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1.  A cross-sectional study of determinants of indoor environmental exposures in households with and without chronic exposure to biomass fuel smoke 
Environmental Health  2014;13:21.
Background
Burning biomass fuels indoors for cooking is associated with high concentrations of particulate matter (PM) and carbon monoxide (CO). More efficient biomass-burning stoves and chimneys for ventilation have been proposed as solutions to reduce indoor pollution. We sought to quantify indoor PM and CO exposures in urban and rural households and determine factors associated with higher exposures. A secondary objective was to identify chronic vs. acute changes in cardiopulmonary biomarkers associated with exposure to biomass smoke.
Methods
We conducted a census survey followed by a cross-sectional study of indoor environmental exposures and cardiopulmonary biomarkers in the main household cook in Puno, Peru. We measured 24-hour indoor PM and CO concentrations in 86 households. We also measured PM2.5 and PM10 concentrations gravimetrically for 24 hours in urban households and during cook times in rural households, and generated a calibration equation using PM2.5 measurements.
Results
In a census of 4903 households, 93% vs. 16% of rural vs. urban households used an open-fire stove; 22% of rural households had a homemade chimney; and <3% of rural households participated in a national program encouraging installation of a chimney. Median 24-hour indoor PM2.5 and CO concentrations were 130 vs. 22 μg/m3 and 5.8 vs. 0.4 ppm (all p<0.001) in rural vs. urban households. Having a chimney did not significantly reduce median concentrations in 24-hour indoor PM2.5 (119 vs. 137 μg/m3; p=0.40) or CO (4.6 vs. 7.2 ppm; p=0.23) among rural households with and without chimneys. Having a chimney did not significantly reduce median cook-time PM2.5 (360 vs. 298 μg/m3, p=0.45) or cook-time CO concentrations (15.2 vs. 9.4 ppm, p=0.23). Having a thatched roof (p=0.007) and hours spent cooking (p=0.02) were associated with higher 24-hour average PM concentrations. Rural participants had higher median exhaled CO (10 vs. 6 ppm; p=0.01) and exhaled carboxyhemoglobin (1.6% vs. 1.0%; p=0.04) than urban participants.
Conclusions
Indoor air concentrations associated with biomass smoke were six-fold greater in rural vs. urban households. Having a homemade chimney did not reduce environmental exposures significantly. Measures of exhaled CO provide useful cardiopulmonary biomarkers for chronic exposure to biomass smoke.
doi:10.1186/1476-069X-13-21
PMCID: PMC3978088  PMID: 24655424
Biomass smoke; Biomass fuel; Cookstoves; Biomarkers; Exhaled carbon monoxide; Environmental exposure
2.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
doi:10.1513/AnnalsATS.201207-036OT
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
3.  A cross-sectional study of differences in 6-min walk distance in healthy adults residing at high altitude versus sea level 
Background
We sought to determine if adult residents living at high altitude have developed sufficient adaptation to a hypoxic environment to match the functional capacity of a similar population at sea level. To test this hypothesis, we compared the 6-min walk test distance (6MWD) in 334 residents living at sea level vs. at high altitude.
Methods
We enrolled 168 healthy adults aged ≥35 years residing at sea level in Lima and 166 individuals residing at 3,825 m above sea level in Puno, Peru. Participants completed a 6-min walk test, answered a sociodemographics and clinical questionnaire, underwent spirometry, and a blood test.
Results
Average age was 54.0 vs. 53.8 years, 48% vs. 43% were male, average height was 155 vs. 158 cm, average blood oxygen saturation was 98% vs. 90%, and average resting heart rate was 67 vs. 72 beats/min in Lima vs. Puno. In multivariable regression, participants in Puno walked 47.6 m less (95% CI -81.7 to -13.6 m; p < 0.01) than those in Lima. Other variables besides age and height that were associated with 6MWD include change in heart rate (4.0 m per beats/min increase above resting heart rate; p < 0.001) and percent body fat (-1.4 m per % increase; p = 0.02).
Conclusions
The 6-min walk test predicted a lowered functional capacity among Andean high altitude vs. sea level natives at their altitude of residence, which could be explained by an incomplete adaptation or a protective mechanism favoring neuro- and cardioprotection over psychomotor activity.
doi:10.1186/2046-7648-3-3
PMCID: PMC3909455  PMID: 24484777
Six-minute walk test; High altitude adaptation; Hypoxia; Functional capacity
4.  Multiple Norovirus Infections in a Birth Cohort in a Peruvian Periurban Community 
Serial norovirus infections with multiple genotypes were found among a Peruvian birth cohort early in infancy. Protection against the subsequent infection was genotype specific, suggesting that norovirus vaccines may need to target multiple genotypes.
Background. Human noroviruses are among the most common enteropathogens globally, and are a leading cause of infant diarrhea in developing countries. However, data measuring the impact of norovirus at the community level are sparse.
Methods. We followed a birth cohort of children to estimate norovirus infection and diarrhea incidence in a Peruvian community. Stool samples from diarrheal episodes and randomly selected nondiarrheal samples were tested by polymerase chain reaction for norovirus genogroup and genotype. Excretion duration and rotavirus coinfection were evaluated in a subset of episodes.
Results. Two hundred twenty and 189 children were followed to 1 and 2 years of age, respectively. By 1 year, 80% (95% confidence interval [CI], 75%–85%) experienced at least 1 norovirus infection and by 2 years, 71% (95% CI, 65%–77%) had at least 1 episode of norovirus-associated diarrhea. Genogroup II (GII) infections were 3 times more frequent than genogroup 1 (GI) infections. Eighteen genotypes were found; GII genotype 4 accounted for 41%. Median excretion duration was 34.5 days for GII vs 8.5 days for GI infection (P = .0006). Repeat infections by the same genogroup were common, but repeat infections by the same genotype were rare. Mean length-for-age z score at 12 months was lower among children with prior norovirus infection compared to uninfected children (coefficient: −0.33 [95% CI, −.65 to −.01]; P = .04); the effect persisted at 24 months.
Conclusions. Norovirus infection occurs early in life and children experience serial infections with multiple genotypes, suggesting genotype-specific immunity. An effective vaccine would have a substantial impact on morbidity, but may need to target multiple genotypes.
doi:10.1093/cid/cit763
PMCID: PMC3905757  PMID: 24300042
norovirus; infant diarrhea; gastroenteritis; birth cohort; natural infection
5.  Feasibility intervention trial of two types of improved cookstoves in three resource-limited settings: study protocol for a randomized controlled trial 
Trials  2013;14:327.
Background
Exposure to biomass fuel smoke is one of the leading risk factors for disease burden worldwide. International campaigns are currently promoting the widespread adoption of improved cookstoves in resource-limited settings, yet little is known about the cultural and social barriers to successful improved cookstove adoption and how these barriers affect environmental exposures and health outcomes.
Design
We plan to conduct a one-year crossover, feasibility intervention trial in three resource-limited settings (Kenya, Nepal and Peru). We will enroll 40 to 46 female primary cooks aged 20 to 49 years in each site (total 120 to 138).
Methods
At baseline, we will collect information on sociodemographic characteristics and cooking practices, and measure respiratory health and blood pressure for all participating women. An initial observational period of four months while households use their traditional, open-fire design cookstoves will take place prior to randomization. All participants will then be randomized to receive one of two types of improved, ventilated cookstoves with a chimney: a commercially-constructed cookstove (Envirofit G3300/G3355) or a locally-constructed cookstove. After four months of observation, participants will crossover and receive the other improved cookstove design and be followed for another four months. During each of the three four-month study periods, we will collect monthly information on self-reported respiratory symptoms, cooking practices, compliance with cookstove use (intervention periods only), and measure peak expiratory flow, forced expiratory volume at 1 second, exhaled carbon monoxide and blood pressure. We will also measure pulmonary function testing in the women participants and 24-hour kitchen particulate matter and carbon monoxide levels at least once per period.
Discussion
Findings from this study will help us better understand the behavioral, biological, and environmental changes that occur with a cookstove intervention. If this trial indicates that reducing indoor air pollution is feasible and effective in resource-limited settings like Peru, Kenya and Nepal, trials and programs to modify the open burning of biomass fuels by installation of low-cost ventilated cookstoves could significantly reduce the burden of illness and death worldwide.
Trial registration
ClinicalTrials.gov NCT01686867
doi:10.1186/1745-6215-14-327
PMCID: PMC3852602  PMID: 24112419
Improved cookstove; Ventilated cookstove; Behavior change; Adoption; Indoor air pollution; DLCO; Spirometry; Biomass fuel
6.  OBSTRUCTIVE LUNG DISEASE AND EXPOSURE TO BURNING BIOMASS FUEL IN THE INDOOR ENVIRONMENT 
Global heart  2012;7(3):265-270.
It is estimated that up to half of the world’s population burns biomass fuel (wood, crop residues, animal dung and coal) for indoor uses such as cooking, lighting and heating. As a result, a large proportion of women and children are exposed to high levels of household air pollution (HAP). The short and long term effects of these exposures on the respiratory health of this population are not clearly understood. On May 9–11, 2011 NIH held an international workshop on the "Health Burden of Indoor Air Pollution on Women and Children," in Arlington, VA. To gather information on the knowledge base on this topic and identify research gaps, ahead of the meeting we conducted a literature search using PubMed to identify publications that related to HAP, asthma, and chronic obstructive pulmonary disease (COPD). Abstracts were all analyzed and we report on those considered by the respiratory sub study group at the meeting to be most relevant to the field. Many of the studies published are symptom-based studies (as opposed to objective measures of lung function or clinical examination etc.) and measurement of HAP was not done. Many found some association between indoor exposures to biomass smoke as assessed by stove type (e.g., open fire vs. liquid propane gas) and respiratory symptoms such as wheeze and cough. Among the studies that examined objective measures (e.g. spirometry) as a health outcome, the data supporting an association between biomass smoke exposure and COPD in adult women are fairly robust, but the findings for asthma are mixed. If an association was observed between the exposures and lung function, most data seemed to demonstrate mild to moderate reductions in lung function, the pathophysiological mechanisms of which need to be investigated. In the end, the group identified a series of scientific gaps and opportunities for research that need to be addressed to better understand the respiratory effects of exposure to indoor burning of the different forms of biomass fuels.
doi:10.1016/j.gheart.2012.06.016
PMCID: PMC3489498  PMID: 23139916
Biomass smoke; cooking fuel smoke; Indoor air pollution; COPD; asthma
7.  Mortality and Denial of Admission to an Intensive Care Unit 
doi:10.1164/rccm.201202-0343ED
PMCID: PMC3359892  PMID: 22589309
8.  Role of exhaled nitric oxide as a predictor of atopy 
Respiratory Research  2013;14(1):48.
Background
The fractional exhaled nitric oxide (FeNO) is a quantitative, noninvasive and safe measure of airways inflammation that may complement the assessment of asthma. Elevations of FeNO have recently been found to correlate with allergic sensitization. Therefore, FeNO may be a useful predictor of atopy in the general population. We sought to determine the diagnostic accuracy of FeNO in predicting atopy in a population-based study.
Methods
We conducted a cross-sectional study in an age- and sex- stratified random sample of 13 to 15 year-olds in two communities in Peru. We asked participants about asthma symptoms, environmental exposures and sociodemographics, and underwent spirometry, assessment of FeNO and an allergy skin test. We used multivariable logistic regression to model the odds of atopy as a function of FeNO, and calculated area-under-the-curves (AUC) to determine the diagnostic accuracy of FeNO as a predictor of atopy.
Results
Of 1441 recruited participants, 1119 (83%) completed all evaluations. Mean FeNO was 17.6 ppb (SD=0.6) in atopics and 11.6 ppb (SD=0.8) in non-atopics (p<0.001). In multivariable analyses, a FeNO>20 ppb was associated with an increase in the odds of atopy in non-asthmatics (OR=5.3, 95% CI 3.3 to 8.5) and asthmatics (OR=16.2, 95% CI 3.4 to 77.5). A FeNO>20 ppb was the best predictor for atopy with an AUC of 68% (95% CI 64% to 69%). Stratified by asthma, the AUC was 65% (95% CI 61% to 69%) in non-asthmatics and 82% (95% CI 71% to 91%) in asthmatics.
Conclusions
FeNO had limited accuracy to identify atopy among the general population; however, it may be a useful indicator of atopic phenotype among asthmatics.
doi:10.1186/1465-9921-14-48
PMCID: PMC3654880  PMID: 23639047
Allergic sensitization; Asthma; Exhaled nitric; Allergic rhinitis
9.  Revisiting the Relationship of Weight and Height in Early Childhood12 
Advances in Nutrition  2012;3(2):250-254.
Ponderal and linear growth of children has been widely studied; however, epidemiologic evidence of a relationship between the two is inconsistent. Child undernutrition in the form of low height for age and low weight for height continues to burden the developing world. A downward shift in the distribution of height for age in the first 2 y of life is commonly observed in many developing countries and is usually summarized as the percentage stunted (height for age Z-score <−2). Similar shifts are seen in weight for height; however, weight-for-height shifts are often less extreme, perhaps because weight for height is more tightly biologically controlled. Low height for age and low weight for height in childhood share some common factors, including food insecurity, infectious diseases, and inappropriate feeding practices. Reductions in weight for height, generally seen as a short-term response to inadequate dietary intake or utilization, are thought to precede decreases in height for age; however, given an adequate diet and no further insults, catch-up linear growth can occur. Serial instances of decreased weight for height, however, are thought to limit the degree of catch-up growth attained, contributing to linear growth retardation. Additional research is needed to identify the factors associated with recovery of linear growth after a child experiences decreased weight for height. Although the direct relationship between weight for height and height for age is likely limited, each of these measurements indicates important information about the general health of children and their risk of the development of illness or dying; therefore, eliminating the downward shift of height for age and weight for height in developing countries should be prioritized as a public policy.
doi:10.3945/an.111.001099
PMCID: PMC3648729  PMID: 22516736
10.  Household food access and child malnutrition: results from the eight-country MAL-ED study 
Background
Stunting results from decreased food intake, poor diet quality, and a high burden of early childhood infections, and contributes to significant morbidity and mortality worldwide. Although food insecurity is an important determinant of child nutrition, including stunting, development of universal measures has been challenging due to cumbersome nutritional questionnaires and concerns about lack of comparability across populations. We investigate the relationship between household food access, one component of food security, and indicators of nutritional status in early childhood across eight country sites.
Methods
We administered a socioeconomic survey to 800 households in research sites in eight countries, including a recently validated nine-item food access insecurity questionnaire, and obtained anthropometric measurements from children aged 24 to 60 months. We used multivariable regression models to assess the relationship between household food access insecurity and anthropometry in children, and we assessed the invariance of that relationship across country sites.
Results
Average age of study children was 41 months. Mean food access insecurity score (range: 0–27) was 5.8, and varied from 2.4 in Nepal to 8.3 in Pakistan. Across sites, the prevalence of stunting (42%) was much higher than the prevalence of wasting (6%). In pooled regression analyses, a 10-point increase in food access insecurity score was associated with a 0.20 SD decrease in height-for-age Z score (95% CI 0.05 to 0.34 SD; p = 0.008). A likelihood ratio test for heterogeneity revealed that this relationship was consistent across countries (p = 0.17).
Conclusions
Our study provides evidence of the validity of using a simple household food access insecurity score to investigate the etiology of childhood growth faltering across diverse geographic settings. Such a measure could be used to direct interventions by identifying children at risk of illness and death related to malnutrition.
doi:10.1186/1478-7954-10-24
PMCID: PMC3584951  PMID: 23237098
11.  A simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation 
Critical care medicine  2011;39(12):2645-2651.
Objective
Despite improvements in the care of critically-ill patients, hospital mortality for acute lung injury remains high at approximately 40%. We developed a classification rule to stratify mechanically ventilated patients with acute lung injury according to hospital mortality and compared this rule to the APACHE III prediction.
Patients
We used data of 2022 participants in ARDS Network trials to build a classification rule based on 54 variables collected prior to randomization.
Design
We used a classification tree approach to stratify patients according to hospital mortality using a training subset of 1800 participants, and estimated expected prediction errors using tenfold cross validation. We validated our classification tree using a subset of 222 participants not included in model building, and calculated areas under the receiver operating characteristic curves (AUCs).
Measurements and Main Results
We identified combinations of age (>63 years), BUN (>15 mg/dl), shock, respiratory rate (>21 breaths/minute), and minute ventilation (>13.9 L/minute) as important predictors of hospital mortality at 90 days. The classification tree had a similar expected prediction error in the training set (28% versus 26%; p=0.18) and AUC in the validation set (0.71 versus 0.73; p=0.71) as did a model based on APACHE III.
Conclusions
Our tree-based classification rule performed similarly to APACHE III in stratifying patients according to hospital mortality, is simpler to use, contains risk factors that may be specific to acute lung injury, and identified minute ventilation as a potential novel predictor of death in patients with acute lung injury.
doi:10.1097/CCM.0b013e3182266779
PMCID: PMC3227537  PMID: 21725235
12.  The Value of PEEP and FiO2 Criteria in the Definition the Acute Respiratory Distress Syndrome 
Critical care medicine  2011;39(9):2025-2030.
OBJECTIVES:
The criteria that define acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) include PaO2/FiO2 but not positive end-expiratory pressure (PEEP) or FiO2. PaO2/FiO2s of some patients increase substantially after mechanical ventilation with PEEP of 5-10 cm H2O, and the mortality of these patients may be lower than those whose PaO2/FiO2s remain < 200. Also, PaO2/FiO2 may increase when FiO2 is raised from moderate to high levels, suggesting that patients with similar PaO2/FiO2s but different FiO2s have different risks of mortality. The primary purpose of this study was to assess the value of adding baseline PEEP and FiO2 to PaO2/FiO2 for predicting mortality of ALI/ARDS patients enrolled in ARDS Network clinical trials. We also assessed effects of two study interventions on clinical outcomes in subsets of patients with mild and severe hypoxemia as defined by PaO2/FiO2.
DESIGN:
Analysis of baseline physiologic data and outcomes of patients previously enrolled in clinical trials conducted by the National Institutes of Health ARDS Network.
SETTING:
Intensive care units of 40 hospitals in North America.
PATIENTS:
2312 patients with ALI/ARDS.
INTERVENTIONS:
None.
MEASUREMENTS AND MAIN RESULTS:
Only 1.3% of patients enrolled in ARDS Network trials had baseline PEEP < 5 cm H2O, and 50% had baseline PEEP ≥ 10 cm H2O. Baseline PaO2/FiO2 predicted mortality, but after controlling for PaO2/FiO2, baseline PEEP did not predict mortality. In contrast, after controlling for baseline PaO2/FiO2, baseline FiO2 did predict mortality. Effects of two study interventions (lower tidal volumes and fluid-conservative hemodynamic management) were similar in mild and severe hypoxemia subsets as defined by PaO2/FiO2 ratios.
CONCLUSION:
At ARDS Network hospitals, the addition of baseline PEEP would not have increased the value of PaO2/FiO2 for predicting mortality of ALI/ARDS patients. In contrast, the addition of baseline FiO2 to PaO2/FiO2 could be used to identify subsets of patients with low or high mortality.
doi:10.1097/CCM.0b013e31821cb774
PMCID: PMC3157575  PMID: 21532473
Acute lung injury; Clinical trials, randomized; Ventilation, mechanical; Positive end-expiratory pressure
13.  Computerized Lung Sound Analysis as diagnostic aid for the detection of abnormal lung sounds: a systematic review and meta-analysis 
Respiratory medicine  2011;105(9):1396-1403.
Rationale
The standardized use of a stethoscope for chest auscultation in clinical research is limited by its inherent inter-listener variability. Electronic auscultation and automated classification of recorded lung sounds may help prevent some these shortcomings.
Objective
We sought to perform a systematic review and meta-analysis of studies implementing computerized lung sounds analysis (CLSA) to aid in the detection of abnormal lung sounds for specific respiratory disorders.
Methods
We searched for articles on CLSA in MEDLINE, EMBASE, Cochrane Library and ISI Web of Knowledge through July 31, 2010. Following qualitative review, we conducted a meta-analysis to estimate the sensitivity and specificity of CLSA for the detection of abnormal lung sounds.
Measurements and Main Results
Of 208 articles identified, we selected eight studies for review. Most studies employed either electret microphones or piezoelectric sensors for auscultation, and Fourier Transform and Neural Network algorithms for analysis and automated classification of lung sounds. Overall sensitivity for the detection of wheezes or crackles using CLSA was 80% (95% CI 72–86%) and specificity was 85% (95% CI 78–91%).
Conclusions
While quality data on CLSA are relatively limited, analysis of existing information suggests that CLSA can provide a relatively high specificity for detecting abnormal lung sounds such as crackles and wheezes. Further research and product development could promote the value of CLSA in research studies or its diagnostic utility in clinical setting.
doi:10.1016/j.rmed.2011.05.007
PMCID: PMC3227538  PMID: 21676606
Pneumonia; Respiratory disorders; Electronic auscultation; Lung sound analysis
14.  A Community Study of Factors Related to Poorly Controlled Asthma among Brazilian Urban Children 
PLoS ONE  2012;7(5):e37050.
Background
Asthma constitutes a serious public health problem in many regions of the world, including the city of Salvador, State of Bahia – Brazil. The purpose of this study was to analyse the factors associated with poor asthma control.
Methodology/Principal Findings
Two definitions were used for asthma: 1) wheezing in the last 12 months; 2) wheezing in the last 12 months plus other asthma symptoms or asthma diagnosis ever. The definition of poorly controlled asthma was: at least one reported hospitalisation due to asthma and/or high frequency of symptoms, in the last year. Children with poorly controlled asthma (N = 187/374) were compared with wheezing children with controlled asthma regarding age, gender, atopy, parental asthma, rhinitis, eczema, exposure to second hand tobacco smoke, presence of moulds, pets and pests in the house, helminth infections and body mass index. Crude and logistic regression adjusted odds ratios were used as measures of association. There was a higher proportion of poorly controlled asthma among children with eczema (OR = 1.55; 95% CI 1.02; 2.37). The strength of the association was greater among children with eczema and rhinitis (42.6%, 53.4% and 57.7%, respectively, in children who had no rhinitis nor eczema, had only one of those, and had both (p = 0.02 for trend test). The presence of mould in the houses was inversely associated with poorly controlled asthma (OR = 0.54; 95% CI 0.34; 0.87).
Conclusions/Significance
Our results indicate an association between eczema and poor asthma control in this environment, but emphasize the role of various other individual and environmental factors as determinants of poor control.
doi:10.1371/journal.pone.0037050
PMCID: PMC3365022  PMID: 22693565
15.  Effects of distance from a heavily transited avenue on asthma and atopy in a peri-urban shanty-town in Lima, Peru 
Background
Proximity to roadways increases the risk of asthma in developed countries; however, relatively little is known about this relationship in developing countries, where rapid and uncontrolled growth of cities has resulted in urban sprawl and heavy traffic volumes.
Objective
Determine the effect of distance from a heavily transited avenue on asthma symptoms and quantitative respiratory outcome measures in a peri-urban shanty town in Lima, Peru.
Methods
We enrolled 725 adolescents aged 13–15 years, administered a survey on asthma symptoms and measured spirometry, response to allergy skin testing and eNO. We calculated distances from the main avenue for all households and measured indoor PM in 100 households. We used multivariable regression to model the risk of asthma symptoms, risk of atopy, eNO and FEV1/FVC as a function of distance.
Results
Compared against 384 meters, the odds of current asthma symptoms in households living within 100 meters increased by a factor of 2 (p<0.05). The odds of atopy increased by a factor of 1.07 for every 100 meters difference in the distance from the avenue (p=0.03). We found an inverse relationship in pre-bronchodilator FEV1/FVC and distance to the avenue in females (p=0.01) but not in males. We did not find an association between eNO or household PM levels and distance.
Conclusion
Living in close proximity to a high traffic-density avenue in a peri-urban community in Peru was associated with a greater risk of asthma symptoms and atopy. Regulation of mobile source pollutants in peri-urban areas of developing countries may help reduce the burden of asthma symptoms and atopy.
doi:10.1016/j.jaci.2010.11.031
PMCID: PMC3227546  PMID: 21237505
Asthma symptoms; atopy; distance; traffic; particulate matter; spirometry
16.  Epidemiology of tobacco use and dependence in adults in a poor peri-urban community in Lima, Peru 
Background
Tobacco smoking is an important public health concern worldwide leading to both chronic disease and early death. In Latin America, smoking prevalence is estimated at approximately 30% and prior studies suggest that the prevalence in Peru is 22% to 38%. We sought to determine the prevalence of daily smoking in a poor peri-urban community in Lima, Peru.
Methods
We conducted a cross-sectional survey in a random sample of adults ≥40 years of age living in Pampas de San Juan de Miraflores, Lima, Peru. We asked participants to respond to a survey that included questions on sociodemographics, tobacco use and dependence.
Results
We enrolled 316 participants. Average monthly household income was ≤ 400 USD and nearly all homes had running water, sewage, and electricity. Most individuals had not completed high school. Smoking prevalence was 16% overall, yet daily smoking prevalence was 1.9%. Former daily smokers comprised 3.8% of current nonsmokers and 9.1% current occasional smokers. Average scores for the Fagerstrom Test for Nicotine Dependence for daily smokers and occasional smokers were 1.5 and 0, respectively.
Conclusions
Daily use of tobacco is uncommon among adults in peri-urban communities of Lima, Peru, unlike their counterparts in Lima and other Latin American capital cities. Tobacco dependence is also low. Hence, efforts aimed at primary prevention are of utmost importance in these communities. This study provides an accurate baseline using an internationally recognized assessment tool (Global Adult Tobacco Survey), allowing for accurate assessment of tobacco control interventions over time.
doi:10.1186/1471-2466-12-9
PMCID: PMC3323410  PMID: 22429737
17.  The Peru Urban versus Rural Asthma (PURA) Study: methods and baseline quality control data from a cross-sectional investigation into the prevalence, severity, genetics, immunology and environmental factors affecting asthma in adolescence in Peru 
BMJ Open  2012;2(1):e000421.
Objectives
According to a large-scale international survey, Peru has one of the highest prevalences of asthma worldwide; however, data from this survey were limited to participants from urban Lima. The authors sought to characterise the epidemiology of asthma in Peru in two regions with disparate degrees of urbanisation. In this manuscript, the authors summarise the study design and implementation.
Design
A cross-sectional study.
Participants
Using census data of 13–15-year-old adolescents from two communities in Peru, the authors invited a random sample of participants in Lima (n=725) and all adolescents in Tumbes (n=716) to participate in our study.
Primary and secondary outcome measures
The authors asked participants to complete a questionnaire on asthma symptoms, environmental exposures and socio-demographics and to undergo spirometry before and after bronchodilator, skin allergy testing and exhaled nitric oxide testing. The authors obtained blood samples for haematocrit, total IgE levels, vitamin D levels and DNA in all participants and measured indoor particulate matter concentrations for 48 h in a random subset of 70–100 households at each site.
Results
Of 1851 eligible participants, 1441 (78%) were enrolled and 1159 (80% of enrolled) completed all physical tests. 1283 (89%) performed spirometry according to standard guidelines, of which 86% of prebronchodilator tests and 92% of postbronchodilator tests were acceptable and reproducible. 92% of allergy skin tests had an adequate negative control. The authors collected blood from 1146 participants (79%) and saliva samples from 148 participants (9%). Overall amounts of DNA obtained from blood or saliva were 25.8 μg, with a 260/280 ratio of 1.86.
Conclusions
This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting. The authors present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.
Article summary
Article focus
We sought to characterise the epidemiology of asthma in Peru by studying two regions with disparate degrees of urbanisation.
We summarise the study design, implementation and standard operating procedures and provide quality control data for important outcome and exposure variables.
Key messages
We present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.
Strengths and limitations of this study
This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting.
This study is cross-sectional and therefore does not track symptoms over time to directly determine causality. In addition, we did not collect stool samples to assess parasitic infections nor do we have information on respiratory infections in early childhood.
doi:10.1136/bmjopen-2011-000421
PMCID: PMC3289983  PMID: 22357570
18.  Computerised lung sound analysis to improve the specificity of paediatric pneumonia diagnosis in resource-poor settings: protocol and methods for an observational study 
BMJ Open  2012;2(1):e000506.
Introduction
WHO case management algorithm for paediatric pneumonia relies solely on symptoms of shortness of breath or cough and tachypnoea for treatment and has poor diagnostic specificity, tends to increase antibiotic resistance. Alternatives, including oxygen saturation measurement, chest ultrasound and chest auscultation, exist but with potential disadvantages. Electronic auscultation has potential for improved detection of paediatric pneumonia but has yet to be standardised. The authors aim to investigate the use of electronic auscultation to improve the specificity of the current WHO algorithm in developing countries.
Methods
This study is designed to test the hypothesis that pulmonary pathology can be differentiated from normal using computerised lung sound analysis (CLSA). The authors will record lung sounds from 600 children aged ≤5 years, 100 each with consolidative pneumonia, diffuse interstitial pneumonia, asthma, bronchiolitis, upper respiratory infections and normal lungs at a children's hospital in Lima, Peru. The authors will compare CLSA with the WHO algorithm and other detection approaches, including physical exam findings, chest ultrasound and microbiologic testing to construct an improved algorithm for pneumonia diagnosis.
Discussion
This study will develop standardised methods for electronic auscultation and chest ultrasound and compare their utility for detection of pneumonia to standard approaches. Utilising signal processing techniques, the authors aim to characterise lung sounds and through machine learning, develop a classification system to distinguish pathologic sounds. Data will allow a better understanding of the benefits and limitations of novel diagnostic techniques in paediatric pneumonia.
Article summary
Article focus
We seek to characterise lung sounds associated with different respiratory illnesses in children using electronic auscultation and determine whether these sounds can be differentiated from normal through computerised lung sound analysis.
We summarise the study design and methods with standardised protocols for electronic auscultation and chest ultrasound in children.
Key message
We aim to develop a protocol for increased specificity of paediatric pneumonia diagnosis in developing countries.
Strengths and limitations of this study
Our study is limited by the case definitions available. With no gold standard for many paediatric respiratory diseases, we will rely on clinical exam findings and chest radiography.
By investigating a number of novel and commonly used diagnostic tools for a variety of respiratory diseases in children, we will gain valuable information regarding the diagnostic potential of each, with a main focus on the electronic stethoscope.
doi:10.1136/bmjopen-2011-000506
PMCID: PMC3274713  PMID: 22307098
19.  Genome Wide Association Identifies PPFIA1 as a Candidate Gene for Acute Lung Injury Risk Following Major Trauma 
PLoS ONE  2012;7(1):e28268.
Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p<0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated B-lymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.
doi:10.1371/journal.pone.0028268
PMCID: PMC3266233  PMID: 22295056
20.  Addressing geographical variation in the progression of non-communicable diseases in Peru: the CRONICAS cohort study protocol 
BMJ Open  2012;2(1):e000610.
Background
The rise in non-communicable diseases in developing countries has gained increased attention. Given that around 80% of deaths related to non-communicable diseases occur in low- and middle-income countries, there is a need for local knowledge to address such problems. Longitudinal studies can provide valuable information about disease burden of non-communicable diseases in Latin America to inform both public health and clinical settings.
Methods
The CRONICAS cohort is a longitudinal study performed in three Peruvian settings that differ by degree of urbanisation, level of outdoor and indoor pollution and altitude. The author sought to enrol an age- and sex-stratified random sample of 1000 participants at each site. Study procedures include questionnaires on socio-demographics and well-known risk factors for cardiopulmonary disease, blood draw, anthropometry and body composition, blood pressure and spirometry before and after bronchodilators. All participants will be visited at baseline, at 20 and 40 months. A random sample of 100 households at each site will be assessed for 24 h particulate matter concentration. Primary outcomes include prevalence of risk factors for cardiopulmonary diseases, changes in blood pressure and blood glucose over time and decline in lung function.
Discussion
There is an urgent need to characterise the prevalence and burden of non-communicable diseases in low- and middle-income countries. Peru is a middle-income country currently undergoing a rapid epidemiological transition. This longitudinal study will provide valuable information on cardiopulmonary outcomes in three different settings and will provide a platform to address potential interventions that are locally relevant or applicable to other similar settings in Latin America.
Article summary
Article focus
Compare prevalence and risk factors of cardiovascular and chronic obstructive pulmonary disease among three different populations.
Compare rate of disease progression to hypertension and diabetes from a disease-free baseline status between populations.
Compare rate of lung function decline between populations.
Key messages
Our longitudinal study will provide valuable information on cardiopulmonary outcomes in three different settings and will provide a platform to address potential interventions that are locally relevant or applicable to other similar settings in Latin America.
Strengths and limitations of this study
The CRONICAS cohort is the first longitudinal study in Peru to assess cardiopulmonary risk factors among population from different geographical settings.
doi:10.1136/bmjopen-2011-000610
PMCID: PMC3278488  PMID: 22240652
21.  Inference for mutually exclusive competing events through a mixture of generalized gamma distributions 
Epidemiology (Cambridge, Mass.)  2010;21(4):557-565.
Background
Time-to-event data with two or more types of endpoints are found in many epidemiologic settings. Instead of treating the times for one of the endpoints as censored observations for the other, we present an alternative approach where we treat competing events as distinct outcomes in a mixture. Our objective was to determine if and how the mixture was modified in response to an intervention.
Methods
We used a mixture of generalized gamma distributions to concatenate the overall frequency and distribution of the times of two competing events commonly observed in critical care trials, namely unassisted breathing followed by hospital discharge alive and in-hospital death. We applied our proposed methods to data from two randomized clinical trials of critically ill patients.
Results
Mechanical ventilation with lower tidal volumes modified the mixture (P =0.103) when compared with traditional tidal volumes by lowering the overall frequency of death (P = 0.005), rather than through affecting either the distributions of times to unassisted breathing (P = 0.477) or times to death (P = 0.718). Likewise, use of a conservative versus a liberal fluid management modified the mixture (P <0.001) by achieving earlier times to unassisted breathing (P <0.001) and not through affecting the overall frequency of death (P = 0.202) or the distribution of times to death (P = 0.693).
Conclusions
A mixture approach to competing risks provides a means to determine the overall effect of an intervention and insights into how intervention modifies the components of the mixture.
doi:10.1097/EDE.0b013e3181e090ed
PMCID: PMC3227544  PMID: 20502337
22.  Beyond Mortality 
Mortality in National Heart, Lung and Blood Institute–sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.
doi:10.1164/rccm.201001-0024WS
PMCID: PMC2874454  PMID: 20224063
clinical trials; acute respiratory distress syndrome; pulmonary diseases; edema; inflammation
23.  Comparison of Two Types of Epidemiological Surveys Aimed at Collecting Daily Clinical Symptoms in Community-Based Longitudinal Studies 
Annals of epidemiology  2010;20(2):151-158.
BACKGROUND
Investigators use prospective community-based studies to collect longitudinal information on childhood diarrhea. The interval in which data are collected may affect the accuracy and interpretation of results. Our objective was to compare data of reported daily clinical symptoms from surveys conducted daily versus twice-weekly surveys.
METHODS
We conducted our study in Lima, Peru, between October and December 2007. We asked 134 mothers to report daily symptoms by using a twice-weekly survey. We conducted daily surveys for the same data on 25% of participants randomly selected each day. We analyzed intersurvey variability by using Cohen’s kappa and Signal Detection Theory (SDT).
RESULTS
We collected 6157 and 1181 child-days of data through the twice-weekly and daily surveys, respectively. The prevalence of diarrhea, fever, vomiting, and cough were 6.4%, 1.6%, 2.1%, and 22.7% from the twice-weekly survey and, 6.4%, 2.0%, 2.4%, and 26% from the daily survey, respectively. Despite similar prevalence, 20% of days with reported diarrhea were discrepant between the two surveys, and agreement in the report of diarrhea decreased as time between the interviews increased (p = .03).
CONCLUSIONS
Although twice-weekly surveys provide an adequate estimate of diarrheal prevalence compared with daily surveys, the prevalence of other symptoms based on dichotomous questions was lower under the former. Additionally, the agreement between the two surveys in the report of diarrhea decreased as the recall period increased, suggesting that data from daily interviews were of greater quality. Our analysis is a novel application of SDT to measure respondent certainty and bias, from which better inference about the quality of collected data may be drawn.
doi:10.1016/j.annepidem.2009.10.004
PMCID: PMC2837588  PMID: 20123166
Cohort Studies; Diarrhea–Infantile; Epidemiologic Methods; Signal Detection; Psychological
24.  Cytokine Profiles in Asthma Families Depend on Age and Phenotype 
PLoS ONE  2010;5(12):e14299.
Background
Circulating cytokine patterns may be relevant for the diagnosis of asthma, for the discrimination of certain phenotypes, and prognostic factors for exacerbation of disease.
Methodology/Principal Findings
In this study we investigated serum samples from 944 individuals of 218 asthma-affected families by a multiplex, microsphere based system detecting at high sensitivity eleven asthma associated mediators: eotaxin (CCL11), granulocyte macrophage stimulating factor (GM-CSF), interferon gamma (IFNγ), interleukin-4 (IL-4), IL-5, IL-8, IL-10, IL-12 (p40), IL-13, IL-17 and tumor necrosis factor alpha (TNFα). Single cytokine levels were largely similar between asthmatic and healthy individuals when analysing asthma as single disease entity. Regulatory differences between parental and pediatric asthma were reflected by six of the eleven mediators analyzed (eotaxin, IL-4, IL-5, IL-10, IL-12, TNFα). IL-12 (p40) and IL-5 were the best predictor for extrinsic asthma in children with an increased odds ratio of 2.85 and 1.96 per log pg/ml increase (IL-12 (p40): 1.2–6.8, p = 0.019, and IL-5: 1.2–2.5, p = 0.025). Frequent asthma attacks in children are associated with elevated IL-5 serum levels (p = 0.013). Cytokine patterns seem to be individually balanced in both, healthy and diseased adults and children, with various cytokines correlating among each other (IL-17 and IFNγ (rs = 0.67), IL-4 and IL-5 (rs = 0.55), IFNγ and GM-CSF (rs = 0.54)).
Conclusion/Significance
Our data support mainly an age- but also an asthma phenotype-dependent systemic immune regulation.
doi:10.1371/journal.pone.0014299
PMCID: PMC3001464  PMID: 21179211
25.  Lack of an Adverse Effect of Giardia intestinalis Infection on the Health of Peruvian Children 
American Journal of Epidemiology  2008;168(6):647-655.
Giardia intestinalis is a common gastrointestinal protozoan worldwide, but its effects on childhood growth in developing countries are not clearly understood. The authors aimed to describe its effects on child growth. They followed 220 Peruvian children daily for diarrhea, weekly for stool samples, and monthly for anthropometry. The authors modeled the effect of nutritional status on the risk of Giardia infection and the risk of diarrhea attributable to Giardia using negative binomial regression. They modeled the effects of Giardia infection on growth using linear regression, with 85% of children becoming infected with Giardia and 87% of these becoming reinfected. In multivariable analysis, the risk of Giardia infection did not vary with weight for age (relative risk = 1.00, 95% confidence interval: 0.89, 1.12) or height for age (relative risk = 0.92, 95% confidence interval: 0.82, 1.04). Giardiasis did not affect growth at 1 or 2 months following the first infection at any age interval. The longitudinal prevalence of Giardia between 6 and 24 months of age was not associated with height gain in that interval (p = 0.981). Giardia was not associated with an increased risk of diarrhea at any age interval. Study results question the importance of Giardia as a childhood pathogen in developing countries where giardiasis is hyperendemic.
doi:10.1093/aje/kwn177
PMCID: PMC2727197  PMID: 18669932
developing countries; diarrhea; Giardia lamblia; growth; natural history; Peru

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