..
THE PLATINO COHORT STUDY:
THE NATURAL HISTORY OF COPD
June, 2008
Proposal by
Dr. Ana Menezes on behalf of ALAT
Post-Graduate Program in Epidemiology
Faculty of Medicine
Federal University of Pelotas
Address: Av. Domingos de Almeida, 1146/25
96085-470 - Pelotas, RS
Brazil
Phone +55 53 2712442 - Fax +55 53 2712645 - E-mail anamene@terra.com.br
1
Table of contents
BACKGROUND TO THE PROPOSAL
1.
INTRODUCTION
1.1. ESTIMATING THE BURDEN OF COPD
1.2. ESTIMATED COPD DEATHS
1.3. ESTIMATED PREVALENCE OF COPD
2. THE PLATINO PROJECT
3. NATURAL HISTORY OF COPD
4. JUSTIFICATION
5.
OBJECTIVES
4.1. Main objective
4.2. Secondary objectives
6.
METHODOLOGY
6.1. Design
6.2. Target population
6.3. Sample size
6.4. Outcomes
6.5. Exclusion criteria for the study
6.6. Exclusion criteria for spirometry
6.7. Instruments
6.7.1. Questionnaire
6.7.2. Measurements
6.8. Equipment
7. ANALYSES
8. TEAM
9. LOGISTICS
10. QUALITY CONTROL
11. ETHICS
12. REFUSALS
13. LIMITATIONS OF THE STUDY
14. STUDY ORGANIZATION
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15. PUBLICATION AND DATA OWNERSHIP ISSUES
16. PUBLICATIONS GUIDELINES
17. DATA OWNERSHIP
18. ACKNOWLEDGEMENT TO ALAT AND ALL FUNDING COMPANIES
19. TIME TABLE
20. REFERENCES
21. ANNEXES
3
THE PLATINO COHORT STUDY:
THE NATURAL HISTORY OF COPD
BACKGROUND TO THE PROPOSAL
In 2001, representantives of the Asociación Latinoamericana del Tórax (ALAT)
and of Boehringer-Ingelheim agreed to organize a survey for measuring the
prevalence of COPD in selected cities of Latin America. This survey – the
PLATINO study, coordinated by Dr Ana Maria Menezes of Pelotas, Brazil - was
carried out in Caracas, Mexico City, Montevideo, Santiago and São Paulo between
2002-2004. The survey results were disseminated in several publications in highimpact journals.
The PLATINO study revealed an important prevalence of COPD in the region;
Montevideo showed the highest levels. Due to the cross-sectional nature of this
survey, it was unable to provide data on the natural history of COPD, including its
consequences in terms of morbidity, disability and mortality.
ALAT is now proposing to use the existing sample of the PLATINO in
Montevideo as the baseline for a cohort study investigating the natural history of
COPD over a four-year period.
The present proposal describes the justification, objectives, methods, logistics,
timetable and budget for the proposed cohort study.
4
1. INTRODUCTION
1.1.
ESTIMATING THE BURDEN OF COPD
The magnitude of the burden from several diseases is an important input into building the
evidence base for health policies and programs. All available epidemiological information
should be derived from standard and comparable procedures across diseases, including
information on the age at death and the incidence, duration and severity of cases who do not die
prematurely from the disease. A measure for quantifying the magnitude of such burden disability-adjusted life years (DALYs) - has been developed; it simultaneously measures the
amount of disease burden due to premature mortality and the amount due to the nonfatal
consequences of disease (Lopez, 2006).
COPD was responsible for approximately 2.7 million deaths in 2000. The increase in global
COPD deaths between 1990 and 2000 (0.5 million) is likely to be partly real, and partly due to
better methods and more extensive data availability in 2000 (Lopez, 2006).
1.2. ESTIMATED COPD DEATHS AND
ORGANIZATION (WHO) REGION, 2002
DALYs
BY
WORLD
HEALTH
COPD mortality for Latin America was estimated as 90,000 deaths (ranked in the 9th place) and
responsible for 1.7% of regional total DALYs (6th place) from the 14 WHO sub-regions
worldwide (Table 1). The estimation procedure in the absence of good vital registration is
highly uncertain (Murray, 2001).
Table 1. Estimated COPD deaths and DALYs by WHO region, 2002
Region
AFR A
AFR B
AMR A
AMR B*
AMR D
SEAR B
SEAR D
EUR A
EUR B
EUR C
EMR B
EMR D
WPR A
WPR B
World
Deaths thousands
52
65
141
90
10
100
556
140
45
76
15
80
21
1354
2748
DALYs thousands
514
668
1743
1419
195
1420
6740
1744
673
1036
349
989
415
9820
27756
% of regional total DALYs
0.3
0.3
3.7
1.7
1.1
2.3
1.9
3.4
1.8
1.7
1.5
0.9
2.5
4.0
1.9
* AMR B – Latin America (low child and adult mortality) (WHO, 2004)
5
1.3.
ESTIMATED PREVALENCE OF COPD
As the result of the tobacco epidemic, COPD is now prevalent in developed and developing
countries. Despite this fact, prevalence data is scarce in most parts of the world (Barnes, 2000;
Hurd, 2000). There are several reasons for this: progression of the disease, measurement tools,
definitions still different in the literature and the difficulty of carrying out spirometry in several
countries. Murray has estimated the prevalence of COPD based in models which link incidence,
prevalence, duration and case fatality rate. The information on risk factors associated with
COPD is an approach to calculate the relative risk of COPD mortality and to have an estimate of
the prevalence of COPD (Murray, 2001).
Table 2 – Prevalence of COPD by symptoms, physician diagnosis and spirometry in some
regions according WHO.
Prevalence %
Region
Symptoms
Physician diagnosis
Spirometry
AFR D
1-3
AMR A
5-15
1-3
2-5
AMR B
5-13
EMR B
2-10
EUR A
10-20
SEAR D
2-7
WPR A
10-15
2-5
WPR B
2-8
1-3
1-2
2-5
3-7
As it can be seen (Table 2), the estimated prevalence for COPD in Latin America ranges from
5% to 13% based on symptoms and no data is available neither from physician diagnosis nor
for spirometry.
2.
THE PLATINO PROJECT
The aim of the PLATINO study (http://www.platino-alat.org/), launched in 2002, was to
describe the epidemiology of COPD in five major Latin American cities: São Paulo (Brazil),
Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay), and Caracas (Venezuela).
6
These sites were chosen because of their geographical position, population size, and the
availability of local collaborating research centers. They represented the different geographical
areas of Latin America and the largest metropolitan area in each participating country. This
study was conducted from 2002 to 2004 as an initiative from the Associación LatinoAmericana
del Tórax (ALAT) carried out in population-based samples of adults aged 40 years or older. A
similar multistage sampling strategy was used in all five areas. Metropolitan areas were first
stratified into the main city and surrounding municipalities. These two subsets were further
stratified by socioeconomic status. We selected 68 census tracts at each site, taking stratification
into account and using a probability of selection proportionate to the number of households in
each tract. Within each tract, we counted the number of people in each household and every
count was updated from the most recent census. We chose an average of 15 households using
systematic sampling within each tract. All adults aged 40 years or more living in selected
households were invited to participate. The sample was self-weighted in each city.
Sample-size calculations suggested that 800 people would be needed in each area to estimate a
prevalence of up to 30% with a margin of error of less than 4 percentage points. We aimed to
locate about 1020 eligible participants per site, with a predicted 20% refusal rate.
All interviews and examinations took place at home. We obtained data about several factors
potentially associated with COPD, including age, sex, ethnic origin (self-reported), years of
formal education, smoking habits, hospital admissions due to pulmonary problems in childhood,
exposure to domestic biomass and coal pollution, occupational exposure to dust, and body-mass
index. The questionnaire included sections of the American Thoracic Society Division of Lung
Diseases (ATS/DLD) (Ferris, 1978), European Community Respiratory Health Survey II (2002),
and Lung Health Study (2004) instruments. Questions from the SF12 (Ware, 2005 (a 12-item
short form health survey) were also included to assess overall health status. Next,
anthropometric measurements were taken. We measured height with a portable Seca stadiometer
(Curitiba, Brazil; precision 0.1 cm), using the technique recommended by Lohman and
colleagues (1988) Weight was measured with an electronic Tanita scale (precision 200 g,
Curitiba).
A portable, battery operated, ultrasound transit-time based spirometer (Easy-One; NDD Medical
Technologies, Chelmsford MA, USA, and Zurich, Swizerland) was used for pulmonary function
testing of eligible people. Calibration was checked daily with a 3-L syringe. Participants did up
7
to 15 forced expiratory manoeuvres (average five or six) to obtain three American Thoracic
Society (ATS) (Standardization of spirometry, 1995) acceptable manoeuvres, with forced vital
capacity (FVC) and forced expiratory volume in the first second (FEV1) reproducible within 150
mL (the new ATS-ERS 2005 standards). A bronchodilator (salbutamol 200 micrograms) was
then administered by inhalation through a 500-mL spacer, and the test was repeated 15 min later
(average four or five manoeuvres). All spirometric examinations were done with the person
seated and wearing a nose clip and a disposable mouthpiece. During data collection, spirometry
results were sent weekly to Mexico by e-mail, where they were analyzed and quality control
reports prepared for each individual interviewer. Overall, 89% of all tests in the five sites
achieved an acceptable result, and 94% fulfilled the 1994 ATS criteria of quality and 85% the
2005 ATS-ERS standards, unknown at the time of the study . These results were fed back to
each fieldworker on a weekly basis and retraining was undertaken as necessary (Menezes, 2004).
The definition of COPD was the one proposed by the Global Initiative for Chronic Obstructive
Lung Disease (GOLD) (2005): a ratio of the post-bronchodilator FEV1 /FVC below 0.70. This
definition is consistent with recent European Respiratory Society and ATS recommendations.
We also measured severity strata, according to GOLD stages, using predicted values for normal
lung function derived from the data from the present study.
8
The comparison of the census data from the cities studied in the PLATINO project and data obtained
from the study are shown in Table 3, regarding to sex and age of people aged 40 years or more. This
table shows that the sample seen in the PLATINO project was similar to the census data from the
countries (http://www.platino-alat.org).
Table 3. Comparison between the most recent census data in each country and data from the
PLATINO study in terms of sex and age of people aged 40 years or more in five Latin American
cities.
São Paulo (Brazil)
Mexico City (Mexico)
Montevideo (Uruguay)
Santiago (Chile)
Caracas (Venezuela)
Census
PLATINO
Census
PLATINO
Census
PLATINO
Census
PLATINO
Census
PLATINO
Men
46.8%
44.2%
44.6%
40.6%
42.9%
40.3%
47.5%
38.5%
43.7%
34.9%
Women
53.2%
55.8%
55.4%
59.4%
57.1%
59.7%
52.5%
61.5%
56.3%
65.1%
40-49
42.8%
39.0%
41.0%
39.5%
30.8%
26.3%
40.7%
33.7%
41.9%
40.4%
50-59
27.0%
32.0%
28.9%
28.2%
25.3%
26.2%
27.0%
31.5%
27.7%
29.2%
≥ 60
30.2%
28.9%
30.1%
32.3%
43.9%
47.5%
32.3%
34.9%
30.4%
30.4%
Sex
Age (years)
Sources: www.ibge.gov.br (Brazil); www.inegi.gob.mx (Mexico); www.ine.gub.uy
(Uruguay); www.ine.cl (Chile); www.ine.gov.ve (Venezuela)
At the end of the study we had a total sample of 5,571 subjects/questionnaires and 5,315 postbronchodilator (BD) spirometries with stringent quality control. This project allowed us to
measure the prevalence of COPD based on spirometry post bronchodilator (BD). The prevalence
of COPD based on the fixed ratio criteria after BD and its respective 95% confidence interval
was: Sao Paulo 15.8% (13.5%-18.1%), Mexico City 7.8 (5.9%-9.7%), Montevideo 19.7%
(17.2%-22.1%), Santiago 16.9% (14.7%-19.1%) and Caracas 12.1% (10.3%-13.9%) (Menezes,
2005). We also have data using other spirometric criteria such as ATS, ERS, LLN (FEV1/FVC
or FEV1/FEV6)
9
Several important issues were pointed out by the PLATINO project. From the 672 subjects
considered COPD by the fixed ratio criteria, 88.7% had no prior medical diagnosis of either
chronic bronchitis, emphysema or COPD (Talamo, in press). Only 11.5% of all subjects
interviewed had ever had a previous spirometry. The prevalence of undiagnosed COPD was
12.7%, ranging from 6.9% in Mexico City to 18.2% in Montevideo. Among 237 subjects with a
prior COPD diagnosis, only 86 (36.3%) had post bronchodilator FEV1/FVC < 0.7, while 151
(63.7%) had normal spirometric values. In the same group of 237 subjects, only 34% reported
ever having spirometry prior to our study. Therefore, inaccurate diagnostic labeling of COPD
represents an important health problem in Latin America and one of the possible explanations is
the low rate of spirometry for COPD diagnosis (overall rates of spirometry carried out during
life and in the last 12 months were respectively 10.4% and 1.3%). It should be mentioned that
there was a positive association between spirometry and schooling of the subjects, showing that
more educated people (a marker of socioeconomic level) had more probability of having
performed a spirometric test.
The list bellow shows the publications from the PLATINO project. There are four other papers
submitted. Information about the project can also be obtained in the website: http://www.platinoalat.org.
Publications
 A.M.B. Menezes, P.C. Hallal, R. Perez-Padilla, J.R.B. Jardim, A. Muino, M.V. Lopez, G. Valdivia, M.
Montes de Oca, C. Talamo, J. Pertuze, C.G. Victora and for. the Latin American Project for the
Investigation of Obstructive Lung Disease (PLATINO) Team. Tuberculosis and airflow obstruction:
evidence from the PLATINO study in Latin America. Eur Respir J 2007; 30: 1–6.

Maria Montes de Oca, Carlos Talamo, Rogelio Perez-Padilla, Jose Roberto B. Jardim, Adriana
Muino, Maria Victorina Lopez, Gonzalo Valdivia, Julio Pertuze, Dolores Moreno, Ronald J. Halbert,
Ana Maria B. Menezes, For the PLATINO Team. Chronic obstructive pulmonary disease and body
mass index in five Latin America cities: The PLATINO study. Respiratory Medicine (in press)

Rosa FW, Perez-Padilla R, Camelier A, Nascimento OA, Menezes AM, Jardim JR. Efficacy of the
FEV1/FEV6 ratio compared to the FEV1/FVC ratio for the diagnosis of airway obstruction in
subjects aged 40 years or over. Braz J Med Biol Res. 2007 Dec;40(12):1615-21. PDF (490k)

Rogelio Pérez-Padilla, Luis Torre Bouscoulet, Juan Carlos Vázquez-García, Adriana Muiño, María
Márquez, María Victorina López, María Montes de Oca, Carlos Tálamo, Gonzalo Valdivia, Julio
Pertuze, José Jardim y Ana María B. Menezes, en representación del grupo PLATINO*. Valores de
referencia para la espirometría después de la inhalación de 200 μg de salbutamol. Arch
Bronconeumol. 2007;43(10):530-4. PDF (71k)
10

Perez-Padilla R, Hallal PC, Vazquez-Garcia JC, Muino A, Maquez M, Lopez MV, de Oca MM,
Talamo C, Valdivia G, Pertuze J, Jardim J, Menezes AM; PLATINO group. Impact of
bronchodilator use on the prevalence of COPD in population-based samples. COPD. 2007
Jun;4(2):113-20. PDF (274k)

Talamo C, de Oca MM, Halbert R, Perez-Padilla R, Jardim JR, Muino A, Lopez MV, Valdivia G,
Pertuze J, Moreno D, Menezes AM; PLATINO team. Diagnostic labeling of COPD in five Latin
American cities. Chest. 2007 Jan;131(1):60-7. PDF (155k)

Perez-Padilla R, Vazquez-Garcia JC, Marquez MN, Jardim JR, Pertuze J, Lisboa C, Muino A, Lopez
MV, Talamo C, de Oca MM, Valdivia G, Menezes AM; Latin American COPD Prevalence Study
(PLATINO) Team. The long-term stability of portable spirometers used in a multinational study of
the prevalence of chronic obstructive pulmonary disease. Respir Care. 2006 Oct;51(10):1167-71.
PDF (129k)
o

Letter to the Editor: Spirometer Calibration Check Procedures. Respir Care. 2007
March;52(3):341-42. PDF (89k)
Rogelio Pérez-Padilla. Gonzalo Valdivia. Adriana Muiño. María Victorina López. María Nelly
Márquez. María Montes de Oca. Carlos Tálamo. Carmen Lisboa. Julio Pertuzé. José Roberto B
Jardim. Ana María B Menezes (n representación del grupo de trabajo PLATINO*). Spirometric
Reference Values in 5 Large Latin American Cities for Subjects Aged 40 Years or Over . Arch
Bronconeumol. 2006;42:317-25.
o
Español: PDF, 117k; editorial por F Burgos (PDF, 57k)
o
English: PDF, 115k; editorial by F Burgos (PDF, 55k)

Perez-Padilla R, Torre-Bouscoulet L, Muino A, Marquez MN, Lopez MV, de Oca MM, Talamo C,
Menezes AM; Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar (PLATINO)
group. Prevalence of oxygen desaturation and use of oxygen at home in adults at sea level and
at moderate altitude. Eur Respir J. 2006 Mar;27(3):594-9. PMID: 16507861. PDF (328k)

Ana Maria B Menezes, Rogelio Perez-Padilla, José Roberto B Jardim, Adriana Muiño, Maria
Victorina Lopez, Gonzalo Valdivia, Maria Montes de Oca, Carlos Talamo, Pedro C Hallal, Cesar G
Victora, for the PLATINO Team. Chronic obstructive pulmonary disease in five Latin American
cities (the PLATINO study): a prevalence study. Lancet. 2005 Nov; DOI:10.1016/S01406736(05)67632-5 Press release (26k); Full text HTML version

Menezes AM, Jardim JR, Perez-Padilla R, Camelier A, Rosa F, Nascimento O, Hallal PC.
Prevalence of chronic obstructive pulmonary disease and associated factors: the PLATINO Study
in Sao Paulo, Brazil. Cad Saude Publica. 2005 Oct;21(5):1565-1573. Epub 2005 Sep 12. PDF
(73k)

Adriana Muiño, María Victoria López Varela, Ana Maria Menezes. Prevalencia de la enfermedad

Marcela Araya B., Julio Pertuzé R., Gonzalo Valdivia C., Ana María Batista M., Rogelio Pérez P.,
Hilda Fuentes Y., Alejandro Jara V., María N. Márquez, Mónica Cifuentes S. Y Carmen Lisboa B.
pulmonary obstructiva crónica y sus principales factores de riesgo: proyecto PLATINO en
Montevideo. Rev Med Uruguay 2005; 21: 37-48. PDF (596k)
Calidad de las espirometrías en un estudio epidemiológico de terreno. Factores determinantes de
la necesidad de repetir el examen en el estudio Platino-Chile. Rev Chil Enf Respir 2005; 21: 155163. PDF (482k)

Ana MB Menezes , Cesar G Victora and Rogelio Perez-Padilla, for the PLATINO Team.
Platino project: methodology of a multicenter prevalence survey of cronic
11
obstructive pulmonary disease in major Latin American cities. BMC Medical
Research Methodology 2004, 4:15 (17 Jun 2004) Full Text
Theses

Carvalho, Andréa Kelly da Silveira. Dados demográficos e características gerais de saúde de uma
população acima de 40 anos. ESTUDO PLATINO – área metropolitana de São Paulo. Tese
(Mestrado) – Universidade Federal de São Paulo. Escola Paulista de Medicina. Programa de PósGraduação em Pneumologia. 87 f. São Paulo – SP, Brasil. 2007. PDF (386k)

Carmelier, Fernanda Warken Rosa. Diagnóstico de obstrução de vias aéreas pela relação
VEF1/VEF6 comparada à relação VEF1/CVF em um estudo brasileiro de base populacional –
PLATINO. Tese (Doutorado) – Universidade Federal de São Paulo. Escola Paulista de Medicina.
Programa de Pós-Graduação em Reabilitação. 82 f. São Paulo – SP, Brasil. 2006. PDF (787k)
Nascimento, Oliver Augusto. Avaliação do diagnóstico e tratamento da DPOC na região

metropolitana de São Paulo (SP) – Estudo PLATINO – Uma amostra base populacional. Tese
(Doutorado) – Universidade Federal de São Paulo. Escola Paulista de Medicina. Programa de PósGraduação em Pneumologia. 121 f. São Paulo – SP, Brasil. 2006. PDF (639k)
Carmelier, Aquiles Assunção. Avaliação da qualidade de vida relacionada à saúde em pacientes
com DPOC: estudo de base populacional com o SF-12 na cidade de São Paulo-SP. Tese
(Doutorado) – Universidade Federal de São Paulo. Escola Paulista de Medicina. Programa de PósGraduação em Pneumologia. 154 f. São Paulo – SP, Brasil. 2004. PDF (1073k)

Book
3.

PLATINO: Projeto Latino-Americano de Investigação em Obstrução Pulmonar. Ana M. B.
Menezes, Organizadora versão em português, PDF (4500k)

PLATINO: Proyecto Latino-Americano de Investigación en Obstrucción Pulmonar. Ana M. B.
Menezes, Organizadora version en espaãnol, PDF (4500k)
NATURAL HISTORY OF COPD
The development and progression of COPD can vary dramatically between individuals. A low
level of lung function remains the cornerstone of COPD diagnosis and has been used as a key
predictor of prognosis (Mannino, 2006). However, there are other factors determining morbidity
and mortality related to COPD, such as: age, body mass index, exercise limitation, pulmonary
hypertension, peripheral muscle weakness, malnutrition, co-morbidities, exacerbations, among
others. In the statement of the ATS/ERS on COPD it is mentioned the need for a multicomponent staging system that in addition to the degree of impairment incorporates the
perceptive and the systemic consequences of COPD.
12
Chronic Obstructive Pulmonary Disease could be represented as a pulmonary disease that affects
several domains: the respiratory, the perceptive and the systemic domain. Most of the literature
on COPD states that this disease is not only a disease of the lungs, but is also a systemic
inflammatory disorder.
Smoke is a powerful inducer of an inflammatory response. Inflammatory mediators, including
oxidants and proteases, are believed to play a major role in causing lung damage. Smoke can
also alter lung repair responses in several ways. Genetic factors likely play a major role and
probably account for much of the heterogeneity susceptibility to smoke and other factors. Many
factors may play a role, but to date, only alpha-1 protease inhibitor deficiency has been
unambiguously identified (Spurzem and Rennard, 2005).
Recently, some research has been carried out to investigate the role of some specific biomarkers
and their relationship with pulmonary diseases. Pinto-Plata (2006a) studied several serum
biomarkers by a new protein microarray platform technology in 47 patients with COPD and 48
matched control subjects. He found a significant correlation (p < 0.01) between 25 serum
biomarkers and FEV1, DLCO, 6MWD, BODE index and exacerbation frequency. The authors
conclude that serum biomarkers can be useful in the diagnosis and characterization of COPD.
Another publication from Pinto-Plata showed a higher serum levels of C reactive protein (CRP)
in patients with COPD than in controls independently of smoke and ischaemic heart disease. The
authors also showed that CRP was lower in patients using inhaled corticosteroid (Pinto-Plata,
2006b).
A cohort study with a median of 8-years follow-up 1,302 individuals with airway obstruction
were selected from the ongoing Copenhagen City Heart Study. Serum CRP was measured at
baseline, and recorded COPD admissions and deaths were considered as the outcomes. The
absolute 10-year risks for COPD hospitalization and death in individuals with CRP above 3mg/L
amounted to 54% and 57% among those older than 70 years, with a tobacco consumption above
15g/day and FEV1% predicted less than 50%. The authors suggested that CRP was a strong and
independent predictor of future COPD outcomes in individuals with airway obstruction (Dahl,
2006).
13
Hurst (2006) et al also measured plasma biomarkers to confirm exacerbation and predict
exacerbations severity in patients with COPD. They found that CRP was the most selective
biomarker to confirm the diagnosis of exacerbation; however, this was neither sensitive nor
specific alone; the combination of CRP with any one increased major exacerbation symptom
recorded by the patient on that day significantly increased the area under the receiver operating
characteristic curve. There were no significant relationships between biomarker concentrations
and clinical indices of exacerbation severity. The authors suggest that the acute-phase response
is related, separately, to monocytic and lymphocytic-neutrophilic pathways.
It is also argued that systemic inflammation (as airway inflammation) can be related to a decline
in lung function over time. In a cohort of 148 COPD patients, Donaldson (2005) showed that
systemic inflammatory markers (plasma fibrinogen) increase over time and high levels of these
markers are associated with a faster decline in lung function.
Acute exacerbations in patients with COPD are a common feature; they do not only reduce the
quality of life of these patients, but also result in hospitalization, respiratory failure and death.
Lower airway bacterial colonization induces airway inflammation which leads to a vicious circle
of progressive lung damage and disease progression (Sharma and Anthonisen, 2005).
It is possible that inflammatory mediators can be one of the factors that will contribute to the
evolution of the COPD.
Another interesting and important issue to be considered in the natural history of COPD is the
deleterious effects of a low fat-free mass index (FFMI). Vestbo (2006) measured FFMI using
bioelectrical impedance analysis on 1,898 patients with COPD from the Copenhagen Study. He
found that being in the lowest 10th percentile of the general population for FFMI was associated
with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.44.0) for COPD-related mortality. The conclusion was that in addition to BMI, assessment of
FFM should be considered in the routine assessment of COPD.
14
4.
JUSTIFICATION
The prevalence of COPD found in the PLATINO project was as high as nearly 20% in
Montevideo, Uruguay, and its main risk factor – smoking – was around 40% in Santiago, Chile.
It was also detected a very high prevalence of misdiagnosis of COPD and few subjects
performed spirometries – the keystone for the diagnosis of COPD.
In spite of the use of post-BD spirometry, misclassification of COPD status is still possible given
the cutoff criteria used. An important current discussion has been launched around the best
definition of airflow obstruction and COPD. Fixed ratio, produces an increasing rate of false
positives at older ages, and could find false negatives at younger ages. That increasing rate of
false positives is not seen with criteria based on 5th percentile or below the lower limit of normal.
A follow-up study of subjects included in the PLATINO project - repeating the same diagnostic
procedures and adding new exams (such as biomarkers for inflammation, genetic analysis, XRays, CT scans, to perform DLCO, lung volumes and methacoline challenge, among others) will help us to identify more precisely those patients truly affected by COPD, as well as the role
of inflammation in this disease and the genetics of the disease.
The multidimensional index BODE that includes the body mass index, percentage of predicted
FEV1, dyspnea, and the 6-min walk distance is a tool that have been proved to be a better
predictor of all cause and disease specific mortality than the FEV1 . Studies have shown that the
variables contributing to the index are amenable to change by interventions and thus make the
BODE a potential tool to be used in the evaluation of disease-modifying interventions.
The effects of low fat-free mass index should also be investigated.
Pulmonary biomarkers may be useful in predicting disease progression and in predicting
response to current therapies and novel therapies. Better understanding of the natural history of
COPD may lead to better definitions of specific COPD phenotypes, better interventions and
improved outcomes (Manino, 2006).
15
We plan to launch a cohort study based on the PLATINO sample examined in Montevideo in
2004 in order to study the natural history and clinical evolution of COPD. Because of the
prohibitive costs of following up subjects from all five sites of the original project, we decided to
choose the smallest city in the project and also the nearest city to the coordinating centre of the
project (Pelotas, Brazil). Montevideo has complete mortality registration, which is essential for
achieving one of the objectives of the new project, as well as political and economic stability and
low migration rates for individuals aged 40 years or more, factors that contribute to high followup rates and strict quality control.
5.
OBJECTIVES
5.1. Main objective
To study the natural history and clinical evolution of COPD in a sample of subjects aged
40 years or more from the original PLATINO project in Montevideo, Uruguay.
5.2.Secondary objectives
To verify the stability of the diagnosis used in the PLATINO study (post BD spirometry);
To evaluate different definitions of COPD in terms of their resemblance to disease;
To describe the natural history of COPD in terms of:
a) survival
b) morbidity history
c) functional capacity
d) occupational history
e) management
f) hospitalization
g) oxygen saturation
h) quality of life
i) absenteeism
j) nutrition
16
6.
METHODOLOGY
6.1. Design – a cohort design.
It is planned to do a follow-up of the baseline sample of the PLATINO project as
follows:
(a) all subjects with abnormal spirometry in 2004 (168 subjects, minus deaths and losses
to follow up); by the FEV1/FVC<70 criteria and also by the <LLN criteria.
(b) all subjects who were not diagnosed with COPD in 2004, but had irreversible airflow
obstruction (COPD) in the 2008 screening by both criteria.
(c) a sub-sample of 170 subjects from those without COPD in 2004, matched by age and
sex to those with COPD. They do not have airflow obstruction by any of the two main
criteria.
Group (a) above will be divided into two subgroups:
(a1) will include who are confirmed with COPD (fixed ratio criterion and also by
the <LLN criteria,) in 2008 while group
(a2) will include those whose diagnosed in 2004 but do not present COPD (fixed
ratio and also by the <LLN criteria) in 2008, that is, subjects who were “falsepositives” in 2004.
Classification of subjects into these four groups will allow the following comparisons:
17
Comparison
Issues to be addressed and applications
A1 x A2
Factors associated with persistent COPD diagnosis relative to a “falsepositive” COPD diagnosis at baseline; will propose indicators for
refining criteria for COPD diagnosis.
A1 x C
Natural history of COPD and its consequences (on morbidity,
mortality, economic productivity, disability, quality of life, etc) relative
to a group without COPD at baseline; will help quantify the clinical and
economic burden of COPD in the population.
BxC
Risk factors (measured in 2004) for developing COPD during the
period 2004 to 2008; will allow identification of preventable factors
associated with the development of COPD.
This cross classification matrix can be done for subjects with airflow obstruction
according to all diagnostic criteria of COPD.
6.2. Target population - subjects from the original PLATINO project, Montevideo, Uruguay.
6.3. Sample size - the estimated numbers of available subjects are 130 in group A1, 30 in
group A2, 160 in group A, 34 in group B and 170 in group C. With 80% statistical power
and 95% confidences (one-tailed) it will be possible to detect differences of 20
percentage points between groups A1 and C, 30 percentage points between groups B and
C, and 35 points between A1 and A2.
6.4. Outcomes - the following outcomes will be measured:
6.4.1. Lung function – to be measured with the same spirometers in the baseline of
the project (Easy One, from NDD) during the home visits;
6.4.2. Oxygen saturation – to be measured by pulse oximetry at home;
18
6.4.3. Economic productivity – to be investigated through the questionnaire applied
at home;
6.4.4.Quality of life – to be evaluated through the SF-12 and SF-36 questionnaire;
6.4.5. Mortality – to establish long-term mortality surveillance through a
continuous system for flagging deaths among PLATINO study members in the
national routine mortality registration database; mortality in the period 2004-08 will
be collected retrospectively, and a prospective system will be set up to continue
monitoring in the future;
6.4.6. Morbidity – information on hospital admissions since the baseline survey will
be collected in the home visit; hospitals will be visited and case-notes will be
abstracted using standardized forms. Information will also be collected on medical
attendances in the 12 months preceding the current survey;
6.4.7. BODE index – to carry out the measurements necessary to evaluate the
BODE index at the hospital; the following variables and point values will be used
for the BODE index (Celli, 2004):
FEV1 (% pred)
6MWD (m)
Dyspnea scale
BMI kg/m2
0
65
350
0–1
>21
1
0-64
250 349
2
21
2
36 49
150 249
3
--
3
35
149
4
--
Points
BMI: body mass index; FEV1: forced expiratory volume in 1 s.
6.4.8. Exacerbation – defined as a sustained worsening of the patient’s condition,
from the stable state and beyond normal day-to-day variations, that is acute in onset
and necessitates a change in regular medication in a patient with underlying COPD
(Rodrigues-Roisin, 2000);
19
6.4.9. Dyspnea scale – the MRC is a grading system indicating dyspnea associated
with walking that produces a single score . Patients are assigned to one of four
grades, based on their difficulty with mobility, from Grade 0 "not troubled with
breathlessness except with strenuous", to Grade 4, "too breathless to leave the house
or breathless after undressing”(http://www.copd-ternational.com/library/stages.htm).
6.4.5. Fat-free mass index – evaluated through bioelectrical impedance analysis
(BIA).
6.5. General exclusion criteria for the study (for both phases of PLATINO):
Institutionalized subjects
Subjects with mental diseases
Other severe conditions that preclude carrying out the examinations (to be specified)
6.6. Exclusion criteria for spirometry:
Subjects with current tuberculosis (questions about current and ever treated
tuberculosis)
Heart attack in the last three months
Upper pulse limit over 120 beats/minute *
Lower pulse limit < 60 beats/minute *
Thoracic or abdominal surgery in the last 3 months
Other conditions to be specified
* The subject should be advised to see a cardiologist if the pulse beats is over
120 or below 60/minute.
6.7. Instruments
6.7.1. Questionnaire - the questionnaire to be used in this survey is the same
previously used in the PLATINO project (a combined version of the ATS-DLD
questionnaire, the European Community Respiratory Health Survey II [9], and Lung
Health Study [10]). The questionnaire had already been translated to Spanish.
20
6.7.2. Equipment and measurements
The measurements at home will include spirometry and anthropometry (weight and
height information are required for calculating lung function).
Height will be measured with a portable Seca® stadiometer (precision 0.1 cm) using
the technique recommended by Lohman (1988); for weight, an electronic Tanita®
scale (precision 200 g); for waist circumference, an inextensible Fiberglass® tape
(precision 0.1 cm). All anthropometric measurements will be carried out twice on
each subject, and the average value will be used .
Spirometry will be carried out with portable, battery operated, ultrasound transit-time
based EasyOne™ spirometers (Medical Technologies, Chelmsford, Massachusetts
and Zürich, Switzerland) (already mentioned in item 2).
Bioimpedance analysis – bio-electrical impedance is a simple technique that assesses
the two main components of body composition with suitable accuracy. The
equipment is non-invasive, portable, quick to use and relatively cheap, making it
viable for studies in most environments (Jebb, 2000). Tanita is a bioelectrical
technique measuring impedance from foot to foot rather than from hand to foot. This
adaptation allows the equipment to function similarly to household bathroom scales,
with the subject required only to stand briefly on clearly marked foot-plates. Unlike
conventional BIA, there is no need for the attachment of electrodes at specific
anatomical sites, and weight is measured simultaneously with impedance such that
height is the only additional measurement required. These characteristics make footto-foot impedance highly convenient for large-scale studies. Model of the
equipment: Weight and Body Composition Analyzers Model TBF-300A
Six Minute Walk Distance (6MWD) will follow the guidelines from ATS (2002); it
will be performed (at home or at the hospital) along a long, flat, straight, enclosed
corridor with a hard surface that is seldom traveled. The walking course must be 30
21
m in length. A 100-ft hallway is, therefore, required. The length of the corridor
should be marked every 3m. The turnaround points should be marked with a cone. A
starting line, which marks the beginning and end of each 60-m lap, should be marked
on the floor using brightly colored tape. The subject should sit at rest in a chair,
located near the starting position, for at least 10 minutes before the test starts.
Absolute contraindications for the 6MWD include the following: unstable angina
during the previous month and myocardial infarction during the previous month.
Relative contraindications are: a resting heart rate of more than 120, a systolic blood
pressure of more than 180 mm Hg, and a diastolic blood pressure of more than 100
mm Hg.
Blood will be collected (at home or at the hospital) for measuring biomarkers. After
centrifugation of the blood, plasma will be kept in freezer at -80 degree C. A
sample of 8-10 ml of blood will allow us to have enough plasma for having several
aliquots per subject (examples of serum biomarkers which have been identified as
associated to COPD (Pinto-Plata, 2006 a).
Pathobiological
Function
Chemoattractants
IP-10/iTAC, Eot2, MPIF 1, MCP1, MIP1b, IL-8,
TARC
Inflammation
IL-15, IL-1ra, IL-17, TNFa/TNF R1, IFNg, IL_12P40
IL-2Rg, IL-6
Destruction and repair
TGFa, VEGF, AR, BDNF, bNGF, MMP9, TIMP1
Novel markers
PAI_II, Prolactin
22
7.
ANALYSES
Data collected in 2008 will be added to the database prepared in 2004. The above described
groups (section 6.1) will be compared using chi-squared tests for heterogeneity and linear trend
for categorical outcomes, whereas one-way ANOVA and T-tests will be used for continuous
outcomes. ROC curves will be used to compare the predictive ability of different spirometric
indices regarding mortality, morbidity and functional outcomes. The sensitivity, specificity and
predictive values of the GOLD, ERS, ATS and FR criteria for predicting these outcomes will
also be calculated.
In the multivariable analysis, logistic and linear regression models will be carried out, as
applicable. Adjustment for age, sex and socioeconomic factors will be carried out. All analyses
will take the clustering of the sample into account, and the significance level used will be 5%.
All tests will be one-tailed.
8.
TEAM
The site team will include two Principal Investigators (Dr. Lopez and Dr. Muino), a coordinator
in spirometry (Edilberto Pacheco), a secretary, two field supervisors, interviewers, one person in
charge of the mortality registry and two people in charge of the hospitalization records. The
Principal Investigators will be in charge of preparing the site protocol, submitting the protocol to
the ethical committee, contacting local authorities, recruiting staff and overseeing all aspects of
the study. It is envisaged that these persons should dedicate no less than 20% of her time to the
study.
The main coordinator of the study (Dr Menezes) will visit the center to supervise the training,
data collection and quality control activities.
A Site Secretary will be in charge of copying, distributing and collecting questionnaires and
other administrative activities related to the study.
23
The field workers will be selected in the site, of whom two will become field supervisors (most
of them will be the same who had worked in the baseline project). The same nutritionist as in the
first phase of PLATINO will be responsible for the training in measurements of weight and
height. Spirometry will be trained by the central coordinator of spirometries from Mexico (Dr.
Perez Padilla) and by the local coordinator in spirometries – Edilberto Pacheco (from
Montevideo).
The Site Data Manager will be a statistical technician who will be directly responsible for
overseeing data entry and who will personally carry out data cleaning, editing, and preparation
of data files in the coordinating centre in Pelotas, Brazil. Two clerks will work under the data
manager.
9.
LOGISTICS
We plan to start data collection in the second semester of 2008. The research team who was in
charge of the baseline phase of the PLATINO study will be responsible for data collection. This
will ensure standardization and high data quality; all spirometric tests will be analyzed in
Mexico, as done in the baseline phase.
We plan to achieve at least 90% of acceptable maneuvers according to the ATS criterion, as it
was achieved in the baseline study. Likewise, all interviewers and spirometry technicians will be
standardized regularly during the field work.
We will carry out repeat visits in 2008 to 885 subjects examined in 2004 (PLATINO sample
with valid spirometric results). These subjects will be located on the basis of the addressed
provided in that occasion. For those who moved, we will contact relatives in order to trace the
subjects. They will undergo a screening examination for COPD using the same criteria used in
2004, including post-BD spirometry.
24
For the mortality surveillance and for the review of hospital case-notes we will abstract death
certificates and hospital records, as well to interview the relatives of deceased subjects. A
separate research team will be responsible for this task.
The individual questionnaire, anthropometric measurements, pre and post-bronchodilator
spirometry and pulse oximetry will be applied during the home visits.
Experience from the baseline survey in Montevideo shows that it is possible to complete an
interview and all measurements in one hour, at home. Sufficient time must be allowed to reach
the cluster, locate eligible subjects at home, and carry out all measurements.
For security and logistical reasons, interviewers will work in pairs. Both members of each pair
will be trained both in interviewing technique and in spirometry, but one will be designate as the
lead spirometrist.
Each pair will be expected to complete two clusters (30 interviews) in a 6-day week. 9-10 weeks.
These calculations assume that each pair will carry a full set of equipment.
The two supervisors will repeat a short interview and re-measurement session with 10% of all
subjects included, as well as to closely follow the work of each interviewer.
A survey headquarters will be established which will serve as the basis for all operations.
Clinical examinations (if necessary) will be carried out at the Maciel Hospital, in Montevideo
(blood samples and BODE index). DNA samples will be processed and stored for future genetic
analyses.
10. QUALITY CONTROL
Several measures will be taken to ensure strict quality control in the study. These will include:
25

Use of pre-tested, standardized data collection forms and detailed interviewer guides

Careful evaluation of interviewers

Thorough training course on interviewing techniques

Central training of the Site Technical Coordinator on anthropometric and spirometric
measurements, followed by standardization sessions with assessment of intra and interobserver variability

Local training in Montevideo by the Site Technical Coordinator on anthropometric and
spirometric measurements, followed by standardization sessions with assessment of intra
and inter-observer variability.

Frequent calibration of weighing and spirometric equipment

Regular standardization sessions (every two weeks) throughout the data collection period

Repeated attempts (no fewer than 3) to interview all subjects in order to reduce nonresponse

Repetition of 5-10% of all interviews and measurements by a field supervisor using a
shortened version of the questionnaire, with calculation of the kappa statistic for interobserver reliability
11. ETHICAL ISSUES
The project will be submitted to the ethical committees of the Federal University of Pelotas and
of the Universidad de la Republica in Montevideo. Written informed consent will be obtained.
The confidentiality of the data collected will be guaranteed. Spirometry results will be delivered
to all subjects. Those with pulmonary function deficits or any other problem in the performed
exams will receive a written referral note to be taken to a clinic affiliated with the local
institution carrying out the research.
12. REFUSALS
A small questionnaire concerning sociodemographic, smoking and health status data should be
performed in all subjects who refused to participate in the study.
26
13. LIMITATIONS OF THE STUDY
The main limitation of the study is the fact that it will provide representative information for
only one of the five sites studied in the original project. Results cannot be necessarily
extrapolated to the other sites of PLATINO, since some important differences were found among
the sites. Nevertheless, its results will produce important information for assessing the natural
history of COPD. Anther limitation for some measurements is that the proposal is for only a
second measurement and the best information can be obtained after several measurements, that
take into account longer time variability. For example, decline in lung function requires several
measurements etc. Further measurements are to be requested in the future to solve that issue.
14. STUDY ORGANIZATION
The organizational framework for the multicenter study is as follows: President of ALAT (Dr.
Rogelio Perez Padilla), the director of the department of COPD in ALAT (Dr.Alejandro Casas),
director of the funding companies, main coordinator of the project (Dr.Menezes), Principal
investigators from Montevideo (Dr. Lopez and Dr.Muino), local coordinator of the spirometries
(Edilberto Pacheco), and the Principal Investigators from the other sites in the baseline of the
project (Dr. José Jardim, Dr. Gonzalo Valdivia, Dr. Maria Montes de Oca and Dr. Carlos
Talamo). All of them will make up the Steering Committee which will have full responsibility
for the design and implementation of the study.
The Executive committee comprises Dr. Menezes, Dr. Perez Padilla, Dr. Lopez and Dr. Muino.
The Advisory Committee will comprise prominent external experts on the subject who, when
requested by the steering committee, will provide guidance on study design, implementation and
analysis (Dr. Bartolomé Celli, Dr. Sonia Buist, Professor Peter Burney and some other names to
be defined later).
27
15. PUBLICATION GUIDELINES
The General Coordinator will present the final report of the study by the end of 2009 to all
funding companies and to the Steering Committee.
Main papers
One of the main papers will be on the methodology of the cohort study. There is a growing
interest in making protocols widely available, and some electronic journals, for example,
BioMed Public Health, encourage such publication. Another paper will describe the natural
history of COPD. The submission will be soon after the results and after the approval by the
Steering Committee.
If any of the investigators involved in the study have special interest in pursuing a specific topic
using data, they should obtain consent from the Steering Committee. These papers must be
approved by the Steering Committee before publication. Authorship by up to three individual
authors involved in the analysis and writing up and by the “PLATINO Study Group” is
recommended.
Authorship should follow international recommendations, i.e. all authors should have
contributed substantially (see http://bmj.com/advice/article_submission.shtml).
Presentations at local, regional and international meetings
Members will be encouraged to present results from the PLATINO study in such meetings. The
Steering Committee should receive a copy of the abstract at the time it is being submitted.
Presenters are encouraged but not required to share their presentation materials with ALAT and
FUNDING COMPANIES.
Acknowledgement of ALAT/FUNDING COMPANIES support
should be included in the presentation along the lines suggested in item 17.
28
16. DATA OWNERSHIP
The contract between ALAT and the funding companies will specify that all data derived from
the PLATINO study are a joint property of ALAT and the funding companies.
As soon as the data sets are entered and cleaned, a copy should be made available to
ALAT/funding companies.
ALAT/FUNDING COMPANIES will examine requests for data use before their transfer into the
public domain from individuals or institutions not involved in the PLATINO data collection on a
case-by-case basis. These applications should include a detailed plan for analyses and
publications, list the specific variables being requested and indicate how each of these variables
will be used in the analysis. Complete data sets will not be released. ALAT/FUNDING
COMPANIES will then consult with the coordinator of the study and the Steering Committee. If
all parties agree that they are not interested in taking the lead in the analyses being suggested, the
partial data set may be released.
Two years after publication of the main results paper, the full data set will be made available in
the public domain. The anonymity of all study participants will be ensured.
17.
ACKNOWLEDGEMENT TO ALAT AND ALL FUNDING COMPANIES
The following language is recommended when acknowledging the research: “This work is part
of The PLATINO cohort study: the natural history of COPD coordinated by Associacion
Latino-Americana del Torax and supported by ALL FUNDING COMPANIES”.
29
18.
TIME TABLE
Semester/Year First semester/2008 Second semester/2008
Month 1
2
3



Finalization of proposal
Development of instruments

4
5
6



7
8
PI visits (to Montevideo)

Training (in Montevideo)
T
T
Field data collection: (Montevideo)
F
F
Data entry: (Pelotas)
Data analysis (Pelotas)
Preliminary report
First semester/2009
9 10 11 12 1

F
F


F
F
2
3
4

F
5
Second semester/2009
6
7
8
9 10 11 12







F
D D D D D D D D

Final report


Preparation of papers



T= training
F = field data collection
D=data entry and cleaning
31
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21. ANNEXES – the main questionnaire (in Spanish) used during the baseline of the project will
be used in the follow-up (see the website of PLATINO: http://www.platino-alat.org). New
instruments will be developed for the registries of the hospital tests and for the mortality data.
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