Preserved ratio impaired spirometry (PRISm) is described as an intermediate pulmonary phenotype between normal lung function and chronic obstructive pulmonary disease (COPD). It carries an elevated risk of progression to COPD. Epidemiological observations indicate that the detection rate of PRISm is significantly higher in high-altitude environments than in lowland or plain areas. The review attributes this increased prevalence to the distinctive environmental conditions at altitude, particularly hypobaric hypoxia, but emphasizes that many specific causal links remain incompletely defined.
High-altitude settings impose multiple chronic physiologic stresses on the respiratory and cardiovascular systems. The authors summarize current thinking on how these stresses might shift the spectrum of lung function in exposed populations toward patterns consistent with PRISm, and they highlight the public health and research implications of an elevated PRISm burden in highland communities.
The review presents several plausible, potentially interacting mechanisms by which high-altitude hypoxia may contribute to the onset and progression of PRISm. These proposed pathways are derived from available physiological and pathobiological knowledge rather than from definitive causal trials at altitude:
Systemic inflammatory responses: Chronic hypoxia at altitude can provoke low-grade systemic inflammation, which may adversely affect airway and parenchymal lung function and contribute to impaired spirometric patterns.
Oxidative stress injury: Hypoxia and reoxygenation cycles can increase oxidative stress, leading to cellular and tissue injury in the lung that may manifest as reduced spirometric measures.
Abnormal activation of hypoxia-inducible factor (HIF) signaling pathways: Prolonged or dysregulated HIF pathway activity under hypoxic conditions may alter pulmonary cellular responses and remodeling processes relevant to lung function.
Increased cardiopulmonary compensatory burden: The physiologic demand for enhanced cardiopulmonary compensation at altitude (for example, increased pulmonary vascular workload and hematologic adaptation) may indirectly contribute to changes in measured lung function consistent with PRISm.
The authors underline that while these mechanisms are biologically plausible, direct evidence clarifying their specific roles in high-altitude PRISm is still inadequate and warrants mechanistic investigation.
The review identifies several risk markers and exposures that appear to be associated with PRISm in high-altitude populations:
These factors are noted as characteristic highland risk indicators reported in available studies or clinical observations. The authors caution that the relative contribution of each factor to PRISm development and progression at altitude has not been fully quantified in prospective research.
The review highlights multiple limitations in the present literature on PRISm at high altitude:
Lack of altitude-specific diagnostic criteria and lung-function reference values: Standard spirometric reference norms derived from lowland populations may misclassify or obscure lung-function abnormalities in high-altitude cohorts.
Insufficient epidemiological data: There is a need for larger, multicenter prevalence and incidence studies across diverse high-altitude communities to characterize the true burden and natural history of PRISm.
Limited mechanistic exploration: Direct experimental and translational data linking high-altitude exposures to cellular and molecular pathways that drive PRISm are sparse. Multi-omics and longitudinal pathophysiologic studies are largely absent.
Screening and intervention tools not tailored to altitude: Existing screening and prevention frameworks for early lung disease have not been adapted or validated for highland settings.
The authors explicitly note that specific mechanistic evidence remains to be established and that these gaps limit the ability to draw firm causal inferences.
To address the outlined gaps, the review recommends several priorities:
Establish altitude-specific lung-function reference values to improve diagnostic accuracy for spirometry patterns such as PRISm in highland populations.
Conduct multicenter longitudinal cohort studies to define prevalence, risk factors, natural history, and the rate of progression from PRISm to COPD at altitude.
Implement multi-omics mechanistic research (for example, integrating genomics, transcriptomics, proteomics, metabolomics) to elucidate molecular pathways by which hypoxia and other high-altitude exposures affect lung structure and function.
Develop and validate screening, preventive, and interventional tools that are appropriate for high-altitude contexts, considering local health-system capacity.
Promote interdisciplinary collaboration among respiratory medicine, high-altitude physiology, epidemiology, and public health to design and implement comprehensive prevention and control systems for PRISm in highland regions.
The authors also call for policy and programmatic efforts to integrate these research outputs into practical prevention and management strategies tailored to populations living at altitude.
Conflict of interest and funding
The review declares that all authors reported no conflicts of interest. Funding sources supporting the work are listed in the original article metadata. The review reiterates that many proposed mechanistic links remain hypotheses pending direct evidence from targeted studies at high altitude.