Pulmonary Manifestations of “Long COVID” (Post–COVID-19)
Stephen L. Demeter
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) infections began in late 2019/early 2020 and quickly achieved pandemic proportions. Of significance is that, while most individuals recover, some do not. Those who have persistent symptoms are diagnosed with long COVID, or post-COVID syndrome. Individuals with long COVID develop symptoms related to multiple organ systems. One of the more frequent systems affected is the pulmonary system. Individuals develop shortness of breath and/or fatigue. These are sometimes unrelated to any abnormalities on physiological or radiographic testing. More frequently, however, there are abnormalities found radiographically (especially on computed tomography) and on physiological testing (generally, abnormalities in the diffusion capacity for carbon monoxide or in a 6-minute walk test with the oxygen saturation being measured during the test). This article reviews many published articles and is organized by the duration of signs, symptoms, and/or testing abnormalities after the initial diagnosis of COVID-19. The date of maximum medical improvement is suggested to be 12 months, although currently this cannot be definitively supported. More time will need to pass so that appropriate data can be collected.

Introduction

The AMA Guides® Newsletter has published six articles on impairment from various manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) infection. In 2020, Talmage et al1 described methods for rating permanent impairment. In the same issue, Snyder and Talmage2 discussed causation issues when rating COVID-19 patients. A second general article was published by Caruso et al3 in 2021. Talmage et al,4 in 2021, updated their prior article, titling it “COVID 19: Achieving Maximum Medical Improvement and Assessing Permanent Impairment.” These four articles described rating methods for a variety of clinical conditions, including those involving the cardiac and the pulmonary systems. In 2021, Gulick et al5 described the psychological effects of COVID infections, and in 2022, Hirsch et al6 discussed neurological and psychological issues. This article focuses on pulmonary issues, updating these prior articles and using the medical literature since early 2021.

Pulmonary problems associated with acute COVID can occur de novo or present as worsened problems in individuals with pre-existing pulmonary problems. UptoDate states:

  • The most common symptoms in individuals with long COVID, with one-third or more experiencing more than one symptom, are:

    • fatigue (13%-87%),

    • dyspnea (10%-71%),

    • chest pain or tightness (12%-44%), and

    • cough (17%-34%).

  • Persistent symptoms may vary depending on the COVID-19 variant.

  • Symptom resolution depends on a variety of factors, including premorbid risk factors, the severity of the acute illness, and the spectrum of symptoms.

  • Individuals with a shorter vs longer symptom intervals and individuals who are hospitalized vs those who are not can develop symptoms of long COVID, although, in general, those with longer duration of symptoms and who were hospitalized are more prone to develop longer-lasting symptoms.

  • The need for chest imaging is determined by previous abnormal findings on chest imaging studies as well as the current symptoms. Generally, individuals who did not have chest imaging studies performed during their acute illness or while experiencing current pulmonary symptoms require no further imaging studies. Further imaging studies are recommended for patients who had infiltrates, had new or worsening pulmonary symptoms, or had abnormal findings on cardiopulmonary physical examination.

  • For most individuals, a plain chest X ray is sufficient; however, if more severe illness is possible, a computed tomography (CT) scan is recommended.

  • In general, the expectation of lung damage, as defined radiographically, resolves within 2 to 4 weeks, but full resolution may require 12 weeks or longer. There are studies suggesting that changes may occur within the first year, especially in patients who had severe disease.

  • CT angiography is recommended in individuals who have unexplained cardiopulmonary symptoms and/or low oxygen saturations, despite normal chest radiography findings, to eliminate the possibility of thromboembolism.

  • Pulmonary function studies are recommended for individuals with persistent, progressive, or new respiratory symptoms. Pulmonary function studies are also recommended for individuals with severe pulmonary problems, a history of COVID-19-related acute respiratory distress syndrome (ARDS), or neuromuscular weakness.

  • When pulmonary function studies are performed, a full pulmonary function test (PFT) is recommended (a spirometry with tests of lung volumes and gas diffusion).

  • In general, it is recommended that the PFT be performed between 6 and 12 weeks after discharge. If abnormalities are found either radiographically or on physiological studies, repeat testing at 6 months is recommended. Thereafter, it is recommended that testing be performed for an additional 5 years.

  • For individuals with unexplained respiratory symptoms after the initial cardiopulmonary evaluation (which includes an evaluation to eliminate the possibility of venous thromboembolic disease and/or heart disease), a six-minute walk test (6-MWT) is recommended.

  • Nocturnal oximetry is generally not recommended, unless there are symptoms during sleep.

  • If there are unexplained, persistent symptoms following the above evaluations, consideration for a cardiopulmonary exercise stress test and/or a complete cardiac evaluation is recommended.7

Other review articles, while supporting the above, have also stated the following:

  • At this time, COVID-19 is considered a systemic infection, involving multiple systems and causing chronic complications. In comparison with other postviral fatigue syndromes, persistent problems and/or symptoms associated with COVID-19 are considered to be broader and more intense. The most frequent symptoms are profound fatigue; shortness of breath; sleep difficulties; anxiety/depression; reduced lung capacity, memory, and cognitive impairment; and difficulty with the sense of smell. Risk factors include the severity of the illness, more than five symptoms in the first week of the disease, female gender, older age, the presence of comorbidities, and a weak anti-SARS-CoV-2 antibody response.8

  • In patients who are at least 18 years old who were followed for 4 to 12 months after having COVID-19, the Centers for Disease Control and Prevention stated that 30% experience an incident condition compared with 16% of controls, with conditions affecting many organ systems, including the cardiovascular, pulmonary, hematological, renal, endocrinological, gastrointestinal, musculoskeletal, neurological, and psychiatric systems.9

  • In 44 patients studied 6 months after hospital discharge, 60% had persistent lung CT scan abnormalities, 18% to 43% had at least one PFT abnormality (a reduction in the diffusing capacity of the lungs for carbon monoxide [DLCO] and the mean inspiratory pressure were the most frequent [43%], and a decrease in the forced expiratory volume in 1 second [FEV1] was the least frequent [18%]). Female gender, the comorbidity index, and older age were associated with worse lung function. Long-term lung dysfunction is relatively common in survivors of severe COVID-19 and impacts negatively on activities of daily living and the intensity of dyspnea.10

A list of other recent review articles published in the past 18 months is provided after this article's reference section.

Lastly, a 2022 position paper11 titled “Cardiopulmonary Assessment Prior to Returning to High-Hazard Occupations Post-Symptomatic COVID-19 Infection: A Position Statement of the Aviation and Occupational Cardiology Task Force of the European Association of Preventive Cardiology” was reviewed. It is worthwhile to examine this paper when performing an independent medical evaluation/return to work report.

The biochemical mechanisms, while interesting and important, have minimal value when performing an independent medical evaluation; references to articles reviewing biochemical mechanisms are also provided after this article's reference list.

Symptoms, radiographic abnormalities, and physiology are all considered together in one section in this article, with persisting symptoms or abnormalities organized by duration (eg, long COVID signs or symptoms within 1-3 months following hospital discharge vs 3-6, 6-12, and >12 months). There is a clear degression of abnormalities as time passes.

For a review of pulmonary vascular abnormalities, including thromboemboli, see the article by Demeter12 on cardiac manifestations of long COVID.

Long COVID Symptoms

As stated previously, the most common pulmonary symptoms in individuals with long COVID are shortness of breath, fatigue, exercise intolerance, and cough. In addition to noting the varying lengths of duration of abnormalities, it should be acknowledged that these symptoms may be multifactorial in origin. For example, shortness of breath, fatigue, and exercise intolerance may be caused by pulmonary, cardiac, hematological, and deconditioning issues. At times, they can be objectively supported by exercise studies showing diminished oxygen saturations, arterial oxygen concentrations, diminished V̇O2, etc. On the other hand, these symptoms may also represent subjective concerns without significant objective abnormalities:

  • Beaudry et al13 stated that “up to 53% of individuals who had mild COVID-19 experience symptoms for >3 months following infection (Long-CoV). Dyspnea is reported in 60% of Long-CoV cases and may be secondary to impaired exercise capacity (V̇O2peak) as a result of pulmonary, pulmonary vascular, or cardiac insult.” In their study, no test of pulmonary function, cardiac physiology, or pulmonary vascular pressure was abnormal. The authors13 stated that “persistent dyspnea after COVID-19 was not associated with overt cardiopulmonary pulmonary impairment or exercise intolerance.”

  • Cassar et al14 stated that “cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls.” In their study, persistent symptoms at 6 months after COVID-19 were not associated with objective abnormalities of cardiopulmonary health.

  • Dysfunctional breathing (DB) is characterized by an irregular tidal volume and breathing frequency without hyperventilation. It is also characterized by persistent dyspnea and erratic or inappropriate ventilation at rest or exercise. In a study by Frésard et al,15 the authors stated, “we found that DB evaluated by CPET [cardiopulmonary exercise testing] occurs in almost one-third of the patients living with ‘long COVID’ and complaining of dyspnoea in our centre. DB was associated with younger age and previous mild/moderate acute COVID. Additionally, DB was still recognisable more than 200 days after SARS-CoV-2 infection in patients complaining of persistent dyspnoea. Although DB has already been suspected in patients living with ‘long COVID,’ this is the first study to our knowledge to describe an erratic type of breathing mainly without hyperventilation best corresponding to the periodic deep sighing type of breathing.” For technical reasons, they also stated that the frequency of this cause of shortness of breath may have been overreported in their article. In their review of other articles, the authors stated that “respiratory limitation (RL) and deconditioning seem to be the main patterns limiting exercise.” They concluded by stating that their findings “suggest that DB without hyperventilation could be an important pathophysiological mechanism of disabling dyspnoea in younger patients following SARS-CoV-2 infection, which appears to be a feature of COVID-19 not described in other viral diseases.”15

  • Spiesshoefer et al16 stated that “up to 30% of coronavirus disease 19 (COVID-19) survivors report dyspnea on exertion that could not be explained by routine clinical diagnostic measures and prevented most of them from returning to the original work and life.” Ten patients were evaluated 1 year after discharge. The authors concluded that “diaphragm dysfunction with impaired voluntary activation can be present 1 year after severe COVID-19 ARDS and may relate to exertional dyspnea.”16

On the other hand, it would be disingenuous to state that all individuals who have long COVID and who have persistent pulmonary symptoms have no physiological or radiographic abnormalities (ie, objective evidence) that could explain their current condition. Furthermore, the estimated date of maximum medical improvement (MMI) may still be unknown for patients with long COVID. For example, Fortini et al17 looked at persistent symptoms and pulmonary function abnormalities at 3 to 6 months and at 1 year. They noted that one-third of patients had respiratory changes that persisted. They stated that these individuals “will need prolonged follow-up.”17

Lehmann et al18 stated in 2022 that “longer follow-up trials and larger populations are needed to better understand the pathophysiology of long COVID, its outcome, and mismanagement.”

Long COVID Symptoms 1 to 3 Months After Infection and/or Hospital Discharge

Lehmann et al18 studied 135 individuals from 60 to 116 days following COVID infection (mean, 85 days); 57.8% complained of persistent pulmonary symptoms. Individuals with persistent respiratory symptoms were sick a little longer with a lower forced vital capacity (FVC) and diffusing capacity. Shortness of breath with exertion was seen in 50%, cough in 10%, and chest pain in 16%; 29% were asymptomatic. High-resolution CT scans of the lungs showed persistent ground-glass opacities and/or consolidations in 38.5% of the symptomatic patients.18

Marazzato et al19 reviewed 29 patients who recovered from COVID-19 pneumonia (time not specified). Pleural abnormalities were found in 66%. A lung ultrasound showed abnormal diaphragmatic thickness and excursion, which correlated with abnormalities on CT examination in 93%.

Franquet et al20 studied 48 patients at least 30 days after hospital discharge, with a median of 72.5 days. “Parenchymal abnormality was found in 50% (24/48) of patients and included air trapping (37/48, 77%), ground-glass opacities (19/48, 40%), reticulation (18/48, 38%), parenchymal bands (15/48, 31%), traction bronchiectasis (9/48, 19%), mosaic attenuation pattern (9/48, 19%), bronchial wall thickening (6/48, 13%), and consolidation (2/48, 4%).” Regarding the presence of air trapping, it was absent in 11 patients (23%), mild in 20 (42%), moderate in 13 (27%), and severe in 4 (8%). “Independent predictors of air trapping were, in decreasing order of importance, gender (P= .0085), and age (P = .0182).”

Touman et al21 reviewed the records of 38 patients with COVID-19. Half (19) had persistent parenchymal changes 10 weeks after the acute illness (group 1) and were compared with the other 19 patients (controls) who had accelerated clinical and/or radiological improvement (group 2). Group 1 was found to have the more severe clinical and radiological disease, with a higher peak value of inflammatory biomarkers. Two risk factors were identified: a neutrophil-lymphocyte ratio greater than 3.13 at admission (this increased the odds ratio [OR] of chronic parenchymal changes by 6.42 and 5.92 in the univariate and multivariate analyses, respectively) and the need for invasive mechanical ventilation (this increased the ORs by 13.09 and 44.5 in the univariate and multivariate analyses, respectively). There were no significant differences between the two groups with respect to ages, gender, smoking history, body mass index, history of chronic obstructive pulmonary disease, history of asthma, or biochemical abnormalities. Radiographic abnormalities included ground-glass opacities (100%), parenchymal bands (79%), thickened interlobular septa, linear opacities, traction bronchiectasis (50%), and focal consolidations (16%). Honeycombing was not seen.21

Philip et al22 reviewed the cases of 4,500 people with asthma (median age, 50-59 years; female, 81%). There were 471 individuals in the COVID-19 group. Those individuals reported increased inhaler usage and worse asthma management. There were no significant differences with respect to gender, ethnicity, or household income. Compared with individuals without long COVID, the patients with long COVID reported that their breathing was worse after the initial illness, that they had worse or much worse asthma management, and that they had an increase in their inhaler usage. Unfortunately, in this study, the time following the COVID-19 infection was not reported in detail.22

Gattoni et al23 studied symptoms, pulmonary function abnormalities, and metabolic power in professional football (ie, soccer) players. They stated23:

This study aimed at: (1) Reporting COVID-19 symptoms and duration in professional football players; (2) comparing players' pulmonary function before and after COVID-19; (3) comparing players' metabolic power (Pmet) before and after COVID-19. Thirteen male players (age: 23.9 ± 4.0 years, V̇O2peak: 49.7 ± 4.0 mL/kg/min) underwent a medical screening and performed a running incremental step test and a spirometry test after COVID-19. Spirometric data were compared with the ones collected at the beginning of the same season. Players' mean Pmet of the 10 matches played before COVID-19 was compared with mean Pmet of the 10 matches played after COVID-19. Players completed a questionnaire on COVID-19 symptoms and duration 6 months following the disease. COVID-19 positivity lasted on average 15 ± 5 days. “General fatigue” and “muscle fatigue” symptoms were reported by all players during COVID-19 and persisted for 77% (general fatigue) and 54% (muscle fatigue) of the players for 37 ± 28 and 38 ± 29 days after the disease, respectively. No significant changes in spirometric measurements were found after COVID-19, even though some impairments at the individual level were observed. Conversely, a linear mixed-effects model analysis showed a significant reduction of Pmet (−4.1% ± 3.5%) following COVID-19 (t = −2.686, P <.05). “General fatigue” and “muscle fatigue” symptoms may persist for several weeks following COVID-19 in professional football players and should be considered for a safer return to sport. Players' capacity to compete at high intensities might be compromised after COVID-19.

Vianello et al24 in a 2021 article stated, “pulmonary fibrosis…is a key component of the ‘post-acute COVID-19 syndrome’…Although inconclusive, available data suggest that more than one-third of hospitalized COVID-19 patients develop lung fibrotic abnormalities after their discharge from hospital.”24 Robey et al25 evaluated 221 patients (44 intensive care unit [ICU] patients and 177 general hospital admissions) 2 months after hospitalization. All ICU patients and 21% of general hospitalized patients had persistent radiographic abnormalities. Findings from CT examinations at an average of 18 weeks after discharge showed persistence of ground-glass opacities in 44% and fibrosis in 21%, “equating to 7% of the entire cohort.”25

Long COVID Symptoms 3 to 6 Months After Infection and/or Hospital Discharge

Sperling et al26 studied 218 patients, 3 months after discharge for COVID-19. They found that the “mean DLCO was 80.4% (95% CI: 77.8, 83.0) and 45% had a DLCO <80%. Mean DLCO was significantly reduced in patients treated in the ICU (70.46% [95% CI: 65.13, 75.79]). The highest FAS [fatigue assessment scale] and HADS [hospital anxiety and depression scale] were seen in patients with the shortest period of hospitalization (2.1 days [95% CI: 1.4, 2.7]) with no need for oxygen.” These patients underwent a complete pulmonary function study and a 6-MWT. The mean time from hospitalization to follow-up was 120 days; the most prevalent symptoms were fatigue (61%), shortness of breath (55%), and impaired concentration (34%). Overall, 86% of patients reported at least one symptom; 13% had an FEV1 less than 80% predicted, with 5% having an FEV1 below 60% predicted. The DLCO was less than 80% of predicted in 45% of patients and less than 60% in 16% of patients. “The FEV1, FVC, DLCO, TLC [total lung capacity], and RV [residual volume] were all significantly lower in patients admitted to the ICU compared to patients not needing oxygen therapy. However, only DLCO is decreased below the lower limit of normal.”26

Long et al27 reviewed articles published between January 1, 2020, and February 23, 2021. They included 4478 COVID-19 patients from 16 cohort studies in their meta-analysis. The authors stated, “fatigue or weakness (47%) were the most prevalent physical effects of post-acute COVID-19 syndrome, while psychosocial (28%) symptoms were the most common manifestations among several systems. Abnormalities in lung function of recovering patients, ie, DLCO <80% (47%, 95% CI: 32%-61%) persisted for long periods. Severe patients were more likely to present joint pain (OR 1.84, 95% CI: 1.11-3.04) and decreased lung functions compared with nonsevere patients, with pooled ORs for abnormal TLC, FEV1, FVC, and DLCO of 3.05 (95% CI: 1.88-4.96), 2.72 (95% CI: 1.31-5.63), 2.52 (95% CI: 1.28-4.98), and 1.82 (95% CI: 1.32-2.50), respectively.”27

Wallis et al28 in a 2021 article stated that the long-term consequences of COVID-19 are still unknown. However, “long-term progression to pulmonary fibrosis has previously been identified following infection with other species of the coronavirus family, eg, severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV).” They also stated that “short-term follow-up studies of patients with COVID-19 have demonstrated that fibrotic changes in the lungs can be detected for as little as 3 weeks.” In their study, 32% of individuals had persistent radiographic abnormalities at 3 months. Factors related to increased incidence were extended length of stay, obesity, increased serum lactate dehydrogenase, and smoking status.28

Jutant et al29 stated:

Among the 478 patients, 78 (16.3%) reported new-onset dyspnoea, and 23 (4.8%) new-onset cough. The patients with new-onset dyspnoea were younger (56.1±12.3 versus 61.9±16.6 years), had more severe COVID-19 (ICU admission 56.4% versus 24.5%) and more frequent pulmonary embolism (18.0% versus 6.8%) (all P≤.001) than patients without dyspnoea. Among the patients reassessed at the ambulatory care visit, the prevalence of fibrotic lung lesions was 19.3%, with extent <25% in 97% of the patients. The patients with fibrotic lesions were older (61±11 versus 56±14 years, P=.03), more frequently managed in an ICU (87.9% versus 47.4%, P<.001), had lower total lung capacity (74.1%±13.7% versus 84.9%±14.8% pred, P<.001) and diffusing capacity of the lung for carbon monoxide (DLCO) (73.3%±17.9% versus 89.7%±22.8% pred, P<.001). The combination of new-onset dyspnoea, fibrotic lesions and DLCO <70% pred was observed in eight out of 478 patients. Conclusions: New-onset dyspnoea and mild fibrotic lesions were frequent at 4 months, but the association of new-onset dyspnoea, fibrotic lesions, and low DLCO was rare.

In this study, fibrotic lesions were seen, radiographically, in less than 25% of the lung parenchyma. As noted, the participants were interviewed 3 to 4 months after discharge from the hospital (telephonically). The CT examinations were high-resolution CT scans (HRCT) of the lungs. In this study, full pulmonary function studies and 6-MWTs were performed. In the 118 patients with new-onset dyspnea, 19.2% also had new-onset cough, 61% had abnormal HRCT, but only 17 (25%) had an abnormality on the diffusing capacity. In those individuals without new-onset dyspnea, only 6% had a new-onset cough. There was no significant difference in the results of the 6-MWT or the pulmonary function studies. Significantly fewer patients had HRCT abnormalities on CT examination.29

Kersten et al30 studied 367 individuals (age, 47.3 ± 14.8 years; female, 57.5%) at least 3 months after hospitalization. Symptom severity correlated with initial disease severity. There was also a significant correlation between the symptom severity and a reduced exercise tolerance in a 6-MWT and a reduction in the diffusing capacity. The authors concluded: “Highly symptomatic long COVID patients show impaired diffusion capacity and 6-MWT despite average or mildly affected mechanical lung parameters. It must be further differentiated whether this corresponds to a transient functional impairment or whether it is a matter of defined organ damage.”30

Ladlow et al31 studied 113 individuals within a mean of approximately 5 months after their acute illness. The authors stated that hospitalized individuals “had the least favorable body composition (body mass, body mass index, and waist circumference) compared with controls. Hospitalized-symptomatic and community-symptomatic individuals had lower oxygen uptake (V̇O2) at peak exercise. They concluded by stating that community-recovered individuals did not differ in cardiopulmonary fitness from physically active healthy controls.31

Lindahl et al32 looked for evidence of small airflow obstruction in 20 individuals 3 to 6 months after hospitalization. “None of the patients had small airway obstruction, nor increased nitric oxide concentration in the alveolar level. None of the patients had a reduced FEV1/FVC or significant bronchodilator response in iOS [impulse oscillometry] or spirometry. In conclusion, we found no evidence of inflammation or dysfunction in the small airways.”32

Kang et al33 stated, “cough is the most common symptom of acute COVID-19, but cough may persist in some individuals for weeks or months after recovery from acute phase.” They described a case and discussed the potential mechanisms, management, and clinical implications.33

Long COVID Symptoms 6 to 12 Months After Infection and/or Hospital Discharge

Fernández-de-las-Peñas et al34 interviewed by telephone 1950 patients 11.2 months after hospital discharge; 19% were free of any respiratory post–COVID-19 symptoms. “The prevalence of long-term cough, chest pain, dyspnea, and fatigue was 2.5%, 6.5%, 23.3%, and 61.2%, respectively…No clear risk factor associated to long-term post-COVID-19 cough was identified.”34

The effect of obesity was studied by Lacavalerie et al35 in 51 consecutive patients diagnosed with long COVID. “More than half of patients with chronic post-COVID-19 had a significant alteration in aerobic exercise capacity (V̇O2peak) 6 months after hospital discharge. Obese long COVID-19 patients also displayed a marked reduction in oxygen pulse (O2pulse). Conclusion: Obese patients were more prone to have pathological pulmonary limitation and pulmonary gas exchange impairment to exercise compared with nonobese COVID-19 patients.” In these individuals, shortness of breath and fatigue were the most frequent symptoms. A restrictive ventilatory pattern (defined as a combination of FEV1/FVC >0.70 and FVC <80% of predicted was found in 59% of individuals. In addition, 53% had a V̇O2peak <75% of predicted values. Radiographic abnormalities were not described.35

Prestes et al11 studied 44 patients 6 months after hospital discharge. CT abnormalities on lung scanning (no mention was made regarding if the CT scans were high-resolution) were found in 24 individuals (60%), with ground-glass capacities found in 15 of 24 and fibrosis in 9 of 24. Desaturation on a 6-MWT was found in 15%. Only 8 individuals had a diminished FEV1, but 19 had a decrease in the diffusing capacity. The authors concluded by stating that “in general, female gender, comorbidity index, and age were associated with worse lung function.”11

Hennigs et al36 studied 67 individuals approximately 5 months after acute infection. They measured “neuroventilatory activity P0.1 (the occlusion pressure at 100 msec), inspiratory muscle strength (PImax) and total respiratory muscle strain (P0.1/PImax) in addition to standard pulmonary functions tests, capillary blood gas analysis, 6-min walking tests, and functional questionnaires.” They concluded that their findings “point towards respiratory muscle dysfunction as a novel aspect of COVID-19 sequelae. Thus, we strongly advocate for systemic respiratory muscle testing during the diagnostic workup of persistently symptomatic, convalescent COVID-19 patients.”36

In a similar study, McNarry et al37 found that inspiratory muscle training significantly improves breathlessness and respiratory muscle in individuals with long COVID. Other articles suggesting similar outcomes include those by Nopp et al38 and Simon and Simmons.39 On the other hand, findings from the study by Soril et al40 were less positive regarding the results of pulmonary rehabilitation.

Long COVID Symptoms 12 Months After Infection and/or Hospital Discharge

In a 12-month survey performed by Steinbeis et al,41 the authors stated:

Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6, and 12 months after onset of COVID-19 symptoms. Chest CT scans, pulmonary function, and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19.

Results: Median age of all patients was 57 years, 37.8% were female. Higher age, male sex, and higher BMI were associated with acute-COVID-19 severity (P < .0001, .001 and .004, respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, DLCO from 60.18 to 68.98, and KCO [carbon monoxide transfer coefficient] from 81.28 to 87.80 (percent predicted values; P = .002, .045, .0002 and .0005). The CT score of lung involvement in the acute phase was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with initially mild disease.

Conclusion: Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection.

Fortini et al17 looked at persistent symptoms and pulmonary function abnormalities between 3 and 6 months and 1 year. They stated that the “mean DLCO was significantly improved at the 1-year visit (from 64% of predicted at 3-6 months to 74% of predicted at 1 year; P = .003). A clinically significant increase in DLCO (10% or greater) was observed in 11 patients (65%) with complete normalization (>80% of predicted) in 6 (35%); in the other 6 (35%) it remained unchanged. The prevalence of exertional dyspnea (65%-35%, P = .17), cough (24%-18%, P = 1), and fatigue (76%-35%, P = .04) decreased at the 1-year visit. Conclusion: These results suggest that DLCO and respiratory symptoms tend to normalize or improve 1 year after hospitalization for COVID-19 in most patients. However, there is also a nonnegligible number of patients (about one-third) in whom respiratory changes persist and will need prolonged follow-up.”17

Xiang at al42 stated:

The most commonly reported lingering symptoms of COVID-19 at discharge are fatigue, muscle weakness, sleep disturbances, abnormal lung dispersion, anxiety, and depression …A meta-analysis of 16 cohort studies showed that discharged patients could develop residual symptoms in multiple organs, including cardiopulmonary (chest pain, dyspnea, cough, sore throat, and palpitations), nerve (dysmnesia, cognitive disorder, headache, dysgeusia, and dysosmia), gastrointestinal tract (diarrhea, vomiting, abdominal pain, and anorexia), eyes (conjunctivitis), skin (urticaria), musculoskeletal system (myalgia and arthralgia), etc. In addition to the psychological impact, there is overwhelming evidence that the lung is the most severely affected organ in COVID-19 patients, both in the progressive and convalescent stages. In a 6-month follow-up study involving 1733 discharged patients, those requiring high flow nasal catheter (HFNC), noninvasive ventilation (NIV), or intermittent mandatory ventilation (IMV) had an odds ratio (OR) of 4.60 (after multivariable adjustment) for diffusion disorders compared with those requiring no supplemental oxygen. 36% of patients in the severest group had dyspnea with a modified Medical Research Council (mMRC) score >1 (severe dyspnea) at 6 months. 50% of patients who completed high-resolution computed tomography chest scans across different severity scales had at least one CT anomaly, with GGO [ground-glass opacities] being the most common, followed by irregular lines. Revisiting the survivors after 12 months showed a slight increase in the rate of dyspnea. There was no improvement in pulmonary diffusion impairment. And the incidence of pulmonary diffusion impairment was 23% in the no oxygen group, 31% in the oxygen-required group, and 54% in the group with HFNC, NIV, or IMV. The proportion of CT abnormalities decreased significantly over time.

Kanne et al43 reviewed articles discussing radiographic aspects of individuals at least 1 year after COVID-19 infection. They concluded:

  • Approximately one-third of patients hospitalized with COVID-19 pneumonia have abnormalities at chest CT 12 months after infection.

  • CT abnormalities range from residual parenchymal bands to fibrosis as well as air trapping and bronchiectasis.

  • A very small number of patients have a persistently elevated risk of venothromboembolic disease after acute infection.

  • The late histopathologic findings of COVID-19 are similar to those of other causes of acute lung injury with a mix of organizing and chronic fibrosing histologic patterns. Additionally, these findings are comparable to those reported with the SARS epidemic.

This excellent review discussed the chronic, residual radiographic abnormalities following COVID-19 pneumonia and correlated those abnormalities with pathological abnormalities. The authors stated that the acute changes were those of organizing pneumonia or diffuse alveolar damage. The chronic changes were those of “fibrosis” with the following abnormalities and frequencies on CT examination:

GGO and “fibrotic-like changes” 21%
Bronchiectasis 10%
Interlobular septal thickening 8%
Reticular opacity 6%
Consolidation 3%

Fibrotic-like changes were characterized by architectural distortion with traction bronchiectasis and bronchiolectasis with honeycombing and volume loss.

Furthermore, they focused on airway abnormalities, as seen in the table below, which summarizes their findings:

Large airway Peripheral, central, or diffuse bronchiectasis associated with residual opacities
Anterior bronchiectasis with fibrosis and air cysts (in ARDS survivors)
Small airway Mosaic attenuation during inspiration
Air trapping during expiration
Ventilatory defects and abnormal gas diffusion as seen with hyperpolarized 129Xe MRI

Regarding 129Xe (xenon) magnetic resonance imaging (MRI), Matheson et al44 reviewed studies of individuals with post-acute COVID-19 syndrome and found that radioactive xenon can be measured in ventilated alveoli. It is dissolved in the interstitial tissue and taken up by red blood cells in the capillaries. As such, the 129Xe MRI tracks the passage of xenon along the oxygen uptake pathway through the lungs. Matheson et al stated that the gas exchange and CT vascular density measurements were abnormal and were related to the diffusing capacity of the lung for carbon monoxide, the FEV1, exercise limitation, and exertional dyspnea. See also the studies by Wild and Collier45 and Grist et al.46

Watanabe et al47 performed a meta-analysis of pulmonary problems in patients who had a confirmed COVID infection. The articles included in the review studied only individuals who have been followed for at least 1 year. Fifteen articles were selected for the meta-analysis, comprising 3134 patients. They found CT abnormalities in 32.6% of patients, consisting of ground-glass opacities in 21.2% and fibrotic-like changes in 20.6%. They also noted that there had been gradual recovery, with 52.9% having CT abnormalities at 6 months and 32.6% at 1 year. The frequency of CT abnormalities was higher in patients with greater severity of illness than in individuals who had mild or moderate cases (37.7% vs 20.7%). They noted that fibrotic changes “showed little improvement between 4-7 months and 1 year after COVID infection.” Pulmonary function studies showed a decrease in the diffusing capacity for carbon monoxide, especially in severely ill and critical care patients. Additionally, they found bronchiectatic changes in 9.6%, interlobular septal thickening in 8.4%, reticular opacities in 5.5%, and consolidation in 2.6%.

Health outcomes were measured in 1192 COVID-19 patients at 6 months, 12 months, and 24 months after symptom onset in a study by Huang et al.48 The authors found that the sequelae of COVID-19 diminished with time. The following table is a summary of the incidence of various signs and symptoms, segregated by time:

Test Result or Symptom 6 mo 12 mo 24 mo
At least one symptom 68% 49% 55%
Chest pain 5% 7% 7%
mMRC dyspnea score = 0 74% 70% 86%
mMRC dyspnea score ≥1 26% 30% 14%
Distance walked in 6 minutes (meters) 495 495 512
FEV1 <80% of predicted 7% 4% 4%
FVC <80% of predicted 5% 4% 4%
FEV1/FVC <70% 7% 6% 6%
TLC <80% of predicted 12% 6% 19%
DLCO <80% of predicted 22% 24% 32%
  • With respect to the PFTs, 349 participants completed the test at 6 months, 244 completed the test at 12 months, and 230 completed the test at 24 months. The values for the incidence of an abnormality on the PFT was presented in a bar graph. The above numerical values represent a close approximation, as the actual numbers were not provided in the article.

  • The mMRC refers to the modified Medical Research Council dyspnea scale. A score of 0 represents dyspnea only with strenuous exercise; a score of 1 represents dyspnea when hurrying or walking up a slight hill; a score of 2 means that an individual walks slower than people of the same age because of shortness of breath or has to stop for breath when walking at his or her own pace. The mMRC also includes a score of 3 and 4.

Summary and Recommendations

In patients with long COVID-19, there is a continuous decrease in the symptoms, radiographic abnormalities, and physiological abnormalities over time. Some articles suggest that there is no further decrease by 1 year postinfection. Others suggest that there is continuous improvement. Only one article can be found referencing symptoms and PFT abnormalities at 2 years. This suggests, but does not definitively prove, continued improvement between 12 and 24 months. Further data need to be obtained so that a more definitive date of MMI can be suggested.

There are variety of radiographic abnormalities ascribed to long COVID. These are best identified using a high-resolution CT scan. The frequent findings include ground-glass opacities and fibrotic-like changes. Less frequent abnormalities include bronchiectasis, interlobular septal thickening, reticular opacities, air trapping, and consolidation. As of the date of this article, approximately one-third of individuals hospitalized with COVID will have residual abnormalities on CT scanning at 1 year.

With PFTs, the most frequent abnormality in individuals with long COVID is a decrease in the diffusing capacity. Additionally, oxygen desaturation during a 6-MWT is also seen frequently. During routine office testing, a screening spirometry is often performed. This provides information on airflow obstruction (for example, the FEV1, FEF25–75, and others) suggesting either large or small airflow obstruction. Unfortunately, large and small airflow obstruction are unlikely in patients with long COVID-19 when tested with a screening spirometry. Still, the office screening spirometry is useful so that a measure of restriction (the FVC) can be obtained. It is also useful to exclude the presence of other problems such as chronic bronchitis, asthma, and other issues. At times, a pre- and postbronchodilator test would be of value. A 6-MWT can also be performed in an office setting. This may be as sensitive as performing a diffusing capacity on full PFT when evaluating these patients.

Lastly, while shortness of breath with exertion is one of the more frequent symptoms of long COVID, as is fatigue, many individuals with these symptoms may have no objective abnormalities on formal physiological testing. Thus, during an impairment evaluation, objective verification of subjective symptoms is mandatory but may be difficult to obtain.

Symptomatic individuals should have a high-resolution CT scan to determine if abnormalities, especially interstitial abnormalities, are present. If interstitial abnormalities are present, there may be a correlation with an abnormal 6-MWT. If these results are confusing, discrepant, or incomplete, further testing is recommended consisting of a full PFT followed by (if needed) a CPET.

Of major importance is the concept of MMI with respect to the timing of testing in these individuals. As discussed, the timing of MMI is suggested but not definitively proven to be 12 months following infection. Waiting vs performing testing at the time of the impairment evaluation is a clinical decision best made by an individual skilled in the medical issues of long COVID, reflecting the above discussion, and in the performance of an impairment evaluation.

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ADDITIONAL READING (General articles published in the past 18 months)

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Biochemical Mechanisms

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PFTs and Exercise

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  • 1.

    Talmage JB, Hyman MH, Snyder RB. Rating survivors of COVID-19 for permanent impairment. AMA Guides Newsletter. 2020;25(4):37.

  • 2.

    Snyder RB, Talmage JB. Rating survivors of COVID-19 for permanent impairment. AMA Guides Newsletter. 2020;25(4):811.

  • 3.

    Caruso GM, Kertay L, Brigham CR. Evaluating post-COVID-19 conditions. AMA Guides Newsletter. 2021;26(6):314.

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    Talmage JB, Hyman MH, Brigham CR, et al.COVID-19: achieving maximum medical improvement and assessing permanent impairment. AMA Guides Newsletter. 2021;26(3):312.

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    • Export Citation
  • 5.

    Gulick SH, Mandel S, Maitz EA, et al.Psychological effects of COVID-19 and preliminary treatment recommendations. AMA Guides Newsletter. 2021;26(5):1316.

    • Search Google Scholar
    • Export Citation
  • 6.

    Hirsch J, Mandel S, Kertay L, et al.Long COVID-19 neurological and psychological claims: assessment guidelines. AMA Guides Newsletter. 2022;27(3):127.

    • Search Google Scholar
    • Export Citation
  • 7.

    Mikkelsen ME, Abramoff B. COVID-19: evaluation and management of adults with persistent symptoms following acute illness (“long COVID”). UpToDate. Accessed August 18, 2022. https://www.uptodate.com/contents/covid-19-evaluation-and-management-of-adults-with-persistent-symptoms-following-acute-illness-long-covid.

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    • Export Citation
  • 8.

    Boaventura P, Macedo S, Ribeiro F, et al.Post-COVID-19 condition: where are we now? Life. 2022;12:517. doi: 10.3390/life12040517.

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