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Research Article

Incidence and predictive factors of hyperventilation syndrome in patients after COVID 19 pneumonia: a prospective cohort study

[version 1; peer review: 2 approved]
Hela CHERIF
https://orcid.org/0000-0002-2086-918X
1-3, Salma Mokaddem
https://orcid.org/0000-0002-7775-3073
1,2, Soumaya Debiche
https://orcid.org/0009-0003-9211-3095
1-3, Slim Kalboussi1,2, Ferdaous Yangui
https://orcid.org/0000-0003-2465-0019
1-3, Mohamed Ridha Charfi1-3
Hela CHERIF
https://orcid.org/0000-0002-2086-918X
1-3, Salma Mokaddem
https://orcid.org/0000-0002-7775-3073
1,2, [...] Soumaya Debiche
https://orcid.org/0009-0003-9211-3095
1-3, Slim Kalboussi1,2, Ferdaous Yangui
https://orcid.org/0000-0003-2465-0019
1-3, Mohamed Ridha Charfi1-3
PUBLISHED 06 Dec 2024
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Background

This study investigates the incidence and predictive factors of Hyperventilation Syndrome (HVS) in patients after COVID 19 pneumonia, addressing the clinical overlap between these conditions.

Methods

A one-month prospective study was conducted, tracking survivors of COVID-19 pneumonia. Patients were evaluated for ongoing clinical status, including HVS and post-traumatic syndrome disorder (PTSD), using clinical questionnaires, mMRC, Post-COVID-19 Functional Status (PCFS) Score, Nijmegen score, and PTSD Checklist for DSM-5 questionnaire.

Results

Our study included 222 patients (median age: 57 years, male predominance 62.6%). Somatic comorbidities, primarily metabolic disorders, were reported in 71.2% of cases. The majority had severe or critical infection forms (78.4%), and 91.9% experienced acute symptoms, with 86.5% having three or more symptom clusters. At one month follow-up, dyspnea (52.9%) and asthenia (21.7%) persisted. Functional limitations (PCFS Grade > 2) were observed in 19.6% of patients. The overall incidence of HVS was 158 per 1000 patients, and PTSD was 445 per 1000 patients. Multivariate logistic regression identified cognitive impairment (acute phase), persistent weight loss (post-COVID-19 phase), PCFS grade > 2, and PTSD as independent factors for developing HVS, with relative risks (RRs) of 3.47 (95%CI [1.48-8.31]; p = 0.004), 11.87 (95%CI [1.25-112.88]; p = 0.031), 3.24 (95%CI [1.34-7.86]; p = 0.009), and 5.98 (95%CI [2.27-15.77]; p < 0.001), respectively.

Conclusion

HVS is prevalent in the post-COVID-19 phase, affecting 15.6 % of survivors. Identified predictive factors suggest the convergence of psychosomatic pathophysiological mechanisms. Further research is crucial for a detailed understanding of these mechanisms in long COVID-19 patients.

Keywords

Hyperventilation Syndrome; COVID-19 pneumonia; Post-Traumatic Stress Disorder; Prospective Studies; Incidence

Corresponding author: Hela CHERIF
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2024 CHERIF H et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: CHERIF H, Mokaddem S, Debiche S et al. Incidence and predictive factors of hyperventilation syndrome in patients after COVID 19 pneumonia: a prospective cohort study [version 1; peer review: 2 approved]. F1000Research 2024, 13:1497 (https://doi.org/10.12688/f1000research.152196.1) First published: 06 Dec 2024, 13:1497 (https://doi.org/10.12688/f1000research.152196.1) Latest published: 06 Dec 2024, 13:1497 (https://doi.org/10.12688/f1000research.152196.1)

Introduction

Covid-19 acute pneumonia presents a diverse clinical spectrum, ranging from asymptomatic cases to severe and critical forms.1,2 Characterized by acute respiratory symptoms, it may also exhibit nonspecific multisystemic manifestations such as fever, gastrointestinal issues, and neuropsychiatric signs, forming distinct symptom clusters.1,3,4 While the acute phase is extensively documented, attention has shifted to the significant concern of the consequences of COVID-19.5,6

Hyperventilation Syndrome (HVS) is delineated by an array of somatic symptoms induced by physiologically inappropriate and reproducible hyperventilation, either entirely or partially instigated by voluntary hyperventilation.7–10 The estimated prevalence of HVS ranges from 6% to 10% within the general population, predominantly afflicting women.7,11 Operating as an exclusion diagnosis, HVS may manifest as an acute crisis triggered by physical or psychological stress, mimicking medical emergencies such as acute coronary syndrome or hypocalcemic spasms. This acute presentation is marked by agitation, dyspnea, and symmetrical paresthesias. In its chronic forms, although more prevalent, diagnosis proves challenging as the hyperventilation component may not be prominently featured. Patients may manifest general indicators such as chronic fatigue, headaches, dyspnea, cough, atypical chest pain, palpitations, or peripheral vasospasm.7,10,12–14

Given the significant clinical symptom overlap between long COVID-19 and HVS, some authors suggest that HVS may play a notable role in the post-COVID-19 phase.15,16 Therefore, our study aims to determine the incidence rate and predictive factors of HVS within a prospective cohort of survivors of COVID-19 pneumonia.

Methods

1. Study design and settings

This study is a prospective cohort investigation conducted at the Pulmonology Outpatient Department of the Internal Security Forces Hospital, La Marsa, Tunisia, from September 2020 to December 2021. The study focuses on patients admitted for SARS-CoV-2 acute pneumonia, with follow-up examinations conducted one month after the acute COVID-19 infection.

2. Participants selection

Eligible participants for this study were individuals aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 pneumonia, who actively participated in post-COVID-19 follow-up appointments. The confirmation of SARS-CoV-2 pneumonia involved the detection of the viral genome in the upper airways using RT-PCR on nasopharyngeal swabs, complemented by a chest CT scan indicating the presence of lung damage. Individuals who declined to participate in this study were excluded from consideration.

Exclusions encompassed patients without a confirmed SARS-CoV-2 infection, and those who presented a normal chest CT scan during the acute infection phase. Furthermore, during the follow-up period, patients who did not complete the Nijmegen Questionnaire were excluded from the analysis.

3. Data collection and outcomes measures

3.1. Step 1: Inclusion at hospital discharge

Clinical data of the enrolled patients were systematically noted. Demographic and clinical features, encompassing age, gender, BMI, cigarette smoking, somatic and psychiatric comorbidities were meticulously obtained. A comprehensive examination of acute COVID-19 pneumonia infection was conducted, focusing on COVID 19-related symptoms. Patients were asked about these symptoms, which were categorized into five symptomatic clusters:

  • ▪ Constitutional Signs: Fatigue, fever, and weight loss

  • ▪ Cardiorespiratory Cluster: Dyspnea, cough, palpitations, and chest pain

  • ▪ Gastrointestinal Cluster: Nausea, vomiting, and diarrhea

  • ▪ Musculoskeletal Cluster: Myalgia and arthralgia

  • ▪ Neuropsychiatric Cluster: Dysgeusia, anosmia, headache, dizziness, and cognitive impairment

Additionally, dyspnea was assessed using the modified Medical Research Council (mMRC) dyspnea scale. Markers of the severity of acute COVID-19 pneumonia were noted, including therapeutic features such as the intensity of oxygen requirement (low or high-flow oxygen therapy), admission to the intensive care unit (ICU), anticoagulation therapy, and the occurrence of complications, particularly pulmonary embolism.

3.2. Step 2: One-month follow-up appointment

Patients’ one-month follow-up appointments were scheduled following their discharge date and communicated to them via phone calls. Key outcome measures assessed during this examination included:

Evaluation of the ongoing clinical status after recovery from acute COVID-19:

  • ▪ Post-COVID-19 Follow-up Questionnaire: Patients were queried about symptoms related to SARS-CoV-2 infection, assessing both residual and newly developed symptoms. Response options were recorded as “yes” or “no”. This questionnaire maintained the same five symptomatic clusters as in the initial assessment.

  • ▪ mMRC Dyspnea Scores: Dyspnea evaluation was tracked using the mMRC dyspnea scale to monitor changes over time.

  • ▪ Post-COVID-19 Functional Status (PCFS) Score17: All patients were administered the validated Arabic version of the PCFS questionnaire, categorizing individuals into five grades based on the degree of functional limitations experienced.

Screening for Hyperventilation Syndrome: The Nijmegen score, assessing the clinical probability of HVS, was administered to all patients during the one-month follow-up. A score higher than 23/64 indicated the presence of HVS.12,18

Screening for Post-Traumatic Stress Disorder (PTSD): COVID-19 survivors were screened for PTSD using the PTSD Checklist for DSM-5 (PCL-5) questionnaire, which has been validated in Arabic. A PCL-5 cutoff score higher than 33/80 suggested probable PTSD.19

Arterial Blood Gas Test (ABG): Patients underwent an ABG test to measure post-recovery blood levels of various gases, including oxygen (O2) and carbon dioxide (CO2).

4. Data analysis

The collected data underwent thorough statistical analysis, with due consideration for variable normality assessed using the Kolmogorov-Smirnov normality test. Nominal values were presented as frequencies and percentages, while continuous non-Gaussian variables were expressed using medians (M) and quartiles [Q1-Q3].

To discern predictive factors for the occurrence of HVS, the sample was divided into two groups: patients with HVS (HVS+) and patients without HVS (HVS-). Initial analytical comparisons were conducted between these two groups to reveal factors associated with HVS. Continuous variables were compared using the Mann-Whitney U test, whereas discrete variables were assessed using the chi-squared or Fisher’s exact test, as appropriate.

Subsequently, a multivariate logistic regression model was employed to evaluate the influence of explanatory variables on the incidence of HVS. Coefficients (β) associated with each independent variable were estimated, and relative risks (RRs) were calculated by exponentiating these coefficients (exp(β)). A 95% confidence interval (95% CI) for each relative ratio was computed to gauge the precision of the estimate. The overall fit of the model was evaluated using the Hosmer-Lemeshow test, with a non-significant result (p > 0.05) indicative of an acceptable fit. Additionally, the model’s explanatory power was assessed through the calculation of the Adjusted R2.

For each value, the data was tabulated using the Microsoft Excel software. All statistical analyses were conducted with a significance threshold set at a p-value of 0.05 considered significant for all data analyses.

5. Ethical considerations

This study involving human subjects is ethically sound. Participants were thoroughly briefed on procedures and objectives, providing verbal consent. It was elected to minimize physical contact and the handling of documents, thereby reducing the risk of transmission in the context of the ongoing epidemic at the time of the study Data confidentiality is assured, adhering to rigorous ethical standards. Ethical committee approval was obtained from the Ethical committee of the FSI hospital under the approval number 05/2020 on September16, 2020.

Results

1. Baseline patient characteristics

Our prospective cohort comprised 222 patients hospitalized for SARS-CoV-2 acute pneumonia. Table 1 provides a summary of their baseline demographic and clinical characteristics. The median age was 57 years [50-67], with a male predominance of 62.6%. Among participants, 35.6% were ever smokers. The average BMI was 29.7 kg/m2 [26.8-32.8]. Notably, 48.1% of patients were classified as obese, and 39.6% were overweight.

Table 1. Baseline Demographic and Clinical Features in the Studied Cohort.

All cohort (n=222)Patients with HVS (n=35)Patients without HVS (n=187) p-value
GenderMale 62.6%48.6%65.2%0.061
Female 38.3%51.4%34.8%
Age (years)57 [50-67]58 [51-67]57 [49-67]0.827
BMI (Kg/m2)29.7 [26.8-32.8]31.2 [28.0-33.1]29.4 [26.7-32.8]0.160
Vaccinated24.8%25.7%24.6%0.888
EverSmoker35.6%30.3%39.9%0.300
Comorbidities
OverallComorbiditiesNone 28.8%14.3%31.6%0.038*
≥1 71.2%85.7%68.4%
Anxiety5.4%11.4%4.3%0.086
Diabetes35.1%25.7%36.9%0.203
Hypertension41.9%51.4%40.1%0.213
Obesity48.1%63.6%45.3%0.052
CoronaryHeartDisease7.2%11.4%6.4%0.293
Dyslipidemia19.4%28.6%17.6%0.133
Asthma8.6%17.1%7%0.048*

Somatic comorbidities were reported in 71.2% of cases, predominantly metabolic disorders. Following obesity, the most prevalent comorbidities were hypertension (41.9%), diabetes (35.1%), and dyslipidemia (19.4%). Cardiorespiratory diseases were less common, with asthma noted in 8.6% and coronary heart disease in 7.2% of patients. A history of anxiety was reported in 5.6% of patients.

2. Acute features of COVID-19 pneumonia

Symptoms manifested in 91.9% of the enrolled patients, with 86.5% experiencing three or more symptom clusters, as detailed in Table 2. Predominantly, constitutional (94.1%), cardiorespiratory (92.8%), and neuropsychiatric (79.7%) signs emerged as the most prevalent clusters during the acute phase. Dyspnea and fatigue ranked highest with incidences of 82.4% and 80.5%, respectively. Individuals reporting dyspnea frequently exhibited severe forms of mMRC 3 and 4 in 24.9% and 45.2% of cases, respectively. Approximately two-thirds of participants also reported a weight loss of around 6 kg [3-10].

Table 2. Clinical Presentation in Patients with Acute COVID-19 Pneumonia and during the Post-COVID-19Phase.

COVID symptomsAcute Phase of COVID-19 PneumoniaOne-month post-COVID-19pneumonia
All Cohort (n=222)Patients without HVS (n=187)Patients with HVS (n=35)p-value All Cohort (n=222)Patients without HVS (n=187)Patients with HVS (n=35)p-value
Constitutionalsigns94.1%95.7%85.7% 0.021* 23%23,0%22.9%0.986
 Fatigue80.5%80.6%80%0.93021.7%18.8%37.1%0.016*
 Fever66.1%65.6%68.6%0.7330.5%0.5%0%0.664
 Weightloss67%66.7%68.6%0.8262.3%1.1%8.6%0.006*
 Weightloss (Kg)6 [3-10]6 [3-10]5 [3-10]0.206----
Cardiorespiratory cluster92.8%92.5%94.3%0.71062.2%62.6%60%0.774
 Chest pain41.2%38.2%57.1%0.036* 19.9%19.4%22.9%0.634
 Cough57%57.5%54.3%0.72213.1%11.3%22.9%0.063
 Palpitations35.3%33.9%42.9%0.30713.6%10.8%28.6%0.005
 Dyspnea82.4%81.2%88.6%0.29352.9%52.7%54.3%0.862
 Dyspnea stages
  mMRC 114.7%15%13.3%0.33144.5%47%31.6%0.542
  mMRC 215.3%16.3%10%45.4%43%57.9%
  mMRC 324.9%26.5%16.7%8.4%8%10.5%
  mMRC 445.2%42.2%60%1.7%2%0%
Gastrointestinal Cluster50.5%52.4%40%0.1785.9%5.9%5.7%0.969
 Nausea and vomiting32.6%32.3%34.3%0.8142.3%2.2%2.9%0.796
 Diarrhea37.7%35.7%48.6%0.1490.5%4.8%5.7%0.827
Musculoskeletal cluster73.4%74.9%65.7%0.26128.4%28.9%25.7%0.703
 Myalgia67%66.7%68.6%0.82620.4%18.3%31.4%0.076
 Arthralgia58.8%57.5%65.7%0.36720.4%18.3%31.4%0.076
Neuropsychiatric Cluster79.7%82.4%65.7%0.025* 40.5%40.6%40%0.943
 Headache58.4%57.5%62.9%0.55715.4%13.4%25.7%0.065
 Dizziness40.7%38.2%54.3%0.07514.9%11.8%31.4%0.003*
 Cognitive impairment41.4%36.2%68.6%<0.001* 25%20.5%48.6%<0.001*
 Dysgeusia40.7%37.6%57.1%0.031* 4.1%3.8%5.7%0.592
 Anosmia38.5%34.9%57.1%0.013* 5.4%4.3%11.4%0.088
Overall Clusters
 Asymptomatic0.9%0.5%2.9%0.10123.4%23%25.7%0.194
 1 cluster3.2%2.1%8.6%34.2%32.6%42.9%
 2 clusters9.5%9.1%11.4%18.5%20.9%5.7%
 ≥ 3 clusters86.5%88.2%77.1%23.9%23.5%25.7%

The majority of participants presented with severe or critical infection forms (78.4%). Radiological manifestations of COVID-19pneumonia affected over 50% of the pulmonary parenchyma on chest CT scans in 73.8% of instances. High-flow oxygen therapy was required in 40.3%, while 6% of patients necessitated ICU admission for respiratory support. Pulmonary embolism complicated the course of 10.3% of COVID-19 pneumonias. The median hospital stay in our cohort was 10 days [7-15].

3. One-month follow-up evaluation

3.1. Clinical and functional assessment

The post-COVID-19 phase marked a substantial improvement in all symptoms, demonstrating a significant decrease in symptom occurrence and cluster cumulation compared to the early infection phase. At the one-month appointment, 23.4% of our cohort was asymptomatic, and 34.2% exhibited mono-cluster symptoms. The cardiorespiratory and neuropsychiatric clusters were the most residual, observed in 62.2% and 40.5% of patients, respectively. The most persistent physical complaints were dyspnea (52.9%) and asthenia (21.7%). Notably, dyspnea presentations were less severe, with 89.9% staged as mMRC 1 or mMRC 2. A quarter of participants still reported cognitive impairment at the one-month follow-up. The Post-COVID-19 Functional Status (PCFS) assessment revealed that 47.4% of patients experienced no functional limitations (Grade 0). Negligible (Grade 1) and slight (Grade 2) functional limitations were observed in 16.3% and 16.7% of examined patients, respectively. Severe limitations (Grade 4) affected only 4.2% of cases.

3.2. Screening for HVS and PTSD

The median Nijmegen Score was 9 points [3-18], with 35 participants having a score suggestive of HVS, resulting in an overall hospital Incidence of 158 per 1000 patients, which translates to 15.8%. Post-traumatic stress disorder (PTSD) screening using PCL-5 indicated an average score of 30 points [23-46], with 44.5% of our cohort displaying psychological distress consistent with a PTSD diagnosis.

3.3. Arterial blood gas test

The ABG test was performed on 100 patients. The average PaO2 and PaCO2 were 89 mmHg [81.5-98] and 36.2 mmHg [35-39], respectively. Hypoxemia and hypocapnea were reported in 21% and 24% of ABG tests, respectively. The median bicarbonate concentration was 25 mmol/L [23.5-26], with 17% of tested patients showing levels lower than the limit of normal. The median pH level was 7.43 [7.42-7.45]. Only 4% of patients featured alkalosis.

Comparison between Two Groups: HVS+ and HVS-

The overall patient characteristics of both groups revealed general similarities in demographics and clinical features, as detailed in Table 1. There were no significant differences in age, smoking habits, or BMI between the two groups. Although HVS+ patients showed a trend towards female predominance compared to HVS-, this difference did not reach statistical significance (p=0.061). The presence of one or more comorbidities was significantly associated with HVS+ (85.7% versus 68.4%; p=0.038). However, no significant variations were noted in psychiatric or somatic comorbidities between the two groups, except for asthma, which was statistically associated with HVS+ (p=0.048).

In Figure 1 and Table 2, we highlighted the main distinctions between the two groups concerning the clinical presentation of acute COVID-19 pneumonia and symptoms reported one month after. During the early infectious episode, patients with HVS tended to manifest slightly fewer symptoms and less cluster accumulation than patients without HVS. This trend held true for all symptomatic clusters except for the cardiorespiratory cluster (94.3% versus 92.5%; p=0.710), where complaints like dyspnea (p=0.293) and chest pain (p=0.036) were notably more prevalent in this group. Patients without HVS significantly exhibited, in terms of frequency, more symptoms related to neuropsychiatric cluster (p=0.025) during the acute viral infection, even though specific symptoms such as dysgeusia (p=0.031), anosmia (p=0.013), and cognitive impairment (p<0.001) were significantly associated with HVS.

1f5e89aa-db3b-494c-be52-f6bebbbfbc07_figure1.gif

Figure 1. Comparative Radar Chart Illustrating COVID-19 Symptoms in Acute Pneumonia and the Post-Acute Phase.

(A): Symptoms during the Acute Phase; (B): Symptoms during the Post-Acute Phase; HVS: Hyperventilation Syndrome. Symptoms marked with an asterisk (*) indicate a significant difference between patients with and without HVS (p<0.05)

Concerning the post-acute phase, both groups experienced recovery from most symptoms. However, the HVS+ group showed a significantly slower recovery in terms of signs suggestive of HVS, particularly palpitations (p=0.005) and dizziness (p=0.003). Notably, signs unrelated to the classical clinical constellation of hyperventilation, particularly persistent weight loss (p=0.006) and residual cognitive impairment (p<0.001), were observed.

No marker of COVID-19 pneumonia severity was significantly associated with HVS in our cohort ( Table 3). Substantial differences were not observed between both groups in terms of the clinical severity of COVID-19, the radiological extension of COVID-19 lesions, oxygen requirement, ICU admission, the incidence of pulmonary embolism, or hospital stay duration. No significant difference in ABG tests was encountered in both groups either.

Table 3. Acute COVID-19 Severity Markers and Post-Infection Sequelae in Our Cohort.

All Cohort (n=222) Patients with HVS (n=35) Patients without HVS (n=187) p value
Acute COVID-19 PneumoniaMarkers
 Infection Severity
  Mild to Moderate21.6%71.4%79.7%0.276
  Severe to Critical78.4%28.6%20.3%
 Extension of radiologic lesions on initial Chest CT scan
  <10%3.6%8.6%2.7%0.271
  10-25%22.5%20%23%
  25-50%44.1%37.1%45.5%
  50-75%23.4%22.9%23.5%
  >75%6.3%11.4%5.3%
 Oxygenrequirement
  Low O2 flow59.7%54.3%60.8%0.474
  High O2 flow40.3%45.7%39.2%
  ICU Admission6%6.5%5.9%0.908
  PulmonaryEmbolism10.3%6.9%10.9%0.512
  Hospital Stay (days)10 [7-15]12.5 [8-15.5]10 [7-15]0.084
One-month post-COVID-19 pneumonia
 Post-COVID-19 Functional Status
  Grade 047.4%8.6%55%<0.001*
  Grade 116.3%22.9%15%
  Grade 216.7%25.7%15%
  Grade 315.3%37.1%11.1%
  Grade 44.2%5.7%3.9%
 Nijmegen Score (points)9 [3-18]33 [25-40]7 [2-14]-
 PCL-5 (points)30 [23-46]55 [34-75]28 [22-41]<0.001*
 PTSD44.5%80,00%37.7%<0.001*
Arterial Blood Gas All Cohort (n=100) Patients with HVS (n=17) Patients without HVS (n=83) p-value
PH7.43 [7.42-7.45]7.42 [7.40-7.44]7.43 [7.42-7.45]0.177
PaO2 (mmHg)89 [81.5-98]90 [84-97]89 [81-98]0.993
PaCO2 (mmHg)36.2 [35-39]39 [35-40.2]36 [35-39]0.237
[HCO3-] (mmol/L)25 [23.5-26]25 [23.5-26]24 [23-26]0.941
SaO2 (%)97 [96-98]97 [96-97.4]97 [96-98]0.402

Distinctive functional and psychological outcomes were evident between the compared groups at the one-month appointment ( Table 3). Worse PCFS grades were significantly associated with the HVS+ group, as most patients with HVS presented with PCFS grade > 2 (42.8% versus 15%; p<0.001). The PCL-5 score was significantly higher in patients with HVS (55 [34-75] versus 28 [22-41]; p<0.001). A positive diagnosis of PTSD was significantly associated with HVS (p<0.001).

4. Predictive factors for HVS

To identify predictive factors for HVS within our cohort, logistic regression analysis was conducted, encompassing various variables, including demographic and clinical factors, acute COVID-19 pneumonia presentation, COVID-19 pneumonia severity markers, persistent symptoms, PCFS, and PTSD. As indicated in Table 4, multivariate analysis revealed that presenting with cognitive impairment during the acute phase, persistent weight loss, PCFS grade > 2, and PTSD were independent factors for developing HVS, with a relative risk (RR) of 3.47 (p = 0.004), 11.87 (p = 0.031), 3.24 (p = 0.009), and 5.98 (p < 0.001), respectively.

Table 4. Univariate and Multivariate Logistic Regression Analysis of Factors Influencing theOccurrence of Hyperventilation Syndrome.

UnivariateLogisticRegressionMultivariateLogisticRegression Model*
βSEp-value OR95% CIAdjusted βSEWald χ2p-value RR 95% CI
Constant------3.7560.527
Comorbidities ≥ 11.0170.5080.0452.771.02-7.49
Acute COVID-19 Phase
Constitutionalsigns-1.3160.6030.0290.270.08-0.87
Neuropsychiatric cluster0.8900.4040.0282.431.10-5.38
Chest Pain0.7700.3730.0392.161.04-4.49
Cognitive Impairment1.3460.3950.0013.841.77-8.331.244 0.433 8.23 0.004 3.47 1.48-8.11
Dysgeusia0.7930.3740.0342.211.06-4.60
Anosmia0.9090.3750.0152.481.19-5.17
Post-Phase
Fatigue0.9360.3970.0182.551.17-5.55
WeightLoss2.1550.9330.0218.621.39-53.672.475 1.149 4.64 0.031 11.88 1.25-112.88
Palpitation1.2000.4430.0073.321.39-7.91
Dizziness1.2290.4290.0043.421.47-7.92
Cognitive Impairment1.2960.384<0.0013.651.72-7.76
PCFS > Grade 21.4470.400<0.0014.251.94-9.311.175 0.452 6.75 0.009 3,24 1.34-7.86
PTSD1.8880.449<0.0016.612.74-15.941.788 0.495 13.07 <0.001 5.98 2.27-15.77

* Hosmer-Lemeshow test for model fit (χ2 = 1.379, p = 0.947). Adjusted R2 = 0.32; Significance is determined for all p-values < 0.05; SE: Standard Error; RR: relative risk RR; CI: Confidence Interval; PCFS: Post COVID-19 Functional Status Scale; PTSD: Post-Traumatic Stress Disorder.

The probability (p) of developing HVS based on this multivariate logistic regression model is represented by the following equation:

logit(p)=−3.756+1.244∗X1+2.475∗X2+1.175∗X3+1.788∗X4
where:
X1:Cognitive impairment during the acute COVID−19phase(1if present,0if absent)
X2:Weight loss during the post−COVID−19phase(1if present,0if absent)
X3:PCFS grading(1if PCFS>2,0if PCFS≤2)
X4:PTSD during the post−COVID19phase(1if present,0if absent)

The logistic regression model’s adequacy was assessed through the Hosmer-Lemeshow test, yielding a non-significant result (χ2 = 1.379, p = 0.947), suggesting a satisfactory fit of the model to the data. The model’s explanatory power was further evaluated using the Adjusted R2, revealing a value of 0.32. This indicates that approximately 32% of the variance in the occurrence of HVS in the post-COVID-19 phase is accounted for by these four independent factors.

Discussion

Despite considerable scientific enthusiasm and extensive medical investigations into the clinical aspects and therapeutics of both acute infection and persistent COVID-19 symptoms, researchers have paid limited attention to HVS in survivors of COVID-19 pneumonia.16,20 This study sheds light on this topic through a prospective cohort study involving 222 patients and showed that HVS is prevalent in the post-COVID-19 phase, affecting 15.6% of survivors. Identified predictive factors suggest the convergence of psychosomatic pathophysiological mechanisms.

The mechanisms underlying symptoms in HVS remain incompletely understood. Authors posit that hypocapnia and alkalosis induced by inappropriate hyperventilation play a crucial role. Increased ventilation leads to dyspnea due to the muscular effort it engenders, creating a cycle of stress that perpetuates the process.7,21,22 Furthermore, symptoms potentially related to hypocapnia are inherently anxiogenic. This scenario is frequently observed in response to various stimuli, both organic and psychiatric, such as exercise or stress, imparting psychosomatic components to this syndrome.13,23

To the best of our knowledge, this cohort study is the inaugural contribution in the literature assessing the incidence of HVS in a substantial sample of patients after COVID-19 pneumonia. Our estimation places the incidence of 156 per 1000 patients hospitalized for COVID-19 pneumonia., surpassing the classical reported prevalence of 6-10% in the general population.7,11 Previous studies examining post-COVID-19 patients have been confined to limited case series with cross-sectional designs, thus lacking sufficient statistical power to accurately ascertain the incidence of this condition.15,16,20,24 While HVS is traditionally associated with a higher prevalence in females, with a male-to-female sex ratio ranging from 1:2 to 1:4, our findings suggest an equal gender distribution in survivors of COVID-19.7,11

Within our cohort, patients with somatic comorbidities exhibit a significant susceptibility to developing HVS compared to their healthier counterparts. Interestingly, common chronic conditions like obesity, hypertension, or diabetes did not exhibit a comparable association, suggesting a potential psychological influence rather than a solely somatic component. The stressful atmosphere linked to the COVID-19 pandemic emanates not just from the nature of the disease but also from the extensive attention given by mainstream and social media. This dissemination of overwhelming and alarming information is particularly pronounced for populations with comorbidities.25–27 The persistent perception of threat could potentially trigger HVS in patients recovering from acute COVID-19 pneumonia. This heightened sense of vulnerability may be further exacerbated in individuals with pre-existing respiratory conditions, especially asthma, as supported by the significant association found in our study.28,29

In our investigation, we failed to identify distinct acute clinical presentations reliably predicting the subsequent onset of HVS. Patients who later developed hyperventilation manifested less severe COVID-19 symptoms and a reduced accumulation of symptom clusters during the acute phase in comparison to those who did not develop HVS. An exception regarding anosmia and dysgeusia should be highlighted. Experiencing these latter symptoms during the acute phase was strongly associated with the occurrence of HVS. Similarly, cognitive impairment also emerged as an independent predictive factor for HVS, as identified in our multivariate regression model with a relative risk RR of 3.47.

These findings prompt considerations regarding a potential organic mechanism for HVS in individuals who have contracted COVID. Multiple studies have highlighted the notable neurotropism of SARS-CoV-2.30 This neural spread rapidly leads to disruptions in taste and olfaction from the onset of infection due to alterations in the neuroperception of gustatory and olfactory chemosensors caused by the virus.30–32 Moreover, various authors posit that viral neurotropism contributes to the silent hypoxia reported in 32%–65% of infected individuals, affecting both peripheral and central respiratory chemoreceptors. This spread may induce inflammation and impair the processing of hypoxia signals at higher respiratory centers, resulting in inappropriate normal breathing despite severe hypoxia.33–35 The impairment in the central respiratory command might be proposed as a potential common denominator linking silent hypoxia observed in acute COVID-19 to the later onset of HVS in post-infections. Further neurophysiological studies are imperative to elucidate the precise impact of COVID-19 on chemosensation and nervous respiratory command during and after infection,

Surprisingly, our data do not state any significant association between HVS and markers of COVID-19 infection gravity, including acute COVID-19 form severity, oxygen requirement, radiological extension of pneumonia, and serious complications like ICU admission and pulmonary embolism. Many previous studies also find no substantial correlation between acute pneumonia severity and several clinical and functional outcomes in long COVID-19.36,37

In the post-infection phase, both patients with and without HVS experience symptom relief and a decrease in the accumulation of symptom clusters, consistent with observations in previous studies on cohorts with long COVID-19.1,37 Notably, individuals who develop HVS appear to show a slower improvement in symptoms, continuing to experience residual issues such as dyspnea, palpitations, dizziness, and cognitive impairment. These lingering symptoms, often associated with HVS, suggest a significant contribution of HVS to the overall scenario of long COVID-19.16,20,24

Of importance, continuous weight loss—a physical sign unrelated to the typical presentation of HVS—predicts the occurrence of HVS by approximately 12-fold in our statistical regression model. This novel finding has not been previously reported in the literature. During the early COVID-19 infection, organic factors such as viral aggression, the hospitalization context, and alterations in taste and smell may affect the energy balance with less food intake and increased energy expenditure, leading to weight loss.38,39 At the post-infection stage, persistent weight loss would be rather explained by psychological sequelae associated with COVID-19 and the quarantine, which may have increase depression, anxiety, and other mental health issues.27,40,41 Restrictive feeding behavior is widely observed in patients with long COVID-19 across all age groups.38,42 In one prospective study tracking 1230 COVID-19 survivors, Tosato et al. diagnosed malnutrition in 22% of patients 4-5 months after acute disease. Stress can cause changes in appetite, energy, desires, and interests, and at the same time, it is a triggering factor of HVS.39,41

Furthermore, the PCFS scale may be a valuable tool to suspect HVS in COVID-19 survivors. Our findings identify that individuals displaying functional limitations of grade 3 and 4 are 3.24-fold exposed to developing ventilatory dysfunction during convalescence. Laskovski et al. analyzed PCFS in a longitudinal cohort of 140 COVID-19 survivors and concluded that alterations in PCFS were significantly influenced not only by residual fatigue and dyspnea but also by manifestations of depression and anxiety in COVID-19 survivors, reminding us once again of the HVS manifestations.27,43,44

PTSD symptoms among individuals recovering from COVID-19 present an additional explanatory factor for HVS in the post-COVID-19 phase.45–47 Our multivariate analysis reveals a sixfold increase in the incidence of HVS associated with the presence of PTSD symptoms. A longitudinal observational study in the Netherlands, encompassing 239 patients, highlighted a substantial prevalence of PTSD—37.2% at 3 months and 26.8% at 6 months post-onset of COVID-19 symptoms.48 Similarly, a UK-based online survey, involving 3290 COVID-19 patients, documented a progressive and notable escalation in PTSD prevalence: 15% at 4–8 weeks, 17.3% at 8–12 weeks, and 18.9% at >12 weeks.49

The lasting psychological impact on individuals who have survived the infection may result from the stigma linked with COVID-19, the circumstances of lockdown, and the apprehension of contagion.27,44 This enduring effect could contribute to prolonged psychological consequences. Ongoing intrusive thoughts or images related to traumatic events experienced during COVID-19, along with flashbacks of hospitalization, including witnessing the demise of other infected individuals, may act as triggers for inappropriate hyperventilation in COVID-19 survivors.27,41,44 This rationale aligns with the significant association observed in our study between the PCL-5 score and HVS.

Our study fills a significant gap in the current literature by providing substantial evidence regarding the prevalence of HVS in patients with long COVID. This contributes to a more comprehensive understanding of respiratory dysfunction within this population. We have developed a logistic regression model to assess the likelihood of developing HVS in post-COVID-19 individuals, incorporating predictive factors from both acute and post-infection phases. The prospective design, along with a large sample size, enhances the robustness of our study, minimizing biases and facilitating the generalization of our findings to diverse populations. This could provide valuable assistance to clinicians managing long COVID-19 survivors, aiding in the prompt detection of HVS.

However, a noteworthy limitation is our inability to enhance the accuracy of HVS diagnosis by including a hyperventilation provocation test alongside the Nijmegen questionnaire.12 This limitation stems from the stringent COVID-19 precautions mandated during the pandemic to curb infection spread. Additionally, the study’s follow-up duration was limited to one month for all participants, mainly due to a significant proportion discontinuing their participation or being lost to follow-up after symptom relief.

Conclusion

HVS manifests in 15.6% of COVID-19 pneumonia survivors, underscoring its significance in the post-acute phase. Recognizing this condition is vital for healthcare providers managing lCOVID-19 cases and follow-up, as it significantly contributes to the array of residual symptoms of post-acute pneumonia. The predictive factors for HVS, identified through our multivariate analysis, highlight the convergence of psychosomatic pathophysiological mechanisms. Further investigations, particularly in neurophysiology and psychology, are imperative to elucidate the precise mechanisms promoting HVS in long COVID-19 patients. The development of individualized management strategies can enhance the care and well-being of individuals grappling with the lasting effects of COVID-19.

Author contributions

H. Cherif, MR. Charfi conceived the study design. H. cherif carried out patients follow up and data collection. H. Cherif and S. Kalboussi operated the data analysis. H. Cherif, S. Mokaddem, and S. Debbiche drafted the manuscript. F. Yangui and MR. Charfi supervised the research progression. All authors approved the final version of the manuscript.

Data availability statement

Underlying Data

Repository name: Zenodo. Title of project: Incidence and Predictive Factors of Hyperventilation Syndrome in Patients after COVID-19 Pneumonia: A Prospective Cohort Study. DOI: 10.5281/zenodo.12668621.50

This project contains the following underlying data:

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Extended data

Zenodo: Extended Data, 10.5281/zenodo.14210595.51

This project contains the following underlying data:

  • • Data file 1: ethic statement HVS

  • • Data file 2: STROBE_checklist_cohort

  • • Data file 3: Data collection form

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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CHERIF H, Mokaddem S, Debiche S et al. Incidence and predictive factors of hyperventilation syndrome in patients after COVID 19 pneumonia: a prospective cohort study [version 1; peer review: 2 approved]. F1000Research 2024, 13:1497 (https://doi.org/10.12688/f1000research.152196.1)
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Nesrine Kallel, Faculty of Medicine of Sfax, Sfax, Tunisia 
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https://doi.org/10.5256/f1000research.166928.r371473
This is a prospective study which aim to determine the incidence and predictive factors of Hyperventilation Syndrome (HVS) in patients after COVID 19 pneumonia. Results share  that the principal factors for developing HVS  are cognitive impairment , persistent weight loss ... Continue reading
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Ahmed Ben saad, Faculty of Medicine of Monastir, Monastir, Tunisia 
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https://doi.org/10.5256/f1000research.166928.r371476
This prospective study aimed to determine the incidence and predictive factors of Hyperventilation Syndrome (HVS) in patients after COVID 19 pneumonia. Authors found that cognitive impairment (acute phase), persistent weight loss (post-COVID-19 phase), Post-COVID-19 Functional Status (PCFS) grade > 2, ... Continue reading
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Ben saad A. Reviewer Report For: Incidence and predictive factors of hyperventilation syndrome in patients after COVID 19 pneumonia: a prospective cohort study [version 1; peer review: 2 approved]. F1000Research 2024, 13:1497 (https://doi.org/10.5256/f1000research.166928.r371476)
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  • Author Response 31 Mar 2025
    Hela CHERIF, Pulmonology, University of Tunis El Manar, Tunis, Tunisia
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    Thank you for your thoughtful and positive feedback on our manuscript. We appreciate your careful review and insightful comments.
    Regarding the incidence of Hyperventilation Syndrome (HVS), the correct ... Continue reading
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  • Author Response 31 Mar 2025
    Hela CHERIF, Pulmonology, University of Tunis El Manar, Tunis, Tunisia
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    Dear Reviewer,
    Thank you for your thoughtful and positive feedback on our manuscript. We appreciate your careful review and insightful comments.
    Regarding the incidence of Hyperventilation Syndrome (HVS), the correct ... Continue reading
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