Persistent interstitial lung abnormalities in post-COVID-19 patients: a case series

Vanessa Carvalho Lago Robson Aparecido Prudente Dayane Araujo Luzia Estefânia Thomé Franco Talita Jacon Cezare Amanda Peralta Eloara Vieira M. Ferreira André Luis Pereira Albuquerque Marina Politi Okoshi Bruno Guedes Baldi Suzana Erico Tanni About the authors

Abstract

A new concept of multisystem disease has emerged as a long-term condition following mild-severe COVID-19 infection. The main symptoms of this affection are breathlessness, chest pain, and fatigue. We present here the clinical case of four COVID-19 patients during hospitalization and 60 days after hospital discharge. Physiological impairment of all patients was assessed by spirometry, dyspnea score, arterial blood gas, and 6-minute walk test 60 days after hospital discharge, and computed tomographic scan 90 days after discharge. All patients had fatigue, which was not related to hypoxemia or impaired spirometry values, and interstitial lung alterations, which occurred in both mechanically ventilated and non-mechanically ventilated patients. In conclusion, identifying the prevalence and patterns of permanent lung damage is paramount in preventing and treating COVID-19-induced fibrotic lung disease. Additionally, and based on our preliminary results, it will be also relevant to establish long-term outpatient programs for these individuals.

Keywords
COVID-19; Interstitial lung abnormalities; CT scan

Background

The COVID-19 pandemic has raised numerous questions on the mechanisms involved in lung injuries after mild to severe acute illness. There is great uncertainty about the possible pulmonary complications that patients with more severe manifestations may have in the longer term. We therefore present the characterization of four COVID-19 patients with persistent interstitial lung abnormalities by computed tomographic (CT) scan 90 days after hospital discharge. We also evaluated dyspnea index (baseline dyspnea index - BDI), post-bronchodilator (post-BD) spirometry, room air arterial blood gas, and 6-minute walk distance (6MWD) 60 days after discharge. The 6MWD was performed following the American Thoracic Society Guidelines [11. Crapo RO, Casaburi R, Coates AL, Enright PL, Maclntyre NR, Mckay RT, et al. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7.].

The present project was approved by our local ethics committee (Botucatu Medical School, CAAE: 31258820.5.1001.5411). The Universal Trial Number (UTN) is A27072519840, the register number is RBR-8j9kqy and the public access URL is available at https://ensaiosclinicos.gov.br/rg/RBR-8j9kqy) and all patients signed the informed consent form.

Characterization of each patient is available in Table 1.

Table 1.
Descriptive characteristics of patients and evaluation of spirometry, dyspnea score, 6-minute walk test and blood gas analysis after 60 days of hospital discharge.

Case presentation

Patient 1

A 72 year-old male ex-smoker (36 pack-years) with symptoms starting 13 days before hospitalization was discharged after 18 days. Maximal oxygen supplementation with non-rebreathing mask was 15 L/min during treatment and he was discharged without oxygen supplementation. Sixty days after discharge he reported fatigue and presented BDI 9 and normal post-BD spirometry [forced expiratory volume at the first second (FEV1) 110% of predicted value; forced vital capacity (FVC) 100% of predicted value]. Pulse oximetry (SpO2), partial arterial oxygen pressure (PaO2), and 6MWD were 96%, 94 mmHg, and 551 m (100% of predicted value), respectively [22. Iwama AM, Andrade GN, Shima P, Tanni SE, Godoy I, Dourado VZ. The six-minute walk test and body weight-walk distance product in healthy Brazilian subjects. Braz J Med Biol Res. 2009 Oct 2;42(11):1080-5.]. CT scans at hospital admission and 90 days after discharge are presented in Figure 1 (A and B).

Figure 1.
(A, C, E and G) Chest computed tomography (CT) at admission of patients 1, 2, 3 and 4, respectively. (B, D, F and H) CT 90 days after discharge of patients 1, 2, 3 and 4, respectively. All initial CT scans show bilateral, multilobar and peripheral predominance ground-glass opacities, consolidation, and septal thickening. Although all CT scans after 90 days showed a reduction in the extent and intensity of lung injury, mild ground-glass and reticular opacities with peripheral predominance remained in all patients.

Patient 2

A 59 year-old male ex-smoker (40 pack-years) with systemic arterial hypertension and obesity presented with 15 days of symptoms before hospitalization and was discharged 8 days later. Maximal oxygen supplementation with nasal prong was 4 L/min. He reported fatigue and had a BDI 3 60 days after discharge. Post-BD spirometry was normal (FEV1 93% and FVC 88% of predicted values). SpO2, PaO2, and 6MWD were 96%, 85 mmHg, and 575 m (100% of predicted value), respectively [11. Crapo RO, Casaburi R, Coates AL, Enright PL, Maclntyre NR, Mckay RT, et al. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7.]. CT scans at hospital admission and 90 days after discharge are presented in Figure 1 (C and D).

Patient 3

A 63 year-old female ex-smoker (30 pack-years) with depression, systemic arterial hypertension, and obesity with 10 days of symptoms before hospitalization was discharged 28 days later. She needed mechanical ventilation for 21 days with a maximum fraction of inspired oxygen (FIO2) of 60%. Sixty days after discharge she still reported severe fatigue that prevented BDI calculation and 6MWT. Post-BD spirometry was normal (FEV1 89% and FVC 80% of predicted values). SpO2 and PaO2 were 95% and 78 mmHg, respectively. CT scans at hospital admission and 90 days after discharge are presented in Figure 1 (E and F).

Patient 4

A 62 year-old female ex-smoker (50 pack-years) with diabetes mellitus started symptoms 15 days before hospitalization and was discharged after 26 days. She needed mechanical ventilation for 15 days with a maximum FIO2 of 90%. The patient presented mild dyspnea with BDI 7 60 days after discharge. Post-BD spirometry was normal (FEV1 116% and FVC 113% of predicted values). SpO2, PaO2 and 6MWD were 95%, 83 mmHg and 906 m (178% of predicted value), respectively [11. Crapo RO, Casaburi R, Coates AL, Enright PL, Maclntyre NR, Mckay RT, et al. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7.]. CT scans at hospital admission and 90 days after discharge are presented in Figure 1 (G and H).

Discussion

All patients had more than 25% of pulmonary involvement at initial CT scan with a significant improvement 90 days after discharge. However, despite pulmonary function indexes within the normal range, they presented fatigue and dyspnea, and maintained interstitial lung abnormalities in follow-up CT. Acute radiological pulmonary changes caused by COVID-19 are already well described [33. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-20.,44. Rubin GD, Ryerson CJ, Haramati LB, Sverzellati N, Kanne JP, Raoof S, et al. The role of chest imaging in patient management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society. Chest. 2020;158:106-16.]. Chest CT scan is an essential tool for identifying viral pneumonia and classifying disease severity [44. Rubin GD, Ryerson CJ, Haramati LB, Sverzellati N, Kanne JP, Raoof S, et al. The role of chest imaging in patient management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society. Chest. 2020;158:106-16.]. The most common pulmonary CT abnormalities are ground-glass opacities, consolidations, crazy-paving pattern, and linear opacities, affecting predominantly peripheral areas and lower lobes or presenting a multilobar distribution [55. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, et al. Chest CT findings in Coronavirus disease-19 (COVID-19): Relationship to duration of infection. Radiology. 2020 Feb 20;295:200463.,66. Hu Q, Guan H, Sun Z, Huang L, Chen C, Ai T, et al. Early CT features and temporal lung changes in COVID-19 pneumonia in Wuhan, China. Eur J Radiol. 2020 Jul;128:109017.]. These images are related to interstitial edema and alveolar exudation, which can directly contribute to long-term pulmonary changes. Pulmonary CT scan is still considered as the gold standard to identify and quantify the presence of pulmonary fibrosis. In centers with difficult access to CT scan, the chest X-radiogram (X-Ray) could be used as an alternative, with a risk of twofold negative to find abnormalities in patients with COVID-19 [77. Li B, Li X, Wang Y, Han Y, Wang Y, Wang C, et al. Diagnostic value and key features of computed tomography in Coronavirus Disease 2019. Emerg Microbes Infect. 2020;9(1):787-93.]. However, the X-Ray has low sensibility to detect ground-glass opacities and lung retrocardiac alterations. In this context, the pulmonary ultrasound during the COVID-19 pandemic has been described as a potential tool during acute infection to assess the severity of the pneumonia with a good correlation with pulmonary CT scan [88. Zieleskiewicz L, Markarian T, Lopez A, Taguet C, Mohammedi N, Boucekine M, et al. Comparative study of lung ultrasound and chest computed tomography scan in the assessment of severity of confirmed COVID-19 pneumonia. Intensive Care Med. 2020 Jul 29;46(9):1707-13.,99. Tung-Chen Y, Martí de Gracia M, Díez-Tascón A, Alonso-González R, Agudo-Fernández S, Parra-Gordo ML, et al. Correlation between Chest Computed Tomography and Lung Ultrasonography in Patients with Coronavirus Disease 2019 (COVID-19). Ultrasound Med Biol. 2020 Nov;46(11):2918-26.]. However, none of the lung ultrasound studies evaluated the concordance with CT scan after the acute phase of the disease.

There are speculative questions about possible persistent pulmonary radiological abnormalities and their prevalence [77. Li B, Li X, Wang Y, Han Y, Wang Y, Wang C, et al. Diagnostic value and key features of computed tomography in Coronavirus Disease 2019. Emerg Microbes Infect. 2020;9(1):787-93.,1010. Zhang P, Li J, Liu H. Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study. Bone Res. 2020;8:8.]. A recent follow-up of patients evaluated 15 years after severe acute respiratory distress syndrome (ARDS) showed that 4.6% presented interstitial lung changes [1111.Vasarmidi E, Tsitoura E, Spandidos DA, Tzanakis N, Antoniou KM. Pulmonary fibrosis in the aftermath of the COVID-19 era (Review). Exp Ther Med. 2020 Sep;20(3):2557-60.]. Two of our patients were subjected to mechanical ventilation, which is a potential risk factor for pulmonary fibrosis after ARDS, that can implicate with the pulmonary repair and related to pro-fibrotic pathway. Small number of cases demonstrated that after the fourth week of symptoms onset, the pulmonary injuries can still occur in almost 30% of patients [1212. Han X, Cao Y, Jiang N, Chen Y, Alwalid O, Zhang X, et al. Novel Coronavirus disease 2019 (COVID-19) pneumonia progression course in 17 discharged patients: comparison of clinical and thin-section computed tomography features during recovery. Clin Infect Dis. 2020 Jul 28;71(15):723-31.]. On the other hand, there is a gap of information regarding the pulmonary sequelae after long periods of follow-up [1313. Gentile F, Aimo A, Forfori F, Catapano G, Clemente A, Cademartiri F, et al. COVID-19 and risk of pulmonary fibrosis: the importance of planning ahead. Eur J Prev Cardiol. 2020;27(13):1442-6.]. Male sex is considered a risk factor for the development of severe COVID-19 [1414. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585.]. However, we presented women with more severe disease.

Higher degrees of inflammatory activity are associated with greater alveolar damage; as a consequence, inflammation can be longer than virus survival [66. Hu Q, Guan H, Sun Z, Huang L, Chen C, Ai T, et al. Early CT features and temporal lung changes in COVID-19 pneumonia in Wuhan, China. Eur J Radiol. 2020 Jul;128:109017.,88. Zieleskiewicz L, Markarian T, Lopez A, Taguet C, Mohammedi N, Boucekine M, et al. Comparative study of lung ultrasound and chest computed tomography scan in the assessment of severity of confirmed COVID-19 pneumonia. Intensive Care Med. 2020 Jul 29;46(9):1707-13.]. It has been suggested that continuing respiratory symptoms after discharge can be related to persistently increased inflammatory markers. Our patients presented normal spirometry, exercise capacity and peripheral arterial blood gases, with persistent symptoms, which may be associated to increased inflammatory markers. Unfortunately, it was not possible to confirm this hypothesis as serum inflammatory markers were not assessed. Additionally, we cannot exclude the possibility that their normal functional parameters are lower than the baseline data as patients were not evaluated before the infection.

An excessive expression of cell markers and cytokines occurs in COVID-19 [1515. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020 Aug;8(8):807-15.,1616. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, et al. Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19. Allergy. 2020 Jul;75(7):1564-81.]. Activation of macrophages, epithelial cells, T lymphocytes, natural killer cells (NK), and other inflammatory cells is related to increased production of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor (TNF)-α, and activation of toll like receptors and the NF-κB pathway, all contributing to a cytokine storm [1515. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020 Aug;8(8):807-15.,1717. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3. ]. Some patients have a hyperinflammatory response related to macrophages, with increased IL-1β and inflammatory markers, such as C-reactive protein, D-dimers, IL-6 and TNF-α. On the other hand, patients with inefficient activation of innate immune response may have hyperactivation and decreased number of T lymphocytes, decreased NK cells [1717. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3. ], and increased serum pro-inflammatory markers, especially IL-6. COVID-19 can link to CD147 of T lymphocytes that participate in cell proliferation, apoptosis, and differentiation, mainly under tissue hypoxia. The inflammatory response is thought to be related to viral antigenicity and can contribute to pulmonary fibrosis [1515. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020 Aug;8(8):807-15.,1818. Riggioni C, Comberiati P, Giovannini M, Agache I, Akdis M, Alves-Correia M, et al. A compendium answering 150 questions on COVID-19 and SARS-CoV-2. Allergy. 2020 Oct;75(10):2503-41.].

According to previous studies, a large release of inflammatory cytokines leads to diffuse alveolar damage in the initial phase of ARDS. The dysregulation is followed by an organizing phase, with fibrosis in connective tissue and Type II pneumocyte hyperplasia. The final stage is a fibrotic phase characterized by irreversible collagen deposition in interstitial space [1717. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3. ]. The factors responsible for pulmonary fibrosis development are not clear; drug-induced pulmonary toxicity, non-protective mechanical ventilation, and hyperoxia-induced damage could be involved [1919. Spagnolo P, Balestro E, Aliberti S, Cocconcelli E, Biondini D, Casa GD, et al. Pulmonary fibrosis secondary to COVID-19: a call to arms? Lancet Respir Med. 2020 Aug;8(8):750-2.]. The prevalence of COVID-19-induced pulmonary fibrosis is still unknown [2020. George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A, Forrest I, et al. Respiratory follow-up of patients with COVID-19 pneumonia. Thorax. 2020;2020-215314.]. The increasing number of COVID-19 cases may reveal a large number of patients with long-term interstitial lung abnormalities. Recent studies have shown a decreased diffusion capacity in more than 50% of patients assessed at discharge or 30 days after infection [2121. Mo X, Jian W, Su Z, Chen M, Peng H, Peng P, et al. Abnormal pulmonary function in COVID-19 patients at time of hospital discharge. Eur Respir J. 2020 Jun;55(6):2001217.,2222. Frija-Masson J, Debray MP, Gilbert M, Lescure FX, Travert F, Borie R, et al. Functional characteristics of patients with SARS-CoV-2 pneumonia at 30 days post-infection. Eur Respir J. 2020 Aug;56(2):2001754.]. Thus, we should follow COVID-19 patients to evaluate progression to irreversible fibrotic lung disease and its impact in respiratory symptoms, life quality, and mortality.

Conclusion

In conclusion, long-term follow-up of mild-severely affected patients should also be a major focus in COVID-19 treatment. Identifying prevalence and patterns of permanent lung damage is paramount in preventing and treating COVID-19-induced fibrotic lung disease.

References

  • 1. Crapo RO, Casaburi R, Coates AL, Enright PL, Maclntyre NR, Mckay RT, et al. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7.
  • 2. Iwama AM, Andrade GN, Shima P, Tanni SE, Godoy I, Dourado VZ. The six-minute walk test and body weight-walk distance product in healthy Brazilian subjects. Braz J Med Biol Res. 2009 Oct 2;42(11):1080-5.
  • 3. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-20.
  • 4. Rubin GD, Ryerson CJ, Haramati LB, Sverzellati N, Kanne JP, Raoof S, et al. The role of chest imaging in patient management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society. Chest. 2020;158:106-16.
  • 5. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, et al. Chest CT findings in Coronavirus disease-19 (COVID-19): Relationship to duration of infection. Radiology. 2020 Feb 20;295:200463.
  • 6. Hu Q, Guan H, Sun Z, Huang L, Chen C, Ai T, et al. Early CT features and temporal lung changes in COVID-19 pneumonia in Wuhan, China. Eur J Radiol. 2020 Jul;128:109017.
  • 7. Li B, Li X, Wang Y, Han Y, Wang Y, Wang C, et al. Diagnostic value and key features of computed tomography in Coronavirus Disease 2019. Emerg Microbes Infect. 2020;9(1):787-93.
  • 8. Zieleskiewicz L, Markarian T, Lopez A, Taguet C, Mohammedi N, Boucekine M, et al. Comparative study of lung ultrasound and chest computed tomography scan in the assessment of severity of confirmed COVID-19 pneumonia. Intensive Care Med. 2020 Jul 29;46(9):1707-13.
  • 9. Tung-Chen Y, Martí de Gracia M, Díez-Tascón A, Alonso-González R, Agudo-Fernández S, Parra-Gordo ML, et al. Correlation between Chest Computed Tomography and Lung Ultrasonography in Patients with Coronavirus Disease 2019 (COVID-19). Ultrasound Med Biol. 2020 Nov;46(11):2918-26.
  • 10. Zhang P, Li J, Liu H. Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study. Bone Res. 2020;8:8.
  • 11.Vasarmidi E, Tsitoura E, Spandidos DA, Tzanakis N, Antoniou KM. Pulmonary fibrosis in the aftermath of the COVID-19 era (Review). Exp Ther Med. 2020 Sep;20(3):2557-60.
  • 12. Han X, Cao Y, Jiang N, Chen Y, Alwalid O, Zhang X, et al. Novel Coronavirus disease 2019 (COVID-19) pneumonia progression course in 17 discharged patients: comparison of clinical and thin-section computed tomography features during recovery. Clin Infect Dis. 2020 Jul 28;71(15):723-31.
  • 13. Gentile F, Aimo A, Forfori F, Catapano G, Clemente A, Cademartiri F, et al. COVID-19 and risk of pulmonary fibrosis: the importance of planning ahead. Eur J Prev Cardiol. 2020;27(13):1442-6.
  • 14. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585.
  • 15. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020 Aug;8(8):807-15.
  • 16. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, et al. Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19. Allergy. 2020 Jul;75(7):1564-81.
  • 17. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3.
  • 18. Riggioni C, Comberiati P, Giovannini M, Agache I, Akdis M, Alves-Correia M, et al. A compendium answering 150 questions on COVID-19 and SARS-CoV-2. Allergy. 2020 Oct;75(10):2503-41.
  • 19. Spagnolo P, Balestro E, Aliberti S, Cocconcelli E, Biondini D, Casa GD, et al. Pulmonary fibrosis secondary to COVID-19: a call to arms? Lancet Respir Med. 2020 Aug;8(8):750-2.
  • 20. George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A, Forrest I, et al. Respiratory follow-up of patients with COVID-19 pneumonia. Thorax. 2020;2020-215314.
  • 21. Mo X, Jian W, Su Z, Chen M, Peng H, Peng P, et al. Abnormal pulmonary function in COVID-19 patients at time of hospital discharge. Eur Respir J. 2020 Jun;55(6):2001217.
  • 22. Frija-Masson J, Debray MP, Gilbert M, Lescure FX, Travert F, Borie R, et al. Functional characteristics of patients with SARS-CoV-2 pneumonia at 30 days post-infection. Eur Respir J. 2020 Aug;56(2):2001754.

  • Availability of data and materials

    The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
  • Funding

    Not applicable.
  • Ethics approval and consent to participate

    The present study was approved by the local ethics committee of Botucatu Medical School (CAAE: 31258820.5.1001.5411). It is also registered at the Brazilian Registry of Clinical Trials (ReBEC) (https://ensaiosclinicos.gov.br/rg/RBR-8j9kqy). The Universal Trial Number (UTN) code is A27072519840. Informed consent was obtained from all individual participants included in the study.
  • Consent for publication

    Patients signed informed consent regarding publishing their data.

Publication Dates

  • Publication in this collection
    14 Apr 2021
  • Date of issue
    2021

History

  • Received
    17 Oct 2020
  • Accepted
    25 Jan 2021
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