Long-term Pulmonary Consequences of Coronavirus Disease 2019 (COVID-19)

Coronavirus disease 2019 (COVID-19), a viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 coronavirus), was initially called an outbreak and, in a short period of time, turned out to be the first pandemic from a coronavirus.1 Experts believe that the actual numbers of those infected are probably much higher than the reported confirmed numbers, as most cases of the disease are not diagnosed: not only because many patients have a subclinical or mild form of the disease and will not get medical attention, but also due to the limited diagnostic resources in many countries. Over the last couple of months, the clinical and imaging features of COVID-19 pneumonia have been discussed in numerous publications, and the major imaging findings of the disease have been described in detail. However, the postrecovery course of the disease, including its physical and psychological sequela, is not yet clear.2,3 The long-term effect of COVID-19 on lung parenchyma and pulmonary function remains an outstanding question. Although it is too early to completely answer this question, our limited observations demonstrate significant pulmonary sequela of the disease in some of the survivors (Fig. 1).FIGURE 1: A 56-year-old man presented with shortness of breath and fever for a few days. Chest CT at the time of admission (day 1) demonstrated bilateral peripheral ground-glass opacities (A) suggestive of COVID-19, a diagnosis which was subsequently confirmed by RT-PCR. On day 11 of admission, the ground-glass opacities were near completely replaced by airspace consolidations (B). Follow-up imaging after the discharge (35 d after the initial CT) demonstrates residual parenchymal consolidations with suggestion of fibrotic bands (C, D).In general, survivors of viral pneumonias are at risk of psychological and physical complications of the disease itself, as well as treatment-related lung damage and other organ injuries.4 Long-term lung disability is not uncommon in patients who have recovered from severe viral pneumonias. Although most survivors can return to work and normal life, a significant number of them will show residual ventilation and blood-gas diffusion abnormalities.4 LESSONS FROM SEVERE ACUTE RESPIRATORY SYNDROME (SARS) AND INFLUENZA One of the most important studies in the field, conducted by Zhang et al,5 is a comprehensive 15-year follow-up on health care workers who survived nosocomial SARS infections in 2003. In 27 recovered patients who underwent chest computed tomography (CT) from 2003 to 2018, the extent of pulmonary injury gradually decreased, but the findings were not completely resolved. The evolution and healing of the pulmonary disease were most prominent within the first year after recovery and remained stable afterward until 2018. Among those patients whose postrecovery CT scans showed no abnormalities in 2003, the pulmonary function in 2018 was better than that of 2006. These findings indicate that, even in patients with early complete resolution of chest CT abnormalities, pulmonary function took several years to return to normal. Moreover, 15 years after the initial infection, the forced expiratory flow 25% to 75% value and the forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) were significantly reduced in patients with residual chest CT abnormalities compared with those with complete radiologic recovery. The authors suggested a correlation between chest CT findings and pulmonary functional changes with prognostic implications. Wu et al6 reported follow-up high-resolution computed tomography (HRCT) of 11 patients at 3, 6, and 84 months postdischarge of inpatient treatment for SARS. The average number of involved lung segments decreased from 10 segments per patient at 3 months to 9.6 segments at 6 months and 6.8 segments at 84 months. At 3 months, the predominant CT feature of residual lung abnormality was the presence of ground-glass abnormalities, with or without consolidation. At 6 months, the presence of residual ground-glass abnormalities was still the predominant imaging feature, but approximately one-fourth of patients demonstrated reticulation and interlobular thickening. At 84 months, only 1 patient had no lung abnormality, with most of the remaining patients demonstrating only reticulation and interlobular thickening, and ground-glass opacity or traction bronchiectasis was found in only 3 patients. Chen et al4 performed a 24-month follow-up study on patients with epidemic influenza A (H7N9) virus infection. On the 3-month postrecovery chest CTs, they observed several residual radiologic changes, including linear fibrosis, focal pleural thickening, and small bullous cyst formation. Although these changes showed improvement six months after the hospital discharge, no marked changes were noted after six months, suggesting that some pulmonary changes during the 6-month convalescence period can be irreversible. At the 12-month follow-up imaging, they reported that only 14.6% of patients demonstrated normal chest CTs, while residual parenchymal ground-glass opacities and reticular patterns, pulmonary fibrosis, bronchiectasis, pleural thickening, pneumatocele, pulmonary nodules, and small bullous cysts were identified in 51.2%, 41.5%, 24.4%, 22.0%, 9.8%, 9.8%, and 4.9% of patients, respectively. From a physiological point of view, both ventilation and diffusion pulmonary dysfunction persisted, but decreased throughout the follow-up of these patients. The ventilation dysfunction decreased from 78.7% of the patients at the first visit to 55.0% at the 24-month follow-up visit, and the restrictive ventilation dysfunction ratio reduced from 31.9% to 10.0% at the 24-month visit. Most patients also suffered from a residual impairment of diffusing capacity of the lungs for carbon monoxide, which mild to moderately reduced in severity over time. More importantly, the prevalence of small airway dysfunction and obstructive patterns in survivors tended to increase over time, albeit not significant statistically. Development of acute respiratory distress syndrome (ARDS) was a poor prognostic factor in terms of long-term pulmonary function. Patients with ARDS consistently achieved lower FEV1, Diffusing capacity of lung for carbon monoxide, and FVC indices over the 24-month follow-up period. This can lead to a lower quality of life in patients who have experienced ARDS, as evaluated by the 36-Item Short-Form Health Survey (SF-36). In another short-term follow-up study over a period of 3 months performed by Xie et al,7 residual abnormalities were identified on chest radiographs and HRCT of about 20% of SARS patients. Interstitial thickening, residual ground-glass opacities, hypoinflation/volume loss, and bronchiectasis were the main findings. Among the rehabilitating patients with radiographic features of residual lung disease caused by SARS (such as pulmonary fibrotic changes), 55% of patients showed improvement of abnormality on their follow-up HRCT scan in a month. In a study on 5 patients from the first avian influenza A (H7N9) virus outbreak in Shanghai, China, Tang et al8 compared the 6-month postdischarge chest CTs of these patients with their initial CTs obtained during the hospitalization. They found that, despite the resolution of the majority of pulmonary lesions, all survivors demonstrated bilateral residual imaging abnormalities that could be detected in more than 2 lobes. These residual imaging abnormalities were more frequent in bilateral lower lobes with persistent ground-glass opacities observed in all survivors. Interlobular septal thickening, cystic changes, and subpleural linear opacities were among the other common abnormalities. Interestingly, no consolidations or pleural effusions were reported in their study population. Lu et al,9 in their 12- and 24-month follow-up study on 2 patients with avian influenza A (H5N1) infection, revealed that the resolution of lung lesions is slow with fibrotic reticular and linear thickening and observed small patchy opacities on CT at the seventh month of follow-up of one patient. Antonio et al10 also found that parenchymal fibrosis starts early in the course of the recovery and tends to be more common in the elderly and more seriously affected patients. RECOMMENDATIONS FOR COVID-19 The long-term effect of COVID-19 is still largely unknown. However, based on the previous experiences with other viral pulmonary infections, long-term pulmonary consequences are indeed expected in some patients. As per Xie et al,7 a significant number of patients recovering from the acute viral illness may have significant impairment in overall functional capacity and specifically their pulmonary function in the first few months. More importantly, the radiologic presentation of pulmonary sequela with parenchymal distortion and the physiological damage of pulmonary function may not correlate with clinical symptomatology, and the imaging findings of these viral pneumonias may last for a long time or become permanent.8 The imaging findings correlate with histopathologic features of viral pneumonias, where the lungs histologically show diffuse alveolar damage with interstitial lymphocyte infiltration, edema, fibrosis, alveolar hemorrhage, type 2 cell hyperplasia, and hyaline tissue formation.11 Organizing pneumonia and diffuse alveolar damage seem to be, by far, the most common forms of lung injury associated with COVID-19, and both evolve in a fairly predictable manner.2,3,12 Organizing pneumonia has been shown to be the origin of the later changes and complications in a significant number of viral pulmonary infections.13–15 The ground-glass opacities are usually seen during the initial stages of the COVID-19 disease (acute phase of diffuse alveolar damage). Superimposition of consolidation on the existing ground-glass opacities occurs at the progression/complication stage (evolution to organizing phase of diffuse alveolar damage).2 At this point, the pattern of lesions can progress to pure consolidation or may present the melted sugar sign (gradual resolution of consolidation and turning into ground-glass opacities). It may also manifest by the progression of consolidation to band-like opacities (parenchymal bands) in the later stages of the disease and complicate the recovery phase.13,16 Different factors may play a role in the severity of residual functional or imaging pulmonary abnormalities and the likelihood of residual scar of the disease. The patient’s age, comorbidities, history of cigarette smoking, length of hospital admission, and the severity of the acute disease (such as the need for ICU admission) and the type of medications administered (such as antiviral or corticosteroid therapy) are probably among the most important determinants.7,10,17 Long-term follow-up chest imaging of survivors is needed for a better understanding of the possible irreversible pulmonary damages of SARS-CoV-2 pneumonia. Meanwhile, follow-up evaluation of recovered patients by a pulmonologist is advised. For any clinical suspicion of residual lung damage, further evaluation by pulmonary function tests and/or imaging may be obtained. In terms of imaging, chest x-ray can be the best initial step. However, in patients with residual radiographic or functional impairment, high-resolution chest CT can be indicated not only for further characterization of anatomic abnormalities of the lung parenchyma but also to establish a baseline for possible future follow-ups.