Acute high-altitude illness: risk factors, susceptibility prediction, and personalized prevention and treatment

Background and objectives: Acute high-altitude illness (AHAI) comprises a spectrum of related conditions arising from exposure to high altitude, such as acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). This study aimed to synthesize the existing evidence, delineate the risk factors and susceptibility predictors of AHAI, and outline personalized prevention and treatment strategies, as well as to identify key directions for future research. Methods: A systematic search of PubMed and Web of Science was conducted, such as clinical studies, systematic reviews, and authoritative guidelines published up to August 2025. No formal meta-analysis was performed; a narrative synthesis approach was employed to integrate the existing evidence. Results: Hypoxemia is the central pathophysiological driver of acute AHAI. Immutable host characteristics (age, sex, ethnicity, and genetic susceptibility) and modifiable comorbidities jointly influence baseline risk and disease trajectory. Current predictive approaches include hypoxic exercise testing and multifactorial risk scores; however, prospective, rigorously validated tools suitable for routine clinical use remain limited. Prevention and treatment strategies span non-pharmacological acclimatization, oxygen therapy, and pharmacologic interventions (e.g., acetazolamide, dexamethasone, calcium-channel blockers, and PDE5 inhibitors), with varying levels of evidence. Emerging therapies, such as traditional Chinese medicine, nanoparticle-based approaches, and psychological interventions, show promise. Management of AHAI should be individualized to accommodate patient-specific differences. Conclusion: Hypoxemia is the core pathophysiological driver of AHAI and is closely linked to the development of AMS, HACE, and HAPE. Individual responses to hypoxia show substantial heterogeneity, underscoring the need for personalized prevention and management strategies. Future study should develop more robust multi-parameter risk-prediction models and validate them prospectively across diverse populations and ascent contexts, and integrate wearable sensors, biomarkers, and novel drug-delivery systems into personalized interventions to enhance prevention and clinical outcomes of high-altitude exposure-related diseases.