The Global Significance of PRISm: how data from low- and middle-income countries link physiology to inflammation

We read with great interest the article by Wijnant et al. in the recent issue of ERJ investigating the longitudinal outcomes of patients with preserved ratio impaired spirometry (PRISm) in the Rotterdam cohort.(1) PRISm is a subject of increased investigation as it is associated with respiratory symptoms, cardiovascular disease, metabolic syndrome and, quite clearly in the recent study, increased mortality.(1,2,3) While there have been numerous studies examining outcomes related to PRiSm in high-income countries (HIC), few studies have assessed the clinical significance of this spirometric finding in low and middle income countries (LMICs).

Globally 85% of non-communicable disease deaths occur in LMIC’s. Of these chronic respiratory disease is the fourth leading cause of death and the WHO predicted the largest increase in global mortality to be attributed to these disorders.(4) As the prevalence of chronic respiratory disease in LMIC’s is increasing, it’s clear that PRISm is one of the most common spirometry findings in LMICs.(5, 6) Impairment on spirometry has been demonstrated to be as high as 60% among individuals with preserved FEV₁/FVC in the BOLD study and a more recent cross sectional study in Malawi revealed 38.6% of participants with PRISm.(6) Furthermore, there are unique risk factors that may lead to the development of this spirometric pattern in LMICs. Wijnant et al. found that incident PRISm was significantly higher in patients with elevated BMI (p < 0.001 and p <0.010 respectively) this finding was also present in the COPDGene cohort.(1, 3) While obesity explains PRISm physiologically, it’s association with PRISm is not consistent. In the aforementioned Malawian and BOLD cohort, PRISm was paradoxically associated with lower BMI as well as poverty.(5, 6) There have been even fewer longitudinal studies of PRISm in LMICs. One, a study in urban and rural Peru demonstrated increased lung function decline (FEV1) among those with PRISm compared to normal spirometry, similar to the findings of Wijnant et al.(7) It is worth noting, that although PRISm can result from poorly performed spirometry, however, the studies mentioned here conducted extensive training and ensured quality control checks on all spirometry data.(5,6,8)

How can we reconcile the very high rates of PRISM in LMIC’s if not associated with extra-thoracic restriction? One hypothesis of interest is predicated on the association of PRISm with ambient pollution and organic inhalational exposures. The rates of PRISM are higher in smokers as noted in the COPDGene and MESA study.(3, 8) In LMIC’s the rate of smoking remains much lower than that in HIC’s. However, biomass exposure and farming, which are prevalent through rural areas globally, have been strongly associated with impairment on spirometry in these settings. Additionally, the link between pollution and PRISm has been supported in numerous large cohorts in the US and Europe.(2) Animal models further support this association with links clearly identified between inhalational exposure, inflammation and impaired FVC.(9) All of these risk factors are far more prevalent in LMIC’s and may suggest a clue to the high prevalence in these settings.

So, what could be the common thread between the metabolic syndrome and inhalational exposure. A compelling association, described by Wijnant et al. and demonstrated in LMIC settings, is systemic inflammation. In Peru, individuals with PRISm were more likely to have glucose intolerance and have elevated hs-CRP independent of obesity and other comorbidities, indicating that a similar inflammatory pattern found in high-income settings may be at play.(8) While diabetes has been associated with PRISm in HIC’s, there is evidence that impairment on spirometry precedes glucose intolerance. In the CARDIA study individuals with higher fibrinogen experiences accelerated loss of lung function over time, though with a preserved ratio and a Swedish study reported similar findings with a range of circulatory inflammatory biomarkers. (10, 11)

While compelling, the link between systemic inflammation and PRISm requires additional study. This will involve a commitment to establishing cohorts of PRISm patients in LMIC’s and ensuring that these patients obtain lab, radiologic and detailed exposure assessments. In an ongoing project, our group at Johns Hopkins intend to evaluate PRISm patients from a large existing cohort in Kampala, Uganda with advanced pulmonary function testing and CT scans. This study will allow comparisons of inhalational risk factors associated with this pattern and give additional longitudinal information about a LMIC cohort with high prevalence of PRISm.

Why does this matter in LMIC settings? With such a high prevalence of PRISm and clear evidence of increased mortality among patients with this physiologic pattern there may be a “time bomb” of patients that have thus far been overlooked. The increasing prevalence of spirometry in LMIC’s allows for increased recognition of this problem and the possibility for early intervention. All of these factors compel us to pursue further study of the PRISm phenotype, its associated risk factors and work to bridge the gap between PRISm patients in HIC’s and abroad.