Multi‐disciplinary collaborative consensus guidance statement on the assessment and treatment of breathing discomfort and respiratory sequelae in patients with post‐acute sequelae of SARS‐CoV‐2 infection (PASC)

Abstract

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), may experience lasting sequelae following the acute phase of their index infection.1 The post-acute sequelae of SARS-CoV-2 infection (PASC) can manifest as a wide-ranging constellation of disabling symptoms. These symptoms are sometimes referred to as being part of long COVID, post-acute COVID-19 syndrome, long-haul COVID, chronic COVID, or other terms, but for the purposes of this report, the term PASC will be used. Respiratory symptoms are among the most common symptoms reported by patients, and include shortness of breath, impaired exercise tolerance, cough, and chest pain.2-7 Although the incidence of PASC is not yet fully known, estimates suggest varying length of symptoms post-initial infection and expected recovery. In a study of patients with incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study, a total of 558 participants (13.3%) reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks, and 95 (2.3%) for ≥12 weeks.8 Persistent respiratory symptoms, in particular, may be more common among patients who required hospitalization, as dyspnea was present in 30% of previously hospitalized patients at 12-month follow-up in one longitudinal cohort.9 Despite the prevalence of these sequelae and emerging data on the longevity of symptoms, limited guidance exists regarding the assessment and treatment of PASC. The American Academy of Physical Medicine and Rehabilitation (AAPM&R) Multi-Disciplinary PASC Collaborative ("PASC Collaborative") was convened to address the pressing need for guidance in the care of patients with PASC. This document is part of a larger series addressing PASC, and specifically addresses the assessment and treatment of breathing discomfort and respiratory sequelae. 1 Consider evaluation by a pulmonologist for any of the following, based on assessment recommendations: Referral to a pulmonologist for breathing discomfort in the absence of these abnormalities can be considered on an individual basis when persistent or unexplained. We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to the diagnosis. The PASC Collaborative sought input from patient representatives and patient-led research initiatives to inform recommendations. Literature available at the time of our consensus process suggested that PASC be defined as the persistence of symptoms beyond 3 or 4 weeks from the onset of acute infection.1 Alternative definitions of PASC include symptoms lasting longer than 3 months.10 Following the completion of our consensus process for this report, World Health Organization (WHO) released a definition of “post-COVID condition,” including describing the timing as “usually 3 months from the onset of COVID-19” and lasting “for at least 2 months.”11 Based on patient feedback during our consensus process, we believe that earlier evaluation, diagnosis, and management can improve access to beneficial interventions. For the purposes of this guidance statement, we recommend expanded assessment if symptoms are not improving 1 month after acute symptom onset. The PASC Collaborative was created, in part, to develop expert recommendations and guidance from established PASC centers with extensive experience in managing patients with PASC. The PASC Collaborative is following an iterative modified Delphi approach to achieve consensus on assessment and treatment recommendations for a series of Consensus Guidance Statements focused on the most prominent PASC symptoms.12, 13 The collaborative is composed of 34 established post-COVID-19 or PASC centers, the first of which were established in April to June 2020; over 50 experts spanning clinical disciplines and specialties participate in the monthly meetings. Areas of expertise included physical medicine and rehabilitation, pulmonology, cardiology, primary care, physical therapy, speech therapy, and respiratory therapy, among others. Individual guidance statements include acknowledgement of the total number of centers participating in the Collaborative at the time of the publication, given the evolving nature of this group. Participating PASC centers were asked to designate one expert to be the voting member to assess consensus. Patient representatives were also permitted to vote. These statements were developed by a diverse team of experts, with patient input, and integrate current experience and expertise with available evidence to provide tools to clinicians treating patients. There is an intentional focus on health equity because disparities in care and outcomes are critically important to address. Beyond offering recommendations for assessment and treatment based on experience with care of patients presenting with PASC symptoms, the hope is that a broadened understanding of current patient care practices will help identify areas of future research. As with other PASC Collaborative documents, a detailed literature review was performed prior to initiation of the modified Delphi approach, the full description of our methodology has been published in detail previously.14 These Guidance Statements are intended to reflect current practice in patient assessment, testing, and treatments. At the time of development, must of the literature focused on patients who were not vaccinated, and the incidence and trajectory of PASC in vaccinated patients with “breakthrough” cases (including but not limited to current and emerging variants of the virus) is evolving. The PASC Collaborative took this into account during the development process, and these guidance statements generally apply to individuals who develop PASC regardless of their vaccination status. It is important to note that the recommendations provided in the Guidance Statements should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors. As with any treatment plan, clinicians treating patients with PASC are encouraged to discuss the unknowns of PASC treatments and prognosis, as well as the benefits and risks of any treatment approach. This document specifically addresses post-acute persistent breathing discomfort and respiratory sequelae in the outpatient setting and does not apply to the acute assessment or management of breathing discomfort in urgent or emergency care settings. In addition, the PASC Collaborative recognizes that patients with PASC typically present with a cluster of symptoms that cross multiple body systems, such as fatigue and dysautonomia, which might limit their ability to participate fully in some of these assessment and treatment recommendations. These co-existing conditions must always be considered when suggesting a test or treatment, such as physical rehabilitation. Assessment and treatment of these co-existing conditions has15 and will be addressed in additional AAPM&R consensus statements. Breathing discomfort and respiratory sequelae of COVID-19 may include disabling symptoms, abnormal clinical exam findings, and abnormalities on cardiopulmonary testing or chest imaging studies.16-18 Common symptoms include shortness of breath at rest; disproportionate shortness of breath with activity; chest discomfort that may manifest as pain, tightness, constriction, and/or pressure; inability to take a full deep breath; new or progressive cough; and chest congestion.17-19 These symptoms frequently result in limited activity tolerance.16, 19, 20 Clinical examination may be normal or reveal abnormalities including tachypnea, tachycardia, hypoxemia at rest or with exertion, wheezing, rales, or abnormalities on cardiac exam. On further evaluation, some patients may have evidence of lung disease, such as abnormal pulmonary function tests (PFTs) and/or abnormalities on chest imaging, inclusive of but not limited to chest radiographs and computed tomography (CT) of the chest.16-18 The severity of lung disease and abnormalities in pulmonary function in individuals with PASC appears to be associated with severity of the acute COVID-19 episode. It has been established previously that patients surviving acute respiratory distress syndrome (ARDS) can have persistent abnormalities in pulmonary function.21 Similarly, 4 or more months after severe, or less commonly, moderate COVID-19 infection, changes in pulmonary function and chest imaging have been described, although data on the time course of this process are limited.22-25 The most common abnormality described is impaired diffusion capacity on pulmonary function testing—found in ~40% of patients at 1-year follow up after hospitalization for COVID-19 in China.26 A systematic review of studies examining pulmonary function abnormalities after acute COVID-19 similarly found diffusion capacity impairments in 39% of patients across seven studies.20 Six months after hospitalization for severe COVID-19, one cohort study identified changes concerning for pulmonary fibrosis in approximately one-third of patients—these changes were most common in older patients and those who experienced ARDS.27 At this time, the time course of pulmonary fibrosis identified in individuals with PASC is unknown and it is unclear whether the condition will persist, progress, improve, or resolve. Patients who initially had mild COVID-19, and did not experience hypoxemia or require hospitalization, are less likely to have post-acute pulmonary function or imaging abnormalities.22 However, shortness of breath and breathing discomfort remain common aspects of PASC among patients with initial mild acute COVID-19 and warrant close evaluation, as described in this report.28 As noted in the AAPM&R Multi-Disciplinary PASC Consensus Guidance Statement methodology,14 the recommendations (Tables 1 and 2) are based on expert consensus. Specific guidance recommendations that have been approved by consensus will be noted in the recommendation tables and are accompanied by additional discussion when appropriate. During the initial evaluation of breathing discomfort in the post-acute period, health care providers should determine whether lung disease is present and whether pulmonology evaluation is warranted. The severity of acute COVID-19 may help to initially stratify the risk of lung disease. Thus, history should include a detailed accounting of a patient's acute illness and the trajectory of symptoms since that time, in addition to history of pulmonary or cardiac disease. Characterizing the sensations and severity of breathing discomfort may also help guide further testing and treatment, as discussed in the section that follows. As noted previously, ARDS survivors are more likely to have impairments in pulmonary function testing and persistent interstitial lung abnormalities, when compared to those with less severe acute illness.21, 22 However, when estimating initial severity, clinicians must also account for resource limitations and inequities in care that may confound the characterization of the acute illness—for instance, patients who remained at home and were not hospitalized may have had hypoxemia that was not identified and treated in the acute phase, or may not have had access to inpatient hospitalization or home pulse oximetry (refer to Table 3: Health Equity Considerations and Examples in Patients with PASC: Breathing Discomfort). Understanding that the experience and individual response to breathing symptoms may, in part, be subjective, it should be recognized that sociocultural influences may impact variations in how these symptoms are reported by individuals with PASC. A detailed review of breathlessness as it applies to historical, cultural, and existential relationships is beyond the scope of this report; however, it is important to note that these may play a role in the clinical evaluation.29 Disability Example: People with spinal cord injuries (SCI) Insurance Example: Individuals who are uninsured, underinsured, or cannot afford access to recommended healthcare services Racial / Ethnic Minority Groups Example: People who identify as Black (including African-American), American-Indian/Alaska Native, Pacific Islander, Asian-American, and Mixed Race, and/or Latino/Hispanic (ethnicity) People who identify with minority groups may be at higher risk for COVID-19 infection, severe disease, and mortality. For example, one retrospective study of acute COVID-19 patients found that Hispanic individuals had a 2.76 odds ratio of decompensation and transfer to the intensive care unit within 24 hours of admission.83 As COVID-19 disproportionately affects the case count and severity of disease in Hispanic patients, this cohort may require more respiratory related rehabilitation after hospitalization. In comparison, a cross-sectional study showed that amid patients diagnosed with COVID-19, both Black race and poverty were associated with higher risk of hospitalization, but only poverty was associated with higher risk of intensive care unit admission.84 Similarly, non-Hispanic American Indian and Alaska Native (AI/AN) persons account for 0.7% of the United States population, yet 1.3% of COVID-19 cases.85 Not only diagnosis but assessment and treatment related to breathing can be influenced by race and ethnicity. In two large cohorts, Black patients had nearly three times the frequency of occult hypoxemia that was not detected by pulse oximetry as White patients.31 Although a discrepancy between measurements of pulse oximetry and arterial blood gas oxygen saturation was not found for all Black patients, unadjusted analysis found a discordance in 17% of Black patients and 6.2% in White patients.31 Age Example: Younger individuals and older individuals Younger: Breathing problems may occur in children due to underlying conditions such as asthma and this may be exacerbated by acute COVID-19 infection. The American Academy of Pediatrics has made general recommendations regarding return to play for young athletes, and these are generally based on expert opinion with much of the advice focused on when to refer to cardiology or get cardiac testing.86 Children infected with acute COVID-19 are susceptible to Multisystem Inflammatory Syndrome in Children (MIS-C). Reports have found that some minority groups, such as Black and Hispanic children are disproportionately affected.87 Depending on clinical cardiopulmonary symptoms related to MIS-C, some children will require a gradual return to usual activities and play.88 Older: Patients in older age categories often have worse outcomes. For example, one report notes that individuals over age 55 have had increased hospitalization, delayed clinical recovery, increased pulmonary involvement, and faster disease progression.89 Younger: Clinicians should be prepared to provide medical clearance, complete school forms, pre-participation sports physical examinations, and provide additional prescriptions for medication when needed (eg, rescue inhalers - one to be kept at school, one to be kept at home, one to be kept on their person if maturity level allows). Older: Elderly individuals may need long term services and support after COVID-19 infection. Responsibility for this care can fall to unpaid and untrained family members at home.90 Coordination of safe return to community care after hospitalization in the elderly population is recommended. Environmental exposure Example: People who live in low socioeconomic environments that expose them to various types of environment-related stressors Cough can persist for weeks or months after COVID-19 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnea,93 or pain. Elevated levels of air pollution have shown a positive association with COVID-19 mortality rates after considering area-level confounders.94 Air pollution may also have a negative impact on the immune system as well as exacerbations of asthma and chronic obstructive pulmonary disease.95 Biologic sex Example: Pregnant women At the time of office evaluation, physical examination should include a detailed cardiac and pulmonary exam. Vital sign measurement should include pulse oximetry measurement at rest and with ambulation around the office or the individual's current environment if the visit is conducted virtually and this testing is feasible. This can serve as a simple and widely available screen to guide clinicians when prioritizing the next steps in diagnostic evaluation. Overnight oximetry testing may also be considered for individuals with documented exertional or resting hypoxemia or those with daytime supplemental oxygen requirements, to determine overnight oxygen requirement. Further details regarding sleep disorders and evaluation will be addressed in forthcoming PASC Consensus Guidance Statements. It is notable that clinicians should be aware that patients with darker skin pigmentation may have pulse oximetry readings that are falsely higher than their actual arterial oxygen saturation, and thus experience occult hypoxemia30—previously described as oxygen saturation greater than 92% on pulse oximetry yet less than 88% on concurrent arterial blood testing.31 In a recent retrospective analysis of hospitalized adults who underwent arterial blood gas measurements, Black patients had nearly three times the frequency of occult hypoxemia (11.4%) not detected by pulse oximetry, compared to White patients (3.6%).31 Therefore, if mild hypoxemia accompanies dyspnea in patients with darker skin pigmentation, clinicians should consider repeat testing with an alternative oximeter, ambulatory oximetry, and potentially arterial blood gas if there is concern for occult hypoxemia. Pregnant patients may also have unique explanations for breathing discomfort and testing considerations that differ from those for non-pregnant patients (Table 3: Health Equity Considerations and Examples in Patients with PASC: Breathing Discomfort). Prompt evaluation and workup of new shortness of breath during pregnancy should be considered. For patients with persistent symptoms that are not improving ~8 weeks after symptom onset, or are worsening prior to that time, further evaluation with PFTs should be considered. This serves as a screen for pulmonary disease that may require additional evaluations in consultation with a pulmonologist and may direct specific treatment approaches. Although the exact timing of testing may be individualized, it is our experience that waiting ~8 weeks provides adequate recovery from the acute phase of COVID-19 and reduces the overuse of testing in individuals who would otherwise recover within this time. Given that some degree of breathing discomfort is common in the early post-acute period of COVID-19,5 a period of observation of the trajectory of recovery, prior to extensive testing, may be appropriate when history and examination is otherwise reassuring. Where available, PFTs performed in a dedicated pulmonary function lab are recommended, providing comprehensive and accurate testing, including spirometry, lung volumes, and diffusion capacity. In settings where this is not available, in-office spirometry can be obtained. As discussed later, interpretation and further evaluation of abnormal PFTs can be undertaken in consultation with a pulmonologist. The need for repeat or serial assessment if patients have worsening symptoms can also be considered in consultation with a pulmonologist. Chest imaging is an important additional step for patients with abnormal oxygen saturation, persistent productive or dry cough, abnormal pulmonary exam, and/or impairment on pulmonary function testing. A chest radiograph should be considered as an initial step when performing imaging for most patients. However, if a chest radiograph does not explain the aforementioned abnormalities, in the presence of ongoing signs or testing abnormalities concerning for pulmonary disease, a chest CT scan should be considered to exclude or further characterize a possible pulmonary disorder. This chest CT can be performed as a high-resolution non-contrast scan in most patients, whereas a contrast-enhanced study is indicated if there is clinical concern for acute pulmonary embolism. In addition, a high-resolution non-contrast chest CT should be considered when abnormalities are identified on initial chest radiograph, to better define these abnormalities. Finally, clinicians can consider ordering a chest radiograph in settings where respiratory symptoms are not accompanied by other objective findings yet remain otherwise unexplained. Decisions regarding chest imaging may also be guided by a dedicated PASC clinic or a pulmonologist familiar with PASC, where available. If patients have previous chest imaging available from the acute phase of illness, this should be obtained when possible, for comparison to follow-up imaging. Clinicians should be aware that residual imaging findings following viral pneumonia may persist beyond 4 to 6 weeks,34 and the trajectory of findings along with clinical trajectory are important in this setting. Although follow-up imaging may be valuable in the setting of persistent or new symptoms, routine follow up chest imaging for viral pneumonia is of limited value in the absence of persistent symptoms or other clinical concern.35 Among patients who do not have evidence of lung disease, cardiac causes of dyspnea should also be considered. Cardiac testing is of limited value in many patients with breathing discomfort who do not have a history or physical examination suggestive of a cardiac cause and is best considered on an individual, rather than routine, basis. Assessment and treatment of cardiovascular complications of COVID-19 will be addressed in a subsequent consensus statement by our Collaborative. Clinicians may consider the best approach to testing in consultation with a PASC clinic or cardiologist, where available. Breathing discomfort may be associated with chest pain that can be similar to chest pain reported with coronary artery disease in some patients with PASC. For these patients, clinicians should direct testing to exclude cardiac pathology on an individual basis prior to considering rehabilitation approaches discussed below. Breathing discomfort can be severe and disabling, regardless of whether an etiology can be identified on testing or not. Emotional distress associated with breathing discomfort has been noted, and a supportive and empathic approach by clinicians is essential to achieve functional improvement from these disabling symptoms. Additional contributors and exacerbating factors for dyspnea include muscular deconditioning following acute illness, anxiety, depression, post-traumatic stress disorder, medication effects, anemia, and dysautonomia. Patients who are referred for rehabilitation therapies should be evaluated with objective measures of activity performance. These measures should be individualized to the patient's abilities, including consideration of modifications necessary to accommodate neurological impairment, fatigue with post-exertional malaise, dysautonomia, or other limitations. During a clinician's initial office evaluation, consider in-office measures such as 30-second sit-to-stand and 2-minute step tests.36-41 In a physical therapy setting, more extensive measures such as 6-minute walk test may be performed. Alternative tests exist for patients requiring more in-depth assessment. Individuals with PASC may present with a spectrum of pulmonary sequelae, ranging from shortness of breath and breathing discomfort with or without objective abnormalities on pulmonary testing, to organizing pneumonia, pulmonary fibrosis, and venous thromboembolism.17-19 Patients with more severe initial COVID-19 more often manifest objective abnormalities on pulmonary testing.22 Similar to survivors of ARDS, dyspnea is among the most common symptom of PASC, and patients may have objective abnormalities in cardiopulmonary health and fitness, including a restrictive pattern and impaired diffusion capacity on pulmonary function testing; decreased 6-minute walk distance, with or without hypoxemia; decreased peak oxygen consumption on cardiopulmonary exercise testing; and persistent ground-glass opacities or fibrotic changes on cross-sectional thoracic imaging.16-18 Following initial evaluation, as discussed in the assessment recommendations, patients with objective resting or exertional hypoxemia, abnormal PFTs, and/or abnormal imaging should be evaluated by a pulmonologist to guide additional assessment and treatment. Pulmonology evaluation should also be considered if abnormal breath sounds (such as rales, wheeze, or rhonchi) remain persistent, unexplained, or unresolved after management in the primary care setting. Although progressive inflammatory or fibrosing lung disease following COVID-19 appears uncommon, the long-term trajectory of lung disease for those patients who do develop these changes is not yet known. Some patients may also present with organizing pneumonia necessitating treatment with oral glucocorticoids.23 Thus patients with objective abnormalities in pulmonary testing or chest imaging warrant further evaluation with a pulmonologist. The use of long-term oxygen therapy in patients with hypoxemia is extrapolated from evidence that supplemental oxygen improves survival in patients with chronic obstructive pulmonary disease with severe hypoxemia.42, 43 Symptom mitigation is also significant with correction of resting or activity-induced hypoxemia with appropriate oxygen delivery. Thus in patients with any form of lung disease that results in chronic hypoxemia, oxygen therapy should be provided44 according to established criteria. These criteria refer to measures at sea level, and may be modified for local conditions such as high-altitude settings: We recommend using similar guidelines for the prescription of supplemental oxygen therapy for individuals with PASC who have rest, activity, or nocturnal hypoxemia. During activity and rehabilitation, oxygen flow rate should be titrated to facilitate rehabilitation therapy and maintain oxygen saturations >90%. As mentioned earlier, patients using home pulse oximeters should be advised to obtain U.S. Food and Drug Administration (FDA)–approved devices for optimal accuracy.45 Although adequate oxygenation can be achieved at low flow rates using nasal cannulas, if higher flow rates are needed, a face mask should be considered. Supplemental oxygen can mitigate symptoms and enhance exercise capacity in individuals with PASC and hypoxemia.46 Portable tanks or portable oxygen concentrators can optimize community mobility, ability to participate in rehabilitation, and quality of life. Large tanks, liquid oxygen, and wall plug-in concentrators are acceptable for home use. Humidification should be considered for home O2 delivery systems. Education on the optimal use of oxygen is best done in a setting of pulmonary rehabilitation or in a supervised exercise setting. Self-monitoring of oxygen saturations with FDA-approved pulse oximeters and titration of oxygen flow can also be taught to individuals with PASC who require oxygen therapy to allow for better self-monitoring and appropriate use of oxygen in a home or rehabilitation setting. Rehabilitation therapies for individuals with PASC who are functionally limited by respiratory sequelae can address dyspnea and breathing abnormalities, fatigue, balance impairments, peripheral and pulmonary muscle strength, endurance, gait, and promote energy conservation and facilitate return to activity. In individuals with PASC and lung sequelae who also have accompanying fatigue and/or dysautonomia, the most physically limiting factor should be considered when deciding whether these approaches to rehabilitation are appropriate. For example, if fatigue is the most physically limiting symptom, clinicians should refer to previously published guidance statement regarding the assessment and treatment of fatigue.15 The use of simple functional measurements of capacity, as outlined previously, can allow for monitoring of functional status and measuring improvement over time in response to the rehabilitation therapies. Here, we outline rehabilitation approaches for multiple potential patient populations, including patients with breathing discomfort with and without accompanying impairment in pulmonary function. Figure 1 provides “high-level” considerations for these rehabilitation options, based on the initial assessment parameters. The eventual goal for rehabilitation management is an independent self-monitored home or community-based activity or exercise program. Individuals with PASC who have persistent respiratory symptoms and are functionally limited and have abnormal PTFs that meet criteria for pulmonary rehabilitation or respiratory services should be referred. The benefit of pulmonary rehabilitation and respiratory services for patients with chronic lung conditions is well established,47 and it appears from early studies that there is also benefit in individuals with PASC with lung disease.48-51 Insurance coverage delineates between pulmonary rehabilitation and respiratory services. Pulmonary Rehabilitation for obstructive lung diseases is covered for individuals with Medicare and Medicaid medical insurance by the Centers for Medicare & Medicaid Services (CMS) and billed under the G0424 code. For individuals with Medicare and Medicaid who have restrictive lung disorders, CMS covers Respiratory Services under G237, G238 or G239 codes. Most non-Medicare and Medicaid insurance plans cover Respiratory Services for both obstructive and restrictive lung disorders. Pulmonary rehabilitation programs also provide respiratory services and determine the appropriate billing code based on diagnosis and insuran