Chronic obstructive pulmonary disease (COPD) is a common condition that is characterized by tissue damage and a progressive narrowing of the airways, leading to reduced airflow. Extended exposure to noxious particles or gases, particularly cigarette smoke, may lead to chronic inflammation,

which is associated with anatomical abnormalities in the lungs. Chronic inflammation leads to the narrowing of the airway and a decrease in the ability of the lungs to recoil. The disease often presents with symptoms such as coughing, difficulty breathing, and the production of sputum. The range of symptoms may vary from being asymptomatic to experiencing respiratory failure [1].

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines chronic obstructive lung disease as a condition characterized by a persistent limitation of airflow. Emphysema, chronic bronchitis, and small airway disease are all classified as chronic obstructive pulmonary illnesses. Emphysema is a condition where the walls of the airways beyond the terminal bronchioles become swollen in a way that cannot be reversed and does not include fibrosis. Chronic bronchitis is characterized by the regular expulsion of mucus by coughing, occurring on most days for a duration of three months each year, during a period of two consecutive years. Small airway disease is caused by the restriction of the bronchioles. Bronchial asthma is excluded from this category because changes in the airways associated with it are often reversible [2,3].

The airflow restriction associated with COPD is often progressive, despite being avoidable and becoming increasingly manageable. In addition, COPD is commonly linked to and may affect a wide range of co-occurring conditions that contribute to morbidity and mortality, including metabolic syndrome and heart diseases [4].

Pulmonary arterial hypertension (PAH) refers to a diverse range of conditions characterized by increased pressure in the pulmonary artery. Patients often exhibit progressive shortness of breath during physical activity, accompanied by indications of strain or failure in the right side of the heart [5].

In individuals with chronic obstructive pulmonary disorders (COPD), pulmonary hypertension is often underdiagnosed and under evaluated. Given the association between pulmonary hypertension and a significant mortality rate resulting from complications such as cor pulmonale, it is essential to adopt a cohesive strategy for both diagnosing and treating the condition [6,7].

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is a severe medical condition primarily characterized by severe pneumonia. This pneumonia is frequently accompanied by acute respiratory distress syndrome (ARDS), respiratory failure (RF), and multiple organ dysfunction/failure [8,9].

Post COVID-19, cardiovascular problems occur often, affecting around 20-30% of patients. These consequences are significant and have a detrimental impact on the prognosis [10].

The pulmonary involvement is characterized by bilateral presence of significant interstitial and alveolar inflammatory infiltrates, thickening of alveolar septa, vascular congestion, and lung oedema. These factors may contribute to the development of pulmonary fibrosis in some individuals. Lung parenchymal injury and altered pulmonary circulation may result in the development of pulmonary hypertension [11,12]

A study conducted by Taha H A et al., reported that 70% of post-COVID-19 individuals with suspected symptoms of pulmonary hypertension have been diagnosed with the condition. Advanced age, higher BMI, presence of diabetes mellitus, smoking, lower levels of arterial oxygen tension (PaO2), higher CORADS score, and aberrant results on spirometry are all characteristics that enhance the chance of developing pulmonary hypertension in individuals who have recovered from COVID-19 [13].

The goal is to enhance the patient's quality of life and prognosis by considering appropriate therapeutic interventions. Identifying these patients at an early stage may result in prompt beginning of therapy and improved prognostic outcomes [14,15].

Though there are various studies on pulmonary hypertension and COPD, there are limited studies on pulmonary arterial hypertension in COPD patients & post covid/covid like syndrome patients with COPD, especially in the given study area, thus this study is designed to estimate the incidence and severity of pulmonary hypertension in patients of COPD compared to post Covid or Covid like syndrome patients with COPD helping in starting treatment in early phases.

  AIM

To determine the incidence and severity of pulmonary hypertension in patients with COPD and post Covid/Covid like syndrome patients with COPD. To compare the clinical and investigative findings of both the categories.

This prospective, comparative study was conducted in Department of General Medicine in association with Respiratory Medicine, Akash Institute of Medical Sciences and Research Centre (AIMSRC), Devanahalli, Bengaluru, Karnataka, India. In this study, 100 patients above 40 years of age with a diagnosis of COPD and post Covid/Covid like syndrome with COPD were recruited into this study after obtaining the Institutional Ethics Committee approval and informed consent from study subjects. Sample size was calculated by using the formula: n = Z21-a/2(S.D)2/d2 [16]. The study subjects were divided in two groups, group A: 50 COPD patients and group B: 50 Post covid /Covid like syndrome with COPD patients.

Inclusion Criteria

Patients willing to give informed consent, age above 40 years, patients with diagnosis of COPD based on spirometry post-bronchodilator forced expiratory volume in one second/forced expiratory volume (FEVI /FVC) ratio less than 0.7 as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, post Covid/Covid like syndrome patients with COPD whose diagnosis is established on previous RT-PCR positive lest based on SRF ID or clinical findings of COVID.

Exclusion criteria

Patients not willing for consent, patients age below 40 years, patients with pulmonary hypertension due to conditions other than COPD and post Covid/Covid like syndrome, patients without a diagnosis of COPD, Patients with ongoing COVID infection, patients with diagnosis of tuberculosis.

Data Collection

After taking informed and written consent, consecutive patients aged above 40 years, either with clinical findings of COPD or Post Covid/Covid like syndrome or with confirmed diagnosis of COPD or Post Covid/Covid like syndrome with COPD are selected from the IPD/OPD of General Medicine and Respiratory Medicine of Akash Institute of Medical Sciences and Research Centre (AIMSRC). All are evaluated clinically for incidence of Pulmonary Arterial Hypertension and are then subjected to investigations which include CBC, ECG, Chest X- Ray, Pulmonary Function Test, HRCT Chest, D- Dimer (when indicated), 2D ECHO (when indicated) for confirmation of diagnosis.

The patients are then diagnosed as COPD based on Fev1, values by Pulmonary Function test and classified based on Gold's criteria. The patients are further diagnosed with Pulmonary arterial hypertension and classified using 2D ECHO and the modified Bernoulli equation and Chmela formula.

Assessment tools

The patients arc diagnosed as COPD based on FEV, values by Pulmonary Function test and classified based on Gold’s criteria. The patients are further diagnosed with Pulmonary arterial hypertension and classified using 2D ECHO and the modified Bernoulli equation and Chmela formula.

Statistical analysis

The data will be expressed in form of frequency%, Mean±SD. Chi Square was used for test of statistical significance. Continuous data student t test was used for statistical mean difference between the two groups or variables. p value < 0.05 was considered as statistically significant.

In the present study, in group A, males were 36 (72%) and females were 14 (28%) whereas in group B, males were 32 (64%) and females were 18 (36%). In this study, age was not significant between two groups. Among biochemical and hematological parameters, D-dimer (1.21±0.14) was significantly increased in group B compared to group A whereas other parameters not reached statistical significance as shown in table 1.

Table 1: Biochemical and hematological characteristics of study participants

Significant differences were observed in pulmonary function tests (FVC, FEV1, FEV1/FVC, TLC, RV) between the two groups, indicating that COPD severity and lung function were comparable despite the COVID-19 history in Group B as shown in table 2.

Table 2: Pulmonary Function test among study participants

In the present study, severe (>70 mmHg) pulmonary hypertension was reported in 3 (6%) in group A and 7 (14%) in group B, which was statistically significant where as others were not significant as shown in table 3.

Table 3: Distribution of Pulmonary hypertension among study participants

In this, infiltrates were 18 (36%) in group B compared to group A followed by consolidation in 10 (10%) compared to 9 in group A as shown in table 4.

Table 4: HRCT findings among study participants

In this study, 28 (56%) patients were in stage III in group B. Stage 1 is seen in 26 (52%) and stage 2 in 20 (40%) patients in group A compared to group B, which was statistically significant as shown in table 5.

 Table 5: Gold criteria among study participants

In this study, pulmonary hypertension (28.6±4.1 mmHg) was significantly more in group B compared to group A as shown in table 6.

Table 6: Pulmonary arterial hypertension among study participants

COVID-19 has presented a multitude of challenges globally, prompting studies to investigate its intersection with conditions such as COPD and pulmonary arterial hypertension (PAH). This study aims to uncover the various complications exacerbated by COVID-19. In this study, age was not significant between two groups, indicating that age-related factors are unlikely to confound the comparative analysis between the groups. Also, men were more in both groups. in a study conducted by Morena et al., reported that mean age of study participants was 73 years, with men comprising 56,763 individuals, accounting for 76.8% of total sample [17]. In a study by Assaf et al., found that among the participants, 86 (43%) individuals were in the age group of 51-60 years, which outnumbered those in the ≤50 years age group (n=34, 17%) and those aged ≥61 years (n=80, 40%) [18]. 

In this study, a higher proportion of males in both groups, comprising 68% of the total participants. This may reflect a general trend in COPD patient populations or specific recruitment biases but does not affect the internal comparability between two groups.

Concerned with biochemical parameters like urea, BUN, creatinine, FBS, PPBS, HbA1c, serum total & direct bilirubin, and hematologic parameters like Hb, RBC, WBC were not statistically different between two groups.  However, D-Dimer levels were significantly higher in Group B compared to Group A, indicating a heightened thrombotic risk potentially influenced by COVID-19. These findings

underscore the need for vigilant monitoring and possibly proactive management of thrombotic complications in COPD patients with a history of COVID-19. In support of our findings, Nemec et al., reported that median D-Dimer was 2.35 ug/mL among the COVID-19 patients and found strong correlation between D-Dimer and intubation and mortality rates [19]. Another study by Zhang et al., reported that the D-Dimer was greater than 2 ug/mL in patients with COVID-19 [20].

High levels of D-Dimer have been consistently noted in severe cases of COVID-19. There is a growing consensus that COVID-19 induces a hypercoagulable state, contributing to elevated D-Dimer levels as a marker of increased thrombotic risk. This understanding is pivotal for developing effective strategies to manage and treat COVID-19 patients, particularly in preventing and managing thrombotic complications [21].

Significant differences were observed in pulmonary function tests (FVC, FEV1, FEV1/FVC, TLC, RV) between the two groups, indicating that COPD severity and lung function were comparable despite the COVID-19 history in Group B. Similarly, in our study we found that the above-mentioned parameters were less in patients with post-covid symptoms.

In the context of post-COVID syndrome, severity categorization typically differentiates between asymptomatic or mildly symptomatic cases, which are considered mild, symptomatic cases with significant respiratory symptoms but without distress, classified as moderate, severe pneumonia with respiratory failure or approaching ARDS as severe, and ARDS as critical. This categorization aligns with findings from Blanco et al., who reported altered lung function in patients recovering from COVID-19 [22].

Our study reveals that severe pulmonary hypertension was notably more prevalent in Group B compared to Group A. This substantial difference in PAH severity suggests that COPD patients with a history of COVID-19 or Covid-like syndrome may face a heightened risk of developing severe pulmonary vascular complications. In a study by Singh et al. emphasized that in COPD, hypoxic pulmonary vasoconstriction contributes to elevated pulmonary hypertension through vascular remodelling. Post-COVID syndrome may intensify this process, potentially exacerbating the vascular changes and worsening pulmonary hypertension observed in COPD patients [23].

Sakao et al., and Casa et al., highlighted that hypoxic pulmonary vasoconstriction, which is commonly seen in COPD patients regardless of COVID-19 status, leads to increased fluid shear stress within the pulmonary vessels. In the context of post-COVID syndrome, this condition can be further exacerbated by residual inflammation and vascular changes resulting from the viral infection. This additional stress promotes enhanced platelet aggregation and a heightened risk of thrombus formation, compounding the already elevated thrombotic risk in COPD patients [24,25].

Similarly, Bogaard et al., noted that hypoxic pulmonary vasoconstriction is associated with heightened pulmonary hypertension in COPD due to vascular remodelling, a relationship that COVID-19 could potentially exacerbate. In COPD patients, several mechanisms contribute to poorer COVID-19 outcomes. Key factors include heightened susceptibility to micro-thrombosis, the impact of intrapulmonary shunting, and the potential for secondary bacterial infections [26].

Significant disparities in chest X-ray findings were observed between the groups. Group B exhibited higher rates of infiltrates and consolidation, indicating a greater burden of parenchymal lung disease post-COVID-19 among COPD patients in this cohort.

The GOLD criteria for COPD offer a methodical framework for classifying the severity of the disease according to lung function and directing therapeutic choices. With a predicted FEV1 of 80% or less, Grade 1 (moderate) denotes a minimal airflow limitation and is usually linked to less symptoms and a decreased likelihood of exacerbations. A grade of two (moderate) indicates a moderate restriction in airflow (50 ≤ FEV1 < 80% expected), accompanied by heightened symptoms and sporadic aggravations. Severe airflow limitation (30% ≤ FEV1 < 50% expected), prominent symptoms, and more frequent exacerbations are characteristics of grade 3 (severe). A diagnosis of Grade 4 (extremely severe) indicates extreme airflow limitation (FEV1 < 30% predicted or < 50% predicted in the case of chronic respiratory failure), substantial symptoms, a high probability of exacerbation, and a major impact on day-to-day functioning [27,28]. Regarding GOLD criteria staging, Group B showed a higher proportion of patients classified in more severe stages compared to Group A, suggests that COVID-19 may exacerbate COPD severity, leading to accelerated disease progression in affected individuals. Acute COPD exacerbations can be caused by a variety of viruses, including the SARS-CoV-2 virus. Although coronaviruses are seasonal causes of acute COPD exacerbations, there is disagreement over whether COVID-19 and protracted COVID-19 in a COPD patient qualify as exacerbations.

Our study highlights that COPD patients with a history of COVID-19 experience significantly more severe pulmonary arterial hypertension and elevated thrombotic risk compared to those without a history of COVID-19. These findings suggest that COVID-19 exacerbates both the severity of COPD and associated complications, such as thrombotic risks and pulmonary damage. The elevated D-dimer levels and more severe PAH underscore the critical need for tailored management strategies for COPD patients with a history of COVID-19.

Limitations of the study

The study might include a limited number of participants, study subjects may not be representative of all COPD patients, reliance on patient self-reporting for symptoms, treatment adherence, and history of COVID-19 infection.

Conflict of interest: Nil

Funding: Nil

Acknowledgements: We would like to thank the authorities of Akash Institute of Medical Sciences and Research Centre, Devanahalli, Bengaluru, Karnataka, India.

1. Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR et al., Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019;53(5):1900164. https://doi.org/10.1183/13993003.00164-2019
2. John J. Reilly Jr. Edwin K. Silver man, Steven D Shapiro. Chronic obstructive pulmonary disease” Harrison's Principles of Internal Medicine: Volume 2. Macgraw-Hill; 2011.242:1547 – 57.
3. Seaton A, Leitch AG, Seaton D. Crofton and Douglas's respiratory diseases. John Wiley & Sons; 2008; 5(650).
4. Samp JC, Joo MJ, Schumock GT, Calip GS, Pickard AS, Lee TA. Predicting Acute Exacerbations in Chronic Obstructive Pulmonary Disease. J Manag Care Spec Pharm. 2018;24(3):265-279. https://doi.org/10.18553/jmcp.2018.24.3.265
5. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension [published correction appears in Eur Heart J. 2022;43:3618–3731. https://doi.org/10.1093/eurheartj/ehac237
6. Blanco I, Tura-Ceide O, Peinado VI, Barberà JA. Updated Perspectives on Pulmonary Hypertension in COPD. Int J Chron Obstruct Pulmon Dis. 2020;15:1315-1324.
7. Portillo K, Torralba Y, Blanco I, Burgos F, Rodriguez-Roisin R, Rios J, et al., Pulmonary hemodynamic profile in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015; 10:1313-1320.
8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497-506.
9. World Health Organization Press Conference. The World Health Organization (WHO) Has Officially Named the Disease Caused by the Novel Coronavirus as COVID-19.
10. Deng Q, Hu B, Zhang Y, Wang H, Zhou X, Hu W, et al., Suspected myocardial injury in patients with COVID-19: Evidence from front-line clinical observation in Wuhan, China. Int. J. Cardiol. 2020; 311:116–121.
11. Chen R, Liang W, Jiang M, Guan W, Zhan C, Wang T, et al., Risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in China. Chest. 2020;158:97–105.
12. Pagnesi M, Baldetti L, Beneduce A, Calvo F, Gramegna M, Pazzanese V., et al. Pulmonary hypertension and right ventricular involvement in hospitalised patients with COVID-19. MNJ J Heart. 2020;106:1324–1331.
13. Taha HA, Elshafey BI, Abdullah TM, Salem HA. Study of pulmonary hypertension in post-COVID-19 patients by transthoracic echocardiography. The Egyptian Journal of Bronchology. 2023;17(1):27.
14. Khan AW, Ullah I, Khan KS, Tahir MJ, Masyeni S, Harapan H. Pulmonary arterial hypertension post COVID-19: A sequala of SARS-CoV-2 infection? Respiratory Medicine Case Reports. 2021;33:101429.
15. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. European Respiratory Journal. 2008;32(5):1371-85.
16. Aurangabadkar GM, Lanjewar AV, Jadhav US, Ali SN, Wagh PB. Evaluation of Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease. Cureus. 2022;14(2):e21828.
17. Morena D, Izquierdo JL, Rodríguez J, Cuesta J, Benavent M, Perralejo A, Rodríguez JM. The Clinical Profile of Patients with COPD Is Conditioned by Age. J Clin Med. 2023;12(24):7595.
18. Assaf EA, Badarneh A, Saifan A, Al-Yateem N. Chronic obstructive pulmonary disease patients' quality of life and its related factors: A cross-sectional study of the Jordanian population. F1000 Res. 2022;11:581.
19. Nemec HM, Ferenczy A, Christie BD 3rd, Ashley DW, Montgomery A. Correlation of D-dimer and Outcomes in COVID-19 Patients. Am Surg. 2022;88(9):2115-2118.
20. Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemostasis. 2020; 18(6): 1324-1329.
21. Choi KW, Chau TN, Tsang O, Tso E, Chiu MC, Tong WL, et al., Outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in Hong Kong. Ann Intern Med. 2003;139(9):715-723.
22. Blanco JR, Cobos-Ceballos MJ, Navarro F, Sanjoaquin I, Revillas FADL, Bernal E, et al., Pulmonary long-term consequences of COVID-19 infections after hospital discharge. Clin Microbiol Infect. 2021;27:892–896.
23. Singh D, Mathioudakis AG, Higham A. Chronic obstructive pulmonary disease and COVID-19: interrelationships. Curr Opin Pulm Med. 2022;28(2):76-83.
24. Sakao S. Chronic obstructive pulmonary disease and the early stage of cor pulmonale: a perspective in treatment with pulmonary arterial hypertension-approved drugs. Respir Investig. 2019; 57:325–329.
25. Casa LD, Deaton DH, Ku DN. Role of high shear rate in thrombosis. J Vasc Surg. 2015; 61:1068-1080.
26. Bogaard HJ. Hypoxic pulmonary vasoconstriction in COPD-associated pulmonary hypertension: been there, done that? Eur Respir J. 2017; 50:1191–1194.
27. Singh SJ, Baldwin MM, Daynes E, Evans RA, Greening NJ, Jenkins RG, et al., Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation. Lancet Respir Med. 2023;11(8):709-725.
28. Agustí A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, et al., Global Initiative for Chronic Obstructive Lung Disease 2023 Report: GOLD Executive Summary. Am J Respir Crit Care Med. 2023;207(7):819-837.