Validation Criteria for P(ET)CO(2) Kinetics during the Hyperventilation Provocation Test in the Diagnosis of Idiopathic Hyperventilation Syndrome

Background: The hyperventilation provocation test (HPTest) is a diagnostic tool for idiopathic hyperventilation syndrome (HVS), encountered in some long-COVID patients. However, interpretation of the HPTest remains unclear regarding the relevant P(ET)CO(2) values to focus on and whether subjective symptoms should be considered. This study aimed to re-evaluate objective HPTest results for diagnosing HVS by determining accurate P(ET)CO(2) kinetics in two groups of patients previously screened via the Nijmegen questionnaire (NQ). Methods: The kinetics of P(ET)CO(2) during the HPTest were mathematically modeled and compared between 37 HVS patients (NQ ≥23/64) and 37 healthy controls (NQ <23/64) matched for gender, age, and body dimensions. AUC values with sensitivity and specificity were calculated, and analysis was monitored in a validation cohort of 152 routine HPTests. Results: A threshold value of a less than 12.8 mmHg increment of P(ET)CO(2) at the 5th minute of the recovery phase of the HPTest diagnosed HVS patients with excellent sensitivity (0.92) and specificity (0.84). These results were confirmed in the validation cohort, highlighting the presence of 24% false positives/negatives when diagnosing on the basis of complaints in the NQ. Conclusions: For HVS diagnosis, we suggest considering the HPTest, which can more reliably reflect the mechanisms of CO(2) homeostasis and the response of the respiratory center to a stimulus, regardless of the subjective onset of symptoms.