Post-COVID Interstitial Lung Disease And Other Lung Sequelae Part 2

Hospitalized Patients

PASC affects people along the entire disease spectrum—from minimal/mild symptoms to critical illness. Among hospitalized patients, a telephone interview of 488 survivors, 60 days after symptom onset, found that 32% had persistent symptoms defined as a conglomerate of shortness of breath, cough, chest tightness, wheezing, difficulty ambulating, breathlessness with stairs, oxygen use, and continuous positive airway pressure (CPAP) use, with only 16% being able to return to work.67 Another survey of 143 hospitalized patients performed at 60 days after initial diagnosis found that 87% had at least one persistent symptom and 55% had three or more; only 12% stated that they were completely free of symptoms.68 Halpin and colleagues69 performed a crosssectional evaluation of 100 hospitalized patients at 4 to 8 weeks post-symptom onset; 70% continued to experience fatigue and 50%  endorsed dyspnea. Huang and colleagues performed an analysis of 17 different symptoms in 1733 hospitalized patients at 6 months postadmission, dividing the cohort into severity scales; 76% of the total cohort had at least one symptom, and symptom burden increased with severity of illness. Muscle weakness (63%), sleeping difficulties (26%), and anxiety or depression (23%)  were the most common reported symptoms. Of note, 23% of the patients had a decreased age-adjusted 6MWD and diffusion defects which correlated with illness severity.

Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.

Click on Covid Fatigue

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Nonhospitalized Patients

Similar observations have been made in non-hospitalized patients. Jacobsen and colleagues found that in a survey of 118 patients (96 outpatients),  symptom burden was statistically similar between inpatient versus outpatient status and 67% of patients continued to experience symptoms,  including a mean 6MWD of 59% of expected. Likewise, at a median follow-up of 169 days Logue and colleagues72 found a similar burden of persistence of at least one symptom (33 vs. 31%) in outpatients versus inpatients, respectively. Patients are also more likely to use health system resources  including outpatient primary care and outpatient  hospital visits.73

Risk Factors

The risk factors for PASC remain unknown, and data remain discordant. Wynberg and colleagues74 found that female gender (adjusted hazard ratio [aHR] 0.65, CI 0.47–0.92) and body mass index (BMI) greater than 30 (aHR 0.62 CI 0.39–0.97) were associated with slower recovery and symptoms beyond 6 months correlated with decreased chance of resolution. A large study of 2,149 healthcare professionals identified 323 participants who had no or mild symptoms and were found to be seropositive; 83% were women and 15% reported at least one persistent symptom at 8 months, as compared with seronegative participants (relative risk [RR] 4.4 [95 CI, 2.9–6.7]), causing significant disruption in work life, home life, and in any Sheehan Disability Scale category.75 Among patients who survived hospitalization, the presence of ICU admission, need for respiratory support, premorbid lung problems,  higher age, higher BMI, and BAME (Black, Asian, and Minority Ethnic) predicted breathlessness post-discharge.69 Another study suggested that women were more likely to develop fatigue and anxiety/depression and presenting symptoms of palpitations, rhinitis, dysgeusia, insomnia, hyperhidrosis, anxiety, sore throat, and headache predicted PASC.76 Sudre77 and colleagues found that PASC was more likely with increasing age, female gender, higher BMI, and having five or more symptoms within the first week of onset A cohort study of 189 people similarly found that only female gender and preexisting anxiety disorder predicted PASC compared with controls; in this group of patients with predominantly mild/moderate initial infection, there was no association between developing PASC and any modality of diagnostic testing (PFTs, echocardiogram, serologic testing/inflammatory markers, and cognitive testing), though participants with PASC had significantly lower scores on the SF-36 Health Survey. There  was no evidence of abnormal systemic immune  activation, autoimmune disease, or persistent viral  infection.78

Post-Acute Sequelae of SARS-CoV-2 Phenotypes

Various phenotypes of PASC may exist. Defining them is complex due to the dynamic nature of both the initial illness and subsequent sequelae across illness severities. For example, a survivor of ARDS and ICU admission may develop dyspnea and abnormal PFTs that correlate with residual postinfectious fibrosis and overlap with the post-intensive care syndrome (PICS). A patient with only a mild illness without a known history of pneumonia or hospitalization may also develop dyspnea out of proportion to imaging abnormalities and PFT derangements. Anecdotally, the latter is a remarkably common finding seen in our PASC clinic where most of the referrals are patients with no history of hospitalization and, generally, no known history of prior pneumonia. Several classification systems have been proposed. Becker proposed a system based on the severity and evolution of symptoms over time.79 Yong proposed subtypes based on long-term clinical and physiologic sequelae.80 Tables 4 and 5 summarize these two different schemas of subtyping PASC phenotypes. These descriptions will likely change over time and another schema will likely emerge, illustrating the complex nature of PASC  that will undoubtedly continue to evolve along with our understanding. A newer schema would,  ideally, group patients into phenotypes that also correlate with clinically relevant outcomes. No formal guidelines currently exist to define PASC  phenotypes.

Mechanism(s) of Post-Acute Sequelae of SARS-CoV-2

A unifying mechanism for the variety and variability of symptoms of PASC remains elusive. Several studies have sought to clarify the causes of exercise intolerance as this is both a common and debilitating symptom. Studies using cardiopulmonary exercise testing (CPET) at various time points from illness and recovery have demonstrated predominantly circulatory and anaerobic threshold limitations when compared with matched controls81–83; however, ventilatory inefficiency has also been suggested.82 Cassar and colleagues 83 performed a longitudinal evaluation of 58 survivors and 30 matched controls via symptom questionnaires, cardiac and lung magnetic resonance imaging (CMR), and CPET at 3 and 6 months. By 6 months, survivors demonstrated normalization of cardiac abnormalities noted on previous CMR  imaging, though persistent (and improved) lowgrade abnormalities of parenchymal abnormalities and peak VO2 persisted in 52% of participants;  importantly (and congruent with our real-world experience), these abnormalities did not correlate with cardiopulmonary symptoms. These impairments could be related to direct damage to muscle tissue, impaired oxygen extraction/utilization, or simple deconditioning from prolonged hospital stay and critical illness. To this end, the sheer breadth of physical, neuropathic, and neuropsychiatric symptoms is likely not explained by these mechanisms alone, and certainly not all patients will experience dyspnea or exercise intolerance.

Other proposed mechanisms include ACE-2/ Ang 1 to 7 receptor downregulation with deleterious upstream effects,84 autoantibody production targeting cytokines, chemokines, complement system, or cell surface proteins85, and proinflammatory cytokines.86,87 The nature of the initial immune response may also have a bearing on both the clinical disease course and the long-lasting sequelae.88

Triage, Workup, and Treatment

Owing to the massive influx of patients with multitudes of symptoms, many centers around the United States and abroad have initiated multispecialty COVID clinics to help triage, treat, and address the paucity of knowledge and expertise in this disease process. Clinics may have providers representing various medical specialties including neurology,  neuropsychiatry and psychology, ear, nose and throat, cardiology, pulmonary, physical medicine and rehab, and physical and occupational therapy,  among many others. No standardized approach has yet been validated but it is generally recommended that patients are approached holistically based on the severity of illness and symptom burden. 55,89,90 Basic laboratory testing such as complete blood count, basic metabolic panels, liver function, and thyroid function is likely reasonable. More specialized testing, for example, looking for evidence of vitamin deficiencies, inflammatory markers, rheumatological conditions, myocardial injury, and so forth, should be guided by symptoms and clinical gestalt. Advanced testing may include chest and cardiac imaging, electrocardiograms, and invasive testing such as heart catheterization or CPET if a high clinical suspicion exists. It should be noted that a “shot-gun” approach to testing is not recommended given dubious clinical utility, increasing cost and emotional burden on the patient.

In the author’s experience (MB), patients often have trouble navigating their new symptoms and finding understanding from their families,  peers, and even other healthcare providers. A survey of 114 mostly female (80/114) medical professionals (51/114) with PASC in the United Kingdom described a heavy sense of loss and stigma, trouble accessing and navigating services,  and difficulty being taken seriously.91 The clinician should consider then, the extra burden placed on their non-medical patients. Acknowledging symptoms is very important, as are validating statements like “what you are going through is very real” and “there are many others just like you, learning to navigate this new illness”; for example,  after a thorough history and examination, we focus heavily on first, setting expectations that the time course of illness and recovery is unknown. Once both patient and provider are ready to move forward, appropriate testing is ordered to diagnose both preexisting and new conditions. Emphasis should be placed on symptomatic and supportive therapy.60 Our practice is skewed heavily toward physical and occupational therapy as fatigue and the sensation of dyspnea are often quite prevalent and debilitating. Patients should be counseled on paying particular attention to “post-exertional malaise,” a debilitating state of fatigue onset from both physical and/or mental overexertion which has been well characterized in the setting of CFS/ME.92 Healthy dietary habits, sleep hygiene, and modification of daily routines to prioritize certain activities over others are encouraged. Individualized reconditioning protocols should be implemented by experienced physical and occupational therapists with experience treating PASC patients.55 The triage, evaluation, and treatment of patients suffering from PASC remains dynamic, and a holistic approach is  paramount.60,93–96

SUMMARY

Post-COVID sequelae including lung injury and PASC are complex and poorly understood, representing heterogeneous manifestations, mechanisms, and short- and long-term outcomes. The mainstay of therapy remains mostly supportive,  though robust research is underway to better understand and characterize pathways for intervention. Historical insight remains important to clarify whether current observations are truly novel or representative of previously ignored or misunderstood syndromes.

CLINICS CARE POINTS

DISCLOSURE

The authors have nothing to disclose.

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