US Pharm. 2022;47(7):23-28.
ABSTRACT: Current research efforts to combat the COVID-19 virus are geared toward developing therapies to treat the infection and prevent the COVID-19 virus. Moreover, health experts are learning more each day about the long-term health consequences associated with post-COVID-19 infection, including patient populations at greater risk for these complications. The CDC indicates that post-COVID-19 infection, the most common persistent symptoms reported by patients may include fatigue, cough, dyspnea, chest tightness, trouble concentrating, arthralgia, olfactory dysfunction, and headache. While most people recover from the virus, some patients, particularly those with severe infection and chronic comorbidities, may be at risk for and/or develop pulmonary fibrosis. To date, there is no definitive therapy for managing post-COVID-19 pulmonary fibrosis, but clinical trials are underway to explore the role of antifibrotic therapies.
Early in the COVID-19 pandemic, health experts indicated that patients with mild-to-moderate COVID-19 infections were thought to have a short-term course of acute illness lasting around 2 weeks, after which symptoms completely resolved.1-3 However, based on available and ongoing clinical data, health experts are learning that a subgroup of patients who were infected with the COVID-19 virus are experiencing a prolonged course of symptoms in varying degrees of severity that last several weeks to months.1-3 The persistent complications are commonly referred to as long-haul COVID-19, which is a term used to refer to individuals in the United States who have lingering or delayed symptoms from the COVID-19 virus.1 Both the National Institutes of Health (NIH) and the CDC refer to long-term COVID-19 symptoms as postacute sequelae of SARS-CoV-2 (PASC) and other terms commonly used, including post-COVID syndrome, long COVID, or long-term COVID.3-5 The CDC also indicates that while there is not an established standard definition, in general terms, “post-COVID conditions can be considered as a lack of return to a typical state of health for an individual after recovering from acute COVID-19 illness.”6 Moreover, the CDC states that post-COVID conditions might also include development of new or recurrent symptoms that occur after the symptoms of acute illness have resolved.6
The most commonly reported protracted symptoms include fatigue, cough, dyspnea, chest tightness, difficulty concentrating, arthralgia, olfactory dysfunction, and headache.5-7 Findings from recent research efforts indicate that while advanced age, existence of comorbid medical conditions, and severity of COVID-19 infections are suspected risk factors for PASC, young and previously healthy individuals with mild COVID-19 are also at risk.7 Ongoing research efforts are exploring the incidence and impact of long-haul COVID-19.
While the exact incidence of patients experiencing long COVID-19 symptoms remains unknown, according to findings from a recent study published in JAMA, an estimated 10% of patients may become “long-haulers.”1,8 The American Lung Association indicates that while researchers are still learning more each day about the long-term effects of COVID-19, early studies reveal that 50% to 80% of patients studied continued to suffer from symptoms even after a negative subsequent viral test.1
Findings from a recent study published in JAMA Network Open indicated that an estimated 33% of individuals in the U.S. who had COVID-19 reported continual symptoms up to 9 months after the initial infection.9
Another recent publication in the Journal of General Internal Medicine revealed that an estimated 30% of hospitalized patients and high-risk outpatients with COVID-19 develop PASC. The researchers found that 29.8% of the 1,038 patients with longitudinal follow-up developed PASC. In hospitalized patients, the most common persistent symptom reported was fatigue, followed by shortness of breath (31.4% and 15.4%, respectively); in outpatients, anosmia was the most common persistent symptom.10 Factors independently linked with PASC included hospitalization for COVID-19, having diabetes, and higher BMI.10 They also noted that factors inversely correlated with PASC were Medicaid versus commercial insurance and organ transplant. The authors concluded that in their cohort, three in 10 survivors with COVID-19 developed a subset of symptoms related to PASC. They also noted that while ethnic minorities, older age, and socioeconomic disadvantage are correlated with more serious, acute COVID-19 infection and elevated mortality risk, the study discovered no relationship between these factors and PASC.10
According to the Infectious Diseases Society of America, while the exact mechanism associated with post-COVID-19 is not fully elucidated, researchers theorize that it may manifest as a result of virus-specific pathophysiologic changes, protracted inflammatory response to the acute infection, and sequelae of post–intensive-care illness.11-13 Moreover, findings from recent research revealed four risk factors for post-COVID conditions, including early SARS-CoV-2 COVID-19 RNA serum level, certain autoantibodies, Epstein-Barr virus reactivation, and type 2 diabetes mellitus.11,14
Health experts indicate that one of the most alarming long-term complications associated with COVID-19 is progressive fibrotic pulmonary disease, also known as post-COVID pulmonary fibrosis, which is associated with nonreversible lung dysfunction and scarring.15 While the exact etiology of post-COVID-19 pulmonary fibrosis remains unidentified, one theory is that the cytokine storm, which is the result of an abnormal immune mechanism, may result in the initiation of pulmonary fibrosis, and researchers are still exploring why some individuals recover without any complication, while others develop pulmonary fibrosis.15,16 Other research suggests that patients with severe COVID-19 pneumonia are at greater risk of interstitial lung disease (ILD) and chronic pulmonary vascular disease.17
Clinical Findings Related to Pulmonary Fibrosis and PASC
Numerous studies have explored the impact and potential risk factors that may heighten an individual’s risk of long-haul COVID-19 symptoms, and clinical trials are ongoing. Below is a synopsis of a few published studies that investigated the respiratory effects correlated with PASC.
Multiple studies have indicated that the risk factors for idiopathic pulmonary fibrosis and COVID-19 are analogous. Following a severe COVID-19 infection, there is an augmented risk of developing pulmonary fibrosis.16 Researchers also note that this manifestation is commonly observed in older patients, in males, and in those with a history of smoking and other comorbidities, such as diabetes, hypertension, or coronary artery disease.16 Research also indicates that the inflammatory process generated by the virus could augment the occurrence of fibrosis in some individuals.18
Research findings also disclose that two of the most frequently occurring respiratory manifestations of COVID-19 include substantial decreases in the diffusing capacity of the lungs (DLCO) and associated pulmonary interstitial damage.19,20 Moreover, research findings note that 1 year post moderate COVID infection, the incidence of impaired DLCO and persistent lung damage still surpasses 30%. In addition, due to lung fibrosis progression, one-third of the patients have severe DLCO impairment and fibrotic lung damage, and the persistent respiratory complications may cause considerable rates of morbidity, long-term disability, and even death.19,20
Data from observational studies indicate that an estimated 90% of COVID patients experience some degree of COVID sequelae, such as respiratory problems, diminished exercise tolerance, and damage to pulmonary tissue.21
In a study exploring the chest CT features of 46 patients who had COVID-19, fibrosis was clinically established in 56% of the patients who experienced moderate COVID symptoms. Three months post COVID recovery, an estimated 71% of patients still had severe symptoms.22
In another study, researchers examined the lung fibrotic alterations in a cohort of 173 patients who had moderate-to-severe COVID-19. They also attempted to identify possible risk factors, finding that an estimated 50% of the patients in the study had pulmonary fibrosis, and the patients with severe COVID-19 pneumonia were at heightened risk of pulmonary fibrosis.23
In a cohort study of 238 patients, researchers indicated that more than 50% of participants experienced considerable decrease in DLCO for carbon monoxide and/or measurable functional impairment 4 months post COVID-19 recovery.24 Study authors indicated that 51.6% of the participants had less than 80% normal lung function, and 15.5% of the participants had less than 60% normal lung function.24
A study exploring the pathological sequelae of long-haul COVID outlined the respiratory manifestations associated with acute COVID-19 and post COVID-19, shown in FIGURE 1.25
Respiratory Manifestations of Long-Haul COVID-19
According to findings from a recent publication in JACC: Heart Failure, the American College of Cardiology notes that months after their initial COVID-19 diagnosis, many long-haul COVID-19 patients experience chronic fatigue syndrome and other respiratory issues.26 The study involved 41 patients and revealed that an estimated 88% of patients experienced abnormal breathing patterns, referred to as dysfunctional breathing. Moreover, researchers observed low CO2 values at rest and with exercise, implying chronic hyperventilation. In addition, 58% of patients had evidence of circulatory impairment to peak exercise performance from either cardiac dysfunction and/or abnormal pulmonary or peripheral perfusion.26
In another study, researchers evaluated the recovery of 145 primarily hospitalized patients diagnosed with COVID-19 between March 2020 and June 2020 who participated in the Austrian clinical study called Development of Interstitial Lung Disease in COVID-19. They discovered that at the 6-month follow-up, an estimated 49% of study participants reported persistent symptoms.27 An estimated 22.8% experienced breathlessness on exertion, and 34.7% reported impaired physical performance. The researchers also found that 6 months post diagnosis, a third of patients (33.6%) had impaired lung function. Almost half of patients (48.5%) had chest scans indicating structural lung irregularities, with one in five patients (19.4%) having moderate-to-severe lung alterations.27 The authors concluded that the prolonged inflammation following COVID-19 is robustly correlated to long-term modifications in lung structure and function. They also noted that to recognize those patients at greater risk for long-term pulmonary issues, clinicians should monitor for markers of inflammation post-COVID-19 infection.27
A meta-analysis aimed to investigate the incidence of post-COVID-19 pulmonary fibrosis (PCPF) and possible risk factors. The systematic search initially revealed a total of 618 articles, of which only 13 studies reporting 2018, patients were included. Researchers revealed that patients with fibrosis were more likely to experience persistent symptoms of dyspnea, cough, chest pain, fatigue, and myalgia (P <.05). The factors related to COVID-19 severity that were connected with PCPF development involved CT score of ≥18; ICU admission; invasive/noninvasive mechanical ventilation; longer hospitalization period; and steroid, antibiotic, and immunoglobulin treatments (P <.05).28 They also found that an estimated 44.9% of patients post COVID-19 seem to develop pulmonary fibrosis, and severity of infection was strongly correlated with development of PCPF.28
Findings from a study published in the Lancet Respiratory Medicine involving more than 2,320 patients hospitalized with COVID-19 revealed that only 25% of patients reported that they felt completely recovered 1 year post recovery from COVID-19.29
Another study examined the incidence and risk factors associated with PCPF among patients discharged from the hospital after infection. Results revealed that a sizable percentage of patients experienced incessant fatigue (45.1%), breathlessness (36.5%), myalgia (20.5%), and psychological symptoms (19.5%). The authors noted that PCPF was observed in 9.5% of the patients and was correlated with persistent breathlessness at 6 weeks and inpatient ventilation (adjusted OR 5.02 [1.76-14.27] and 4.45 [1.27-15.58]), respectively.30 Study authors also noted that patients who had severe COVID-19 infection, especially those who were intubated and who have persistent breathlessness, are at risk of developing PCPF and should be monitored.30
Findings from examination of lung tissue from autopsy samples and tissue samples from explanted lungs of lung-transplant recipients in those patients with severe COVID-19 pneumonia revealed histopathology, such as end-stage pulmonary fibrosis without active SARS-CoV-2 infection.31 The researchers note that some individuals may develop pulmonary fibrosis following resolution of active COVID-19 infection.31
Potential Role of Antifibrotic Therapies in PCPF
While there has been tremendous progress in understanding the management of COVID-19, a more in-depth understanding is warranted with regard to the management of long-term sequelae in patients, particularly with regard to pulmonary fibrosis.32 Currently, there are no treatments for PCPF, but clinical trials are underway to explore possible treatment options. Research demonstrates that patients with diffuse pulmonary disease post-COVID-19 are often treated with corticosteroids.32,33 Studies also reveal that when utilized in the management of symptoms associated with acute respiratory distress syndrome caused by COVID-19, corticosteroids may improve clinical outcomes and reduce mortality rates; however, more research is warranted.33-35 Additionally, according to the NIH COVID-19 Treatment Guidelines, numerous randomized trials indicate that systemic corticosteroid therapy improves clinical outcomes and reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen, probably by mitigating the COVID-19–induced systemic inflammatory response that can cause injury to pulmonary tissue and multisystem organ dysfunction.35,36 They also note that there is no observed benefit of systemic corticosteroids in hospitalized patients with COVID-19 who do not need supplemental oxygen, and there are no data to support the use of systemic corticosteroids in nonhospitalized patients with COVID-19.36
Due to the similarity of pulmonary fibrosis’ pathophysiological mechanisms between idiopathic pulmonary fibrosis (IPF) and COVID-19 infection, researchers are exploring the efficacy and potential role of the antifibrotic drugs pirfenidone and nintedanib as possible treatment options for those with PCPF.32 In some cases, a lung transplant may be the only lifesaving treatment option.32 Clinical data reveal that nintedanib and pirfenidone are antifibrotic medicines that, in spite of distinct and different mechanisms of action, are similarly efficacious in slowing down and/or preventing the decrease of respiratory function by ~50% and, on average, may increase the life expectancy in some IPF patients by 2.5 years.16 At the present time, the role of antifibrotic drugs in prevention and treatment of PCPF is not clear; however, this drug class is thought to be advantageous in patients with acute exacerbations of ILD (both IPF and other fibrotic ILDs), thus diminishing pulmonary damage and reducing both rates of morbidity and mortality in high-risk individuals.16 Currently there are trials exploring the use of these agents in PCPF (see TABLE 1).37-39
The Role of the Pharmacist
As one of the most accessible healthcare providers, pharmacists can be instrumental in identifying patients at greater risk for post-COVID-19 complications and reminding patients to stay up to date with recommendations for COVID-19 vaccinations and to continue to adhere to universal infection control measures to reduce their risk of infection. Pharmacists can also recognize patients who may be experiencing post-COVID-19 symptoms and encourage them to seek further medical care from their primary healthcare providers. Pharmacists can also provide both prescribers and patients with the most current clinical data regarding the identification and management of PCPF, including information about ongoing clinical trials. In addition, pharmacists can make clinicians aware of the CDC’s guidance for caring for patients with post-COVID-19 complications (see SIDEBAR 1).40
While research is ongoing and constantly updated as more clinical data become available, health experts agree that pulmonary fibrosis is one of the most concerning and major long-term complications in patients, especially in those with severe COVID-19.32 Furthermore, research indicates that risk factors like advanced age with limited lung function and preexisting comorbidities such as diabetes, cardiovascular disease, hypertension, and obesity increase the risk of developing fibrotic lung changes in survivors who present with reduced exercise tolerance.32 Numerous publications have explored the impact of the health complications associated with post-COVID-19 infections, and health experts note that there is still much more to learn about predictive risk factors and the long-term effects associated with PCPF; therefore it is imperative to routinely monitor patients, especially those patients at greater risk for complications.
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2. Infectious Diseases Society of America. Post COVID conditions (e.g. long COVID). Updated August 5, 2021. www.idsociety.org/covid-19-real-time-learning-network/disease-manifestations-complications/post-covid-syndrome. Accessed April 20, 2022.
3. Johns Hopkins Medicine. Long COVID: long-term effects of COVID-19. www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/covid-long-haulers-long-term-effects-of-covid19. Accessed June 14, 2022.
4. Yale Medicine. Long COVID (post-acute sequelae of SARS CoV-2 infection, PASC). 2021. www.yalemedicine.org/conditions/long-covid-post-acute-sequelae-of-sars-cov-2-infection-pasc. Accessed June 14, 2022.
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22. Fu Z, Tang N, Chen Y, et al. CT features of COVID-19 patients with two consecutive negative RT-PCR tests after treatment. Sci Rep. 2020;10(1):11548.
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25. Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23(2):194-202.
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www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/corticosteroids/. Accessed May 6, 2022.
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40. Tanzi M. CDC releases guidance on caring for ‘COVID longhaulers.’ APhA Pharmacy Today. 2021;27(9):22. https://www.pharmacytoday.org/article/S1042-0991(21)00636-8/fulltext. Accessed June 14, 2022.
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