Mountain sickness in altitude inhabitants of Latin America: A systematic review and meta-analysis

J Pierre Zila-Velasque; Pamela Grados-Espinoza; P Alejandra Goicochea-Romero; Gustavo Tapia-Sequeiros; J Enrique Pascual-Aguilar; Arturo J Ruiz-Yaringaño; Shamir Barros-Sevillano; Jhon Ayca-Mendoza; Wendy Nieto-Gutierrez

doi:10.1371/journal.pone.0305651

. 2024 Sep 24;19(9):e0305651. doi: 10.1371/journal.pone.0305651

Mountain sickness in altitude inhabitants of Latin America: A systematic review and meta-analysis

J Pierre Zila-Velasque ¹, Pamela Grados-Espinoza ¹, P Alejandra Goicochea-Romero ^1,², Gustavo Tapia-Sequeiros ^1,³, J Enrique Pascual-Aguilar ¹, Arturo J Ruiz-Yaringaño ^1,^4,⁵, Shamir Barros-Sevillano ⁶, Jhon Ayca-Mendoza ¹, Wendy Nieto-Gutierrez ^7,^*

Editor: Esteban Ortiz-Prado⁸

¹Red Latinoamericana de Medicina en la Altitud e Investigación (REDLAMAI), Pasco, Peru

²Facultad de Ciencias de la Salud, Carrera de Medicina Humana, CHANGE Research Working Group, Universidad Científica del Sur, Lima, Peru

³Facultad de Ciencias de la Salud, Universidad Privada de Tacna, Tacna, Peru

⁴Sociedad Científica de San Fernando, Lima, Peru

⁵Facultad de Medicina Humana, Universidad Nacional Mayor de San Marcos, Lima, Peru

⁶Facultad de Ciencias de la Salud, Escuela de Medicina, Universidad César Vallejo, Trujillo, Perú

⁷Unidad de Investigación para la Generación de Síntesis de Evidencia en Salud, Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru

⁸Universidad de Las Americas, Quito-Ecuador, ECUADOR

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: wendy_nieto22@hotmail.com

Roles

J Pierre Zila-Velasque: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Pamela Grados-Espinoza: Conceptualization, Data curation, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

P Alejandra Goicochea-Romero: Data curation, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Gustavo Tapia-Sequeiros: Data curation, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing

J Enrique Pascual-Aguilar: Data curation, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Arturo J Ruiz-Yaringaño: Data curation, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing

Shamir Barros-Sevillano: Data curation, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Jhon Ayca-Mendoza: Data curation, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing

Wendy Nieto-Gutierrez: Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Software, Supervision, Visualization, Writing – review & editing

Esteban Ortiz-Prado: Editor

PMCID: PMC11421813 PMID: 39316567

Abstract

Objective

Chronic and acute mountain sickness is known worldwide, but most of the available information comes from the eastern continent (Himalayas) without taking into account the west which has the most recent group located at altitude, the Andes. The aim of this study was to synthesize the evidence on the prevalence of acute and chronic mountain sickness in Latin American countries (LATAM).

Methods

A systematic search of the variables of interest was performed until July 8, 2023 in the Web of Science, Scopus, PubMed and Embase databases. We included studies that assessed the prevalence of mountain sickness in high-altitude inhabitants (>1500 m.a.s.l) who lived in a place more than 12 months. These were analyzed by means of a meta-analysis of proportions. To assess sources of heterogeneity, subgroup analyses and sensitivity analyses were performed by including only studies with low risk of bias and excluding extreme values (0 or 10,000 ratio). PROSPERO (CRD42021286504).

Results

Thirty-nine cross-sectional studies (10,549 participants) met the inclusion criteria. We identified 5 334 and 2 945 events out of 10,000 with acute and chronic mountain sickness in LATAM countries. The most common physiological alteration was polycythemia (2,558 events), while cerebral edema was the less common (46 events). Clinical conditions were more prevalent at high altitudes for both types of MS.

Conclusion

Acute mountain sickness (AMS) occurs approximately in 5 out of 10 people at high altitude, while chronic mountain sickness (CMS) occurs in 3 out of 10. The most frequent physiological alteration was polycythemia and the least frequent was cerebral edema.

Introduction

Latin America (LATAM) is home to the world’s most extended mountain range, which traverses Argentina, Bolivia, Chile, Colombia, Ecuador, Peru and part of Venezuela. This mountain range boasts an average altitude ranging from 1,500 to over 4,000 meters above sea level (m) [1]. Consequently, LATAM is inhabited by approximately 40 million people who reside at high altitudes, with over 5 million of them living at altitudes exceeding 4,000 m. [1, 2], making them susceptible to mountain sickness (MS).

MS is a syndrome affecting both the cerebral and pulmonary systems and occurs due to hypoxia following an initial ascent to higher altitudes [3]. The diagnosis is based on clinical evaluation, requiring the identification of characteristic hypoxic symptoms. However, these symptoms can vary in severity [4], potentially leading to conditions like pulmonary and cerebral edema, polycythemia, hemorrhage, ataxia, and even coma in some cases [5–7], and depend on the duration of the exposure [5].

Previous studies have reported the frequency of MS in different regions of the world [8–10]. However, these reports are mainly from eastern areas (such as Nepal Himalaya and Ethiopian highlands) with comparatively scarce information with other mountainous places in the world, such as the Andes [11]. In fact, a previous systematic review [12] determined a global prevalence of MS at approximately 12%; however, they omitted to include studies from LATAM despite being from regions with cities over 4000 m. with residents susceptible to MS [13–15].

Likewise, none of the reports describe the frequencies of MS according to the types of symptoms (mild and severe), exposure (acute or chronic), and complications (exaggerated pulmonary hypertension, pulmonary and cerebral edema). The absence of this information can result in the mishandling of data and a lack of appropriate solutions for managing symptoms and allocating health resources efficiently, in addition to the fact that little research from the Andean countries is evident [16]. Therefore, the present study aims to synthesize the evidence on the prevalence of acute and chronic MS in Latin American countries.

Methods

Protocol registration and research question

A systematic review was performed followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) (S1 Checklist) [17] and the Cochrane Handbook [18]. The protocol of the study was registered in the International prospective register of systematic reviews—PROSPERO (CRD42021286504) [19].

The research question was “What is the prevalence of Mountain Sickness in Altitude Inhabitants of Latin America?”, with the following PECO (where the means of P: population E: exposure, O: outcome) structure: 1) population: altitude inhabitants (defined as a person who live in a place more than 12 months); 2) exposure: altitude (following the ranges of intermediate altitude 1500–2500 m, from where physiological changes are detectable), high altitude (2500–3500 m), very high altitude (3500–5800 m), extreme altitude (>5800 m.), and “death zone” (>8000 m.a.s.l.) [20]; and 3) outcome: prevalence of AMS and CMS, according to each disease and study.

Systematic search

A systematic search was performed up to July 8, 2023 in the databases of Web of Science (WoS), Scopus, Medline (thought PubMed) and Embase. We adapted the search strategy for each of the databases using keywords related to “mountain sickness” and “Latin America”. Also, we include terms for each Latin America country that report a high altitude (Peru, Chile, Argentina, Bolivia, Venezuela, Ecuador, and Colombia), taking into account all the cities located at high altitudes. The search strategy of each database is available in S2 Table. Also, we evaluated the references of included studies to identify potentially eligible studies that weren’t found in the systematic search.

Study selection and data extraction

Duplicates were removed by two independent reviewers using Endnote v.20. The study selection was performed by four blinded and independent reviewers (JEPA, AJRY, PAGR, GTS) divided into two groups of two. The selection was performed in two stages, the first, a selection to evaluate the title and abstract, and the second, to evaluated the full-text. If there were discrepancies, these were resolved by consensus. The selection process was described in Fig 1.

We included observational studies (cross-sectional or cohort studies) that report the prevalence of MS in people living at altitude in some Latin America country. We excluded editorials, commentaries, opinions, congress abstract, and reviews. No publication date or language restrictions were applied. The studies that were excluded and the reason for exclusion are described in S1 Table.

The data extraction was performed by four independent authors (JEPA, AJRY, PAGR, GTS) divided into two groups of two. We extracted variables like the first author, year of publication, study design, country, sample size, age, sex, type of resident (native: defined as a person who has been born and raised at altitude, or resident: defined as a person who leaves his or her city of birth to settle elsewhere and who at altitude has a period of stay of more than 12 months), altitude level, time of residence, place of residence (urban: defined like a place that has at least 100 houses together forming blocks or blocks and includes population centers that are district capitals and rural: defined as a place that does not meet the criteria of an urban area [21]), time of exposure, sample of people with acute and chronic mountain sickness, number of events, and type of symptoms. The discrepancies were resolved by a consensus.

Risk of bias

Four authors (PGE, PAGR, AJRY, JAM) independently assessed the methodological quality of prevalence studies using the Joanna Briggs Institute Critical Appraisal Tool [22]. This scale has 9 items (1, Was the sample frame appropriate to address the target population? 2. Were study participants sampled appropriately?, 3. Was the sample size adequate?, 4. Have the study subjects and environment been described in detail?, 5. Has the data analysis been performed with sufficient coverage of the identified sample?, 6. Were valid methods used to identify the condition?, 7. Was the condition measured in a standard and reliable way for all participants?, 8. Was there adequate statistical analysis?, 9. Was the response rate adequate and, if not, was the low response rate adequately managed?), with possible answers of "Yes", "No" and "Unclear". The quality score was considered as one point for "Yes" and zero points for "No" and "Unclear". We estimated the overall risk of bias by considering the lowest risk of bias reported among the items (S1 Fig).

Synthesis of the evidence

We used summary statistics to describe the studies, subjects, and outcomes. For the meta-analysis, we pooled the proportions (events over the total population) using a generalized linear mixed random model. To stabilize the variances, we applied the Freeman-Tukey Double Arcsine transformation, and we estimated the confidence intervals for individual study results using the Clopper-Pearson method. We assessed the presence of heterogeneity between studies through visual inspection of forest plots for all outcomes and supplemented this with an evaluation of the I² parameter. The proportions were expressed per 10,000 population. The bias of publication was evaluated using the graphic of funnel plot.

As a priori subgroup analysis, we explored the proportion of MS across different altitudes, countries, types of symptoms (mild or severe), and complications (pulmonary edema, cerebral edema, exaggerated pulmonary hypertension, and exaggerated polycythemia). These measured outcomes were extracted as reported in the included studies, which were likely defined according to established international criteria. Sensitivity analysis was performed by including only studies with a low risk of bias and excluding extreme values (0 or 10,000 proportion). All analyses were conducted using R Studio.

Results

Characteristic of the studies

After eliminating duplicates, we identified 2,492 articles, of which 139 were evaluated in full text, and only 39 studies were included. The studies included evaluated a sample population of 10 549 with an altitude ranging from 2 640 in Colombia [23], to 6 487, in Argentina [24]. We did not identified studies from Brazil, Costa Rica, Cuba, Guatemala, Haiti, Honduras, Dominican Republic and Panama. Of the 39 studies, acute mountain sickness (AMS) was evaluated in 15 studies [24–38] (n = 2 945), chronic mountain sickness (CMS) in 22 [13, 23, 39–58] (n = 7 448), and both in 2 [59, 60] (n = 156). Regarding the studies that evaluated AMS, most of the studies were from Chile (n = 8 studies) and Peru/Argentina (n = 4 studies), which are the countries that contributed the most research on the subject. There was an altitude ranging from 2 700 m. [31] to 6 487 m [24]. On the other hand, most of the studies that analyzed CMS were from Peru (n = 18 studies), with an altitude ranging from 2 240 m. [51] to 5 300 m. [13] (Table 1).

Table 1. Characteristics of studies assessing the prevalence of acute and chronic mountain sickness in Latin America.

Author-Year	Study design	Country	Altitude level (m)	Type to exposure	Sample size (n)	Age (yr)	Female (%)	Native (%)	Urban (%)
Appenzeller O, et al. 2004 [41]	Prospective cohort	Peru	4338	Chronic	31	42.2 ± 1.5^*	-	100	-
Appenzeller O, et al. 2006 [40]	Prospective cohort	Peru	4338	Chronic	9	36.9 ± 2.8^*	0	100	-
Bilo G, et al. 2020 [42]	Cross-sectional	Peru	4340	Chronic	289	38.3 ± 13.2^*	49.5	100	-
Brito J, et al. 2007 [59]	Cross-sectional	Chile	3550	Both		48.7 ± 2^*	0	50	-
Brito J, et al. 2018 [29]	Cross-sectional	Chile	4400–4800	Acute		41.8 ± 0.7^*	0	100	-
Cabello G, et al. 2017 [30]	Prospective cohort	Chile	3500	Acute		NR	12	-	-
Caravedo MA, et al. 2022 [38]	Prospective cohort	Peru	3350	Acute		21 (20–25) ^a	57.0	0	100
De Ferrari A, et al. 2014 [43]	Cross-sectional	Peru	3825	Chronic	1065	55.3 ± 12.6^*	51	0	49
Garófilo A, et al. 2010 [31]	Prospective cohort	Argentina	2700–4300	Acute		34 (18–50) ^**	1.59	-	-
Gazal S, et al. 2019 [44]	Prospective cohort	Peru	4380	Chronic	312	46.8 ± 13.4^*	0	100	-
Gonzales GF, et al.1998 [32]	Prospective cohort	Peru	3400	Acute		21–30 ^b	0	-	-
Gonzales GF, et al. 2009 [46]	Prospective cohort	Peru	4340	Chronic	41	47.3 ± 1.2^*	0	100	-
Gonzales, GF, et al. 2011 [47]	Cross-sectional	Peru	4340	Chronic	41	44.7 ± 9.3^*	0	100	-
Gonzales GF, et al. 2011 [58]	Cross-sectional	Peru	4340	Chronic	103	45.4 ± 0.8^*	0	100	-
Gonzales GF, et al. 2013 [45]	Cross-sectional	Peru	4100	Chronic	506	35–75 ^b	69	-	-
Hancco I, et al. 2020 [13]	Cross-sectional	Peru	5100–5300	Chronic	1594	32 (23–39) ^a	14.7	0	-
Irarrazaval S, et al. 2017 [33]	Prospective cohort	Chile	3920	Acute		30.1 (24.9–32.7) ^a	0	-	-
Jefferson JA, et al. 2004 [60]	Cross-sectional	Peru	4300	Both		36.6 (23–58) ^**	-	0	100
Lang M, et al. 2021 [34]	Prospective cohort	Chile	3300	Acute		12.5 ± 1.1^*	57.1	-	100
Leon-Velarde F, et al. 1993 [52]	Cross-sectional	Peru	4300	Chronic	2875	20–69 ^b	-	0	-
Leon-Velarde F, et al. 1994 [53]	Cross-sectional	Peru	4300	Chronic	97	NR	0	87	-
Leon-Velarde F, et al. 1997 [55]	Cross-sectional	Peru	4300	Chronic	112	37 ± 5.23^*	100	0	100
Leon-Velarde F, et al. 2001 [54]	Cross-sectional	Peru	4300	Chronic	33	NR	100	0	100
Maignan M, et al. 2009 [48]	Cross-sectional	Peru	4300	Chronic	57	NR	0	0	100
Moraga FA, et al. 2002 [36]	Prospective cohort	Chile	3500–4400	Acute		NR	-	-	-
Moraga FA, et al. 2008 [35]	Prospective cohort	Chile	3500	Acute		4.3 ± 1^*	43.8	-	-
Peñaloza D, et al. 1963 [61]	Cross-sectional	Peru	4540	Chronic	38	22 ± 3.8^*	0	100	0
Pesce C, et al. 2005 [37]	Retrospective cohort	Argentina	5088	Acute		36.5 ± 10.1^*	15.4	-	-
Quispe-Trujillo MM, et al. 2020 [50]	Cross-sectional	Peru	5200	Chronic	51	44 ± 7^*	0	0	-
Riaño López L, et al. 2021 [23]	Case series	Colombia	2640	Chronic	6	11 ± 3^*	16.7	0	100
Richalet JP, et al. 2002 [39]	Prospective cohort	Chile	3800–4600	Chronic	29	25 ± 5^*	0	-	-
Salazar H, et al. 2012 [25]	Cross-sectional	Peru	3400	Acute		32 (25–49) ^a	55.2	-	-
Seoane L, et al. 2011 [26]	Prospective cohort	Argentina	3500–5000	Acute		35 (26–44) ^**	50.4	87.5	-
Serrano-Dueñas M. 2005 [27]	Prospective cohort	Ecuador	4100–5800	Acute		26.1 (18–41) ^**	35.7	0	-
Siques P, et al. 2009 [28]	Prospective cohort	Chile	3550	Acute		17.9 ± 0.1^*	0	-	-
Steele AR, et al. 2021 [57]	Cross-sectional	Peru	4380	Chronic	24	40 ± 12^*	0	0	100
Valencia-Flores M, et al. 2004 [51]	Prospective cohort	Mexico	2240	Chronic	57	42.7 ± 12.1^*	59.6	-	100
Van Roo JD, et al. 2011 [24]	Prospective cohort	Argentina	4365–6487	Acute		42.1 (39.2–45.1) ^**	9.1	-	-
Vizcarra-Escobar D, et al. 2015 [56]	Cross-sectional	Peru	4100–4300	Chronic	78	NR	0	-	0

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NR: No Reported, yr (year), d (day).

* Mean age ± SD.

** Mean age (range)

^a Median age (IQR)

^b Age range

Native: defined as a person who has been born and raised at altitude.

Urban: defined like a place that has at least 100 houses together forming blocks or blocks and includes population centers that are district capitals.

Prevalence of mountain sickness

We identified 39 studies which it has the necessary information for analyzed the overall prevalence. We identified that in 10 000 people, 5 334 reported AMS (95% CI: 3 780–6 857, I2 = 97.0%, n = 2 989) and 2 945 reported CMS (95% CI: 1 795–4 237, I2 = 98.0%, n = 7 518) (Fig 2).

The number of events of AMS by 10 000 people according to the levels of altitude the events were 5 728 (95% CI: 2 497–8 659, I2 = 94.0%, n = 1 067–4 studies) at high altitude, 5 323 (95% CI: 3 339–7 258, I2 = 96.0%, n = 1 027–12 studies) at very high altitude, and 4 179 (95% CI: 3 853–4 509, n = 895–1 study) at extreme altitude. In relation to CMS, we identified that the totally of people had symptoms at intermediate altitude (n = 57) and high altitude (n = 6). However, 2 520 (95% CI: 1 609–3 551, I2 = 97.0%, n = 7 455–21 studies) events of CMS were reported in high altitude in a population of 10 000 persons (Fig 3).

We included 25 and 21 studies to mild (headache) and severe (pulmonary and cerebral edema, pulmonary hypertension and polycythemia) symptoms, which were reported 3 932 (95% CI: 2 678–5 259, I2 = 98.0%, n = 9 569) and 1 776 (95% CI: 675–3 220, I2 = 99.0%, n = 9 658) that in 10 000 persons, respectively (Fig 4). According to the order of frequency, we found that polycythemia was most frequent with 2 558 events (95% CI: 1 151–4 278, I2 = 99.0%, n = 6 831–14 studies), followed by pulmonary hypertension with 2 035 (95% CI: 0. 00–5 825, I2 = 96.0%, n = 149–4 studies), pulmonary edema with 1 124 (95% CI: 0.00–5 320, I2 = 91.0%, n = 1 181–5 studies) and finally cerebral edema was present in 46 events (95% CI: 1.14–129, I2 = 7.0%, n = 982–2 studies) out of 10 000 persons in all the aforementioned pathologies (Fig 5).

In relation to the differences by country, we found that a highest prevalence of AMS was in Peru (6 171 events per 10 000 persons, CI 95% 3 628–8 425, I2 = 94%, n = 4 studies) and Chile (5 896 events per 10 000 persons, CI 95% 3 619–7 996, I2 = 95%, n = 9 studies), and for CMS was in Mexico (10 000 events per 10 000 persons, CI 95% 9 701–10 000, n = 1 study) and Colombia. (3 333 events per 10 000 persons, CI 95% 130–7 636, I2 = 95%, n = 1 study) (Fig 6).

Risk bias assessment, publication bias, and sensitivity analysis

We assessed a high risk of bias in the overall included studies and for each outcome individually. Only three studies [28, 38, 45] are considered to have a low risk of bias in all domains, and only one [43] is classified as having an unclear risk. The domain with the highest risk was “Was the sample size adequate?” followed by “Was the response rate adequate and, if not, was the low response rate adequately managed?”. On the other hand, the domain with the lowest risk was “Have the study subjects and environment been described in detail?” (S1 Fig).

The studies with low risk of bias shows a lower prevalence of AMS (4 134 events in 10 000; 95% CI 3 836–4 437 vs 5 334 events in 10 000; 95% CI 3 780–6 857) and CMS (1 621 events in 10 000; 95% CI: 1 310–1 971 vs 2 945 events in 10 000; 95% CI: 1 795–4 237) compared with main analysis; however, their confidence intervals overlap. (S2 Fig). In the same way, the sensitivity analysis excluding the outliers shows a lower prevalence of AMS (4,526 events in 10,000; 95% CI 3,294–5,787 vs. 5,334 events in 10,000; 95% CI 3,780–6,857) and CMS (2,533 events in 10,000; 95% CI: 1,637–3,542 vs. 2,945 events in 10,000; 95% CI: 1,795–4,237) compared with the main analysis, but with overlapping confidence intervals. (S3 Fig).

We observed an asymmetry in the funnel plot for studies reporting the prevalence of acute and chronic mountain sickness, raising suspicions of publication bias (S4 Fig).

Discussion

This systematic review focused on investigating the prevalence of MS in moderate to high altitude inhabitants in Latin America, which originates from a failure to adapt adequately to high altitudes and its severity is determined by hypoxemia according to the altitude and the time of exposure [40]. To our knowledge, this is the first study to report the prevalence of both acute and chronic MS along with each of their symptoms revealing significant variability in the prevalence of MS across different countries and altitudes in LATAM. There was a notable absence of data from certain countries in the region, suggesting the need for further research in those areas as also evidenced by a 40-year bibliometric analysis in which the south American countries with the highest altitude and the greatest number of publications were Peru, Bolivia and Colombia [16]. The results of this review show that both acute MS (AMS) and chronic MS (CMS) are significant issues in altitude populations in Latin America. The prevalence of AMS and CMS varied depending on altitude, country, and the presence of mild or severe symptoms. Overall, a higher prevalence of AMS was observed in Peru and Chile, while the prevalence of CMS was higher in Mexico and Colombia.

Acute mountain sickness

Our study found that 5 out of 10 persons had AMS in LATAM countries, slightly higher occurrence compared to estimations for Europe (3 to 4 events out of 10 persons) [62]. However, our study involved a higher average altitude compared to the European study (3500 vs. 4,023). On the other hand, the meta-analysis included acclimatized high-altitude inhabitants of LATAM, while in Europe the majority of mountain ascents are for tourism or sport by low altitude residents [62]. AMS can manifest itself variably according to the physiological adaptation to altitude of each individual, however, a greater severity of symptoms is observed in low altitude residents who ascend to higher altitudes [63].

AMS is a complex disorder triggered by high-altitude hypoxia, initiating a pulmonary response characterized by an increase in tidal volume and respiratory rate, leading to subsequent respiratory alkalosis [63]. Simultaneously, cerebral vasodilation occurs [51], manifesting as headaches [61]. The onset of AMS typically occurs six to 12 hours after high-altitude climbing, but can manifest as quickly as within one to two hours or as late as 24 hours [64]. Given this variability, it is challenging to precisely identify the occurrences of this disease, and there is a possibility that some events may not be captured in our estimations.

The most common symptoms of AMS were headaches, while more severe complications such as pulmonary and cerebral edema, pulmonary hypertension, and polycythemia were also present, albeit to a lesser extent. These findings underscore the importance of considering a wide range of symptoms and complications when assessing the burden of MS in the region.AMS is characterized by the presence of mild symptoms [63, 65], primarily resulting from mechanisms of adaptation to hypoxemia [5, 66]. These symptoms encompass headache, fatigue, anorexia, nausea, dizziness as well as sleep disorders. Identifying the symptoms will be necessary to diagnose AMS, using the Lake Louise clinical score [64]. In our study, we identified that these symptoms were present in four of 10 people, with headaches being the most commonly reported, aligning with findings from previous reviews [67]. The occurrence of headaches in AMS can be explained by various mechanisms, including cerebral edema due to hypoxia, leading to increased intracranial pressure, the elevation of cerebral blood flow, difficulty in draining cerebral venous outflow and the activation of the trigeminal vascular system due to the release of nitrous oxide and vasodilation [5, 66]. Even a higher female biological susceptibility to MSA has been proposed, however, the few studies that have investigated it showed variability for [51, 64] and against it [63, 65]. Therefore, studies with larger population and methodological quality are recommended.

Chronic mountain sickness

Lack of long-term altitude adaptation remains the cause of CMS. Our study identified that 3 out of 10 people had CMS, a significantly higher prevalence compared to the previous study conducted in Asia (1 event out of 10), which confirms that lack of adaptation is its genesis. However, despite the pathological mechanisms and the exact biological mechanism remains unknown [68], factors associated to the context such as environmental pollution, malnutrition, the lack in basic public health needs and poverty have also been described [66]. The diagnosis of CMS is based on the Qinghai CMS Score, which includes the evaluation of common symptoms such as shortness of breath, palpitations, sleep disturbances, heart failure, peripheral venous insufficiency, paresthesia, headache, cognitive impairment, exaggerated polycythemia and pulmonary hypertension [67].

The CMS is related with the severe symptoms, considering the mechanism involved and the chronic exposures. We identified that approximately 3 out of 10 persons has severe symptoms, higher than that reported by a study in Qinghai, China, where only 2.4% of more than 1000 residents had severe symptoms [68]. However, there are some severe symptoms such as acute pulmonary edema, that it was present in 1 event out of 10 persons, which is related to the AMS that develops approximately 4 to 12 hours after arrival [58]. The cerebral edema is also related with AMS, this has a progressive presentation and is usually associated with neurological symptoms such as decreased consciousness and/or ataxia, and can even result in coma [5, 45]. We identified lower prevalence of cerebral edema (less than 1 event out of 10 persons), but slightly lower than European estimations (1 event out of 10 persons) [46]. Other complications like exaggerated pulmonary hypertension are related to chronic exposure to altitude, being the most frequent severe symptom (2 event out of 10 persons). Our estimation differs from others reported in India where the prevalence was less than 1 event out of 10 people [33]. In relation to its origin, it is known that the chronic hypoxic stimuli of living at high altitude can cause "permanent pulmonary vascular remodeling" due to increased pulmonary vascular resistance and define a subgroup of pulmonary hypertension known as high-altitude pulmonary hypertension (HAPH) [60]. It’s important to note that complicated of this can progress to cor pulmonale and congestive heart failure [33]. Polycythemia was presented approximately 3 events out of 10 persons. Our result was different from the study conducted in Tibetans where the prevalence was 1 event out of 10 [34]. It is possible that genetic differences influence the prevalence of polycythemia, due to the variation in the levels of soluble erythropoietin receptors (sEpoR) present in the blood of each individual, which buffers the increase in hemoglobin [52]. In addition, the existence of inherited genetic factors in susceptibility to these MSA and CMS has been suggested [69, 70], and thus there may be differences in disease prevalence between native and non-native but acclimatized residents, and it would be of interest to involve them in future research.

Implications of the results and recommendations for future studies

There are few systematic reviews related to altitude, in relation to MS in LATAM, no data on the prevalence of this pathology have been reported, however, the research found focuses on the general population without considering important variables such as the type of resident (immigrant or native), the generational period and the comorbidities that influence the development of the pathology, therefore it is suggested that future primary studies analyze variables such as quality of life, carry out studies in larger samples and at different altitudes. In the present review, we found a higher prevalence of AMS and CMS in LATAM high-altitude population compared to other high-altitude populations. However, it is worth recognizing that high-altitude regions present certain difficulties, including low coverage of essential primary health care services, unequal access to essential medicines, and an absence of programs for the prevention, treatment and management of MS. As a consequence, complications of the disease may present themselves earlier, in addition, an adaptive response to high-altitude with exaggerated polycythemia and pulmonary hypertension are associated with the development of arterial hypertension [53] and others such as the development of cognitive impairment. To limit the development of these, it is recommended to strengthen primary care through the use of protocols for the management of each pathology, improve the relationship between the community, health personnel and patients.

For future research, addressing these limitations by employing more rigorous study designs and including a greater number of studies with a low risk of bias is recommended. Furthermore, it would be beneficial to further explore risk factors and underlying mechanisms of MS in LATAM, as well as evaluate the effectiveness of prevention and treatment strategies. We suggest that future research considers including specific ethnic groups from the high-altitude regions in the Andes to facilitate genetic studies aimed at further understatement of their physiological responses to high altitude. Finally, the results presented are intended to generate adequate epidemiological information.

Limitations and strengths of the review

Limitations in this review should be noted. First, the prevalence estimates were not standardized due to the different sample sizes of each study and the statistical methods used. Additionally, there was great heterogeneity between the studies reviewed, thus limiting their evidence certainty, and some studies did not have the necessary information to be include in the meta-analysis or to conduct subgroup analyses. Most of the studies had small sample size, which generated imprecision about individual studies that generated a low evidence certainty and a high risk of bias identified in most of the included studies, which could affect the validity and generalizability of the results. Similarly, a potential bias is the poorly defined target population in some studies, with a bias towards AMS due to variability regarding the inclusion of climbing tourists with AMS or the exclusion of long-term high-altitude residents. Finally, evidence of publication bias was observed, suggesting that studies with negative results may not have been published.

The study has some strengths as the first systematic review and meta-analysis on the prevalence of MS in LATAM that has the Andes as an altitudinal group, therefore the data presented can serve as background for future studies and the systematized information can be useful for researchers, public health professionals working in high altitude regions and the development of national strategies for the prevention and treatment of AMS and CMS in mid and high-altitude regions. Also, we address a clear gap in the literature when considering high-altitude residents in LATAM for presenting unique characteristics such as shorter residence time at altitude.

Conclusion

This systematic review provides an overview of the prevalence of AMS in altitude inhabitants in LATAM which occurs in 5 out of 10 people at high altitude, while CMS occurs in 3 out of 10. The most frequent symptom type was polycythemia and the least frequent was cerebral edema. The results underscore the importance of addressing this public health issue and highlight the need for further research including more participants and data from the different Andean countries to obtain more representative results and a better understanding of its epidemiology and address its clinical and public health implications in the region.

Supporting information

S1 Checklist. PRISMA checklist.

(DOCX)

pone.0305651.s001.docx^{(21.3KB, docx)}

S1 Table. Excluded studies.

(DOCX)

pone.0305651.s002.docx^{(24.6KB, docx)}

S2 Table. Search strategy.

(DOCX)

pone.0305651.s003.docx^{(14.5KB, docx)}

S1 Fig. Risk of bias of included studies.

(DOCX)

pone.0305651.s004.docx^{(16.7MB, docx)}

S2 Fig. Sensitivity analysis on prevalence of Acute (A) and Chronic (B) Mountain Sickness between risk of bias.

(DOCX)

pone.0305651.s005.docx^{(638.2KB, docx)}

S3 Fig. Sensitivity analysis on prevalence of Acute (A) and Chronic (B) Mountain Sickness excluding outliers.

(DOCX)

pone.0305651.s006.docx^{(692.9KB, docx)}

S4 Fig. Publication bias on the prevalence of acute (A) and chronic (B) mountain sickness.

(DOCX)

pone.0305651.s007.docx^{(165.1KB, docx)}

Data Availability

All data used for the study has been included in the manuscript and supplementary material. Supplementary material associated with this article can be found in the online version at doi: 10.6084/m9.figshare.24501796.

Funding Statement

The author(s) received no specific funding for this work.

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PONE-D-23-42448Mountain sickness in altitude inhabitants of Latin America: a systematic review and meta_analysisPLOS ONE

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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: GENERAL COMMENTS

I consider the review/meta-analysis study to be adequate and provides an interesting overview to date on the prevalence of mountain sickness (acute and chronic types) in Latin American countries. However, the study suffers, in my opinion, from the analysis of some aspects that I consider interesting, and some sections of the manuscript should be made more solid. There are also some typos that should be corrected and minor changes that I propose that should be taken into account. I specify all of this, point by point, in the following sections:

SPECIFIC COMMENTS

ABSTRACT:

It states that the information on acute and chronic disease only comes from the Himalayas, but this is not true, as there are numerous studies done in the Andes, as shown in this meta-analysis. I suggest the following “...but the information mostly comes from the eastern continent (Himalayas)…”.

It is noted that polyglobulia is a “pathology” and below it appears as a “symptom”, and cerebral edema as a “symptom”. These are an error that should be corrected, as polyglobulia per se is a physiological response to hypoxia, and can only be considered pathological if it is excessive for a given altitude. Likewise, cerebral edema is a physiological alteration and a clinical picture, not a symptom.

I suggest deleting the last sentence: “Therefore, we recommend…”

INTRODUCTION:

In my opinion this section is somewhat poor in illustrating the subject. It should be slightly enriched.

Line 92: in this paragraph it should not be said that there are no studies that do not include information from the Andes, but rather that the information is comparatively scarce with other mountainous places throughout the world.

Line 94: “…Nepal Himalya and Ethiopian”. Put it this way: “…Nepal Himalaya and Ethiopian highlands” (I suggest adding also the reference: Xing et al. Adaptation and mal-adaptation to ambient hypoxia; Andean, Ethiopian and Himalayan patterns. PLoS One, 2008).

Line 98: “pulmonary hypertension” is not a complication but a physiological response of the organism to the hypoxia of altitude; the complication would be an “exaggerated pulmonary hypertension”...

The bibliography in this Introduction section should be enriched (I suggest referencing here some articles, such as Monge 1942, Hancco et al. 2020 [already in the reference list], Champigneulle et al. 2023, Waterlow and Bunjé 1966, Sánchez et al. 2022, etc., as well as some others that appear in the Supplementary material-3). At least this would further illustrate the Introduction section, even if there are articles that are then excluded in the meta-analysis.

METHODS:

Line 113: define the acronym PECO

Lines 116-117: use the acronyms AMS and CMS.

Line 123: perhaps mention should be made here to “mountain sickness” and make reference to the Supplementary material-2. The keyword “Andes” would also have been useful in the search.

Line 185: “pulmonary hypertension, and polycythemia” should only be considered pathological responses if they are excessive for a given altitude (I think this should be stated in this paragraph).

Lines 195-200: total sample population included (10,549) does not match the sum of AMS (3,087) and CMS (7,448). Is it a mistake, or what is the reason? If it is a misinterpretation on my part, it is possible that other readers may have the same misinterpretation as me.

Lines 199-200: “Regarding the studies that evaluated AMS, most of the studies were from Chile (n = 8 studies) and Peru/Argentina (n = 4 studies)…”. Do these refer to studies that included larger samples?

Lines 223-225: Data from AMS (5,334/10,000) and CMS (2,945/10,000) are not consistent with those shown in lines 197-198: AMS (3,087/10,549) and CMS (7,448/10,549). The authors should clarify this apparent discrepancy, so that there are no errors in the interpretation of the data shown in two different places in this Results section (these discrepant figures may lead to significant confusion in the interpretation of the data by readers).

DISCUSSION:

I suggest that the authors rework this section. I propose that you make a more in-depth analysis and focus on the context of the results obtained through the extensive review/meta-analysis performed, and make less continuous allusion to the pathophysiological aspects of MS and its different forms of presentation (AMS, CMS) and derived clinical complications (cerebral edema, pulmonary edema, etc.). I also suggest that the definitions of AMS and CMS should appear succinctly in the Introduction section and less so in the Discussion. In my opinion, the entire Discussion section lacks sufficient narrative strength and makes for uninspiring reading, but I think that especially the first part of this section (lines 286-341) is somewhat convoluted in terms of the concepts presented. Therefore, I encourage you to make an effort to rewrite this section to improve it, and thus achieve better quality of the manuscript and not detract from the value and effort that has gone into the research of the study, as reflected in the Material and Results sections.

I also add the following specifications:

Lines 287-290: Given that the meta-analysis includes acclimatized high-altitude inhabitants of LATAM, this high percentage of AMS is striking compared to the prevalence in Europe (where the majority of mountain ascents are for tourism or sport by low altitude residents). The authors could make a small allusion to this detail, despite the fact that the average altitude reached in the studies analyzed is comparatively only 500 meters higher. Perhaps, in order to give more solidity to the comparative data with Europe, a reference to some other studies on the subject carried out in European mountains could be added here.

Line 290: the physiological explanations here are very succinct “Physiologically,…”. I suggest to the authors a sentence like this: “AMS is a complex disorder triggered by high-altitude hypoxia and can present with diverse clinical manifestations”.

Line 301: “dizziness” is missing, as well as it would be appropriate to name (and include a reference to) the Lake Louise clinical score, which is the most widely used for the diagnosis of AMS.

Line 305: also add “difficulty in draining cerebral venous outflow”.

Line 308: “Lack of adequate adaptation to altitude remains the cause of CMS”. To avoid getting into interpretative differences between ‘acclimatization’ and ‘adaptation’, I suggest that for the majority of readers it should be specified as such: “long-term adaptation”.

Line 311: I suggest including here the most typical manifestations of CMS (exaggerated polycythemia and pulmonary hypertension, heart failure, fatigue, peripheral venous insufficiency, headache and cognitive impairment, etc.) as well as naming the Qinghai Score (include reference) used for the diagnosis and clinical evaluation of CMS.

Line 316: The study by Richalet et al. (ref. 72) is not on CMS, and is compared here with this present study!

Line 329-330: the “pulmonary hypertension” perhaps it should be expressed here as an “exaggerated pulmonary hypertension”.

Line 332: “personas” (correct to English).

Line 335: define HAPH acronym (high-altitude pulmonary hypertension).

Line 344: also use here the acronym MS (“…mountain sickness…”).

Line 344: In my opinion, it lacks some further analysis of AMS and CMS in native and non-native highlanders (*).

Line 350: use acronyms AMS and CMS.

Line 354: use acronym MS.

Line 356: “poliglobulia and pulmonary hypertension are considered as pathologies associated…”. I suggest writing it in the following way: “an adaptive response to high-altitude with exaggerated polyglobulia and pulmonary hypertension are associated…”

Line 366: use acronyms “…MS in LATAM…”

(*) a) Regarding of AMS, one aspect that I think it would be very interesting to analyze is why high-altitude residents (non-native but have been acclimatized to hypoxia for at least 12 months) develop this type of mountain sickness. Is it because they ascend or move to areas of even higher altitude than their usual altitude residence? And even, are there differences in the prevalence of AMS between Andean natives and non-natives?

(*) b) Regarding the CMS, are there differences in the prevalence of CMS between Andean natives and non-natives residents who have been living at high altitude for years? Table 1 shows the percentages of the samples with exclusively Andean natives (8 studies), exclusively non-natives residents (13 studies), and both types (3 studies). Likewise, it would be interesting to analyze the probable percentage difference in CMS between men and women (Table 1 shows 8 studies that include samples of both sexes in chronic exposure).

I also believe it would be very interesting to analyze all these aspects (a and b) and you could even add those statistical data in the RESULTS section. In the event that it is impossible to extract or deduce the data I propose (on the published studies included in the review/meta-analysis), however, the authors should also refer to these aspects in the Discussion and this section would be more enriched.

CONCLUSSION:

It is correct, but in my opinion it is very brief.

TABLE 1: in the first column “et al.” should be specified in studies with multiple authors. Likewise, at the end of each author’s name I suggest including the corresponding reference number supraindexed (that would facilitate the search in the bibliographic list).

Typographical errors:

Garofilo (incorrect), Garófoli (correct); Valencia (incorrect), Valencia-Flores (correct); Penaloza (incorrect), Peñaloza (correct); Riano (incorrect), Riaño (correct); Salazar 2011 (incorrect), Salazar 2012 (correct).

FIGURES 2 and 3: In these 2 figures I would recommend specifying the acronyms AMS and CMS, instead of “A” and “B”, as in my opinion it would be more illustrative. Also correct it when the respective Figures are mentioned in the text.

FIGURES 2, 3, 4 and 5: I suggest that “et al.” be included in those studies carried out by more than 1 author.

FIGURE 6: in the wording “Prevalence of Acute and Chronic Mountain Sickness by country”, it should be specified that it is the “reported prevalence based on published studies”. As the legend goes, it seems that in Mexico (in its population residing at high altitude) there is more susceptibility to CMS than in Peru, for example, which is hard to believe as true.

REFERENCES LIST:

There are references that are repeated in the list: e.g. ref. 5 and 8 (note this when referenced in the text).

Some journal names are not abbreviated correctly.

Some of the articles’ statements appear with initial capital letters and others do not (to unify the criteria according to the journal’s standards).

Ref. 24: the name of the first author is “van Roo” (match with Table 1).

Ref. 27: the journal’s name is spelled incorrectly. I think it is “Cephalalgia”.

Ref. 31: the journal’s name is spelled incorrectly. I think it is “Medicina (B Aires)”.

Ref. 52: the journal’s name is spelled incorrectly. I think it is “Int J Obes Relat Metab Disord”.

SUPPLEMENTARY MATERIAL. FIGURES 5 and 6: I suggest including “et al.” in those studies performed by more than one author. Likewise, in these 2 figures I would recommend specifying the acronyms AMS and CMS, instead of “A” and “B”, as in my opinion it would be more illustrative.

Reviewer #2: This paper is an attempt to resolve the global discrepancies in study and publication regarding a condition which mainly occurs in the lower income regions of the worlds and hence a good and deserving effort.

Manuscript needs to be read by native English speaker.

Abstract: better define dwellers at high altitude in the abstract. It only requires a few words and is done in Methods, but raises some confusion as to who is your target population: long term residents as well as people in transit such as tourists?

Also for limitations sector it is wise to stress your awareness of the fact that inclusion or exclusion of tourist climbers with AMS potentially distorts your findings towards AMS.

Line 125 l197 says 'y' instead of and; Dominican Republic?

Polyglobulia is used initially, then polycythemia vera and eventually in line 356 it is again polyglobulia. Advice is to stick to polycythemia and define both better in case you intend to use it distinctly.

From line 79 perhaps choose to omit a.s.l. as this is obvious from that point onwards.

L 184-186 outcome measures pulmonary oedema cerebral oedema polycythemia and pulmonary hypertension need to be defined according to international standards (references have been given).

l 114-116 and results section: define the altitude ranges and classes in Methods.

l 281-282 A potential bias is the ill defined target population as stated above with a bias towards AMS in populations which exlude the long term dwellers on altitude. This may have to be stressed a bit more firmly here.

L 287-289, 315-316, 328-329 perhaps good to describe your denominator better than ** out of ** people: what is the target population you base the statistics on? (If you define it once, you do not have to do it again)

Finally as a recommendation based on your study you could indicate that the inclusion of certain ethnic groups would call for genetic studies of such populations in order to further investigate their physiology on high altitude. After all the Andean high altitude population is rather unique in their habitat!

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PLoS One. 2024 Sep 24;19(9):e0305651. doi: 10.1371/journal.pone.0305651.r002

Author response to Decision Letter 0

29 May 2024

Dear Editor and reviewers

Thanks for reviewing our manuscript and giving us an opportunity to improve it. Please find enclosed a rebuttal letter containing the responses point by point to each of the recommendations/observations, as well as the corrected and revised manuscript.

Response to recommendations:

Reviewer #1:

Comment 1: It states that the information on acute and chronic disease only comes from the Himalayas, but this is not true, as there are numerous studies done in the Andes, as shown in this meta-analysis. I suggest the following “...but the information mostly comes from the eastern continent (Himalayas)…”.It is noted that polyglobulia is a “pathology” and below it appears as a “symptom”, and cerebral edema as a “symptom”. These are an error that should be corrected, as polyglobulia per se is a physiological response to hypoxia, and can only be considered pathological if it is excessive for a given altitude. Likewise, cerebral edema is a physiological alteration and a clinical picture, not a symptom.

I suggest deleting the last sentence: “Therefore, we recommend…”.

� Response 1: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below:

“…but most of the available information comes from the eastern continent (Himalayas), …”

“… The most common physiological alteration was polycythemia (2,558 events), while cerebral edema was the less common (46 events). Clinical conditions were more prevalent at high altitudes for both types of MS.”

Deleted the last sentence: “Therefore, we recommend…”

Comment 2: In my opinion this section is somewhat poor in illustrating the subject. It should be slightly enriched. Line 92: in this paragraph it should not be said that there are no studies that do not include information from the Andes, but rather that the information is comparatively scarce with other mountainous places throughout the world.

� Response 2: We agree with the reviewer’s observation; this section has been corrected according to the reviewer's suggestions as shown below.

“…. However, these reports are mainly from eastern areas (such as Nepal Himalaya and Ethiopian highlands) with comparatively scarce information with other mountainous places in the world, such as the Andes 11.”

Comment 3: Line 94: “…Nepal Himalya and Ethiopian”. Put it this way: “…Nepal Himalaya and Ethiopian highlands” (I suggest adding also the reference: Xing et al. Adaptation and mal-adaptation to ambient hypoxia; Andean, Ethiopian and Himalayan patterns. PLoS One, 2008).

� Response 3: We agree with the reviewer’s observation; the reference has been added in the manuscript as shown below.

“… such as Nepal Himalaya and Ethiopian highlands)”

References:

11. Xing G, Qualls C, Huicho L, et al. Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns. PLOS ONE. 2008;3(6):e2342. doi:10.1371/journal.pone.0002342

Comment 4: Line 98: “pulmonary hypertension” is not a complication but a physiological response of the organism to the hypoxia of altitude; the complication would be an “exaggerated pulmonary hypertension”...

� Response 4: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

�

“……, and complications (exaggerated pulmonary hypertension, pulmonary and cerebral edema).

Comment 5: The bibliography in this Introduction section should be enriched (I suggest referencing here some articles, such as Monge 1942, Hancco et al. 2020 [already in the reference list], Champigneulle et al. 2023, Waterlow and Bunjé 1966, Sánchez et al. 2022, etc., as well as some others that appear in the Supplementary material-3). At least this would further illustrate the Introduction section, even if there are articles that are then excluded in the meta-analysis.

� Response 5: We agree with the reviewer’s suggestion; the references has been added in the manuscript as shown below.

“Previous studies have reported the frequency of MS in different regions of the world 8,9,10. However, these reports are mainly from eastern areas (such as Nepal Himalaya and Ethiopian highlands) with comparatively scarce information with other mountainous places in the world, such as the Andes 11. In fact, a previous systematic review 12 determined a global prevalence of MS at approximately 12%; however, they omitted to include studies from LATAM 13–15.”

References:

13. Hancco I, Bailly S, Baillieul S, et al. Excessive Erythrocytosis and Chronic Mountain Sickness in Dwellers of the Highest City in the World. Front Physiol. 2020;11:773. doi:10.3389/fphys.2020.00773

14. Champigneulle B, Brugniaux JV, Stauffer E, et al. Expedition 5300: limits of human adaptations in the highest city in the world. J Physiol. 2023;n/a(n/a). doi:10.1113/JP284550

15. Monge C. Life in the Andes and Chronic Mountain Sickness. Science. 1942;95(2456):79-84. doi:10.1126/science.95.2456.79

Comment 6: Line 113: define the acronym PECO.

� Response 6: We agree with the reviewer’s observation and suggestion; we have added the components of the PECO acronym as shown below.

“….. the following PECO (where the means of P: population E: exposure, O: outcome) structure: 1) population: altitude inhabitants (defined as a person who live in a place more than 12 months); 2) exposure: altitude ( following the ranges of intermediate altitude 1500-2500 m, from where physiological changes are detectable), high altitude (2500-3500 m), very high altitude (3500-5800 m), extreme altitude (>5800 m.), and “death zone” (>8000 m.a.s.l.) 20); and 3) outcome: prevalence of AMS and CMS, according to each disease and study”

Comment 7: Lines 116-117: use the acronyms AMS and CMS.

� Response 7: We agree with the reviewer’s observation and suggestion; the wording has been corrected in the manuscript as shown below.

“…..outcome: prevalence of AMS and CMS, according to each disease and study”

Comment 8: Line 123: perhaps mention should be made here to “mountain sickness” and make reference to the Supplementary material-2. The keyword “Andes” would also have been useful in the search.

� Response 8: We agree with the reviewer’s observation and suggestion; the wording has been corrected in the manuscript as shown below.

“…. using keywords related to “mountain sickness” and “Latin America”. Also, we include terms for each Latin America country that report a high altitude (Peru, Chile, Argentina, Bolivia, Venezuela, Ecuador and Colombia), taking into account all the cities located at high altitudes. The search strategy of each database is available in Supplementary 2”

On the other hand, although the term “Andes” might have been useful in the search, we have added reference terms for each Latin American country that reports high altitudes, so it is unlikely that the term “Andes” would have affected the search results.

Comment 9: Line 185: “pulmonary hypertension, and polycythemia” should only be considered pathological responses if they are excessive for a given altitude (I think this should be stated in this paragraph).

� Response 9: We agree with the reviewer’s observation and suggestion; the wording has been corrected in the manuscript as shown below.

“……, and complications (pulmonary edema, cerebral edema, exaggerated pulmonary hypertension, and exaggerated polycythemia).”

Comment 10: Lines 195-200: total sample population included (10,549) does not match the sum of AMS (3,087) and CMS (7,448). Is it a mistake, or what is the reason? If it is a misinterpretation on my part, it is possible that other readers may have the same misinterpretation as me.

� Response 10: We agree with the reviewer’s observation. There was an error in the wording, the population of AMS was 2,945. CMS was 7,448 and two studies with both populations of 156, which now add up correctly. The wording has been corrected in the manuscript as shown below.

“…. Of the 39 studies, acute mountain sickness (AMS) was evaluated in 15 studies 24–38 (n=2 945), chronic mountain sickness (CMS) in 22 13,23,39–58 (n=7 448), and both in 2 59,60 (n=156).”

Comment 11: Lines 199-200: “Regarding the studies that evaluated AMS, most of the studies were from Chile (n = 8 studies) and Peru/Argentina (n = 4 studies)…”. Do these refer to studies that included larger samples?

� Response 11: Thank you for your comment. It actually refers to the countries that contributed the most number of the studies.

“….. Regarding the studies that evaluated AMS, most of the studies were from Chile (n = 8 studies) and Peru/Argentina (n = 4 studies), which are the countries that contributed the most research on the subject.”

Comment 12: Lines 223-225: Data from AMS (5,334/10,000) and CMS (2,945/10,000) are not consistent with those shown in lines 197-198: AMS (3,087/10,549) and CMS (7,448/10,549). The authors should clarify this apparent discrepancy, so that there are no errors in the interpretation of the data shown in two different places in this Results section (these discrepant figures may lead to significant confusion in the interpretation of the data by readers).

� Response 12: The discrepancy in the sum of the previously included sample has been clarified and corrected. The data from AMS (5,334/10,000) and CMS (2,945/10,000) mentioned by the reviewers refers to the prevalence (not to the sample) calculated per 10,000 people.

Comment 13: I suggest that the authors rework this section. I propose that you make a more in-depth analysis and focus on the context of the results obtained through the extensive review/meta-analysis performed, and make less continuous allusion to the pathophysiological aspects of MS and its different forms of presentation (AMS, CMS) and derived clinical complications (cerebral edema, pulmonary edema, etc.). I also suggest that the definitions of AMS and CMS should appear succinctly in the Introduction section and less so in the Discussion. In my opinion, the entire Discussion section lacks sufficient narrative strength and makes for uninspiring reading, but I think that especially the first part of this section (lines 286-341) is somewhat convoluted in terms of the concepts presented. Therefore, I encourage you to make an effort to rewrite this section to improve it, and thus achieve better quality of the manuscript and not detract from the value and effort that has gone into the research of the study, as reflected in the Material and Results sections.

� Response 13: We agree with the reviewer’s observation and suggestion. We have decided to rewrite all the discussion. You will be able to see the changes in the manuscript.

Comment 14: Lines 287-290: Given that the meta-analysis includes acclimatized high-altitude inhabitants of LATAM, this high percentage of AMS is striking compared to the prevalence in Europe (where the majority of mountain ascents are for tourism or sport by low altitude residents). The authors could make a small allusion to this detail, despite the fact that the average altitude reached in the studies analyzed is comparatively only 500 meters higher. Perhaps, in order to give more solidity to the comparative data with Europe, a reference to some other studies on the subject carried out in European mountains could be added here.

� Response 14: We agree with the reviewer’s observation; we have added information on the topic in the manuscript as shown below.

“….. the meta-analysis included acclimatized high-altitude inhabitants of LATAM, while in Europe the majority of mountain ascents are for tourism or sport by low altitude residents 99. AMS can manifest itself variably according to the physiological adaptation to altitude of each individual, however, a greater severity of symptoms is observed in low altitude residents who ascend to higher altitudes 100.

Comment 15: Line 290: the physiological explanations here are very succinct “Physiologically,…”. I suggest to the authors a sentence like this: “AMS is a complex disorder triggered by high-altitude hypoxia and can present with diverse clinical manifestations”.

� Response 15: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

“…. AMS is a complex disorder triggered by high-altitude hypoxia, initiating a pulmonary response characterized by an increase in tidal volume and respiratory rate, leading to subsequent respiratory alkalosis 64”

Comment 16: Line 301: “dizziness” is missing, as well as it would be appropriate to name (and include a reference to) the Lake Louise clinical score, which is the most widely used for the diagnosis of AMS.

� Response 16: We agree with the reviewer’s observation; the wording has been corrected and we added information in the manuscript as shown below.

“…..These symptoms encompass headache, fatigue, anorexia, nausea, dizziness as well as sleep disorders. Identifying the symptoms will be necessary to diagnose AMS, using the Lake Louise clinical score.”

Comment 17: Line 305: also add “difficulty in draining cerebral venous outflow”.

� Response 17: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

“……leading to increased intracranial pressure, the elevation of cerebral blood flow, difficulty in draining cerebral venous outflow and the activation of the trigeminal vascular system due to the release of nitrous oxide and vasodilation 5,69.”

Comment 18: Line 308: “Lack of adequate adaptation to altitude remains the cause of CMS”. To avoid getting into interpretative differences between ‘acclimatization’ and ‘adaptation’, I suggest that for the majority of readers it should be specified as such: “long-term adaptation”.

� Response 18: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

“Lack of long-term altitude adaptation remains the cause of CMS…”

Comment 19: Line 311: I suggest including here the most typical manifestations of CMS (exaggerated polycythemia and pulmonary hypertension, heart failure, fatigue, peripheral venous insufficiency, headache and cognitive impairment, etc.) as well as naming the Qinghai Score (include reference) used for the diagnosis and clinical evaluation of CMS.

� Response: We agree with the reviewer’s observation; we added information in the manuscript as shown below.

“The diagnosis of CMS is based on the Qinghai CMS Score, which includes the evaluation of common symptoms such as shortness of breath, palpitations, sleep disturbances, heart failure, peripheral venous insufficiency, paresthesia, headache, cognitive impairment, exaggerated polycythemia and pulmonary hypertension 105.”

Comment 20: Line 316: The study by Richalet et al. (ref. 72) is not on CMS, and is compared here with this present study!

� Response 20: We agree with the reviewer’s observation; we have added new information and replaced the previously mentioned reference as shown below.

“… We identified that approximately 3 out of 10 persons has severe symptoms, higher than that reported by a study in Qinghai, China, where only 2.4% of more than 1000 residents had severe symptoms 106.”

Comment 21: Line 329-330: the “pulmonary hypertension” perhaps it should be expressed here as an “exaggerated pulmonary hypertension”.

� Response 21: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

“Other complications like exaggerated pulmonary hypertension are related to chronic exposure …..”

Comment 22: Line 332: “personas” (correct to English).

� Response 22: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

“Our estimation differs from others reported in India where the prevalence was less than 1 event out of 10 people 76.”

Comment 23: Line 335: define HAPH acronym (high-altitude pulmonary hypertension).

� Response 23: We agree with the reviewer’s observation; the wording has been corrected in the manuscript as shown below.

“……. vascular resistance and define a subgroup of pulmonary hypertension known as high-altitude pulmonary hypertension (HAPH) 77.”

Comment 24: Line 344: also use here the acronym MS (“…mountain sickness…”).

� Response 24: We agree with the reviewer’s observation; the wording has been corrected

PLoS One. doi: 10.1371/journal.pone.0305651.r003

Decision Letter 1

Esteban Ortiz-Prado

4 Jun 2024

Mountain sickness in altitude inhabitants of Latin America: a systematic review and meta_analysis

PONE-D-23-42448R1

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PLoS One. doi: 10.1371/journal.pone.0305651.r004

Acceptance letter

Esteban Ortiz-Prado

20 Jul 2024

PONE-D-23-42448R1

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. PRISMA checklist.

(DOCX)

pone.0305651.s001.docx^{(21.3KB, docx)}

S1 Table. Excluded studies.

(DOCX)

pone.0305651.s002.docx^{(24.6KB, docx)}

S2 Table. Search strategy.

(DOCX)

pone.0305651.s003.docx^{(14.5KB, docx)}

S1 Fig. Risk of bias of included studies.

(DOCX)

pone.0305651.s004.docx^{(16.7MB, docx)}

S2 Fig. Sensitivity analysis on prevalence of Acute (A) and Chronic (B) Mountain Sickness between risk of bias.

(DOCX)

pone.0305651.s005.docx^{(638.2KB, docx)}

S3 Fig. Sensitivity analysis on prevalence of Acute (A) and Chronic (B) Mountain Sickness excluding outliers.

(DOCX)

pone.0305651.s006.docx^{(692.9KB, docx)}

S4 Fig. Publication bias on the prevalence of acute (A) and chronic (B) mountain sickness.

(DOCX)

pone.0305651.s007.docx^{(165.1KB, docx)}

Data Availability Statement

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PERMALINK

Mountain sickness in altitude inhabitants of Latin America: A systematic review and meta-analysis

J Pierre Zila-Velasque

Pamela Grados-Espinoza

P Alejandra Goicochea-Romero

Gustavo Tapia-Sequeiros

J Enrique Pascual-Aguilar

Arturo J Ruiz-Yaringaño

Shamir Barros-Sevillano

Jhon Ayca-Mendoza

Wendy Nieto-Gutierrez

Roles

Abstract

Objective

Methods

Results

Conclusion

Introduction

Methods

Protocol registration and research question

Systematic search

Study selection and data extraction

Fig 1. PRISMA flow chart for the study selection process.

Risk of bias

Synthesis of the evidence

Results

Characteristic of the studies

Table 1. Characteristics of studies assessing the prevalence of acute and chronic mountain sickness in Latin America.

Prevalence of mountain sickness

Fig 2. Meta-analysis on the prevalence of Acute (A) and Chronic (B) Mountain Sickness.

Fig 3. Prevalence of Acute (A) and Chronic (B) Mountain Sickness by altitude.

Fig 4. Meta-analysis on the prevalence of mild (A) and severe (B) symptoms of Mountain Sickness.

Fig 5. Meta-analysis on the prevalence of complications of mountain sickness.

Fig 6. Prevalence of acute and chronic mountain sickness by country, based on the number of published studies.

Risk bias assessment, publication bias, and sensitivity analysis

Discussion

Acute mountain sickness

Chronic mountain sickness

Implications of the results and recommendations for future studies

Limitations and strengths of the review

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Esteban Ortiz-Prado

Roles

Author response to Decision Letter 0

Decision Letter 1

Esteban Ortiz-Prado

Roles

Acceptance letter

Esteban Ortiz-Prado

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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