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Vásquez-Velásquez, Cinthya, Diego Fano-Sizgorich, and Gustavo F Gonzales. Death risk response of high-altitude resident populations to COVID-19 vaccine: Retrospective cohort study. High Alt Med Biol. 00:00-00, 2024. Background: Peru had one of the highest mortality rates caused by the coronavirus disease 2019 (COVID-19) pandemic worldwide. Vaccination significantly reduces mortality. However, the effectiveness of vaccination might differ at different altitudinal levels. The study aimed to evaluate the effect modification of altitude on the association between vaccination and COVID-19 mortality in Peru. Methodology: A retrospective cohort, using open access databases of deaths, COVID-19 cases, hospitalizations, and vaccination was obtained from the Peruvian Ministry of Health. Deaths due to COVID-19 were evaluated in vaccinated and nonvaccinated patients. Crude (RR) and adjusted relative risks (aRR) were calculated using generalized linear models of Poisson family with robust variances. Models were adjusted for age, sex, pandemic wave, and Human Development Index. To evaluate the interaction by altitude, a stratified analysis by this variable was performed. The variable altitude was categorized as, 0-499 m (828,298 cases), 500-1,499 m (64,735 cases), 1,500-2,499 m (106,572 cases), and ≥2,500 m (179,004 cases). The final sample studied included 1,362,350 cases. Results: The vaccine showed a considerable reduction of death risk with the second (aRR: 0.41, 95% confidence interval [CI]: 0.38-0.44) and third doses (aRR: 0.21, 95% CI: 0.20-0.23). In the adjusted and interaction model, it can be observed that medium and high altitude present a higher risk of death compared to sea level (aRR: 2.58 and 2.03, respectively). Likewise, the two doses' group presents an aRR:1.22 for medium altitude (1,500-2,499 m) and 1.6 for high altitude (≥2,500 m), compared with low-altitude population, suggesting that the action of vaccination at high altitude is altered by the effect of the altitude itself. Conclusions: Altitude might modify the protective effect of SARS-CoV-2 vaccine against COVID-19 death.

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BACKGROUND: Anemia prevalence is high in countries where high proportion of the population lives at high altitude (HA) due perhaps to the unsuitability hemoglobin correction factor proposed by the WHO. The present study has been designed to evaluate a new approach to establish thresholds of hemoglobin (Hb) when defining anemia at HA. MATERIALS & METHODS: Cross-sectional study evaluating 217 women aged 18 to 75 years-old, residents of 2 cities at low altitude (LA) (130 and 150 meters) and 2 at HA (3800 and 4300 meters). Hb, pulse oxygen saturation (SpO2), arterial oxygen content (CaO2), and inflammatory markers were measured. Three definitions of anemia diagnoses were used: uncorrected Hb, WHO-corrected Hb, and Silubonde's criteria based on ferritin as a gold standard. STATA v18.0 was use for data analysis, p<0.05 indicated significant difference. RESULTS: HA residents present higher Hb values than at LA. Likewise, the highest area under the curve (AUC) ROC (Receiver Operating Characteristic) was observed for uncorrected Hb (AUC = 0.8595; CI95% 0.858-0.86) for the diagnosis of anemia using serum ferritin as the gold standard. Anemia prevalence was higher when using WHO-corrected Hb, 27%, and Silubonde's criteria, 41% (Hb cut-off of 11.10, 12.73, 15.80 and 16.60 g/dl for altitudes of 130, 150, 3800 and 4300 meters, respectively), than using uncorrected Hb to define anemia (7.7%). Serum Ferritin and CaO2 values are lower only in the group with anemia defined with uncorrected Hb than in the groups of anemia using the WHO-corrected Hb or the Silubonde´s criteria. CONCLUSIONS: The correction factor of hemoglobin for altitude of residence overestimates the prevalence of anemia in adult women. Likewise, CaO2 could be a potential marker to determine the transport of oxygen in LA and HA populations. Further studies in adult men are required to confirm the present findings.

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BACKGROUND: The anemia prevalence is higher in highlands populations. It is assumed that iron deficiency anemia (IDA) in children is mainly due to low dietary intake. However, other suggest that high prevalence of anemia is due to an inappropriate hemoglobin (Hb) adjustment for altitude. MATERIALS AND METHODS: Cross-sectional study conducted in 338 preschoolers (PSC) from Puno-Peru. Hb was measured in whole blood, and ferritin, Soluble transferrin receptor, and Interleukin 6 in serum.The dietary iron intake was assessed by 24-h dietary recall, using NutriCap Software. Hb concentration was assessed as adjusted or unadjusted for altitude. RESULTS: With unadjusted Hb, the anemia prevalence was 4.7%, whereas after Hb correction, the prevalence raised-up to 65.6% (p < 0.001). Reciprocally, erythrocytosis proportion decreased from 20.35 to 0.30% (p < 0.001). Total Body Iron (TBI) showed that 7.44% had ID and 0.32% had IDA. PSC with normal unadjusted Hb levels have more protein and micronutrients intake than anemic ones. PSC with erythrocytosis consumed less fat, and more niacin and ascorbic acid than anemics. Total iron intake was lower in anemic than the other groups, but without statistical significance due to the standard deviation of the data in a small number of anemic PSC (n = 16). TBI, unadjusted Hb, and adjusted Hb were not different between groups consuming or not multimicronutrients. CONCLUSIONS: The consumption of iron and iron status in children who live at high altitude is adequate, and that anemia could be due to other micronutrient deficiencies and/or that the adjustment of Hb by altitude is inappropriate.

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RESUMEN Evaluar la asociación entre la temperatura máxima aparente (HImax) durante el embarazo con el peso al nacer en recién nacidos de la provincia de Piura, 2011 a 2016. Estudio semi-ecológico en el que se evaluaron datos materno-perinatales del Hospital Santa Rosa (N=17,788) y datos de temperatura máxima aparente. Se analizaron cuatro ventanas de exposición: todo el embarazo y cada trimestre gestacional, que se asignaron según la fecha de nacimiento y la edad gestacional, clasificadas en cuartiles. Se construyeron modelos de regresión lineal para evaluar la asociación entre las variables. Se encontró una asociación negativa entre el peso al nacer y el HImax en todas las ventanas de exposición, excepto en el primer trimestre. La mayor disminución del peso al nacer se observó en el grupo de exposición P95 en las ventanas de exposición de todo el embarazo (-38,50 IC95% -71,46 a -5,53) y del tercer trimestre (-70,48 IC95% -102,69 a -38,28), pero no en el del segundo trimestre. El HImax durante el embarazo se asocia con un menor peso al nacer, pero con diferente susceptibilidad según la etapa del embarazo.

ABSTRACT To evaluate the association between maximum apparent temperature (HImax) during pregnancy with birth weight in newborns in the province of Piura, 2011-2016. Semi-ecological study in which maternal-perinatal data from Santa Rosa Hospital (N=17,788) and apparent maximum temperature data were evaluated. Four exposure windows were analyzed: the entire pregnancy and each gestational trimester, which were assigned according to date of birth and gestational age, categorized into quartiles. Linear regression models were constructed to evaluate the association between variables. A negative association was found between birth weight and HImax in all exposure windows except in the first trimester. The largest decrease in birth weight was observed in the P95 exposure group in the whole pregnancy (-38.50 95%CI -71.46; -5.53) and third trimester (-70.48 95%CI -102.69; -38.28) exposure windows, but not in the second trimester. HImax during pregnancy is associated with lower birth weight, but with different susceptibility depending on the stage of pregnancy.

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RESUMEN La anemia durante la gestación es considerada un problema de salud pública debido a las prevalencias alarmantes que se presentan a nivel mundial. La medida optada por los diversos gobiernos es la administración masiva con suplementos de hierro. Sin embargo, actualmente existe evidencia contradictoria sobre el consumo de hierro, el exceso de su consumo y los potenciales riesgos durante la gestación tanto para la madre como para el producto. Para la gestación se requiere de 1 gramo adicional de hierro para la madre, el feto, la placenta y el parto. Esto genera un aumento de la masa roja del 20%; pero, para evitar la hemoconcentración el volumen plasmático se expande casi el 50%, generando una hemodilución fisiológica. Para la gestante no se ha establecido un criterio que permita diferenciar la anemia por deficiencia de hierro, de la anemia fisiológica debido al proceso normal de hemodilución. En el caso de Perú y de países con población residente de altura, se suma una problemática adicional, el factor de corrección de hemoglobina por residencia en la altura, el cual es un valor determinado de forma matemática y arbitraria. Las evidencias recientes sugieren que este factor debe ser reevaluado, debido a que no considera la etnia y el tiempo generacional de residencia en la altura. La presente revisión muestra una actualización y discusión de los criterios de diagnóstico de anemia, la suplementación con hierro, el factor de corrección de hemoglobina por altura de residencia y el impacto de la contaminación ambiental sobre el proceso de gestación.

ABSTRACT Anemia during pregnancy is considered a public health problem, due to the alarming prevalence worldwide. The measure chosen by various governments is massive iron supplements. However, there is currently contradictory evidence on iron intake, excess consumption, and potential risks during pregnancy for both the mother and child. For gestation, an additional 1 gram of iron is required for the mother, fetus, placenta, and delivery. This generates an increase in red mass of 20% but to avoid hemoconcentration the plasma volume expands by almost 50% generating a physiological hemodilution. For pregnant women, no criteria have been established to differentiate iron deficiency anemia and physiological anemia due to the normal process of hemodilution. In the case of Peru and countries with high altitude resident population, there is an additional problem, the hemoglobin correction factor for high altitude residence, which is a mathematically and arbitrarily determined value. Recent evidence suggests that this factor should be reevaluated because it does not consider ethnicity and generational time of residence at high altitude. The present review provides an update and discussion of the diagnostic criteria for anemia, iron supplementation, the hemoglobin correction factor for altitude of residence, and the impact of environmental pollution on the gestation process.

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We evaluated the available literature on the diagnostic performance of hemoglobin (Hb) in the diagnosis of iron deficiency anemia (IDA) in high-altitude populations. We searched PubMed, Web of Science, Scopus, Embase, Medline by Ovid, the Cochrane Library, and LILCAS until 3 May 2022. We included studies that evaluated the diagnostic performance (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), receiver operating characteristic (ROC) curves, and accuracy) of Hb (with and without an altitude correction factor) compared to any iron deficiency (ID) marker (e.g., ferritin, soluble transferrin receptor (sTFR), transferrin saturation, or total body iron (TBI)) in populations residing at altitudes (≥1000 m above sea level). We identified a total of 14 studies (with 4522 participants). We found disagreement in diagnostic performance test values between the studies, both in those comparing hemoglobin with and in those comparing hemoglobin without a correction factor for altitude. Sensitivity ranged from 7% to 100%, whereas specificity ranged from 30% to 100%. Three studies reported higher accuracy of uncorrected versus altitude-corrected hemoglobin. Similarly, two studies found that not correcting hemoglobin for altitude improved the receiver operating characteristic (ROC) curves for the diagnosis of iron deficiency anemia. Available studies on high-altitude populations suggest that the diagnostic accuracy of Hb is higher when altitude correction is not used. In addition, the high prevalence of anemia in altitude regions could be due to diagnostic misclassification.

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