Ventilation and perfusion abnormalities following recovery from noncritical COVID-19

Abstract

RATIONALE: Dyspnea and respiratory impairment are sequelae of COVID-19.

OBJECTIVES

The objectives of this study were to observe the prevalence and clinical relevance of ventilation (V) and perfusion (Q) impairment, evaluated by ventilation/perfusion-single-photon emission computed tomography-computed tomography (VQ-SPECT-CT), in individuals with no history of lung disease 4-weeks after recovery from noncritical COVID-19.

METHODS

We enrolled 25 COVID-19 patients’ post-recovery and 11 control subjects. All participants underwent VQ-SPECT-CT using ^99mTc-Technegas for V and ^99mTc-macroaggregated albumin for Q, spirometry, six-minute-walk-test, blood draw and completed the modified Medical Research Council (mMRC) dyspnea-scale and St. Georges Respiratory Questionnaire (SGRQ). VQ-SPECT-CT was reviewed to report lung function and structure abnormalities and ventilation-heterogeneity was quantified to evaluate associations with symptoms, exercise-capacity and inflammatory markers.

MEASUREMENTS AND MAIN RESULTS: Of 25 post-COVID-19 participants, 9 were hospitalized and 16 home-isolated during acute-infection. A total of 88% of hospitalized and 44% of home-isolated participants were reported to have V defects (matched VQ defects: 63% and 44%; mismatched V defects: 38% and 13%), compared to 30% of never-COVID-19 controls (matched VQ defects: 30%, mismatched V defects: 10%) (P = 0.02 and P = 0.68, respectively). Ventilation-heterogeneity was greater in hospitalized (P = 0.003), but not home-isolated participants, compared to the never-COVID-19 controls. Post-COVID-19 ventilation-heterogeneity correlated with the dyspnea-scale (r = 0.45, P = 0.03), SGRQ-score (r = 0.41, P = 0.04), 6MWD (r=-0.49, P = 0.02), SpO2 (P = -0.55, P = 0.005), CT parenchymal opacities (r = 0.42, P = 0.04) and neutrophil percent (r = 0.45, P = 0.04), but not pro-inflammatory cytokines, C-reactive protein or D-dimer.

CONCLUSIONS

This small functional lung imaging study revealed ventilation impairment in individuals with no history of lung disease recovering from noncritical COVID-19 that was associated with parenchymal opacities, respiratory symptoms and exercise-capacity.

RÉSUMÉ

JUSTIFICATION: La dyspnée et l’insuffisance respiratoire sont des séquelles de la COVID-19.

OBJECTIFS: Observer la prévalence et la pertinence clinique de l’altération de la ventilation (V) et de la perfusion (Q), évaluée par TEMP/TDM V/Q, chez les personnes sans antécédents de maladie pulmonaire quatre semaines après la guérison de la COVID-19 non critique.

MéTHODES: Nous avons recruté 25 patients atteints de COVID-19 après la récupération et 11 sujets témoins. Tous les participants ont subi une TEMP/TDM V/Q en utilisant ^99mTc-Technegas pour l’albumine V et ^99mTc-macroagrégée pour Q, une spirométrie, un test de marche de six minutes et un prélèvement sanguin, en plus de remplir l’échelle de dyspnée modifiée du Medical Research Council (mMRC) et le questionnaire respiratoire de St. Georges (SGRQ). La TEMP/TDM V/Q a été examinée afin de déclarer les anomalies de la fonction et de la structure pulmonaires et l’hétérogénéité de la ventilation a été quantifiée afin d’évaluer les associations avec les symptômes, la capacité d’exercice et les marqueurs inflammatoires.

MESURES ET PRINCIPAUX RéSULTATS: Sur 25 participants post-COVID-19, 9 ont été hospitalisés et 16 isolés à domicile pendant l’infection aiguë. 88 % des participants hospitalisés et 44 % des participants isolés à domicile présentaient des anomalies de type V (anomalies de type V/Q appariées : 63 % et 44 % ; anomalies de type V non appariées : 38 % et 13 %), comparativement à 30 % des témoins n’ayant jamais été atteints de Covid-19 (anomalies de type V/Q appariées : 30 %, anomalies de type V non appariées : 10 %) (p = 0,02 et p = 0,68 respectivement). L’hétérogénéité de la ventilation était plus élevée chez les participants hospitalisés (p = 0,003), mais pas chez les participants isolés à domicile, par rapport aux témoins jamais atteints de la COVID-19. L’hétérogénéité de la ventilation post-COVID-19 est corrélée avec l’échelle de la dyspnée (r  = 0,45, p = 0,03), le score SGRQ (r = 0,41, p = 0,04), la 6MWD (r = -0,49, p = 0,02), la SpO2 (p =-0,55, p = 0,005), les opacités parenchymateuses CT (r = 0,42, p = 0,04) et le pourcentage de neutrophiles (r = 0,45, p = 0,04), mais pas avec les cytokines pro-inflammatoires, la protéine C-réactive ou le D-dimère.

CONCLUSIONS: Cette petite étude d’imagerie pulmonaire fonctionnelle a révélé une altération de la ventilation chez les personnes n’ayant aucun antécédent de maladie pulmonaire se remettant d’une COVID-19 non critique associée à des opacités parenchymateuses, des symptômes respiratoires et la capacité d’exercice.

Keywords:

• COVID-19
• perfusion
• Technegas^TM
• ventilation
• VQ SPECT-CT

Disclosure statement

T. Ho reports grants from Fisher and Paykel and personal fees from Sanofi, outside the submitted work. P. Nair reports grants from AstraZeneca, Teva, Roche, Novartis, Sanofi and Foresee, and personal fees from AstraZeneca, Teva, Roche, Novartis, Merck and Equillium, outside the submitted work. M. Mukherjee reports grants from Methapharm Specialty Pharmaceuticals, and personal fees from AstraZeneca and GlaxoSmithKline, outside the submitted work. S. Svenningsen reports grants from Cyclomedica during the conduct of the study; personal fees from AstraZeneca, Novartis, Polarean, and Arrowhead Pharmaceuticals, outside the submitted work. C. Venegas, C.J.C. Marriott, K. Son, R. Jamil, M. Jamal, M. Kjarsgaard, C. Huang, K. Radford, M.B. Dolovich, C.E. Farrow, T.H. Farncombe, M. Lubanovic and E. Haider have nothing to disclose.

Author contributions

C. Venegas and S. Svenningsen were responsible for data acquisition, analysis and interpretation, and for preparing the first draft of the manuscript. C.J.C. Marriott, T.H. Farncombe, C.E. Farrow and M. Jamal were responsible for VQ SPECT-CT acquisition, analysis and/or interpretation. M. Lubanovic and E. Haider were responsible for interpretation of CT scans. K. Son, R. Jamil, K. Radford and M. Mukherjee were responsible for molecular analysis. C. Venegas, T. Ho and P. Nair were responsible for recruiting study participants and for clinical interpretation of the data. P. Nair, M. Mukherjee and S. Svenningsen were responsible for the study design. All authors contributed to manuscript development and had an opportunity to review and revise the manuscript and approved its final submitted version.

Additional information

Funding

This was an investigator-initiated study funded by Cyclomedica Australia Pty Ltd. The funder (Cyclomedica Australia Pty Ltd) had no role in the design of the study, the collection and analysis of the data or the preparation of the manuscript.

T. Ho is supported by the McMaster Department of Medicine Early Career Research Award. P. Nair is supported by the Frederick E. Hargreave Teva Innovation Chair in Airways Disease. M. Mukherjee is supported by an early career award from Canadian Institutes of Health Research and Canadian Asthma Allergy Immunology Foundation. S. Svenningsen is supported by the Canada Research Chairs program and holds a Tier 2 Canada Research Chair.