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Decreasing the burden of postacute sequelae of SARS-CoV-2 infection: What we know
On March 11, 2020, the World Health Organization (WHO) declared SARS-CoV-2 a pandemic. As of October 2021, there are over 240 million confirmed COVID-19 cases and over 4 million deaths globally, with the United States having the highest incidence of both cases and deaths (https://covid.cdc.gov/covid-data-tracker/#datatracker-home). As many as 87% of COVID-19 survivors experience persistent symptoms that last beyond the acute phase of illness (Carfi A, et al. JAMA. 2020;324[6]:603-5). In February 2021, the National Institutes of Health (NIH) called for a consensus term to describe this protracted form of COVID-19, and defined it as Post-acute Sequelae of SARS-CoV-2 infection (PASC) (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid).
What are the PASC manifestations?
PASC has a heterogeneous presentation with a broad spectrum of manifestations and can vary from single to multiorgan system involvement. Commonly, PASC involves pulmonary abnormalities (shortness of breath, exercise intolerance, abnormal pulmonary functional test [PFT] and chest imaging), neurocognitive impairments (difficulty concentrating and memory loss), mental health disorders (anxiety, depression, and post-traumatic stress disorder), functional mobility impairments, as well as general and constitutional symptoms (fatigue and muscle weakness) (Groff D, et al. JAMA Netw Open. 2021;4[10]). The most prevalent pulmonary physiologic impairment is reduced diffusion capacity that has been shown to be associated with the severity of acute illness, while the most common radiologic abnormalities on chest CT scan are ground glass opacities. Some studies have shown a temporal improvement in pulmonary physiology and exercise capacity; however, persistent physiological and radiographic abnormalities persist in some patients up to 12 months after discharge (Wu X, et al. Lancet Respir Med. 2021;9:747-54). An abnormal or persistent hyper-inflammatory state, viral-induced autoimmune reaction, and ongoing viral activity have been proposed as possible biological mechanisms for PASC; however, the pathophysiology remains mostly unknown.
Who does PASC affect?
PASC affects patients irrespective of premorbid condition and severity of symptoms in the acute phase. It spans from those who had mild disease not requiring hospitalization to those who had critical illness requiring intensive care unit (ICU) management. COVID-19 ICU survivors seem to have an overlap of PASC and post-intensive care syndrome (PICS), defined by new or worsening physical, cognitive, and/or psychiatric impairments after critical illness. (Biehl M, et al. Cleve Clin J Med. 2020 Aug 5).
Who do we evaluate for PASC?
Given the complexity and chronicity of the associated symptoms and their impact on several major organ systems, a comprehensive and multidisciplinary approach is essential to assist with diagnosis and management of PASC. Listening empathically to patients and acknowledging their symptoms are key factors. Access to ambulatory care, establishment of rapport, effective collaboration and coordination of care among different disciplines, management of comorbidities, continuity of care, access to rehabilitation programs, and reduction of disease burden are some of the principles that guided the creation of dedicated COVID-19 clinics throughout the world. The most common services offered are primary care, pulmonology, cardiology, mental health, neurology, speech and language pathology, physical and occupational therapy, pharmacy, and case management. The involvement of specialties varies depending on the specific patient’s needs (Parker A, et al. The Lancet Respir Med. 2021;S2213-2600[21]00385-4).
The development of diagnostic and care pathways by different specialties ensures standardization of clinical assessment and management while allowing for individualized care. The commonly used tools to assess the respiratory system are the 6-minute walk test, PFT, chest imaging including radiographs and high-resolution CT scan, ventilation perfusion scan, and echocardiography. Some patients exhibit persistent cardiopulmonary symptoms with no evidence of organ injury. These patients have persistent exertional and functional limitation with normal PFT, resting echocardiography, and chest imaging. Cardiopulmonary exercise testing (CPET) and, more specifically, invasive CPET can be used to further investigate the decreased exercise capacity. CPET studies have identified an augmented exercise hyperventilation, and the causes of exercise limitation varied from anemia and reduced oxygen extraction by peripheral muscles to deconditioning, obesity, and lower ventilatory efficiency. A study looking at invasive CPET showed reduced peak exercise aerobic capacity in post COVID-19 patients compared with control participants and was associated with impaired systemic oxygen extraction and an exaggerated hyperventilatory response (Singh, et al. Chest. 2021;S0012-3692[21]03635). A subset of COVID-19 survivors presents with symptoms of autonomic dysfunction such as orthostatic intolerance and postural orthostatic tachycardia. These symptoms have been reported after other viral infections and could be secondary to gastrointestinal fluid loss, prolonged bed rest, and deconditioning of the cardiovascular system. More research is needed to characterize the dysautonomia in patients post–COVID-19.
What is the treatment?
Therapies depend on symptoms and organ involvement. The duration of pulmonary symptoms in long-haulers is not yet known, with cough and exercise intolerance/dyspnea ranking among the most common complaints in these patients. Exercise therapy plays an essential part in the rehabilitation of long-haulers and several studies are underway to assess different exercise and rehabilitation programs. For most patients with normal laboratory, physiologic, and imaging tests, post–COVID-19 clinics are offering physical therapy, occupational therapy, and neuropsychological rehabilitation. While steroids have been shown to improve mortality in hospitalized patients with COVID-19 requiring mechanical ventilation or supplemental oxygen, their role in outpatient COVID-19 infections and for post–COVID-19 lung disease/organizing pneumonia remains unclear. In a UK study of patients admitted to the hospital with COVID-19 disease of varying severity, interstitial abnormalities were noted in ~5% of patients at 6 weeks postdischarge and in 10.8% of patients with persistent respiratory symptoms (Myall, et al. Ann Am Thorac Soc. 2021;18[5]:799). The most common radiological findings (in > 50% of cases) were consistent with organizing pneumonia. Patients with persistent physiological abnormalities and interstitial findings improved with steroids. However, since the trajectory of the disease is unknown, further studies are required to understand the natural history of the disease and assess treatment strategies in patients with persistent inflammatory lung changes. Several studies looking at systemic or inhaled steroids in different phases of COVID-19 infection and varying disease severity are ongoing (ClinicalTrials.gov). Antifibrotics used to treat idiopathic pulmonary fibrosis and progressive fibrotic ILD are also being investigated in COVID-19 lung disease. The rationale for their use is to treat and prevent severe COVID-19 lung injury and prevent lung fibrosis.
The role of vaccinations
Whether patients who were infected with COVID-19, and, more specifically, patients with long-term symptoms post-COVID-19, should get vaccinated is actively being investigated. Vaccinations are protective at preventing infections and severe illness. Studies showed that patients who had COVID-19 infection and got vaccinated had a significantly higher antibody response than previously uninfected vaccine recipients. A review showed that the protective effect of prior SARS-CoV-2 infection on reinfection is high and similar to that of vaccination. However, a recent study of hospitalized patients revealed higher rates of COVID-19 among unvaccinated adults with previous infection compared with vaccinated adults (http://dx.doi.org/10.15585/mmwr.mm7044e1). On the other hand, the impact of vaccine on long-hauler symptoms has raised interest. A UK survey (not peer reviewed) on more than 800 long-haulers reported about 57% with overall improvement in their symptoms, 24% no change, and 19% with worsening symptoms after their first dose of vaccine, suggesting that the chances of experiencing an overall worsening of symptoms after vaccination is small, with more than half experiencing improvement (go.nature.com/3yfqem2). While awaiting longitudinal trials, the main argument to guide vaccination in long-haulers is that COVID-19 vaccinations provide protection from reinfection and appear to have the potential to improve symptoms.
The availability of a patient’s support system, peer support, and patient advocacy groups assist in providing equitable care and are critical in sustaining the recovery of COVID-19 survivors. Providing social, financial, and cultural support is imperative in decreasing the burden of COVID-19. The dedicated post–COVID-19 clinics will not only offer care to COVID-19 survivors, but will also help our understanding of the determinants and course of PASC, and will provide opportunities for research. Long-term longitudinal observational studies and clinical trials are critical to identify those at high risk for PASC, clarify the extent of health consequences attributable to COVID-19, and define best practices for COVID-19 survivors.
Dr. Biehl is Staff Physician, Pulmonary & Critical Care Medicine, Director, Post-ICU Recovery Clinic Respiratory Institute, Cleveland Clinic; Dr.Farha is with Respiratory and Lerner Institutes, Cleveland Clinic.
On March 11, 2020, the World Health Organization (WHO) declared SARS-CoV-2 a pandemic. As of October 2021, there are over 240 million confirmed COVID-19 cases and over 4 million deaths globally, with the United States having the highest incidence of both cases and deaths (https://covid.cdc.gov/covid-data-tracker/#datatracker-home). As many as 87% of COVID-19 survivors experience persistent symptoms that last beyond the acute phase of illness (Carfi A, et al. JAMA. 2020;324[6]:603-5). In February 2021, the National Institutes of Health (NIH) called for a consensus term to describe this protracted form of COVID-19, and defined it as Post-acute Sequelae of SARS-CoV-2 infection (PASC) (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid).
What are the PASC manifestations?
PASC has a heterogeneous presentation with a broad spectrum of manifestations and can vary from single to multiorgan system involvement. Commonly, PASC involves pulmonary abnormalities (shortness of breath, exercise intolerance, abnormal pulmonary functional test [PFT] and chest imaging), neurocognitive impairments (difficulty concentrating and memory loss), mental health disorders (anxiety, depression, and post-traumatic stress disorder), functional mobility impairments, as well as general and constitutional symptoms (fatigue and muscle weakness) (Groff D, et al. JAMA Netw Open. 2021;4[10]). The most prevalent pulmonary physiologic impairment is reduced diffusion capacity that has been shown to be associated with the severity of acute illness, while the most common radiologic abnormalities on chest CT scan are ground glass opacities. Some studies have shown a temporal improvement in pulmonary physiology and exercise capacity; however, persistent physiological and radiographic abnormalities persist in some patients up to 12 months after discharge (Wu X, et al. Lancet Respir Med. 2021;9:747-54). An abnormal or persistent hyper-inflammatory state, viral-induced autoimmune reaction, and ongoing viral activity have been proposed as possible biological mechanisms for PASC; however, the pathophysiology remains mostly unknown.
Who does PASC affect?
PASC affects patients irrespective of premorbid condition and severity of symptoms in the acute phase. It spans from those who had mild disease not requiring hospitalization to those who had critical illness requiring intensive care unit (ICU) management. COVID-19 ICU survivors seem to have an overlap of PASC and post-intensive care syndrome (PICS), defined by new or worsening physical, cognitive, and/or psychiatric impairments after critical illness. (Biehl M, et al. Cleve Clin J Med. 2020 Aug 5).
Who do we evaluate for PASC?
Given the complexity and chronicity of the associated symptoms and their impact on several major organ systems, a comprehensive and multidisciplinary approach is essential to assist with diagnosis and management of PASC. Listening empathically to patients and acknowledging their symptoms are key factors. Access to ambulatory care, establishment of rapport, effective collaboration and coordination of care among different disciplines, management of comorbidities, continuity of care, access to rehabilitation programs, and reduction of disease burden are some of the principles that guided the creation of dedicated COVID-19 clinics throughout the world. The most common services offered are primary care, pulmonology, cardiology, mental health, neurology, speech and language pathology, physical and occupational therapy, pharmacy, and case management. The involvement of specialties varies depending on the specific patient’s needs (Parker A, et al. The Lancet Respir Med. 2021;S2213-2600[21]00385-4).
The development of diagnostic and care pathways by different specialties ensures standardization of clinical assessment and management while allowing for individualized care. The commonly used tools to assess the respiratory system are the 6-minute walk test, PFT, chest imaging including radiographs and high-resolution CT scan, ventilation perfusion scan, and echocardiography. Some patients exhibit persistent cardiopulmonary symptoms with no evidence of organ injury. These patients have persistent exertional and functional limitation with normal PFT, resting echocardiography, and chest imaging. Cardiopulmonary exercise testing (CPET) and, more specifically, invasive CPET can be used to further investigate the decreased exercise capacity. CPET studies have identified an augmented exercise hyperventilation, and the causes of exercise limitation varied from anemia and reduced oxygen extraction by peripheral muscles to deconditioning, obesity, and lower ventilatory efficiency. A study looking at invasive CPET showed reduced peak exercise aerobic capacity in post COVID-19 patients compared with control participants and was associated with impaired systemic oxygen extraction and an exaggerated hyperventilatory response (Singh, et al. Chest. 2021;S0012-3692[21]03635). A subset of COVID-19 survivors presents with symptoms of autonomic dysfunction such as orthostatic intolerance and postural orthostatic tachycardia. These symptoms have been reported after other viral infections and could be secondary to gastrointestinal fluid loss, prolonged bed rest, and deconditioning of the cardiovascular system. More research is needed to characterize the dysautonomia in patients post–COVID-19.
What is the treatment?
Therapies depend on symptoms and organ involvement. The duration of pulmonary symptoms in long-haulers is not yet known, with cough and exercise intolerance/dyspnea ranking among the most common complaints in these patients. Exercise therapy plays an essential part in the rehabilitation of long-haulers and several studies are underway to assess different exercise and rehabilitation programs. For most patients with normal laboratory, physiologic, and imaging tests, post–COVID-19 clinics are offering physical therapy, occupational therapy, and neuropsychological rehabilitation. While steroids have been shown to improve mortality in hospitalized patients with COVID-19 requiring mechanical ventilation or supplemental oxygen, their role in outpatient COVID-19 infections and for post–COVID-19 lung disease/organizing pneumonia remains unclear. In a UK study of patients admitted to the hospital with COVID-19 disease of varying severity, interstitial abnormalities were noted in ~5% of patients at 6 weeks postdischarge and in 10.8% of patients with persistent respiratory symptoms (Myall, et al. Ann Am Thorac Soc. 2021;18[5]:799). The most common radiological findings (in > 50% of cases) were consistent with organizing pneumonia. Patients with persistent physiological abnormalities and interstitial findings improved with steroids. However, since the trajectory of the disease is unknown, further studies are required to understand the natural history of the disease and assess treatment strategies in patients with persistent inflammatory lung changes. Several studies looking at systemic or inhaled steroids in different phases of COVID-19 infection and varying disease severity are ongoing (ClinicalTrials.gov). Antifibrotics used to treat idiopathic pulmonary fibrosis and progressive fibrotic ILD are also being investigated in COVID-19 lung disease. The rationale for their use is to treat and prevent severe COVID-19 lung injury and prevent lung fibrosis.
The role of vaccinations
Whether patients who were infected with COVID-19, and, more specifically, patients with long-term symptoms post-COVID-19, should get vaccinated is actively being investigated. Vaccinations are protective at preventing infections and severe illness. Studies showed that patients who had COVID-19 infection and got vaccinated had a significantly higher antibody response than previously uninfected vaccine recipients. A review showed that the protective effect of prior SARS-CoV-2 infection on reinfection is high and similar to that of vaccination. However, a recent study of hospitalized patients revealed higher rates of COVID-19 among unvaccinated adults with previous infection compared with vaccinated adults (http://dx.doi.org/10.15585/mmwr.mm7044e1). On the other hand, the impact of vaccine on long-hauler symptoms has raised interest. A UK survey (not peer reviewed) on more than 800 long-haulers reported about 57% with overall improvement in their symptoms, 24% no change, and 19% with worsening symptoms after their first dose of vaccine, suggesting that the chances of experiencing an overall worsening of symptoms after vaccination is small, with more than half experiencing improvement (go.nature.com/3yfqem2). While awaiting longitudinal trials, the main argument to guide vaccination in long-haulers is that COVID-19 vaccinations provide protection from reinfection and appear to have the potential to improve symptoms.
The availability of a patient’s support system, peer support, and patient advocacy groups assist in providing equitable care and are critical in sustaining the recovery of COVID-19 survivors. Providing social, financial, and cultural support is imperative in decreasing the burden of COVID-19. The dedicated post–COVID-19 clinics will not only offer care to COVID-19 survivors, but will also help our understanding of the determinants and course of PASC, and will provide opportunities for research. Long-term longitudinal observational studies and clinical trials are critical to identify those at high risk for PASC, clarify the extent of health consequences attributable to COVID-19, and define best practices for COVID-19 survivors.
Dr. Biehl is Staff Physician, Pulmonary & Critical Care Medicine, Director, Post-ICU Recovery Clinic Respiratory Institute, Cleveland Clinic; Dr.Farha is with Respiratory and Lerner Institutes, Cleveland Clinic.
On March 11, 2020, the World Health Organization (WHO) declared SARS-CoV-2 a pandemic. As of October 2021, there are over 240 million confirmed COVID-19 cases and over 4 million deaths globally, with the United States having the highest incidence of both cases and deaths (https://covid.cdc.gov/covid-data-tracker/#datatracker-home). As many as 87% of COVID-19 survivors experience persistent symptoms that last beyond the acute phase of illness (Carfi A, et al. JAMA. 2020;324[6]:603-5). In February 2021, the National Institutes of Health (NIH) called for a consensus term to describe this protracted form of COVID-19, and defined it as Post-acute Sequelae of SARS-CoV-2 infection (PASC) (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid).
What are the PASC manifestations?
PASC has a heterogeneous presentation with a broad spectrum of manifestations and can vary from single to multiorgan system involvement. Commonly, PASC involves pulmonary abnormalities (shortness of breath, exercise intolerance, abnormal pulmonary functional test [PFT] and chest imaging), neurocognitive impairments (difficulty concentrating and memory loss), mental health disorders (anxiety, depression, and post-traumatic stress disorder), functional mobility impairments, as well as general and constitutional symptoms (fatigue and muscle weakness) (Groff D, et al. JAMA Netw Open. 2021;4[10]). The most prevalent pulmonary physiologic impairment is reduced diffusion capacity that has been shown to be associated with the severity of acute illness, while the most common radiologic abnormalities on chest CT scan are ground glass opacities. Some studies have shown a temporal improvement in pulmonary physiology and exercise capacity; however, persistent physiological and radiographic abnormalities persist in some patients up to 12 months after discharge (Wu X, et al. Lancet Respir Med. 2021;9:747-54). An abnormal or persistent hyper-inflammatory state, viral-induced autoimmune reaction, and ongoing viral activity have been proposed as possible biological mechanisms for PASC; however, the pathophysiology remains mostly unknown.
Who does PASC affect?
PASC affects patients irrespective of premorbid condition and severity of symptoms in the acute phase. It spans from those who had mild disease not requiring hospitalization to those who had critical illness requiring intensive care unit (ICU) management. COVID-19 ICU survivors seem to have an overlap of PASC and post-intensive care syndrome (PICS), defined by new or worsening physical, cognitive, and/or psychiatric impairments after critical illness. (Biehl M, et al. Cleve Clin J Med. 2020 Aug 5).
Who do we evaluate for PASC?
Given the complexity and chronicity of the associated symptoms and their impact on several major organ systems, a comprehensive and multidisciplinary approach is essential to assist with diagnosis and management of PASC. Listening empathically to patients and acknowledging their symptoms are key factors. Access to ambulatory care, establishment of rapport, effective collaboration and coordination of care among different disciplines, management of comorbidities, continuity of care, access to rehabilitation programs, and reduction of disease burden are some of the principles that guided the creation of dedicated COVID-19 clinics throughout the world. The most common services offered are primary care, pulmonology, cardiology, mental health, neurology, speech and language pathology, physical and occupational therapy, pharmacy, and case management. The involvement of specialties varies depending on the specific patient’s needs (Parker A, et al. The Lancet Respir Med. 2021;S2213-2600[21]00385-4).
The development of diagnostic and care pathways by different specialties ensures standardization of clinical assessment and management while allowing for individualized care. The commonly used tools to assess the respiratory system are the 6-minute walk test, PFT, chest imaging including radiographs and high-resolution CT scan, ventilation perfusion scan, and echocardiography. Some patients exhibit persistent cardiopulmonary symptoms with no evidence of organ injury. These patients have persistent exertional and functional limitation with normal PFT, resting echocardiography, and chest imaging. Cardiopulmonary exercise testing (CPET) and, more specifically, invasive CPET can be used to further investigate the decreased exercise capacity. CPET studies have identified an augmented exercise hyperventilation, and the causes of exercise limitation varied from anemia and reduced oxygen extraction by peripheral muscles to deconditioning, obesity, and lower ventilatory efficiency. A study looking at invasive CPET showed reduced peak exercise aerobic capacity in post COVID-19 patients compared with control participants and was associated with impaired systemic oxygen extraction and an exaggerated hyperventilatory response (Singh, et al. Chest. 2021;S0012-3692[21]03635). A subset of COVID-19 survivors presents with symptoms of autonomic dysfunction such as orthostatic intolerance and postural orthostatic tachycardia. These symptoms have been reported after other viral infections and could be secondary to gastrointestinal fluid loss, prolonged bed rest, and deconditioning of the cardiovascular system. More research is needed to characterize the dysautonomia in patients post–COVID-19.
What is the treatment?
Therapies depend on symptoms and organ involvement. The duration of pulmonary symptoms in long-haulers is not yet known, with cough and exercise intolerance/dyspnea ranking among the most common complaints in these patients. Exercise therapy plays an essential part in the rehabilitation of long-haulers and several studies are underway to assess different exercise and rehabilitation programs. For most patients with normal laboratory, physiologic, and imaging tests, post–COVID-19 clinics are offering physical therapy, occupational therapy, and neuropsychological rehabilitation. While steroids have been shown to improve mortality in hospitalized patients with COVID-19 requiring mechanical ventilation or supplemental oxygen, their role in outpatient COVID-19 infections and for post–COVID-19 lung disease/organizing pneumonia remains unclear. In a UK study of patients admitted to the hospital with COVID-19 disease of varying severity, interstitial abnormalities were noted in ~5% of patients at 6 weeks postdischarge and in 10.8% of patients with persistent respiratory symptoms (Myall, et al. Ann Am Thorac Soc. 2021;18[5]:799). The most common radiological findings (in > 50% of cases) were consistent with organizing pneumonia. Patients with persistent physiological abnormalities and interstitial findings improved with steroids. However, since the trajectory of the disease is unknown, further studies are required to understand the natural history of the disease and assess treatment strategies in patients with persistent inflammatory lung changes. Several studies looking at systemic or inhaled steroids in different phases of COVID-19 infection and varying disease severity are ongoing (ClinicalTrials.gov). Antifibrotics used to treat idiopathic pulmonary fibrosis and progressive fibrotic ILD are also being investigated in COVID-19 lung disease. The rationale for their use is to treat and prevent severe COVID-19 lung injury and prevent lung fibrosis.
The role of vaccinations
Whether patients who were infected with COVID-19, and, more specifically, patients with long-term symptoms post-COVID-19, should get vaccinated is actively being investigated. Vaccinations are protective at preventing infections and severe illness. Studies showed that patients who had COVID-19 infection and got vaccinated had a significantly higher antibody response than previously uninfected vaccine recipients. A review showed that the protective effect of prior SARS-CoV-2 infection on reinfection is high and similar to that of vaccination. However, a recent study of hospitalized patients revealed higher rates of COVID-19 among unvaccinated adults with previous infection compared with vaccinated adults (http://dx.doi.org/10.15585/mmwr.mm7044e1). On the other hand, the impact of vaccine on long-hauler symptoms has raised interest. A UK survey (not peer reviewed) on more than 800 long-haulers reported about 57% with overall improvement in their symptoms, 24% no change, and 19% with worsening symptoms after their first dose of vaccine, suggesting that the chances of experiencing an overall worsening of symptoms after vaccination is small, with more than half experiencing improvement (go.nature.com/3yfqem2). While awaiting longitudinal trials, the main argument to guide vaccination in long-haulers is that COVID-19 vaccinations provide protection from reinfection and appear to have the potential to improve symptoms.
The availability of a patient’s support system, peer support, and patient advocacy groups assist in providing equitable care and are critical in sustaining the recovery of COVID-19 survivors. Providing social, financial, and cultural support is imperative in decreasing the burden of COVID-19. The dedicated post–COVID-19 clinics will not only offer care to COVID-19 survivors, but will also help our understanding of the determinants and course of PASC, and will provide opportunities for research. Long-term longitudinal observational studies and clinical trials are critical to identify those at high risk for PASC, clarify the extent of health consequences attributable to COVID-19, and define best practices for COVID-19 survivors.
Dr. Biehl is Staff Physician, Pulmonary & Critical Care Medicine, Director, Post-ICU Recovery Clinic Respiratory Institute, Cleveland Clinic; Dr.Farha is with Respiratory and Lerner Institutes, Cleveland Clinic.
