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Pulmonary Considerations in COVID-19


Preeti Dalawari

Preeti Dalawari, MD, MSPH
Medical Director
RGA U.S. Mortality Markets

The virus aptly named SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, can cause a wide array of pulmonary symptoms and complications, of which acute respiratory distress syndrome (ARDS) is the most severe. SARS-CoV-2 enters cells by binding its spike protein to the angiotensin converting enzyme 2 (ACE2) receptor on the host. These ACE2 receptors are found on alveolar lung and upper respiratory tract epithelial cells (as well as endothelial cells of arteries and veins, arterial smooth muscle, small intestine epithelium, immune cells) and correlates with COVID-19 pulmonary symptoms and organ dysfunction.1-3 Suppression of ACE2 expression is thought to have a role in the pathologic changes (e.g., interstitial and alveolar exudative inflammation), leading to pneumonia and ARDS.1,2 Pulmonary involvement (e.g., coughing, sneezing) also aids in high viral transmission.

Intuitively, it makes sense that those with preexisting lung conditions are at an increased risk for severe disease. The CDC guidelines include those individuals with chronic lung diseases such as moderate-to-severe asthma, COPD, pulmonary fibrosis, and cystic fibrosis.4 According to surveillance data, about one-third of admitted US patients have chronic lung disease.5 Data from March 1 - April 4 of 5,700 COVID-19 positive hospitalized patients within the Northwell Health system in New York, found respiratory comorbidities of: asthma 9%, COPD 5.4%, and obstructive sleep apnea 2.9%.

While predominant symptoms vary among countries and regions, most studies indicate initial nonspecific viral symptoms such as fever, cough, myalgias/fatigue.7,8 Current US data obtained through COVID-NET§ notes cough and shortness of breath are among the predominant respiratory symptoms upon admission to the hospital, indicating a progression of disease from upper to lower respiratory tract.6 The median time interval from symptom onset to hospitalization was seven days.5

Earlier studies from China show a similar clinical course for those hospitalized; with dyspnea occurring at the beginning of the second week (days 5-8) corresponding with hospitalization.7   

Most infected individuals are asymptomatic or pauci-symptomatic. Of 44,415 confirmed COVID-19 cases, the Chinese CDC found 81% were mild (no or mild pneumonia). However, 14% were severe, defined as dyspnea, hypoxemia with oxygen saturations ≤ 93%, respiratory rate of ≥ 30, >50% lung involvement on imaging in 24-48 hours of hospitalization, or partial pressure of arterial oxygen to fraction of inspired oxygen ration < 300 mm Hg (a finding of early acute respiratory distress syndrome), and 5% were critical (respiratory failure, shock, and multiple organ dysfunction).9 


§ per CDC website/MMR weekly: COVID-NET (COVID-19-Associated Hospitalization Surveillance Network) data arises from population-based surveillance for laboratory-confirmed COVID-19 hospitalizations in 14 states (California, Colorado, Connecticut, Georgia, Iowa, Maryland, Michigan, Minnesota, New Mexico, New York, Ohio, Oregon, Tennessee, and Utah). This area distribution represents 10% of the US population.


Chest CT of Rapidly Progressing Phase in COVID-19 Pneumonia

Chest CT of Rapidly Progressing Phase in COVID-19 Pneumonia

https://commons.wikimedia.org/wiki/File:COVID19CT1.webp Creative Commons Attribution 4.0

A few studies have looked at prognostic factors for disease progression and hospitalization. A systematic review by Zheng et al. noted that shortness of breath/dyspnea was significantly associated with progression of disease in those critical patients (OR 4.16) compared to noncritical hospitalized patients.10 Another study in the US found an admission pulse-oximetry reading of <88% was positively associated with admission and critical illness (OR 6.99), along with certain inflammatory markers and older age.11 Of the 1,099 hospitalized patients with an outcome (discharged alive or dead), 28% required invasive mechanical ventilation and 18.5% died or were discharged to hospice. Among critical cases, the fatality rate was 45%, similar to the findings by the Chinese CDC of 49%.11 

There are many contributing factors to morbidity and mortality of COVID-19, one of which is ARDS. Lung injury in ARDS arises from an intense host cytokine-mediated inflammatory response with resultant cell death leading to alveolar flooding, diminished lung compliance, and ventilation perfusion mismatches.12 This leads to respiratory failure, hypoxemia, and mechanical ventilation.13 Because there have been reports of preserved lung compliance with hypoxemia, there is speculation on whether the pulmonary pathophysiology in critical COVID-19 patients is consistent with ARDS.14 Newer studies show many critical COVID-19 patients having a similar hyperinflammatory response and downstream effects as traditional ARDS patients. 12,15 Thus, from an underwriting perspective, the long-term sequelae of ARDS needs consideration. 

Studies have shown parenchymal lung changes on CT scan of the chest in 75-87% of patients six months to five years post-ARDS but involving less than 25% of the lung.16 The coarse reticular pattern and ground glass opacities noted is thought to be fibrosis of the lung. Accordingly, those patients whose ARDS was due to pulmonary pathology, who spent more time on a ventilator, and had higher positive end expiratory pressure, were more likely to develop fibrosis.16 While many patients may be left with radiographic changes, the clinical impact of these findings are unclear.

There are conflicting studies on the long-term residual effects to lung function as measured by pulmonary function tests (six-minute walk test, spirometry, carbon monoxide diffusing capacity, etc.). Some studies find residual restrictive (range in studies of 15% to 58% of patients), obstructive (range of 6% to 43% of patients), or mixed-pattern disease on PFTs; others indicate resolution of these findings within six months to a year and remaining stable five years post-ARDS.16,17 Median diffusion capacity returned to near normal levels at 12 months and resolved by four years and remained stable. It is also important to note that muscular weakness, as opposed to or in addition to pulmonary dysfunction, may contribute to abnormalities, if noted on spirometry or the six-minute walk test.16,17 Given the conflicting evidence, it seems reasonable at this time, to be cognizant of possible long-term complications of ARDS associated with COVID-19. 

Underwriting Takeaways

  • Those with COPD, pulmonary fibrosis, cystic fibrosis, and moderate to severe asthma are at greater risk of morbidity and mortality related to SARS-CoV-2
  • Long-term pulmonary complications are not currently known but may be similar to long-term respiratory sequelae found in ARDS:
    • Coarse reticular pattern and ground glass opacities on CT chest 
    • Pulmonary function tests are very often abnormal, but the pattern is quite variable. If complications develop, they typically are apparent by one year’s time. 

It is worth mentioning that many of the current data and studies, especially within the US, are case series or hospitalized-population based with incomplete data or lack of final outcomes. Thus much of the data is preliminary and subject to change as more information or outcomes are known.


References

  1. Jain A. COVID-19 and lung pathology. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Apr 29]; 63:171-2. Available from: http://www.ijpmonline.org/text.asp?2020/63/2/171/282688
  2. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286
  3. Liu Peter P., Blet Alice, Smyth David, and Li Hongliang. “The Science Underlying COVID-19: Implications for the Cardiovascular System.” Circulation 0, no. 0. Accessed April 30, 2020. https://doi.org/10.1161/CIRCULATIONAHA.120.047549.
  4. CDC. “Coronavirus Disease 2019 (COVID-19).” Centers for Disease Control and Prevention, February 11, 2020. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html.
  5. Garg, Shikha. “Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, 2020.” MMWR. Morbidity and Mortality Weekly Report 69 (2020). https://doi.org/10.15585/mmwr.mm6915e3.
  6. Richardson, Safiya, Jamie S. Hirsch, Mangala Narasimhan, James M. Crawford, Thomas McGinn, Karina W. Davidson, Douglas P. Barnaby, et al. “Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.” JAMA, April 22, 2020. https://doi.org/10.1001/jama.2020.6775.
  7. Huang, Chaolin, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, et al. “Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China.” The Lancet 395, no. 10223 (February 15, 2020): 497–506.
  8. Tu, Huilan, Sheng Tu, Shiqi Gao, Anwen Shao, and Jifang Sheng. “The Epidemiological and Clinical Features of COVID-19 and Lessons from This Global Infectious Public Health Event.” Journal of Infection, April 18, 2020. https://doi.org/10.1016/j.jinf.2020.04.011.
  9. Wu, Zunyou, and Jennifer M. McGoogan. “Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention.” JAMA 323, no. 13 (April 7, 2020): 1239–42. https://doi.org/10.1001/jama.2020.2648.
  10. Zheng, Zhaohai, Fang Peng, Buyun Xu, Jingjing Zhao, Huahua Liu, Jiahao Peng, Qingsong Li, et al. “Risk Factors of Critical & Mortal COVID-19 Cases: A Systematic Literature Review and Meta-Analysis.” Journal of Infection, April 23, 2020. https://doi.org/10.1016/j.jinf.2020.04.021.
  11. Petrilli, Christopher M., Simon A. Jones, Jie Yang, Harish Rajagopalan, Luke F. O’Donnell, Yelena Chernyak, Katie Tobin, Robert J. Cerfolio, Fritz Francois, and Leora I. Horwitz. “Factors Associated with Hospitalization and Critical Illness among 4,103 Patients with COVID-19 Disease in New York City.” Preprint. Intensive Care and Critical Care Medicine, April 11, 2020. https://doi.org/10.1101/2020.04.08.20057794.
  12. Luks, Andrew M, and Erik R Swenson. “COVID-19 Lung Injury and High Altitude Pulmonary Edema: A False Equation with Dangerous Implications.” Annals of the American Thoracic Society, April 24, 2020, AnnalsATS.202004-327FR. https://doi.org/10.1513/AnnalsATS.202004-327FR.
  13. Matthay, Michael A., Rachel L. Zemans, Guy A. Zimmerman, Yaseen M. Arabi, Jeremy R. Beitler, Alain Mercat, Margaret Herridge, Adrienne G. Randolph, and Carolyn S. Calfee. “Acute Respiratory Distress Syndrome.” Nature Reviews Disease Primers 5, no. 1 (December 2019): 18. https://doi.org/10.1038/s41572-019-0069-0.
  14. Gattinoni, Luciano, Silvia Coppola, Massimo Cressoni, Mattia Busana, Sandra Rossi, and Davide Chiumello. “Covid-19 Does Not Lead to a ‘Typical’ Acute Respiratory Distress Syndrome.” American Journal of Respiratory and Critical Care Medicine, March 30, 2020, rccm.202003-0817LE. https://doi.org/10.1164/rccm.202003-0817LE.
  15. Ziehr, David R., Jehan Alladina, Camille R Petri, Jason H. Maley, Ari Moskowitz, Benjamin D Medoff, Kathryn A Hibbert, B. Taylor Thompson, and C. Corey Hardin. “Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study.” American Journal of Respiratory and Critical Care Medicine, April 29, 2020, rccm.202004-1163LE. https://doi.org/10.1164/rccm.202004-1163LE.
  16. DiSilvio, Briana, Meilin Young, Ayla Gordon, Khalid Malik, Ashley Singh, and Tariq Cheema. “Complications and Outcomes of Acute Respiratory Distress Syndrome.” Critical Care Nursing Quarterly 42, no. 4 (December 2019): 349–361. https://doi.org/10.1097/CNQ.0000000000000275.
  17. Chiumello, Davide, Silvia Coppola, Sara Froio, and Miriam Gotti. “What’s Next After ARDS: Long-Term Outcomes.” Respiratory Care 61, no. 5 (May 1, 2016): 689. https://doi.org/10.4187/respcare.04644.