A pulmonary function test (PFT) is an invaluable tool in the evaluation of respiratory disease, and various PFT patterns have been identified using an algorithmic approach to help diagnose pulmonary disorders.1,2 One such pattern is a normal forced exhalation volume in one second/forced vital capacity (FEV1/FVC) ratio with a reduced FEV1, which has been referred to as preserved ratio impaired spirometry (PRISm).3 Non-specific pattern (NSP) can be thought of as a subgroup of PRISm that also includes a normal total lung capacity (TLC) measurement and was initially investigated in the 1990s by Hyatt et al.4 These terms have been used interchangeably in much of the research in this field despite likely representing distinct patient populations.

There is growing research interest into PRISm given its high prevalence,5,6 increased risk of all-cause mortality,5,7–10 and association with the development of chronic obstructive pulmonary disease (COPD).7,11,12 Clinical symptoms in patients with PRISm, such as wheezing, have been linked to the future development of COPD.11 The same has not yet been described in NSP, though this pattern has been shown to remain stable or evolve into either obstructive or restrictive patterns over time.13 Additionally, there lacks consensus on whether to use pre-BD or post-BD values in the definition of NSP, and whether a correlation exists between a positive BD response and a clinical diagnosis of obstructive lung disease in subjects with NSP.13 Our aim was to explore the clinical characteristics and spirometric data associated with a clinician's diagnosis of obstructive lung disease in a population with NSP.

A total of 16,156 complete and partial PFTs were extracted for the study period between 1/1/2004 and 7/1/2020. Of those who had a complete study (n=9447), 545 PFTs demonstrated NSP (prevalence of 5.8%). After excluding multiple PFTs from the same study subject (n=9) and restricting the study period start date to 1/1/2014 (n=11,059) to reflect the availability of the electronic medical record, 111 subjects with NSP were identified that met the final inclusion criteria. TLC was determined by body plethysmography in the majority (92%) of these 111 subjects.

Our study found a significant association between certain clinical characteristics and spirometric values and a clinician's diagnosis of obstructive lung disease in a cohort of study subjects with NSP. These results are informative given that the interpretation of NSP in clinical settings presents challenges for physicians both prognostically and therapeutically. In this study, nearly two thirds of patients with NSP carried a clinical diagnosis of obstructive lung disease and they were more likely to endorse classical symptoms consistent with this group of disorders – cough, sputum production and wheezing.

Approximately one third of patients with NSP in this study were not assigned an obstructive lung disease diagnosis by their treating physician and this highlights the uncertain nature of NSP and the broader diagnostic potential within this group. Given these findings, clinicians should strongly consider the clinical context and presence of supporting symptoms before assigning a fixed diagnosis to those with NSP.

While it is standard to use post-BD spirometric values in the definition of COPD,20 the same has not been established for NSP. The role for the addition of a BD challenge with NSP was suggested by Pellegrino et al.,1 but there is a lack of evidence in support of this. Iyer et al.13 demonstrated that in those with NSP, a positive BD response, a history of smoking, and higher TLC – alveolar volume (VA) values were all predictors of the development of obstruction on a subsequent PFT when excluding specific airway resistance. Our study provides evidence that in those with NSP, whether identified using pre- or post-BD spirometry values, the presence of a positive BD response is associated with a clinical diagnosis of obstructive lung disease. This observation supports the importance of incorporating BD testing into standard PFT interpretation algorithms for those demonstrating NSP.

The clinical trajectory of patients with PRISm has been the subject of investigation in recent years,7-9,21 specifically assessing whether new spirometric abnormalities are likely to develop on subsequent testing and whether patients can be recategorized when using different classification criterion. For example, Blagev et al.22 showed that 20% of PFT's that originally demonstrated NSP were reclassified as obstructive when utilizing the largest measured vital capacity (VCmax) instead of the classically used FVC. To our knowledge, our study is the first attempt at clinically characterizing subgroups of patients based on the presence or absence of NSP in pre- and post-BD spirometric values. The clinical relevance of this grouping is unknown at this time, but identifying and describing such subgroups is a first step.

We advocate for utilizing precise definitions for PFT patterns of NSP and PRISm. They are similar but separate entities that should not be used interchangeably. The term PRISm should only be used when TLC data is unavailable. The use of detailed definitions becomes even more imperative with the emergence of the newer Global Lung Initiative (GLI) spirometric prediction equations23 and the lack of consensus on whether to use pre- or post-BD spirometric values in the definition of NSP.

Despite a large PFT database, a large number of study subjects were excluded due to lack of access to electronic medical records prior to 1/1/2014. The study was also limited by its retrospective nature at a single acute care center as well as a relatively small sample size. Additionally, obstructive sleep apnea was not included as a relevant comorbidity in our cohort, which may have provided additional associations of interest. There were no obvious survival difference signals between the obstructive and non-obstructive groups, but diffusing capacity was not included in this study. A low diffusing capacity has been shown to be a significant risk factor for all-cause mortality in subjects with PRISm24 so including diffusing capacity in future NSP studies is necessary. In retrospect, using the updated GLI reference equations would have been reasonable and even more astute given the potential for misinterpretation of PFT results and the inaccuracies with the older equations. Prospective studies involving NSP utilizing GLI equations are warranted.

In conclusion, this study demonstrated that subjects with NSP that carried an obstructive lung disease diagnosis (approximately two thirds of the study population) were more likely to be affected by symptoms consistent with this group of disorders, such as cough, wheezing and sputum production. It also supported the role of BD testing in subjects with NSP given that a positive response was associated with a clinical diagnosis of obstruction.

This work has been presented in part at the Annual Research Day of Steward – St. Elizabeth's Medical Center, Boston, MA, USA (May 5, 2022), and the American Thoracic Society Annual Conference in San Francisco, CA, USA (May 13–18, 2022).

The data collection and analysis portion of this project was supported in part by Tufts University – Clinical and Translational Science Institute (Grant Number UL1TR002544).

James Tasch: conceptualization, data curation/acquisition, formal analysis, writing – original draft, writing – review & editing.

Samer Abujaber: data acquisition, writing – review & editing.

Laith Hattar: data acquisition.

Aju Jose: data acquisition.

Lori Lyn Price: formal analysis, writing – review & editing.

Peter LaCamera: conceptualization, writing – review & editing.

Hernan Avella: conceptualization, data curation, writing – review & editing.

All authors have no conflicts of interests to disclose that could have appeared to influence the work reported in this paper.