γ-Linolenic acid in maternal milk drives cardiac metabolic maturation.

Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production1,2. This adaptation is triggered in part by post-partum environmental changes3, but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA-RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism.

A positively selected FBN1 missense variant reduces height in Peruvian individuals.

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study in Lima, Peru.

Rationale: The persistent burden of tuberculosis (TB) disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions toward those at high risk of developing and transmitting TB is a public health priority. Objectives: We aimed to identify characteristics of individuals involved in TB transmission in a community setting, which may guide the prioritization of targeted interventions. Methods: We collected clinical and sociodemographic data from a cohort of patients with TB in Lima, Peru. We used whole-genome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs, and we assumed that the first diagnosed patient in a pair was the transmitter and the second was the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct TB transmission. Measurements and Main Results: Analyzing data from 2,518 index patients with TB, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. Conclusions: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend TB screening to social groups such as young adults and prisoners with limited access to routine preventive care.

Spatial scale of tuberculosis transmission in Lima, Peru.

Spatially targeted interventions may be effective alternatives to individual or population-based prevention strategies against tuberculosis (TB). However, their efficacy may depend on the mechanisms that lead to geographically constrained hotspots. Local TB incidence may reflect high levels of local transmission; conversely, they may point to frequent travel of community members to high-risk areas. We used whole-genome sequencing to explore patterns of TB incidence and transmission in Lima, Peru. Between 2009 and 2012, we recruited incident pulmonary TB patients and their household contacts, whom we followed for the occurrence of TB disease. We used whole-genome sequences of 2,712 Mycobacterial tuberculosis isolates from 2,440 patients to estimate pariwise genomic distances and compared these to the spatial distance between patients' residences. Genomic distances increased rapidly as spatial distances increased and remained high beyond 2 km of separation. Next, we divided the study catchment area into 1 × 1 km grid-cell surface units and used household spatial coordinates to locate each TB patient to a specific cell. We estimated cell-specific transmission by calculating the proportion of patients in each cell with a pairwise genomic distance of 10 or fewer single-nucleotide polymorphisms. We found that cell-specific TB incidence and local transmission varied widely but that cell-specific TB incidence did not correlate closely with our estimates of local transmission (Cohen's k = 0.27). These findings indicate that an understanding of the spatial heterogeneity in the relative proportion of TB due to local transmission may help guide the implementation of spatially targeted interventions.

Chest Radiograph Screening for Detecting Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.

Utility of Mycobacterium tuberculosis genome sequencing snapshots to assess transmission dynamics over time.

We explored the utility of brief Mycobacterium tuberculosis whole-genome sequencing (WGS) "snapshots" at a sentinel site within Lima, Peru for evaluating local transmission dynamics over time. Within a 17 km2 area, 15/70 (21%) isolates with WGS collected during 2011-2012 and 22/81 (27%) collected during 2020-2021 were clustered (p = 0.414), and additional isolates clustered with those from outside the area. Isolates from the later period were disproportionately related to large historic clusters in Lima from the earlier period. WGS snapshots at a sentinel site may not be useful for monitoring transmission, but monitoring the persistence of large transmission clusters might be.

The Contribution of Chest Radiography to the Clinical Management of Children Exposed to Tuberculosis.

Rationale: Although World Health Organization guidelines emphasize contact investigation for tuberculosis (TB)-exposed children, data that support chest radiography as a useful tool are lacking. Objectives: We evaluated the diagnostic and prognostic information of chest radiography in children exposed to TB and measured the efficacy of isoniazid preventive therapy (IPT) in those with relevant radiographic abnormalities. Methods: Between September 2009 and August 2012, we enrolled 4,468 TB-exposed children who were screened by tuberculin skin testing, symptom assessment, and chest radiography. Those negative for TB disease were followed for 1 year for the occurrence of new TB diagnoses. We assessed the protective efficacy of IPT in children with and without abnormal chest radiographs. Measurements and Main Results: Compared with asymptomatic children with normal chest films, asymptomatic children with abnormal radiographs were 25.1-fold more likely to have coprevalent TB (95% confidence interval [CI], 1.02-613.76) and 26.7-fold more likely to be diagnosed with incident TB disease during follow-up (95% CI, 10.44-68.30). Among the 29 symptom-negative and CXR-abnormal child contacts, 20% (3/15) of the isoniazid recipients developed incident TB, compared with 57% (8/14) of those who did not receive IPT (82% IPT efficacy). Conclusions: Our results strongly support the use of chest radiography as a routine screening tool for the evaluation of child TB contacts, which is readily available. Radiographic abnormalities not usually considered suggestive of TB may indicate incipient or subclinical disease, although TB preventive treatment is adequate in most cases.

Smoking Cessation in Tuberculosis Patients and the Risk of Tuberculosis Infection in Child Household Contacts.

BACKGROUND: While previous studies have shown that cigarette smoking increases the infectiousness of tuberculosis patients, the impact of smoking cessation on tuberculosis transmissibility has not been evaluated. METHODS: Between 2009 and 2012, we enrolled 4500 tuberculosis patients and followed 14 044 household contacts in Lima, Peru. Tuberculosis patients were classified into 4 categories: never smoked, quit in the distant past (stopped smoking >2 months prior to time of diagnosis), recently quit (stopped smoking ≤2 months prior to time of diagnosis), and active smokers. We used a modified Poisson generalized estimating equation to assess the risk of tuberculosis infection of child contacts at enrollment and by 6 months of follow-up. RESULTS: In total, 1371 (76.8%) child contacts were exposed to patients who had never smoked, 211 (11.8%) were exposed to distant quitters, 155 (8.7%) were exposed to recent quitters, and 49 (2.7%) were exposed to active smokers. Compared with child contacts of index patients who had never smoked, child contacts of recent quitters had a similar risk of tuberculosis infection at enrollment (adjusted risk ratio, 95% confidence intervals [0.81, 0.50-1.32]) and by six months of follow-up (0.76, 0.51-1.13); and by 6 months of follow-up (aRR, 0.76; 95% CI, .51-1.13); child contacts of recent quitters had a significantly reduced risk of tuberculosis infection compared with contacts of active smokers (enrollment 0.45, 0.24-0.87; 6-month follow-up 0.48, 0.29-0.79). CONCLUSIONS: Our results show that the adverse effects of smoking on the transmissibility of tuberculosis are significantly reduced shortly after quitting smoking, reinforcing the importance of smoking cessation interventions in tuberculosis control.

Success at Scale: Outcomes of Community-Based Neurodevelopment Intervention (CASITA) for Children Ages 6-20 months With Risk of Delay in Lima, Peru.

This study is a randomized controlled trial of a 12-week community-based group parenting intervention ("CASITA") in Lima, Peru. CASITA improved neurodevelopment in a pilot study of 60 Peruvian children and subsequently scaled to 3,000 households throughout the district. The objective of this study was to assess intervention effectiveness when implemented at scale. A total of 347 children ages 6-20 months (52.7% male, 100% identified as "mestizo") at risk for developmental difficulties were randomized to immediate or delayed CASITA. At 3 months after enrollment, the immediate arm showed significantly higher overall development, based on the Extended Ages and Stages Questionnaire and Home Observation for Measurement of the Environment scores (Cohen's ds = .36 and .31, respectively). Programs demonstrably effective at scale could help address children's development risks worldwide.

Isoniazid Preventive Therapy in Contacts of Multidrug-Resistant Tuberculosis.

Rationale: The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections. The recent rise of drug-resistant tuberculosis has complicated the choice of treatment regimen for latent tuberculosis infection.Objectives: To evaluate the effects of INH preventive therapy on the contacts of patients with multidrug-resistant tuberculosis.Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index patients with tuberculosis and 14,044 tuberculosis-exposed household contacts who we followed for 1 year for the occurrence of incident tuberculosis disease. Although Peruvian national guidelines specify that INH preventive therapy should be provided to contacts aged 19 years old or younger, only half this group received INH preventive therapy.Measurements and Main Results: Among 4,216 contacts under 19 years of age, 2,106 contacts (50%) initiated INH preventive therapy at enrollment. The protective effect of INH was more extreme in contacts exposed to drug-sensitive tuberculosis (adjusted hazard ratio, 0.30; 95% confidence interval, 0.18-0.48) and to multidrug-resistant tuberculosis (adjusted hazard ratio, 0.19; 95% confidence interval, 0.05-0.66) compared with those exposed to mono-INH-resistant tuberculosis (adjusted hazard ratio, 0.80; 95% confidence interval, 0.23-2.80). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received INH preventive therapy compared with 3% (8 of 273) of those who did not.Conclusions: Household contacts who received INH preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. INH may have a role in the management of latent multidrug-resistant tuberculosis infection.

Two Clinical Prediction Tools to Improve Tuberculosis Contact Investigation.

BACKGROUND: Efficient contact investigation strategies are needed for the early diagnosis of tuberculosis (TB) disease and treatment of latent TB infections. METHODS: Between September 2009 and August 2012, we conducted a prospective cohort study in Lima, Peru, in which we enrolled and followed 14 044 household contacts of adults with pulmonary TB. We used information from a subset of this cohort to derive 2 clinical prediction tools that identify contacts of TB patients at elevated risk of progressing to active disease by training multivariable models that predict (1) coprevalent TB among all household contacts and (2) 1-year incident TB among adult contacts. We validated the models in a geographically distinct subcohort and compared the relative utilities of clinical decisions based on these tools to existing strategies. RESULTS: In our cohort, 296 (2.1%) household contacts had coprevalent TB and 145 (1.9%) adult contacts developed incident TB within 1 year of index patient diagnosis. We predicted coprevalent disease using information that could be readily obtained at the time an index patient was diagnosed and predicted 1-year incident TB by including additional contact-specific characteristics. The area under the receiver operating characteristic curves for coprevalent TB and incident TB were 0.86 (95% confidence interval [CI], .83-.89]) and 0.72 (95% CI, .67-.77), respectively. These clinical tools give 5%-10% higher relative utilities than existing methods. CONCLUSIONS: We present 2 tools that identify household contacts at high risk for TB disease based on reportable information from patient and contacts alone. The performance of these tools is comparable to biomarkers that are both more costly and less feasible than this approach.

Mycobacterium tuberculosis Beijing Lineage and Risk for Tuberculosis in Child Household Contacts, Peru.

Few studies have prospectively compared the relative transmissibility and propensity to cause disease of Mycobacterium tuberculosis Beijing strains with other human-adapted strains of the M. tuberculosis complex. We assessed the effect of Beijing strains on the risk for M. tuberculosis infection and disease progression in 9,151 household contacts of 2,223 culture-positive pulmonary tuberculosis (TB) patients in Lima, Peru. Child contacts exposed to Beijing strains were more likely than child contacts exposed to non-Beijing strains to be infected at baseline, by 12 months of follow-up, and during follow-up. We noted an increased but nonsignificant tendency for child contacts to develop TB. Beijing strains were not associated with TB in adult contacts. These findings suggest that Beijing strains are more transmissible in children than are non-Beijing strains.

Children as sentinels of tuberculosis transmission: disease mapping of programmatic data.

BACKGROUND: Identifying hotspots of tuberculosis transmission can inform spatially targeted active case-finding interventions. While national tuberculosis programs maintain notification registers which represent a potential source of data to investigate transmission patterns, high local tuberculosis incidence may not provide a reliable signal for transmission because the population distribution of covariates affecting susceptibility and disease progression may confound the relationship between tuberculosis incidence and transmission. Child cases of tuberculosis and other endemic infectious disease have been observed to provide a signal of their transmission intensity. We assessed whether local overrepresentation of child cases in tuberculosis notification data corresponds to areas where recent transmission events are concentrated. METHODS: We visualized spatial clustering of children < 5 years old notified to Peru's National Tuberculosis Program from two districts of Lima, Peru, from 2005 to 2007 using a log-Gaussian Cox process to model the intensity of the point-referenced child cases. To identify where clustering of child cases was more extreme than expected by chance alone, we mapped all cases from the notification data onto a grid and used a hierarchical Bayesian spatial model to identify grid cells where the proportion of cases among children < 5 years old is greater than expected. Modeling the proportion of child cases allowed us to use the spatial distribution of adult cases to control for unobserved factors that may explain the spatial variability in the distribution of child cases. We compare where young children are overrepresented in case notification data to areas identified as transmission hotspots using molecular epidemiological methods during a prospective study of tuberculosis transmission conducted from 2009 to 2012 in the same setting. RESULTS: Areas in which childhood tuberculosis cases are overrepresented align with areas of spatial concentration of transmission revealed by molecular epidemiologic methods. CONCLUSIONS: Age-disaggregated notification data can be used to identify hotspots of tuberculosis transmission and suggest local force of infection, providing an easily accessible source of data to target active case-finding intervention.

Tuberculosis clinical presentation and treatment outcomes in pregnancy: a prospective cohort study.

BACKGROUND: There is limited research to guide TB treatment specifically in pregnant women and few studies have described the presentation of TB in pregnant women. We aimed to understand TB presentation and treatment outcomes in pregnant women in a low HIV burden setting. We describe a cohort of women of childbearing age treated for TB disease in Lima, Peru, and compare clinical presentation and treatment outcomes among pregnant and non-pregnant women between 2009 and 2012, including 36 pregnant women. METHODS: This is a prospective cohort study. Subjects were recruited from across 106 public health centers in Lima, Peru. Baseline demographic, medical history, and drug-susceptibility test results were collected. We used descriptive statistics to describe demographic and clinical characteristics of the women using Pearson chi-squared, Fisher's exact tests, or Kruskal-Wallis. RESULTS: Among 4500 individuals with pulmonary TB disease, 1334 women were included in analysis with 36 (2.69%) pregnant women. Pregnant women had similar demographics, past medical histories, and clinical presentation to non-pregnant women, except being more likely to be married (p = 0.01) and have cardiac disease (p = 0.04) and less likely to have weight loss (p = 0.05). Twenty (71.4%) pregnant women had pan-susceptible TB compared with 616 (63.1%) non-pregnant women; four (14.3%) pregnant women had mono-resistant TB compared with 154 (15.8%) non-pregnant women; and four (14.3%) pregnant women had multi-drug-resistant TB compared with 140 (14.3%) of non-pregnant women (p = 0.53). Twenty-eight (96.6%) pregnant women had a successful outcome (cure, completed treatment, treatment ended early by clinical team) while one (3.4%) had an unsuccessful outcome (treatment failed) and 1074 (97.3%) non-pregnant women had a successful outcome while 30 (2.7%) had an unsuccessful outcome (p = 0.56). CONCLUSION: In this cohort with low HIV co-infection, we found high TB treatment success rates in both pregnant and non-pregnant women, irrespective of drug-susceptibility profiles. If treated appropriately, pregnant women with TB disease can have successful outcomes.

The Use of Wearable Technology to Objectively Measure Sleep Quality and Physical Activity Among Pregnant Women in Urban Lima, Peru: A Pilot Feasibility Study.

INTRODUCTION: Sleep quality and physical activity can affect the mental and physical health of pregnant women and their babies in utero. METHODS: We investigated the feasibility of objectively assessing sleep quality and physical activity among resource-constrained, pregnant women in urban Lima, Peru. Twenty pregnant women were asked to complete written sleep logs and wear ActiSleep, a wristwatch-like device that records sleep quality (consecutive minutes of uninterrupted sleep) and physical activity (steps), for seven consecutive days. Sociodemographic data and pregnancy characteristics were also collected. RESULTS: Of twenty women, 13 (65%) had sufficient data collected for analysis. The mean age of study participants was 26.3 years (SD = 3.9), with a mean sleep duration of 6.9 h (SD = 1.4). The median time for sleep onset was 21:15. The mean time for sleep latency was 17.3 min; and wake after sleep onset was 116 min. The mean number of awakenings was 20.4 (SD = 6.7); and sleep efficiency was 77.9%. For physical activity, participants averaged of 6,029 steps per day (SD = 3,087). DISCUSSION: Objective assessment of sleep quality and physical activity among pregnant women in a resource-constrained setting was promising, despite modest data collection completeness. Wearable technology could be used in health interventions to improve sleep quality and physical activity among this population.

Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis.

BACKGROUND: Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk. METHODS AND FINDINGS: We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25-(OH)D < 50 nmol/L, insufficiency as 50-75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25-(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75-3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04-2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87-4.87; p trend for decreasing 25-(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22-3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85-21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies. CONCLUSION: Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk.

Asthma and atopy prevalence are not reduced among former tuberculosis patients compared with controls in Lima, Peru.

BACKGROUND: Although there are theoretical reasons for believing that asthma and atopy may be negatively correlated with tuberculosis, epidemiological studies have had conflicting findings. OBJECTIVE: To determine if people with confirmed tuberculosis were less likely to be atopic and less likely to have atopic disease including asthma compared to those with no previous tuberculosis. METHODS: Patients in Lima, Peru with a prior history of tuberculosis were identified from clinic records in this cohort study. A representative sample of individuals without a prior tuberculosis diagnosis was recruited from the same community. Allergen skin prick testing was performed to classify atopic status. Allergic rhinitis was identified by history. Asthma was defined by symptoms and spirometry. Eosinophilic airway inflammation was measured using exhaled nitric oxide levels. RESULTS: We evaluated 177 patients with, and 161 individuals without, previous tuberculosis. There was a lower prevalence of atopy among people with prior tuberculosis on univariate analysis (odds ratio 0.57; 95% confidence interval 0.37-0.88) but, after adjustment for potential confounders, this was no longer statistically significant (aOR 0.64, 95% CI 0.41-1.01). The prevalence of allergic rhinitis (aOR 0.76, 95% CI 0.47 to 1.24 and asthma (aOR 1.18, 95% CI 0.69 to 2.00) did not differ significantly between the two groups. We also found no significant difference in the prevalence of elevated exhaled nitric oxide (aOR 1.30, 95% CI 0.78 to 2.17) or a combined index of atopic disease (aOR 0.86, 95% CI 0.54 to 1.36). CONCLUSION: In this urban environment in a middle-income country, prior tuberculosis may be associated with a reduced risk of atopy but does not protect against asthma and atopic disease.

Factors associated with fatal cases of acute respiratory infection (ARI) among hospitalized patients in Guatemala.

BACKGROUND: Acute respiratory infection (ARI) is an important cause of mortality in children and adults. However, studies assessing risk factors for ARI-related deaths in low- and middle-income settings are limited. We describe ARI-related death and associated factors among children aged < 2 years and adults aged ≥18 years hospitalized with ARI in Guatemala. METHODS: We used respiratory illness surveillance data in Guatemala from 2007 to 2013. ARI was defined as evidence of acute infection and ≥ 1 sign/symptom of respiratory disease in hospitalized patients. Clinical, sociodemographic, and follow-up data were gathered. Nasopharyngeal/oropharyngeal swabs were collected from patients with ARI and tested for 6 respiratory viruses; urine was collected only from adults with ARI and tested for pneumococcal antigen. Blood cultures and chest radiographs were performed at the physician's discretion. Radiographs were interpreted per World Health Organization guidelines to classify endpoint pneumonia (i.e. suggestive of bacterial pneumonia). Multivariable logistic regression was used to compare characteristics of patients with fatal cases, including those who died in-hospital or were discharged in a moribund state, with those of patients with non-fatal cases. RESULTS: Among 4109 ARI cases identified in hospitalized children < 2 years old, 174 (4%) were fatal. Median age at admission was 4 and 6 months for children with fatal and non-fatal cases, respectively. Factors associated with fatality included low weight-for-age, low family income, heart disease, and endpoint pneumonia; breastfeeding and respiratory syncytial virus (RSV) detection were negatively associated with fatality. Among 1517 ARI cases identified in hospitalized adults ≥18 years, 181 (12%) episodes were fatal. Median age at admission was 57 years for adults with fatal and non-fatal cases. Low body mass index, male sex, kidney disease, and endpoint pneumonia were significantly more common among patients with fatal versus non-fatal cases. CONCLUSIONS: Our findings highlight some of the factors that must be addressed in order to reduce ARI-related mortality, including promotion of good nutrition, breastfeeding, management and prevention of chronic comorbidities, and poverty reduction. Although no specific pathogen increased risk for death, endpoint pneumonia was significantly associated with fatality, suggesting that the pneumococcal conjugate vaccine could contribute to future reductions in ARI-related mortality.

Vitamin E Status Is Inversely Associated with Risk of Incident Tuberculosis Disease among Household Contacts.

Background: Few studies have previously assessed how pre-existing vitamin E status is associated with risk of tuberculosis (TB) disease progression. Objective: We evaluated the association between baseline plasma concentrations of 3 vitamin E isomers (α-tocopherol, γ-tocopherol, and δ-tocopherol) and TB disease risk. Methods: We conducted a case-control study nested within a longitudinal cohort of household contacts (HHCs) of pulmonary TB cases in Lima, Peru. We defined cases as HHCs who developed active TB disease ≥15 d after the diagnosis of the index patient, and we matched each case to 4 control cases who did not develop active TB based on age by year and gender. We used univariate and multivariate conditional logistic regression to calculate ORs for incident TB disease by plasma concentrations of α-tocopherol, γ-tocopherol, and δ-tocopherol. Results: Among 6751 HIV-negative HHCs who provided baseline blood samples, 180 developed secondary TB during follow-up. After controlling for possible confounders, we found that baseline α-tocopherol deficiency conferred increased risk of incident TB disease (adjusted OR: 1.59; 95% CI: 1.02, 2.50; P = 0.04). Household contacts in the lowest tertile of δ-tocopherol were also at increased risk of progression to TB disease compared to those in the highest tertile (tertile 1 compared with tertile 3, adjusted OR: 2.29; 95% CI: 1.29, 4.09; P-trend = 0.005). We found no association between baseline concentration of γ-tocopherol and incident TB disease. Conclusions: Vitamin E deficiency was associated with an increased risk of progression to TB disease among HHCs of index TB cases. Assessment of vitamin E status among individuals at high risk for TB disease may play a role in TB control efforts.