Abstract
Background: In the developing world, COPD continues to be an under studied, diagnosed and treated disorder. In the present study, we analyzed the prevalence, mortality and resource utilization of COPD in Latin America and the Caribbean (LAC) in order to guide future research and public policies. Methods: A systematic review and meta-analysis was performed following MOOSE and PRISMA guidance. We searched CENTRAL, MEDLINE, EMBASE, LILACS, countries’ Ministries of Health, proceedings, and doctoral theses from January 1990 to October 2012. We included studies with a validated definition of COPD that assessed the incidence, prevalence, use of health care resources or costs since 1985. Using EROS, a web-based software, pairs of reviewers independently selected, performed quality assessment (using a STROBE-based checklist) and extracted the study data. Discrepancies were resolved by consensus. Arcsine transformations and random-effects model were used for proportion meta-analyses. Results: 26 articles met entry criteria. The pooled COPD prevalence defined by GOLD criteria (11 cities, 6 countries) was 13.4% (95%CI, 10.1-17.1). Most patients suffer mild or moderate COPD and were undertreated according to international guidelines. The prevalence increased by age and was 1.75 times higher in men than women. 35 of every 1,000 hospitalizations were due to COPD, most of high economic cost, and the COPD in-hospital mortality ranged from 6.7% to 29.5%. Conclusions: COPD burden in LAC is high, especially for men and older persons; however few persons had severe disease. COPD patients often received inappropriate treatment and had high exacerbation and hospitalization rates leading to high economic costs.
| Abbreviations | ||
| ATS | = | American Thoracic Society |
| BMI | = | Body mass index |
| BOLD | = | Burden of Obstructive Lung Disease |
| CENTRAL | = | The Cochrane Central Register of Controlled Trials |
| COPD | = | Chronic obstructive pulmonary disease |
| EROS | = | Early Reviewer Organizer Software |
| ERS | = | European Respiratory Society |
| FEV1 | = | Forced expiratory volume in 1 second |
| FVC | = | Forced vital capacity |
| DATASUS | = | Hospitalizations Information System of the Brazilian Ministry of Health |
| GOLD | = | Global Initiative for Chronic Obstructive Lung Disease |
| ICD | = | International Classification of Diseases |
| ICU | = | Intensive care unit |
| LAC | = | Latin America and the Caribbean |
| LLN | = | Lower limit of normal |
| MOOSE | = | Meta-analysis Of Observational Studies in Epidemiology |
| PLATINO | = | Spanish abbreviation for Latin American Project for Investigation of Pulmonary Obstruction |
| PRISMA | = | Preferred Reporting Items for Systematic Reviews and Meta-Analyses |
| RCT | = | Randomized controlled trial |
| STROBE | = | Strengthening the Reporting of Observational studies in Epidemiology |
| USD | = | United States Dollar |
| Int$2012 | = | International Dollar 2012 |
| WHO | = | World Health Organization |
Background
According to the World Health Organization (WHO) estimates, 65 million people have moderate to severe chronic obstructive pulmonary disease (COPD), and by 2030 COPD will become the third-leading cause of death worldwide. Almost 90% of COPD deaths occur in low- and middle-income countries, but most of the epidemiological information comes from high-income countries. COPD is also an important cause of disability, and is associated to co-morbidities, such as depression and cardiovascular disease, which adds to the large economic burden associated with this health problem (Citation1–3).
In Latin America and the Caribbean (LAC), COPD continues to be an under studied, diagnosed and treated disorder (Citation4), and its epidemiology has not been well described. It is estimated that 210 million people worldwide suffer with COPD, but with 80% or higher yet undiagnosed, LAC has an outstanding debt to know and understand their epidemiologic data.
The objective of this systematic review and meta-analysis is to describe the prevalence, disease severity, risk factors, co-morbidities, mortality, costs, and resource utilization of COPD in LAC in order to assist public health policies.
Methods
We performed a systematic review, following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analysis (Citation5–7). Since systematic reviews use existing public data, institutional review board approval is not required.
We performed a systematic search without language restrictions between January 1990 and April 2009 using the following databases: The Cochrane CENTRAL, MEDLINE, EMBASE, and LILACS (e-Appendix-Citation1). The simplified search strategy used for MEDLINE were Pulmonary Disease, Chronic Obstructive[mesh] OR COPD[all] OR COAD[all] OR Chronic obstruct*[all] OR emphysem*[all] OR Pulmonary Emphysema[mesh] OR Bronchitis, Chronic[mesh] OR Chronic Bronch*[all] OR Chronic asthma*[all] OR Bronchiectasis[Mesh] OR Bronchiectas*[tiab] OR Bronchial ectasi*[tiab]) AND (Americas[MeSHTerms:noexp] OR America*[all] OR Latin America[Mesh]. In October 2012, an updated search for population-based prevalence studies was run. Regional proceedings or congress’ annals and doctoral theses were also searched. Grey literature was searched from sources like countries’ Ministries of Health in LAC, Pan American Health Organization and hospital reports. Authors were contacted to obtain additional information.
We included randomized controlled trials (RCT), quasi-randomized controlled trials, cohort studies, case-control studies, cross-sectional studies and case-series studies. COPD was defined by the following criteria in subjects at least 40 years of age: 1) FEV1/FVC less than 70% (GOLD criteria), 2) FEV1/FVC less than lower limit of normal ATS/ERS 2005 Criteria, or 3) FEV1/FVC less than 88% in males or 89% in females (ERS 1993) (Citation8, 9). Studies were required to have at least 50 observed cases since 1985 and include data regarding COPD incidence, prevalence, or use of health care resources and costs in LAC. Clinical factors examined were age, socioeconomic level, co-morbidities and risk factors. We also extracted study design, risk of bias components, country, setting, participant number and characteristics.
Early Reviewer Organizer Software (EROS), a web-based software to facilitate the selection of studies, was utilized (Citation10–12). Pairs of reviewers independently screened titles and abstracts from retrieved articles. A second pair of reviewers then assessed the full text articles and, if the articles met inclusion criteria, extracted data, and determined risk of bias considering three major criteria (methods for selecting participants, methods for measuring exposure and outcome variables, and methods to control confounding), and two minor criteria (statistical methods and conflict of interest) (e-Appendix-2). These criteria were based on a checklist of essential items stated in Strengthening the Reporting of Observational studies in Epidemiology (STROBE)(Citation13), and other methodological articles (Citation14–17). Discrepancies were solved by consensus.
Proportion meta-analysis and arc-sine transformation was employed to stabilize the variance of proportions (Citation18). The estimates and its 95% confidence intervals (CIs) were calculated using the DerSimonian-Laird weights for the random effects model where heterogeneity between studies was found (Citation19). We calculated the I2 statistic as a measure of the between-study heterogeneity, considering an I2of 30-60% and more than 60% as moderate and severe heterogeneity respectively (Citation20). Stats-direct and STATA 9.0 were used for all analyses. All reported currencies were transformed to international dollar 2012 (Int$2012).
Results
We first identified 1185 articles and after the updated search 897 additional articles. These articles were screened, 156 full text articles were assessed for eligibility and 26 articles were included in the qualitative synthesis (): 10 discussed prevalence (Citation21–26) or lethality (Citation27–30), 10 resource consumption(Citation31–40), 3 mortality (Citation41–43), 2 COPD severity (Citation44, 45) and 1 COPD exacerbations (Citation27). Two Brazilian ministerial databases were also included. The countries providing data for this systematic review were Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, Uruguay, Trinidad and Tobago, and Venezuela. The characteristics of these studies are described in and its risk of biasing .
Figure 1. Flow chart of studies through the systematic review.
Table 1. Characteristics of included studies
Table 2. Risk of Bias of included studies by quality items*
Prevalence
The prevalence of COPD in the general LAC population, from the six countries assessing this outcome, was evaluated by three studies using the GOLD criteria (Citation21, 22, Citation25) and two studies using the ERS guidelines.
The pooled COPD prevalence in the LAC general population (GOLD criteria) was 13.4% (95%CI, 10.1-17.1), ranging from 7.7% (95%CI, 6.2-9.5) in Colombia to 19.4% (95%CI, 16.9-22.1) in Uruguay (I2 96%) (). An increasing prevalence by age group was observed: 5.2% (95%CI, 3.4-7.5%) for persons 40 to 59 years old, 11.0% (95%CI, 7.4-11.3) for persons 50 to 59 years old, and 24.3% (95%CI, 19.2-29.7) for persons 60 or more years old (). The prevalence for women was 10.4% (95%CI 7.6-13.6) and for men was 18.2% (95%CI 14.1-22.6), which is 1.75 times higher (). The GOLD stage general population prevalence was also analyzed, using data from 6 studies (21-26):8.8% GOLD-1, 4.8% GOLD-2, and less than 1% GOLD-3+4 ().
Figure 2. Proportion Meta-analysis of COPD prevalence in general population.
Figure 3. Proportion Meta-analysis of COPD prevalence by age group.
Figure 4. Proportion Meta-analysis of COPD prevalence by sex.
Table 3. The general population and at risk population* GOLD-specific prevalence
The prevalence of COPD according to the ERS definition was analyzed in two studies (22, 25) and found to be 13.6% (95%CI 10.0-17.6). Analyzing only these two studies, by GOLD criteria, the prevalence was 14.3% (95%CI 10.8-18.1).
The prevalence of COPD in at-risk populations, defined by the presence of smoking, indoor pollution from biomass cooking or occupational dusts and chemicals, was evaluated by three studies (Citation23, 24, Citation26). Two studies evaluated the prevalence COPD (GOLD criteria) in at-risk persons (Citation46,47). The pooled prevalence was 20.7% (95%CI, 19.3-22.2), with GOLD-2being the most prevalent stage: 9.7% (95%CI, 8.4-10.5)(). A third study meeting inclusion criteria, analyzed separately because it not described how applied the GOLD criteria, showed a COPD prevalence among 294 smokers of 46.6% (95%CI, 40.8-52.5)(Citation24).
Hospitalizations/Exacerbations
One Brazilian study followed 120 COPD patients for 12 months, 60 had exacerbation and 25 required hospitalization (Citation27). The median length of hospitalization was 9.5 days (range 6.7–30.2 days).
A second Brazilian study analyzed trends in morbidity due to respiratory diseases in the city of São Paulo from 1995 to 2000 obtained from the Hospitalizations Information System of the Brazilian Ministry of Health (DATASUS)(Citation48). A decrease in the rate of hospitalization for respiratory illnesses was observed. However the opposite was observed for patients with COPD, especially in the elderly.
Our meta-analysis of Brazilian and Mexican ministerial databases showed that 35.7/1,000 (95%CI, 30-41.6) hospitalizations were due to COPD. The number of hospitalizations for COPD rose with age and a nearly double hospitalization rate for men than for women ().
Table 4. COPD hospitalization rate by age group and gender*
COPD in-hospital mortality
Two studies in Brazil and two in Mexico analyzed COPD in-hospital mortality (Citation27–30). In Brazil (follow-up 12 months) the combined COPD in-hospital mortality was 6.7% (95%CI, 3.8-10.4)(27, 30), and in Mexico (follow-up 84–132 months) 29.5% (95%CI, 25.3-33.9) (Citation28, 29). Among these studies, the only one considered of low risk of bias is Rico-Méndez et al. (Citation29), with 32.2% (95%CI, 22.6-43.1).
A review of the Brazilian Mortality Information System (Citation49) between 1980–1998 showed that respiratory diseases accounted for 8–10% of all deaths. COPD accounted for 11–15% of respiratory disease-related deaths during the period 1980-1985 and 33% during 1996–1998. The 3.3-times increase in COPD-related deaths translated to an increase from 7.88/100,000 persons to 19.04/100,000. The highest rates were observed in those aged greater than 64 years old and men, although COPD mortality rose significantly in both sexes (Citation43).
A review of the Argentine database on death certificates from the National Ministry of Health showed a 113% increase in COPD mortality from 12.76/100,000 in 1980 to 27.16/100,000 in 1998 ( p < 0.0001) with marked inter-province differences (Citation42).
Resource utilization
Six studies performed health economic evaluations (Citation31, Citation36–40) and four studies described resource utilization or related costs (Citation32–35).
A Brazilian study showed a decrease in preventable COPD hospitalization rates from 2.5% of admissions in 2000 to 0.7% in 2004, reflecting the system's financial model, which has poor reimbursements for hospitalizations (Citation33).
A prospective study in Bogota (Citation34), Colombia surveyed 61 stable GOLD-3 COPD patients to assess prescriber compliance with GOLD recommendations. Only 23% received bronchodilators, corticosteroid and vaccine, 56% home oxygen therapy, 2% was referred to pulmonary rehabilitation and 8% partook in physical exercise.
A PLATINO secondary study described treatments of 758 COPD patients (Citation32). Of the 86 previously diagnosed, 75.6% had received a respiratory medication in the prior year: 36% received a bronchodilator, 11.6% received an inhaled corticosteroid and 12.8% received a corticosteroid. Of the 53 GOLD stage 3 patients, 32.7% took medications most days, and 7.7% only in response to symptoms; 65.6% had been prescribed a respiratory medicine in the past year, 30.8% a bronchodilator and 13.5% a corticosteroid.
A cross-sectional study of 128 Argentine and 134 Ecuadorian patients with stable COPD studied the appropriateness of their treatment (Citation35). The 11.3% Argentine and 18.7% Ecuadorian patients who had an indication for inhaled corticosteroids were not prescribed them, while 38.6% Argentine and 65.1% Ecuadorian patients who had no indication for inhaled corticosteroids were prescribed them.
Economic evaluations
Three databases of health care cost in Mexico from 1994 to 2005 were examined to determine the outpatient COPD costs, including ambulatory visits, outpatient drug regimens and diagnostic tests (Citation36). Per patient, the estimated monthly ambulatory cost was 30.83 United States Dollars(USD)2007/48Int$2012.
In 2004, 26 patients with COPD at the National Institute of Chest and Hospital del Salvador in Santiago, Chile were recruited to estimate the total monthly cost per patient (Citation38). In a follow-up of 6 months, 9 (34.6%) patients were hospitalized. Monthly costs per patients were 37,213 Chilean Pesos($)2004/118Int$2012 for ambulatory care, 5,697$2004/19Int$2012 for emergency care, 130,142$2004/414Int$2012 for hospitalizations, and 101,456$2004/323Int$2012 for medications and the total 285,230$2004/907Int$2012.
In 2001, COPD or chronic bronchitis pharmaceutical and health care costs were calculated in Argentina, Brazil, Columbia, Ecuador, Mexico, Peru and Venezuela (Citation31). Official costs were provided by health care authorities or from public referral health care centers. Colombia presented the lowest cost for hospitalization (641USD2002/1,906Int$2012) and Argentina the highest (3,120USD2002/7,654Int$2012); Colombia the lowest for ambulatory visits (17USD2002/51Int$2012) and Peru the highest (124USD2002/353Int$2012); and Colombia the lowest for emergency room visits (53USD2002/158Int$2012) and Venezuela the highest (311USD2002/674Int$2012).
A micro-cost analysis, including hospitalizations, ambulatory and emergency visits was performed in Colombia (Citation37). The average cost of one COPD case in the five years following diagnosis was 9,169.60USD2004/25,072Int$2012. A mild COPD was 2,088.80USD2004/5,711Int$2012, a moderate COPD was 2,853.50USD2004/7,802Int$2012 and a severe COPD was 9,229.10USD2004/25,234Int$2012.
The COPD costs was calculated in 12 Mexican centers, using the cost list of the Instituto de Seguros Sociales (Citation39). On average, stable COPD patients annually incurred 2,180Mexican Pesos ($) 2001/401Int$2012 for ambulatory care, 1,790$2001/329Int$2012 for specialty care, 2,658$2001/488Int$2012 for emergency care. Patients with COPD exacerbations incurred 654$2001/120Int$2012 for ambulatory care, 1585$2001/291Int$2012 for specialty care, 4389$2001/329Int$2012 for emergency care, and 50,667$2001/9,311Int$2012 for hospitalizations. Additionally, patients with COPD exacerbations under intensive care unit incurred monthly 61,430$2001/11,289Int$2012.
Vaccination
In 2008, the PLATINO study described the rates of vaccination against influenza in COPD patients (Citation32). In the 12 preceding months, vaccination rates were 32% in Brazil; 52% in Chile; 15% in Mexico; 24% in Uruguay and 5% in Venezuela.
Discussion
This is the first systematic review and meta-analysis assessing the burden of COPD in LAC. To minimize the variability of COPD prevalence, we used internationally accepted spirometry criteria to define COPD (Citation8). Globally, COPD prevalence defined by spirometry has been shown to be 9.2% (7.7–11.0) (Citation50). Our data showed a much higher prevalence (13.4%) and a large inter-country variability. We meta-analyzed the international BOLD study(Citation51) data based to compare them with our findings. Using the same methods that we used in the present study, the prevalence was 18.6% (95%CI, 16.1-21.2), much higher than the prevalence that we found in LAC and also presentedlarge inter-country variability. This variability may be partially explained by geographical differences in tobacco consumption, biomass exposure or age distribution (Citation51,52). Supporting this hypothesis is the finding that smokers or those exposed to indoor pollution showed a higher prevalence of COPD than the general population. COPD was more common in men and older populations, as in developed countries. We also found a higher prevalence in men than women (1.8/1, respectively) and more marked than in the BOLD study (1.4/1) (Citation51). This difference could be partially explained by differences in smoking habits (Citation53).
LAC subjects with COPD are not on appropriate medication regimens and infrequently vaccinated (Citation25, Citation32). Furthermore, a cross-sectional study of Argentine and Ecuadorian patients with stable COPD showed that both under and over prescription exist suggesting an inappropriate use of health resources (Citation35). Our findings also showed that hospitalizations for COPD exacerbations are common, especially among older, male subjects. Additionally most COPD patients from the prevalence studies were classified as mild or moderate. Thus, there is a large opportunity for preventive and treatment interventions that could slow or halt progression of disease (Citation54–56). Increasing awareness of COPD, and implementing effective screening programs in primary care could significantly improve management of the disease (Citation54, Citation57). Primary care physician and patient education may lead to early diagnosis and interventions to curb disease progression or prevent complications. Tobacco control interventions may also reduce tobacco consumption rates, and consequently the burden of COPD (Citation58).
The scale of COPD costs for LAC low-and-middle-income-countries is astronomical. It is plausible that the lack of early diagnosis combined with inappropriate treatment and subsequent high exacerbation/hospitalization rates are the main causes. The COPD-related mortality in Brazil and Argentina is rising and probably without interventions, these trends will likely continue (Citation41–43). This tendency was also observed in the United States, England and Wales, particular among elderly (Citation59, 60). Although changes in the ICD and regional differences over time may partly explain this phenomenon, the consistency between different regions of the world suggests that the growing trend in mortality should be considered.
The major limitation of our study is related to the scarce amount of research in the region coming from only 10 LAC countries. Additionally, as happened in similar studies (Citation50, 51), there was a large data heterogeneity, since it was collected over different time points and in different countries. However, this systematic review has several strengths. First, we adhered strictly to the recommended methodological standards. Second, we considered both English and non-English literature. Third, we performed an exhaustive literature review, including published and unpublished literature. Finally, our study provided an in-depth economic data to complement the epidemiological data.
In summary, the COPD burden in LAC is high. COPD patients are frequently undiagnosed and those that are, often receive inappropriate treatment. They have high exacerbation/hospitalization rates leading to high economic costs. Our study aims to better inform both public health policy and health care providers. This study did not focus on the progress of public health interventions, but our data suggests that such interventions will likely considerably reduce COPD-related morbidity, mortality and cost in LAC.
Declaration of Interest Statement
The authors report no conflicts of interest. The study was supported by an independent grant from GlaxoSmithKline. Agustín Ciapponi is responsible for the content of the manuscript, including the data and analysis. All authors participated of the acquisition of data, critically revised the article and provided final approval of the version to be published. AC, AA and ES also contributed to the study design, analysis and interpretation of data.
The study was supported by GlaxoSmithKline as an independent grant. The sponsor was not involved in the design, analysis of the study, or in any part of the manuscript writing.
Acknowledgments
We would like to thank Daniel Comandé, our librarian, and Luz Gibbons, our statistician, for their contributions.
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