s. La cause la plus frequente de d&c&sdue B la tuberculose etait l’insuffisance respiratoire, suivie d’une defaillance polyviscerale et d’bemoptysie. Le taux de Utalite Ctait bas (1,6%) et n’a pas change au tours de 10 ans. La moitie des cas dont la mot-t Ctait due a la tuberculose n’ont CtCdiagnostiques qu’apres d&&s, et ceci n’a pas varie au tours des 10 ans. On conclut que le d&&s par la tuberculose est rare parmi les cas qui suivent un traitement, et que la cause principale de la mot-t due a la tuberculose est relevee de la meconnaissance du diagnostic et de l’absence de traitement. R E S U M E N . Las fichas clinicas de la totalidad de 10s 1884 cases nuevos de tuberculosis notiftcados durante
un period0 de 5 adios, 1980-1984 en Colombia Britinica, Canada, fueron revisadas, habiendose detectado 201 muertes, comprendiendo 48 cases que fueron diagnosticados solamente despues de1 deceso y 153 que fallecieron mientras eran tratados: 56 de causas no relacionadas con la tuberculosis, 67 en 10s cuales la tuberculosis fue una causa contribuyente y 30 en quienes fue la causa principal. Los elementos significativos de predicci6n de muerte durante el tratamiento (especificos de la tuberculosis) fueron la extension de la enfermedad, 10s antecedentes de enfermedad previa y una baciloscopia positiva para microorganismos acid0 alcohol resistentes. Los elementos significativos de prediction de insuficiencia diagndstica en pacientes fallecidos, fueron la presencia de enfermedad diseminada y la ausencia de antecedentes de enfermedad. Los
Correspondence to: Dr D. A. Enarson, International Union Against Tuberculosis and Lung Disease, 68 Boulevard Saint-Michel, Paris, France. 77
78
Tubercle and Lung Disease
sintomas presentados por 10s fallecidos no fueron diierentes en quienes el diagmktico fue efectuado antes o despues de la muerte. La causa de mortalidad m&sfrecuente provocada por la tuberculosis fue la insuficiencia respiratoria, seguida por la insuficiencia orgiinica multiple y la hemoptisis. La tasa de letalidad fue baja (1,6%) y no vari6 en un period0 de 10 adios. La mitad de 10s pacientes, cuya muerte se debid a la tuberculosis, fueron diagnosticados ~610despues de fallecer, lo cual no se ha modificado en un period0 de 10 afros. Concluimos que la muerte provocada por la tuberculosis es poco frecuente en 10s pacientes que e&in siendo tratados y que la principal causa de mortalidad provocada por la tuberculosis es el hecho que algunos pacientes no son diagnosticados y por tanto no tratados, antes de fallecer por esta enfermedad.
Prior to the introduction of specific chemotherapy for tuberculosis, a high proportion of all tuberculosis patients died of their disease and the mortality rate was a sensitive measure of the size and trend of the tuberculosis problem in any geographic location.‘~*With the introduction of modern chemotherapy, the case fatality rate declined quickly and since then, mortality rate has become more of an indicator of the quality of tuberculosis control.3 In Canada, a major factor contributing to death in tuberculosis patients is the failure to diagnose cases until after they have succumbed to their disease. 4-8 Nevertheless, approximately one-half of patients who die of tuberculosis, die while on treament for their disease. In addition, some patients die of causes other than tuberculosis. The purpose of this study was to review deaths in patients with active tuberculosis in British Columbia during the period 1980-1984 to determine whether there had been any change in the contribution of failure of diagnosis to the overall picture of tuberculosis fatality since a previous, similar, study4 and to determine other factors associated with death in tuberculosis patients.
MATERIAL AND METHODS Notification of cases of active tuberculosis are obtained by the Division of Tuberculosis Control, Ministry of Health, Province of British Columbia, from private physicians, from all laboratories (private or hospital), from all hospitals, from pharmacies supplying antituberculosis medications and from the Division of Vital Statistics. The medical records of all 1884 cases of active tuberculosis notified from 1980 to 1984 were reviewed and variables of interest were abstracted including age, gender, race, current diagnosis, previous documented tuberculosis, presenting symptoms, results of laboratory investigations, concomitant medical conditions, record of hospitalization, location, mode and cause of death. All 201 deaths of patients with active tuberculosis notified to the Division from 1980 to 1984 were reviewed, including 153 who died while on treatment and 48 who were never treated, having been diagnosed only after death Death certificates are routinely sent to the Division when tuberculosis is mentioned on the certificate, and copies of all available medical records
are obtained and reviewed by a single specialist in tuberculosis for assessment of the cause of death. Three categories are used: ‘principal cause’ in which the disease leads directly to organ failure or fatal complications; ‘contributing cause’ in which a death from another cause may have been precipitated by the tuberculosis; ‘unrelated’, in which death from another cause was independent of the presence of tuberculosis. We determined whether a diagnosis was made prior to death; none of the 48 who were diagnosed after death were receiving treatment at time of death, and tuberculosis was not included in the diagnosis at time of death. The standard classilication of cases used in practice for the reporting of patients in Canada’ was used. Alcoholism refers to the intake of alcoholic beverages to the extent that it interferes with the treatment of tuberculosis by causing the patient to miss appointments, to attend clinic in a drunken state or to have medications interrupted because of alcohol toxicity. When multiple variables have been considered, rates have been standardized by the indirect method. In determining the predictors of death, relative risks and their corresponding confidence intervals have been determined by the rate ratios of those with and without the variable of interest. In determining the risk of death from all causes while on treatment, all deaths have been used. In determining the risk of death from tuberculosis, tuberculosis deaths have been compared with deaths unrelated to tuberculosis, as some variables (such as age) are related to likelihood of death, regardless of cause. The risk of dying of tuberculosis undiagnosed was determined by comparing deaths from tuberculosis while on treatment with those in whom tuberculosis was undiagnosed.
RESULTS Of 1884 tuberculosis patients diagnosed in British Columbia between 1980 and 1984, 48 (2.5%) were diagnosed only after death. Of the remainder, 56 (3.1%) died of unrelated causes and 97 (5.3%) died of tuberculosis while on treatment (in 67, 3.6%, tuberculosis was considered a contributing cause and in 30, 1.6%, the principal cause). The most common causes of death in those 123 in whom tuberculosis was not the principal cause were, in order of frequency: malignant
Deaths in tuberculosis
patients in British Columbia,
males
1980-l 984
females
30%
10
20
30
40
50
60
A
_.-
v-
0
70
80
90
0
10
20
age, years
40
30
50
60
70
80
90
age, years _S
cries A
m
Fig. I-Fatality in tuberculosis patients on treatment according to age, gender and cause, British Columbia, cause; B = tuberculosis contributing cause; C = death unrelated to tuberculosis.
disease (3 l%), acute myocardial infarction (25%), liver failure (8%) or respiratory failure associated with other lung diseases (7%). Figure 1 shows the fatality rate by age, sex and cause of death for those who died while on treatment. Three cases under the age of 35 died of unrelated causes and 1 of tuberculosis; of the 60 cases 35-64 years of age, tuberculosis was unrelated in 24 cases, contributing in 25 cases and principal cause of death in 11 cases. Of the 89 cases over 65 years of age, tuberculosis was unrelated in 29, contributing in 42 and principal cause in 18. There was a significantly increased likelihood of death, from all causes and from tuberculosis (Table l),
Table 1. Relative risk of dying, by cause of death, while on treatment. Tuberculosis patients in British Columbia, 198&1984 All causes* (95% CI) RR
Tuberculosist RR (95% CI)
Diagnosis (vs other) Advanced pulmonary Disseminated
2.3 4.8
(2.6, 2.0) (6.2,3.3)
3.8 4.5
(4.7, 2.9) (6.2, 2.8)
Race (vs white) Native Indian Other non-white
3.9 1.7
(4.9,2.8) (2.2, 1.2)
0.5
0.7
(1.0,O.l) (1.5,O.l)
Previous disease (vs none)
1.5
(2.0, 1.0)
3.3
(4.9, 1.7)
Pulmonary smear-positive (vs other pulmonary)
2.7
(3.2, 2.1)
2.8
(4.2, 1.4)
Risk factor
79
95% confidence interval in brackets; adjusted for age, sex and diagnosis. RR = relative risk: *dying vs surviving +principal cause vs unrelated
Series B
0
Series
1980-I 984 A = tuberculosis
C principal
for both disseminated tuberculosis (relative risks of 4.8 and 4.5) and for advanced pulmonary disease (relative risks of 2.3 and 3.8) when compared with all other diagnoses. The risk of death from all causes in Indians and other non-whites (predominantly Asians) was significantly elevated (relative risks 3.9 and 1.7, compared to whites) but the risk of death from tuberculosis was not. A history of previous tuberculosis and the presence*of acid-fast bacilli in the sputum of pulmonary cases were associated with both an increased risk of death from all causes (1.5 and 2.7) and from tuberculosis (3.3 and 2.8). The association of death in tuberculosis patients with concomitant medical conditions is shown in Table 2. Deaths in patients with these conditions, as compared with those without these conditions, were significantly more common in those with chronic renal failure, malignancy or silicosis. The rate of death was increased in those on corticosteroid therapy but the number of cases was small and the increase was not statistically significant. Most (26 cases, 87%) of those whose principal cause of death was tuberculosis, died within 3 months of commencing therapy, whereas a lower proportion (38 cases, 57%) of those in whom tuberculosis was a contributing cause died within the first 3 months (Fig. 2). Of the 30 patients whose principal cause of death was tuberculosis and who died while on treatment, the trend of deaths by the duration of treatment was slightly different for different diagnoses. By the end of 2 weeks of treatment 7 pulmonary cases (37% of deaths) and
80
Tubercle and Lung Disease
Table 2. Concomitant medical conditions treatment, British Columbia, 1980-1984
Condition
All cases
Alcoholism Diabetes Gastrectomy Corticosteroid therapy Chronic renal failure Malignant disease Silicosis Total
and death of tuberculosis
patients while on
Cause of death in relation to tuberculosis Contributing Principal Unrelated
Significance*
253 (100) 68 (100) 28 (100)
10 (4.0) 3 (4.4) 1 (3.6)
8 (3.2) 3 (4.4) 1 (3.6)
5 (2.0) 3 (4.4) 0 (-)
0.752 0.255 0.920
21 (100)
1 (4.8)
3 (14.3)
0
0.060
12 (100)
2 (16.7)
5 (41.7)
1 (8.3)
0.05 from chi-square). The duration of hospitalization in those diagnosed after death is shown in Figure 3. A number of patients
Deaths in tuberculosis
4
=
2
=
patients in British Columbia,
1980-l 984
I
Undiagnosed
m
Diagnosed
81
o= 7 Hospital Fig. 3-Duration 1980-1984.
of hospitalization
9
11
13
15
weeks
prior to death in cases dying undiagnosed,
were in hospital longer than 4 weeks prior to their deaths. The duration of hospitalization prior to death was not different for pulmonary and for disseminated cases. Of the patients who died of tuberculosis, including those who died while on treatment and those who were diagnosed only after death, most (27, 46.6%) died of respiratory failure (27, 46.6%), multiple organ system failure (12, 20.7%) or haemoptysis (5, 8.6%). Respiratory failure was most common in pulmonary cases who died (32 cases, 74%), whereas multiple organ system failure was most common among disseminated cases (9 cases, 53%). Death from haemoptysis was equally common in the groups (pulmonary 3 cases, 7%; disseminated 2 cases, 12%). Death from multiple organ system failure and from haemoptysis occurred as an early event in those patients who died on treatment (5 deaths, 71% and 3 deaths, 75% respectively by the end of 4 weeks) as compared with respiratory failure (10 deaths, 48%). Of interest, 3 patients died after spinal cord compression, 1 following trauma but the other 2 as a result of tuberculosis involving cervical discs. The majority of patients were in hospital at the time of death (93% principal cause, 80% contributing cause and 80% unrelated). Table 5 illustrates the trend over 10 years in the case fatality rate for various forms of tuberculosis and for the rate of failure of diagnosis in patients dying of tuberculosis. Although the total number of cases declined, there was no change in either of these rates.
and prior to diagnosis
in cases dying on treatment,
Table 5. Trend in tuberculosis Columbia
deaths over 10 years in British
Diagnosis
Case fatality rate* 1970-1974 198G1984
All
49
Advanced pulmonary Disseminated Other
38 (4.3) 9 (25.7) 2 (0.1)
(1.7)
British Columbia,
Diagnosed after death’ 1970-1974 19861984
(1.6)
50 (50.5)
28 (48.3)
18 (3.1) 8 (17.8) 4 (0.3)
27 (41.5) 16 (64.0) 7 (77.8)
15 (45.5) 12 (60.0) 1 (20.0)
30
*patients whose principal cause of death was tuberculosis and who were diagnosed during life; ‘cases whose principal cause of death was tuberculosis; % in parentheses.
DISCUSSION Tuberculosis is a curable disease, provided that patients are diagnosed promptly and are given adequate chemotherapy which they take correctly. Nevertheless, some patients still die of this disease. Since tuberculosis has become much less frequent in recent decades in technically advanced countries, physicians have less direct experience with the disease, raising the prospect that misdiagnosis and improper treatment might increase. This study indicates such a possibility in that a continuing high proportion of those dying of tuberculosis are not diagnosed (and therefore not treated) even though most are under medical care. Moreover, there appears to be little that distinguishes between those who are not diagnosed and those who died while on treatment.
82
Tubercle and Lung Disease
Although the permanent cure of tuberculosis requires with multiple drugs, the prolonged treatment prevention of death is much easier. Even treatment regimens, which would normally be considered inadequate, result in a marked reduction in tuberculosis deaths. This explains the rapid decline in tuberculosis mortality rates in Western countries beginning in 1945 with the introduction of streptomycin and before the use of isoniazid.‘,’ It also explains the striking reduction in tuberculosis fatality in many developing countries where poor treatment programs leave large numbers of chronic cases and result in high rates of subsequent relapse.’ Presently the fatality rate for tuberculosis in British Columbia is very low. The most important single factor resulting in death due to tuberculosis is the failure to diagnose (and therefore to treat) the disease. In spite of a good deal of attention to this matterhE the relative contribution of failure of diagnosis to tuberculosis deaths remains unchanged in our area. The consequences of this failure go beyond the dire consequences to the affected patients to include a risk of infection with tuberculosis of staff, other patients and close associates.” The declining rate of autopsies” belies the fact that in as many as one-third of autopsied patients there are major unexpected findings.” The autopsy rate in our area is only 20% of deaths, so it is likely that the number of deaths due to tuberculosis is as much as 3 times greater than the number reported here because of this fact, and that failure of diagnosis is by far the most important cause of death due to tuberculosis. Aside from failure of diagnosis, the factors contributing to death from tuberculosis are largely those which predict survival in any group of patients, such as age, extent of disease and accompanying illnesses. It is of interest that, while alcoholism appeared to be more common in tuberculosis patients than in the general population where the prevalence is 5.4%,13 it was not a significant predictor of death in this series. As in other studies of tuberculosis deaths,‘4x’5 most deaths were in patients with advanced pulmonary or disseminated tuberculosis, with the highest fatality rate in disseminated cases. A suprising number of deaths occurred
many weeks after the commencement of therapy14S’5 even in the face of optimum drug therapy in hospital. With the exception of earlier diagnosis and institution of therapy at a less extensive stage, it is not clear what could have been done to prevent these deaths.
Acknowledgement Supported University
in part by a grant from Special of Alberta Hospital.
Services
and Research,
References 1. Statistics Canada. Tuberculosis statistics. Morbidity and mortality 1986. Minister of Supply and Services Canada 1988, p 20. 2. Styblo K. The epidemiological situation of tuberculosis and the impact of control measures. Bull Int Union Tuberc 1983; 58: 179-186. 3. Grzybowski S, Enarson D A. The fate of cases of pulmonary tuberculosis under various treatment programmes. Bull Int Union Tuberc 1978; 53: 70-75. 4. Enarson D A, Grzybowski S, Dorken E. Failure of diagnosis as a factor in tuberculosis mortality. Can Med Assoc J 1978; 118: 1520-1522. Edlin Cl P. Active tuberculosis unrecognized until necropsy. Lancet 1978; 1: 650-652. Bobrowitz I D. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72: 650-658. Katz I, Rosenthal T, Michaeli D. Undiagnosed tuberculosis in hospitalized patients. Chest 1985; 87: 770-774. Chastonay P, Gardiol D. La tuberculose active etendue a l’autopsie: etude retrospective d’un collectif d’autopsies d’adultes (1961-1985). Schweiz Med Wochenschr 1987; 117: 925-927. 9. Third National Tuberculosis Conference. Classification and reporting of tuberculosis in Canada. Canadian Tuberculosis and Respiratory Disease Association, Ottawa, 1969. 10. Lundgren R, Norrman E, Asberg I. Tuberculosis infection transmitted at autopsy. Tubercle 1987; 68: 147-150. 11. Geller S A. Autopsy. Scientific American 1983; 248: 124-136. 12. Landefeld C S, Chren M M, Myres A, Geller R, Robbins S, Goldman L. Diagnostic yield of the autopsy in a university hospital and a community hospital. N Engl J Med 1988; 318: 1249-1254. 13. Bland R C, Newman S C, Orn H. Period prevalence of psychiatric disorders in Edmonton. Acta Psychiatr Scan 1988; 77 (~~~~1338): 33-42. 14. Humphries M .I, Byfield S P, Darbyshiie J H, Davies P D 0, Nunn A J, Citron K M, Fox W. Deaths occurring in newly notified patients with pulmonary tuberculosis in England and Wales. Br J Dis Chest 1984; 78: 149-158. 15. Davis C E, Carpenter J L, McAllister C K, Bush B A, Ognibene A J. Tuberculosis. Cause of death in antibiotic era. Chest 1985; 88: 726-729.
Ltd
I
I
Deaths in tuberculosis patients in British Columbia, 1980-1984 H. J. Xie, D. A. Em-son,?
C. W. Chao,* E. A. Allen,* S. Grzybowski*
Division of TB Control, Ministry of Health and Respiratory Division, University of British Columbia, Vancouver, British Columbia, Canada and the Department of Medicine, University of Alberta, Canada.
S UMMA R Y. Records of all 1884 newly notified tuberculosis cases, over the 5-year period 1980-1984 in British Columbia, Canada, were reviewed and 201 deaths were identified, including 48 diagnosed only after death, and 153 who died while on treatment; 56 of unrelated causes, 67 in whom tuberculosis was a contributing cause, and 30 in whom it was the principal cause. Significant predictors of death while on treatment (specific to tuberculosis) were the extent of disease, history of previous disease and sputum smearpositive for acid-fast organisms. Significant predictors of failure of diagnosis, in patients who died, were the presence of disseminated disease and the absence of a history of previous disease. The presenting features were not different in those dying, in whom the diagnosis was made before, as compared with after, death. The most frequent mode of death due to tuberculosis was respiratory failure, followed by multiple organ system failure and haemoptysis. The case fatality rate was low (1.6%) and did not change over 10 years. One-half of patients whose death was due to tuberculosis were diagnosed only after death and this had not changed over 10 years. We conclude that death due to tuberculosis is uncommon in patients while on treatment and that the main reason for death due to tuberculosis is that some patients are not diagnosed, and therefore not treated, before they die of the disease. Rf?S UMk. Les dossiers de l’ensemble des 1884 cas de tuberculose nouvellemment recenses ont Cte CtudiCs pendant 5 ans, 1980-1984 au Colombie britannique, Canada, et 201 d&es ont ete identifies, dont 48 diagnostiques seulement aprb de&s et 153 survenus au tours du traitement: 56 d&&s relevaient de causes independantes de la tuberculose. Pour 67 la tuberculose reprdsentait un facteur contributif et pour 30 d&&s elle Ctait le facteur dominant. Les facteurs predictifs significatifs de d&es pendant le traitement (pour tuberculose) Ctaient: l’etendue de la maladie, l’histoire anterieure de la maladie et l’existence de frottis-positif pour les organismes acido-resistants. Les causes significatives de faillite du diagnostic chez les d&d& Ctaient la presence d’une maladie disseminee et l’absence d’une histoire de maladie anterieure dans les ant&da&s. Le tableau symptomatique n’etait pas different dans les cas Cvoluant vet-s la mort compare a celui de sujets diagnostiques apt-es d&&s. La cause la plus frequente de d&c&sdue B la tuberculose etait l’insuffisance respiratoire, suivie d’une defaillance polyviscerale et d’bemoptysie. Le taux de Utalite Ctait bas (1,6%) et n’a pas change au tours de 10 ans. La moitie des cas dont la mot-t Ctait due a la tuberculose n’ont CtCdiagnostiques qu’apres d&&s, et ceci n’a pas varie au tours des 10 ans. On conclut que le d&&s par la tuberculose est rare parmi les cas qui suivent un traitement, et que la cause principale de la mot-t due a la tuberculose est relevee de la meconnaissance du diagnostic et de l’absence de traitement. R E S U M E N . Las fichas clinicas de la totalidad de 10s 1884 cases nuevos de tuberculosis notiftcados durante
un period0 de 5 adios, 1980-1984 en Colombia Britinica, Canada, fueron revisadas, habiendose detectado 201 muertes, comprendiendo 48 cases que fueron diagnosticados solamente despues de1 deceso y 153 que fallecieron mientras eran tratados: 56 de causas no relacionadas con la tuberculosis, 67 en 10s cuales la tuberculosis fue una causa contribuyente y 30 en quienes fue la causa principal. Los elementos significativos de predicci6n de muerte durante el tratamiento (especificos de la tuberculosis) fueron la extension de la enfermedad, 10s antecedentes de enfermedad previa y una baciloscopia positiva para microorganismos acid0 alcohol resistentes. Los elementos significativos de prediction de insuficiencia diagndstica en pacientes fallecidos, fueron la presencia de enfermedad diseminada y la ausencia de antecedentes de enfermedad. Los
Correspondence to: Dr D. A. Enarson, International Union Against Tuberculosis and Lung Disease, 68 Boulevard Saint-Michel, Paris, France. 77
78
Tubercle and Lung Disease
sintomas presentados por 10s fallecidos no fueron diierentes en quienes el diagmktico fue efectuado antes o despues de la muerte. La causa de mortalidad m&sfrecuente provocada por la tuberculosis fue la insuficiencia respiratoria, seguida por la insuficiencia orgiinica multiple y la hemoptisis. La tasa de letalidad fue baja (1,6%) y no vari6 en un period0 de 10 adios. La mitad de 10s pacientes, cuya muerte se debid a la tuberculosis, fueron diagnosticados ~610despues de fallecer, lo cual no se ha modificado en un period0 de 10 afros. Concluimos que la muerte provocada por la tuberculosis es poco frecuente en 10s pacientes que e&in siendo tratados y que la principal causa de mortalidad provocada por la tuberculosis es el hecho que algunos pacientes no son diagnosticados y por tanto no tratados, antes de fallecer por esta enfermedad.
Prior to the introduction of specific chemotherapy for tuberculosis, a high proportion of all tuberculosis patients died of their disease and the mortality rate was a sensitive measure of the size and trend of the tuberculosis problem in any geographic location.‘~*With the introduction of modern chemotherapy, the case fatality rate declined quickly and since then, mortality rate has become more of an indicator of the quality of tuberculosis control.3 In Canada, a major factor contributing to death in tuberculosis patients is the failure to diagnose cases until after they have succumbed to their disease. 4-8 Nevertheless, approximately one-half of patients who die of tuberculosis, die while on treament for their disease. In addition, some patients die of causes other than tuberculosis. The purpose of this study was to review deaths in patients with active tuberculosis in British Columbia during the period 1980-1984 to determine whether there had been any change in the contribution of failure of diagnosis to the overall picture of tuberculosis fatality since a previous, similar, study4 and to determine other factors associated with death in tuberculosis patients.
MATERIAL AND METHODS Notification of cases of active tuberculosis are obtained by the Division of Tuberculosis Control, Ministry of Health, Province of British Columbia, from private physicians, from all laboratories (private or hospital), from all hospitals, from pharmacies supplying antituberculosis medications and from the Division of Vital Statistics. The medical records of all 1884 cases of active tuberculosis notified from 1980 to 1984 were reviewed and variables of interest were abstracted including age, gender, race, current diagnosis, previous documented tuberculosis, presenting symptoms, results of laboratory investigations, concomitant medical conditions, record of hospitalization, location, mode and cause of death. All 201 deaths of patients with active tuberculosis notified to the Division from 1980 to 1984 were reviewed, including 153 who died while on treatment and 48 who were never treated, having been diagnosed only after death Death certificates are routinely sent to the Division when tuberculosis is mentioned on the certificate, and copies of all available medical records
are obtained and reviewed by a single specialist in tuberculosis for assessment of the cause of death. Three categories are used: ‘principal cause’ in which the disease leads directly to organ failure or fatal complications; ‘contributing cause’ in which a death from another cause may have been precipitated by the tuberculosis; ‘unrelated’, in which death from another cause was independent of the presence of tuberculosis. We determined whether a diagnosis was made prior to death; none of the 48 who were diagnosed after death were receiving treatment at time of death, and tuberculosis was not included in the diagnosis at time of death. The standard classilication of cases used in practice for the reporting of patients in Canada’ was used. Alcoholism refers to the intake of alcoholic beverages to the extent that it interferes with the treatment of tuberculosis by causing the patient to miss appointments, to attend clinic in a drunken state or to have medications interrupted because of alcohol toxicity. When multiple variables have been considered, rates have been standardized by the indirect method. In determining the predictors of death, relative risks and their corresponding confidence intervals have been determined by the rate ratios of those with and without the variable of interest. In determining the risk of death from all causes while on treatment, all deaths have been used. In determining the risk of death from tuberculosis, tuberculosis deaths have been compared with deaths unrelated to tuberculosis, as some variables (such as age) are related to likelihood of death, regardless of cause. The risk of dying of tuberculosis undiagnosed was determined by comparing deaths from tuberculosis while on treatment with those in whom tuberculosis was undiagnosed.
RESULTS Of 1884 tuberculosis patients diagnosed in British Columbia between 1980 and 1984, 48 (2.5%) were diagnosed only after death. Of the remainder, 56 (3.1%) died of unrelated causes and 97 (5.3%) died of tuberculosis while on treatment (in 67, 3.6%, tuberculosis was considered a contributing cause and in 30, 1.6%, the principal cause). The most common causes of death in those 123 in whom tuberculosis was not the principal cause were, in order of frequency: malignant
Deaths in tuberculosis
patients in British Columbia,
males
1980-l 984
females
30%
10
20
30
40
50
60
A
_.-
v-
0
70
80
90
0
10
20
age, years
40
30
50
60
70
80
90
age, years _S
cries A
m
Fig. I-Fatality in tuberculosis patients on treatment according to age, gender and cause, British Columbia, cause; B = tuberculosis contributing cause; C = death unrelated to tuberculosis.
disease (3 l%), acute myocardial infarction (25%), liver failure (8%) or respiratory failure associated with other lung diseases (7%). Figure 1 shows the fatality rate by age, sex and cause of death for those who died while on treatment. Three cases under the age of 35 died of unrelated causes and 1 of tuberculosis; of the 60 cases 35-64 years of age, tuberculosis was unrelated in 24 cases, contributing in 25 cases and principal cause of death in 11 cases. Of the 89 cases over 65 years of age, tuberculosis was unrelated in 29, contributing in 42 and principal cause in 18. There was a significantly increased likelihood of death, from all causes and from tuberculosis (Table l),
Table 1. Relative risk of dying, by cause of death, while on treatment. Tuberculosis patients in British Columbia, 198&1984 All causes* (95% CI) RR
Tuberculosist RR (95% CI)
Diagnosis (vs other) Advanced pulmonary Disseminated
2.3 4.8
(2.6, 2.0) (6.2,3.3)
3.8 4.5
(4.7, 2.9) (6.2, 2.8)
Race (vs white) Native Indian Other non-white
3.9 1.7
(4.9,2.8) (2.2, 1.2)
0.5
0.7
(1.0,O.l) (1.5,O.l)
Previous disease (vs none)
1.5
(2.0, 1.0)
3.3
(4.9, 1.7)
Pulmonary smear-positive (vs other pulmonary)
2.7
(3.2, 2.1)
2.8
(4.2, 1.4)
Risk factor
79
95% confidence interval in brackets; adjusted for age, sex and diagnosis. RR = relative risk: *dying vs surviving +principal cause vs unrelated
Series B
0
Series
1980-I 984 A = tuberculosis
C principal
for both disseminated tuberculosis (relative risks of 4.8 and 4.5) and for advanced pulmonary disease (relative risks of 2.3 and 3.8) when compared with all other diagnoses. The risk of death from all causes in Indians and other non-whites (predominantly Asians) was significantly elevated (relative risks 3.9 and 1.7, compared to whites) but the risk of death from tuberculosis was not. A history of previous tuberculosis and the presence*of acid-fast bacilli in the sputum of pulmonary cases were associated with both an increased risk of death from all causes (1.5 and 2.7) and from tuberculosis (3.3 and 2.8). The association of death in tuberculosis patients with concomitant medical conditions is shown in Table 2. Deaths in patients with these conditions, as compared with those without these conditions, were significantly more common in those with chronic renal failure, malignancy or silicosis. The rate of death was increased in those on corticosteroid therapy but the number of cases was small and the increase was not statistically significant. Most (26 cases, 87%) of those whose principal cause of death was tuberculosis, died within 3 months of commencing therapy, whereas a lower proportion (38 cases, 57%) of those in whom tuberculosis was a contributing cause died within the first 3 months (Fig. 2). Of the 30 patients whose principal cause of death was tuberculosis and who died while on treatment, the trend of deaths by the duration of treatment was slightly different for different diagnoses. By the end of 2 weeks of treatment 7 pulmonary cases (37% of deaths) and
80
Tubercle and Lung Disease
Table 2. Concomitant medical conditions treatment, British Columbia, 1980-1984
Condition
All cases
Alcoholism Diabetes Gastrectomy Corticosteroid therapy Chronic renal failure Malignant disease Silicosis Total
and death of tuberculosis
patients while on
Cause of death in relation to tuberculosis Contributing Principal Unrelated
Significance*
253 (100) 68 (100) 28 (100)
10 (4.0) 3 (4.4) 1 (3.6)
8 (3.2) 3 (4.4) 1 (3.6)
5 (2.0) 3 (4.4) 0 (-)
0.752 0.255 0.920
21 (100)
1 (4.8)
3 (14.3)
0
0.060
12 (100)
2 (16.7)
5 (41.7)
1 (8.3)
0.05 from chi-square). The duration of hospitalization in those diagnosed after death is shown in Figure 3. A number of patients
Deaths in tuberculosis
4
=
2
=
patients in British Columbia,
1980-l 984
I
Undiagnosed
m
Diagnosed
81
o= 7 Hospital Fig. 3-Duration 1980-1984.
of hospitalization
9
11
13
15
weeks
prior to death in cases dying undiagnosed,
were in hospital longer than 4 weeks prior to their deaths. The duration of hospitalization prior to death was not different for pulmonary and for disseminated cases. Of the patients who died of tuberculosis, including those who died while on treatment and those who were diagnosed only after death, most (27, 46.6%) died of respiratory failure (27, 46.6%), multiple organ system failure (12, 20.7%) or haemoptysis (5, 8.6%). Respiratory failure was most common in pulmonary cases who died (32 cases, 74%), whereas multiple organ system failure was most common among disseminated cases (9 cases, 53%). Death from haemoptysis was equally common in the groups (pulmonary 3 cases, 7%; disseminated 2 cases, 12%). Death from multiple organ system failure and from haemoptysis occurred as an early event in those patients who died on treatment (5 deaths, 71% and 3 deaths, 75% respectively by the end of 4 weeks) as compared with respiratory failure (10 deaths, 48%). Of interest, 3 patients died after spinal cord compression, 1 following trauma but the other 2 as a result of tuberculosis involving cervical discs. The majority of patients were in hospital at the time of death (93% principal cause, 80% contributing cause and 80% unrelated). Table 5 illustrates the trend over 10 years in the case fatality rate for various forms of tuberculosis and for the rate of failure of diagnosis in patients dying of tuberculosis. Although the total number of cases declined, there was no change in either of these rates.
and prior to diagnosis
in cases dying on treatment,
Table 5. Trend in tuberculosis Columbia
deaths over 10 years in British
Diagnosis
Case fatality rate* 1970-1974 198G1984
All
49
Advanced pulmonary Disseminated Other
38 (4.3) 9 (25.7) 2 (0.1)
(1.7)
British Columbia,
Diagnosed after death’ 1970-1974 19861984
(1.6)
50 (50.5)
28 (48.3)
18 (3.1) 8 (17.8) 4 (0.3)
27 (41.5) 16 (64.0) 7 (77.8)
15 (45.5) 12 (60.0) 1 (20.0)
30
*patients whose principal cause of death was tuberculosis and who were diagnosed during life; ‘cases whose principal cause of death was tuberculosis; % in parentheses.
DISCUSSION Tuberculosis is a curable disease, provided that patients are diagnosed promptly and are given adequate chemotherapy which they take correctly. Nevertheless, some patients still die of this disease. Since tuberculosis has become much less frequent in recent decades in technically advanced countries, physicians have less direct experience with the disease, raising the prospect that misdiagnosis and improper treatment might increase. This study indicates such a possibility in that a continuing high proportion of those dying of tuberculosis are not diagnosed (and therefore not treated) even though most are under medical care. Moreover, there appears to be little that distinguishes between those who are not diagnosed and those who died while on treatment.
82
Tubercle and Lung Disease
Although the permanent cure of tuberculosis requires with multiple drugs, the prolonged treatment prevention of death is much easier. Even treatment regimens, which would normally be considered inadequate, result in a marked reduction in tuberculosis deaths. This explains the rapid decline in tuberculosis mortality rates in Western countries beginning in 1945 with the introduction of streptomycin and before the use of isoniazid.‘,’ It also explains the striking reduction in tuberculosis fatality in many developing countries where poor treatment programs leave large numbers of chronic cases and result in high rates of subsequent relapse.’ Presently the fatality rate for tuberculosis in British Columbia is very low. The most important single factor resulting in death due to tuberculosis is the failure to diagnose (and therefore to treat) the disease. In spite of a good deal of attention to this matterhE the relative contribution of failure of diagnosis to tuberculosis deaths remains unchanged in our area. The consequences of this failure go beyond the dire consequences to the affected patients to include a risk of infection with tuberculosis of staff, other patients and close associates.” The declining rate of autopsies” belies the fact that in as many as one-third of autopsied patients there are major unexpected findings.” The autopsy rate in our area is only 20% of deaths, so it is likely that the number of deaths due to tuberculosis is as much as 3 times greater than the number reported here because of this fact, and that failure of diagnosis is by far the most important cause of death due to tuberculosis. Aside from failure of diagnosis, the factors contributing to death from tuberculosis are largely those which predict survival in any group of patients, such as age, extent of disease and accompanying illnesses. It is of interest that, while alcoholism appeared to be more common in tuberculosis patients than in the general population where the prevalence is 5.4%,13 it was not a significant predictor of death in this series. As in other studies of tuberculosis deaths,‘4x’5 most deaths were in patients with advanced pulmonary or disseminated tuberculosis, with the highest fatality rate in disseminated cases. A suprising number of deaths occurred
many weeks after the commencement of therapy14S’5 even in the face of optimum drug therapy in hospital. With the exception of earlier diagnosis and institution of therapy at a less extensive stage, it is not clear what could have been done to prevent these deaths.
Acknowledgement Supported University
in part by a grant from Special of Alberta Hospital.
Services
and Research,
References 1. Statistics Canada. Tuberculosis statistics. Morbidity and mortality 1986. Minister of Supply and Services Canada 1988, p 20. 2. Styblo K. The epidemiological situation of tuberculosis and the impact of control measures. Bull Int Union Tuberc 1983; 58: 179-186. 3. Grzybowski S, Enarson D A. The fate of cases of pulmonary tuberculosis under various treatment programmes. Bull Int Union Tuberc 1978; 53: 70-75. 4. Enarson D A, Grzybowski S, Dorken E. Failure of diagnosis as a factor in tuberculosis mortality. Can Med Assoc J 1978; 118: 1520-1522. Edlin Cl P. Active tuberculosis unrecognized until necropsy. Lancet 1978; 1: 650-652. Bobrowitz I D. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72: 650-658. Katz I, Rosenthal T, Michaeli D. Undiagnosed tuberculosis in hospitalized patients. Chest 1985; 87: 770-774. Chastonay P, Gardiol D. La tuberculose active etendue a l’autopsie: etude retrospective d’un collectif d’autopsies d’adultes (1961-1985). Schweiz Med Wochenschr 1987; 117: 925-927. 9. Third National Tuberculosis Conference. Classification and reporting of tuberculosis in Canada. Canadian Tuberculosis and Respiratory Disease Association, Ottawa, 1969. 10. Lundgren R, Norrman E, Asberg I. Tuberculosis infection transmitted at autopsy. Tubercle 1987; 68: 147-150. 11. Geller S A. Autopsy. Scientific American 1983; 248: 124-136. 12. Landefeld C S, Chren M M, Myres A, Geller R, Robbins S, Goldman L. Diagnostic yield of the autopsy in a university hospital and a community hospital. N Engl J Med 1988; 318: 1249-1254. 13. Bland R C, Newman S C, Orn H. Period prevalence of psychiatric disorders in Edmonton. Acta Psychiatr Scan 1988; 77 (~~~~1338): 33-42. 14. Humphries M .I, Byfield S P, Darbyshiie J H, Davies P D 0, Nunn A J, Citron K M, Fox W. Deaths occurring in newly notified patients with pulmonary tuberculosis in England and Wales. Br J Dis Chest 1984; 78: 149-158. 15. Davis C E, Carpenter J L, McAllister C K, Bush B A, Ognibene A J. Tuberculosis. Cause of death in antibiotic era. Chest 1985; 88: 726-729.
