and mortality in adults in the

Transcription

1 2 Trends and causes in pneumonia-related morbidity and mortality in adults in the Netherlands Ned Tijdschr Geneeskd. 2003; 147 (9): JJ Oosterheert, MJM Bonten, E Hak, JWJ Lammers, MME Schneider, IM Hoepelman

2 Chapter 21 Abstract Morbidity and mortality due to pneumonia-related disease has increased in the Netherlands in the past 10 years, as shown in several national registrations. There are several possible explanations. An increase in the elderly population is the most likely explanation. An increase in underlying conditions such as chronic obstructive pulmonary disease and diabetes mellitus are also possible explanations. Antibiotic resistance, inadequate treatment or a shift in causative micro-organisms probably don t play a role. Therefore, specifically focusing on pneumonia may not be sufficient to reduce the burden of pneumonia related disease and mortality. 22

3 Chapter 2 Introduction Despite the use of antibiotics and associated decreases in mortality due to respiratory infections, lower respiratory tract infections such as pneumonia remain an important cause for mortality in the Netherlands. Pneumonia ranks 4th in the most frequent causes of death in our country (source: CBS mortality statistics, table 1) and although sepsis and AIDS are associated with high mortality rates, in the western world, respiratory infection is the most important infectious cause of death. (1) Disease Absolute mortality Coronary heart disease Cerebrovascular disease Lung carcinoma Pneumonia COPD Decompensatio Cordis Dementia Colon carcinoma Breast carcinoma Table 1 Important causes of death in the Netherlands in 2000 (Source: CBS doodsoorzakenstatistiek, RIVM kompas voor de volksgezondheid) Usually, pneumonia is categorized in hospital-acquired pneumonia (noscomial pneumonia) or community-acquired pneumonia. (2) Especially the elderly and persons with underlying conditions such as cerebro- and cardiovascular diseases, COPD and alcoholism are at risk for developing lower respiratory tract infections and a complicated course of the infection. (3;4) The mortality-risk of pneumonia is dependent of combinations of underlying illnesses, age and clinical features (5;6) In general, monotherapy with a beta-lactam antibiotic is the indicated initial therapy. Combinations of beta-lactam antibiotics and macrolides are only advised when a strong suspicion of pneumonia caused by M. pneumoniae, C. pneumoniae or L. pneumophila exists, or in severe pneumonia needing treatment in an intensive care unit. (2;7) In recent years, absolute mortality because of pneumonia in the 23

4 Chapter 21 Netherlands has risen and a similar increase in mortality was found in the United States. (8-10) In this chapter, we describe this increase and explore possible explanations for the Dutch situation. Increase in registered pneumonia-related mortality The number of pneumonia-related deaths has risen from 3487 in 1990 to 6533 in (source: CBS mortality statistics). Mortality rates per inhabitants increased from 31.3 to 54.3 and mortality rates standardized for the population of 1990 increased from 31.9 to (table 2, figure1. Source: CBS mortality statistics). This increase is most obvious in the higher age groups. Interestingly, in 2001 and 2002 standardized and age-specific mortality rates for pneumonia seem do decrease. (figure 2). According to registrations of the National Medical Registration (LMR), the number of adults that died from pneumonia in hospitals increased from 3734 in 1991 to 6104 in 2002 (source: LMR) Not only pneumonia related mortality has increased in recent years, in the same period, the number of patients diagnosed with pneumonia by general practitioners (source: Continuous Morbidity Registration) and the number of hospitalisations because of pneumonia in adults has also risen from hospitalisations in 1991 to in (Source: LMR, see table 2) Pneumonia realted morbitity and mortality Difference(%) Absolute mortality in adults Mortality per adults per year 31,3 54,3 73 Mortality standardized for age and sex per adults per year (Source: CBS) 31,9 48,9 53 Absolute hospital mortality Age and sex standardized mortality per adults per year Absolute number of hospitalisations Hospitalisations number standardized for age and sex per adults per year (Source: LMR) , , , ,0 Table 2 Mortality and Morbidity related to pneumonia in adults (20 years and older) in 1991/1991 and 2000/

5 Chapter Figure 1 Standardized mortality (for age and sex, population of 1990 per adults) Source: CBS Explanations The observed increase in pneumonia related mortality can be explained in several ways. First, a seeming increase due to registration methods and possible misclassification has to be ruled out. Subsequently, etiological explanations as altered age patterns in the population and increases in incidences of underlying diseases, changes in environmental factors or changes in causative micro-organisms of lower respiratory tract infections can have contributed to the increase in pneumonia-mortality. These items will be addressed in the rest of this chapter. Registration Methods First, it is important to evaluate whether the registered pneumoniarelated mortality reflects a true increase. In the Netherlands, causes of death are registered by the treating physician, the municipal coroner or an appointed physician. Causes of death are categorized according to the International Classification of Diseases version 9 and from 1996 onwards version 10. (ICD-9 and ICD-10). These data are managed by the Central Statistics Bureau of the Netherlands. 25

6 Chapter 21 Registration for hospital admissions is accounted for by the National Medical Registration (LMR). At discharge, the diagnosis, classified according to ICD-9 Clinical Modification (ICD-9-CM) that was the main cause for hospitalization is registered. This registration method has been unchanged in the period The described methods used for registration have their drawbacks. For example, the use of standardized disease codes like the International Classification of Diseases (ICD-codes) for scientific research is debated. An American study showed a 58.3% sensitivity the most frequently used ICD-codes for the diagnosis communityacquired pneumococcal pneumonia. In addition, sensitivity, positive predictive value and negative predictive value were unsatisfactory and misclassification occurred. (11) Furthermore, sensitivity could have been influenced by increased attention for the disease, possibly as a result of attention for antibiotic resistance or influenza epidemics Figure 2 Age specific pneumonia mortality (per ) (Source: CBS) In registering and classifying causes of death by CBS, in 1996 a switch was made from the ICD-9 to the ICD-10 classification. This could have influenced registered mortality. However, for pneumonia, both ICD-codes are only 70% similar, and use of ICD-9 codes would 26

7 Chapter 2 result in a rise in pneumonia diagnoses. Based on this change rather a decrease than an increase in pneumonia related mortality can be expected. (source: whosis/ bethesda/ documents/bethesda.77.doc) Another registration system, the LMR, retrospectively, i.e. after hospital stay, makes the diagnosis. A drawback of this system is that hospital-acquired pneumonias that were not the primary reason for hospital admission also are registered as pneumonia. It remains therefore unclear whether the diagnosis is based on a communityacquired or a nosocomial pneumonia. However, it is unlikely that the drawbacks in registration systems are an explanation for the observed increase in pneumonia related mortality. First, an acute change in registration procedures would lead to a fast and short lasting increase in mortality and this would remain at a constant level thereafter. Mortality would not gradually increase over a 10-year period. Secondly, an increase in incidence, hospitalisations and mortality of pneumonia as observed in three independent systems (LMR, CBS, CMR) contradicts a systematic registration bias in one of these systems. Third, in other countries, with other registration methods, a increase in pneumonia-related mortality has also been observed. (12;13) Therefore, despite the possibility of misclassification, the increase in pneumonia-related mortality seems real. Age patterns, co-morbidity and environmental factors Because pneumonia is most prevalent in older age groups, it is attractive to explain the increase in pneumonia-related mortality by the ageing of the population. However, the mortality rates standardized for age and sex also show an increase in pneumonia-related mortality (figure 1). In this standardization, mortalitly rates are calculated for a standard population, in this case the adult population of The increase in mortality is present in all age categories, but age specific mortality rates show that pneumonia-related mortality is especially increased in the higher age groups. (figure 2). It is therefore likely that other factors also have contributed to the observed increase in mortality. It is possible that the number of patients with underlying diseases that affect specific and non-specific defense against micro- 27

8 Chapter 21 organisms has increased. The increase in prevalence of diabetes mellitus and COPD as observed in recent years (source: RIVM compass for population health) could have contributed to the increase in the number of deaths because of lower respiratory tract infections. In patients with diabetes the increase in incidence was most outspoken in the age-group year. (source: rapport CMR peilstations 2001, AIM Bartelds) (14) Although a considerable part of pneumonia and influenza related mortality is contributed to diabetes, there is no unequivocal relation between diabetes mellitus and the risk of death from infections. (15;16) In addition, in the Netherlands, this riskgroup is annually vaccinated against influenza with good success and a vaccination level of about 75%. (17) (bron: RIVM kompas voor de volksgezondheid). Influenza related pneumonia mortality was therefore probably not contributory to the observed increase in pneumonia related mortality. The number of new HIV-infections in the Netherlands also has increased in the period In 1990, 250 patients were diagnosed with new HIV infections and 375 in 2000, increasing the number of HIV infected patients to 8496 in (source: RIVM rapport ). A number of facts speaks against a large role of this patient group in the increase in pneumonia-related mortality. First, the patient group of HIV infected patients has a lower mean age than the patient group with the most outspoken increase in pneumonia-related mortality. Second, a European study showed that HIV-infected patients with CD 4 positive cells of > 200 / mm 3 without Pneumocystis Carinii Pneumonia prophylaxis in 18 months had only 3,5% developed pneumonia. A large contribution to the pneumoniarelated mortality, also because of the successful treatment strategies for this group, can therefore be excluded. Interestingly, the annual number of hospitalisations per inhabitants because of pneumonia is higher in urban areas compared to rural areas. (source: RIVM nationaal kompas voor de volksgezondheid). It can therefore be argumented that pneumonia is a disease of densely populated areas, where infectious diseases spread more easily or that the increase in air pollution in the 90 s has contributed to the observed mortality rates. (18) An increase in ageing and the number of patients with chronic 28

9 Chapter 2 illnesses facilitating an infection of the lower respiratory tract are therefore only in part explanatory for the increase in pneumoniarelated morbidity and mortality in recent years. Causative micro-organisms The increase in mortality and hospitalisations in and the decline in , possibly indicates temporal changes in certain causative micro-organisms. Despite S. pneumoniae being the most prevalent causative micro-organism in nearly every study, in recent years, the so-called atypical micro-organisms as Mycplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila have received much attention. (19-26) Especially infections with L. pneumophila is associated with high mortality and infections with C. pneumoniae can also lead to severe pneumonia.. (27-31) The diagnosis of C. pneumoniae infection is however difficult. (32) In addition, the proportion of atypical infections is variable over the years. (33;34) Whether the amount of atypical infections fluctuates in the Netherlands also, is not clear. There is only 1 prospective study evaluating the etiology of pneumonia in the Netherlands in (19) Reported infections with Legionella pneumophila have hardly or not at all risen in and plays a minor role in the etiology of pneumonia, at least, if no outbreak situation, as the Bovenkarspel epidemic of 1999, is present. (35;36) Undertreatment of these atypical infections is therefore no reasonable explanation for the increase in pneumonia related mortality in the Netherlands. (37) In about 50% of pneumonia a causative micro-organism cannot be found. (19-21;24;26;38-40) Because routine investigations in the Netherlands do not include viral diagnostics, part of pneumonias may have a primary viral cause. Recently, a number of new viruses have been discovered that can cause severe lower respiratory tract infections. In children, the in 2001 discovered metapneumovirus is probably an important cause for severe respiratory tract infections. It can also play a etiological role in adults. (41;42) However, it is not probable that an increase in discovered viruses has led to an increase in pneumonia related morbidity and mortality. During epidemics, the influenza virus can lead to serious complications 29

10 Chapter 21 with fatal outcome, particularly in high risk patients and the elderly In 1985/1986, 1989/1990, 1993/1994, 1995/1996 and 1999/2000 influenza epidemics have occurred with high mortality rates. During these epidemics, there were to more deaths than usually in winter periods. (source: CBS Monthly statistics of the population, RIVM kompas voor de volksgezondheid) Whether all of these deaths are classified as pneumonia related mortality is not clear. Only in the season this influenza epidemic seems to have led to a peak in pneumonia related mortality. (figure 1). On the other hand, in mild influenza seasons as and , mortality seems to have decreased. One explanation could be that the weakest population in the severe influenza season died, leading to a decrease in mortality in the succeeding years. Concluding, clear indications of a changing etiologic spectrum contributing to the increase in mortality as a result of lower respiratory tract infections are lacking. Antibiotic resistance Resistance of causative micro-organisms for pneumonia has remained low: in the Netherlands, ± 1% of S. pneumoniae is less susceptible for penicillin and ± 7% of erythromycin. (source: rivm.nl) An increase of less susceptible or resistant S. pneumoniae can therefore not have played a role in the Netherlands and is no explanation for the increase in mortality. Whether in vitro resistance influences clinical outcomes is much debated. (43;44) Conclusion According to several national and international registration systems, in recent years the incidence, the number of hospitalisations and mortality of pneumonia has increased. A simple explanation is absent, but above resistance and changes in causative micro-organisms, the increase of the elderly population and an increase in co-morbidities seem the most important explanations. To reduce the mortality and morbidity burden, an integrated approach of elderly patients and patients with co-morbidity by specialists in geriatrics, internal medicine, pulmonarly medicine and infectious diseases prevails over 30

11 Chapter 2 specifically dealing with solely the problem pneumonia by onesided development of vaccination strategies or newer treatment strategies. Acknowledgements Mrs. drs. A. van der Meulen (Centraal Bureau voor de Statistiek) and mr. W.F. Hoogen Stoevenbeld (Prismant) provided important data. 31

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14 Chapter 21 community-acquired pneumonia in patients hospitalized on the basis of conventional admission criteria. Clin Infect Dis 2001; 33(2): (26) Ruiz M, Ewig S, Marcos MA, Martinez JA, Arancibia F, Mensa J et al. Etiology of community acquired pneumonia: impact of age, comorbidity and severity. Am J Resp Crit Care Med 1999; 160: (27) Gacouin A, Le Tulzo Y, Lavoue S, Camus C, Hoff J, Bassen R et al. Severe pneumonia due to Legionella pneumophila: prognostic factors, impact of delayed appropriate antimicrobial therapy. Intensive Care Med 2002; 28(6): (28) Balis E, Boufas A, Iliopoulos I, Legakis NJ, Zerva L. Severe communityacquired pneumonia with acute hypoxemic respiratory failure due to primary infection with Chlamydia pneumoniae in a previously healthy adult. Clin Infect Dis 2003; 36(12):e155-e157. (29) Ewig S, Torres A. Is Chlamydia pneumoniae an important pathogen in patients with community-acquired pneumonia? Eur Respir J 2003; 21(5): (30) Marrie TJ, Peeling RW, Reid T, De Carolis E. Chlamydia species as a cause of community-acquired pneumonia in Canada. Eur Respir J 2003; 21(5): (31) Miyashita N, Fukano H, Okimoto N, Hara H, Yoshida K, Niki Y et al. Clinical Presentation of Community-Acquired Chlamydia pneumoniae Pneumonia in Adults(*). Chest 2002; 121(6): (32) Tuuminen T, Palomaki P, Paavonen J. The use of serologic tests for the diagnosis of chlamydial infections. J Microbiol Methods 2000; 42(3): (33) Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states. Chest 2001; 119: (34) Yu VL, Vergis EN. New macrolides or new quinolones as monotherapy for patients with community-aquired pneumonia: our cup runneth over? Chest 1998; 113: (35) Hoepelman IM. Legionella epidemie in Nederland. Ned Tijdschr Geneeskd 1999; 143(34): (36) den Boer JW, Friesema IH, Hooi JD. [Reported cases of Legionella pneumonia in the Netherlands, ]. Ned Tijdschr Geneeskd 2002; 146(7): (37) Oosterheert JJ, Bonten MJ, Schneider MM, Hoepelman IM. [Community 34

15 Chapter 2 acquired pneumonia; no reason to revise current Dutch antibiotic guidelines]. Ned Tijdschr Geneeskd 2003; 147(9): (38) Macfarlane JT, Colville A, Guion A, Macfarlane RM, Rose DH. Prospective study of aetiology and outcome of adult lower-respiratory- tract infections in the community. Lancet 1993; 341(8844): (39) Mandell LA. Community-acquired pneumonia. Etiology, epidemiology, and treatment. Chest 1995; 108(2 Suppl):35S-42S. (40) Roson B, Carratala J, Dorca J, Casanova A, Manresa F, Gudiol F. Etiology, reasons for hospitalization, risk classes, and outcomes of community-acquired pneumonia in patients hospitalized on the basis of conventional admission criteria. Clin Infect Dis 2001; 33(2): (41) Kahn JS. Human metapneumovirus: a newly emerging respiratory pathogen. Curr Opin Infect Dis 2003; 16(3): (42) van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001; 7(6): (43) Garau J. Treatment of drug-resistant pneumococcal pneumonia. Lancet Infect Dis 2002; 2(7): (44) Lonks JR, Garau J, Gomez L, Xercavins M, Ochoa de, Gareen IF et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002; 35(5):