Abstract
Subjects with PRISm represent a heterogeneous population encompassing distinct phenotypes with distinct risk factors. A spectrum of mechanisms and risk factors contribute to varying degrees to the pathogenesis of PRISm in different populations. http://bit.ly/2TkHJjK
From the authors:
In a recent paper published in the European Respiratory Journal, we studied the characteristics, trajectory and mortality of subjects with Preserved Ratio Impaired Spirometry (PRISm) in the Rotterdam Study, a prospective population-based cohort study in the Netherlands, a high-income country (HIC) [1]. In an elegant letter to the editor, P. Jackson and T. Siddharthan correctly argue that clinical research on PRISm has been limited so far in its potential to grasp a representative sample of the world population, with marked underrepresentation of studies in low- and middle-income countries (LMICs). Despite potential differences in risk factors, they suggest that systemic inflammation plays a key role in the pathogenesis of PRISm in both HIC and LMICs. In the Rotterdam Study, we showed an increased white blood cell count in subjects with PRISm as compared to subjects with normal spirometry [1]. In addition, subjects with PRISm have higher serum levels of high-sensitive C-reactive protein, a higher granulocyte count, a higher granulocyte to lymphocyte ratio and a higher systemic immune inflammation index (table 1).
P. Jackson and T. Siddharthan state that while extra-thoracic pulmonary restriction, through for example obesity or cardiovascular diseases (encompassing heart failure and/or ischaemic heart disease), is associated with PRISm in HICs, air pollution and organic inhalational exposures are more likely associated with PRISm in LMICs. Since PRISm is a heterogenous syndrome encompassing multiple subgroups, we propose that a spectrum of mechanisms and risk factors contribute to varying degrees to the pathogenesis of PRISm in different populations. With globalisation comes modernisation and westernisation of lifestyles, also in LMICs. Therefore, we argue that also in LMICs, obesity might play an important role in a subgroup of subjects with PRISm. Abdominal obesity may indeed compromise lung volumes through the mechanical effects of truncal obesity and/or the metabolic effects of adipose tissue. To what extent either mechanical or metabolic effects of obesity lead to PRISm is unknown, though the postulated hypothesis by P. Jackson and T. Siddharthan of systemic inflammation linking PRISm in both HIC and LMICs suggests a relatively higher importance of the metabolic effects.
Another, but underappreciated, risk factor for PRISm is impaired lung growth [2]. Especially, but not exclusively, in LMICs, environmental factors such as air pollution, smoking, malnutrition and respiratory infections may limit optimal lung growth during fetal life, childhood and adolescence. Indeed, a history of pneumonia or pleurisy in childhood has been shown to increase the prevalence of PRISm later in life in a HIC [3], with likely larger estimates in LMICs due to higher rates and severity of pulmonary infections (including tuberculosis). Also, a well-balanced nutrition in childhood and adolescence is important for optimal lung growth. For example, in case of endemic deficiency of vitamin A, supplementation of vitamin A in pregnant women was associated with increased lung function in their offspring [4]. Infection, malnutrition and exposure to air pollutants (e.g. organic compounds and particulate matter) likely all play a role in limiting lung function growth and hence, in increasing the prevalence of PRISm in a Malawian study [5], whereas the same risk factors, as well as obesity, may contribute to PRISm in other countries, yet with varying degrees of importance for each specific risk factor and setting.
Lastly, clinical phenotypes (including spirometric measures, such as forced vital capacity (FVC)) are the result of interactions between multiple environmental factors and an individual's unique genome. Indeed, genome-wide association studies have identified multiple genetic variants (mostly single-nucleotide polymorphisms, but also deletions, insertions and copy number variants) associated with FVC in individuals of European ancestry. These genetic variants have been implicated in lung development, repair and response to injury [6]. It is unclear whether genetic susceptibility differs in individuals from non-European ancestry, predisposing to a larger extent of impaired lung growth and PRISm in LMICs.
To conclude, we agree that there is a need for more studies to disentangle risk factors, mechanisms and trajectories of PRISm, especially in LMICs. PRISm has been neglected in many research papers in the past, and as a result is often ignored in clinical practice, despite its unfavourable outcomes. One of the main conclusions of our paper was the heterogeneity of PRISm, a message we need to reinforce: subjects with PRISm represent a heterogeneous population encompassing distinct phenotypes with distinct risk factors. Upon identification of PRISm on spirometry, more efforts towards understanding the individual's specific pathogenesis of PRISm is warranted in order to improve therapeutic approaches. The association of systemic inflammation with PRISm should be further disentangled, as well as replicated in studies from LMICs. Moreover, the relative importance of systemic inflammation in the link between obesity and PRISm should be further clarified. Finally, through large-scale epidemiological research in LMICs, new risk factors for PRISm can be discovered, leading towards a better understanding of this peculiar spirometric phenotype. Prospective studies are warranted to elucidate factors leading to impaired lung growth in childhood and their effects on lung function later in life.
Shareable PDF
Supplementary Material
This one-page PDF can be shared freely online.
Shareable PDF ERJ-00354-2020.Shareable
Footnotes
Conflict of interest: S.R.A. Wijnant reports grants from GlaxoSmithKline, outside the submitted work.
Conflict of interest: L. Lahousse reports grants from AstraZeneca and Chiesi (both awards), and expert consultation for Boehringer Ingelheim GmbH and Novartis, outside the submitted work.
Conflict of interest: G.G. Brusselle reports personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, personal fees for advisory board work from Sanofi, outside the submitted work.
- Received February 18, 2020.
- Accepted February 19, 2020.
- Copyright ©ERS 2020