Post Acute Coronavirus (COVID-19) Syndrome

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Continuing Education Activity

COVID-19 is primarily a respiratory viral illness caused by SARS-CoV-2. Based on the broad-spectrum clinical manifestations associated with the involvement of multiple organs in patients infected with SARS-CoV-2, COVID-19 is now considered a systemic illness. The immediate complications of COVID-19 are well defined and are often associated with increased mortality. However, delayed or long-term complications of COVID-19 are increasingly being recognized and are associated with increased morbidity. This activity highlights the role of the interprofessional team in the evaluation and management of patients with post-acute COVID-19 syndrome.

Objectives:

  • Explain the prevalence of delayed and long-term symptoms in patients with post-acute COVID-19 syndrome.
  • Describe the system-based manifestations of post-acute COVID-19 syndrome.
  • Summarize the methods to identify signs and symptoms of post-acute COVID-19 and discuss the management of post-acute COVID-19 syndrome.
  • Outline the importance of an interprofessional team approach in the management of post-acute COVID-19 syndrome.

Introduction

Coronavirus disease 2019 (COVID-19), the viral illness caused by the novel coronavirus SARS-CoV-2 has resulted in significant morbidity and mortality across the world since the first cases were identified in Wuhan China, in December 2019. Although the majority of the patients who contract COVID-19 are asymptomatic or have mild to moderate disease, approximately 5% to 8% of infected patients develop hypoxia, bilateral lung infiltrates, decreased lung compliance requiring non-invasive ventilation(NIV) or mechanical ventilatory support.[1] The management of COVID-19 infection is mainly supportive. Although many therapeutics such as antiviral drugs (remdesivir), monoclonal antibodies (e.g., sotrovimab), anti-inflammatory drugs (e.g., dexamethasone), immunomodulatory agents (e.g., baricitinib, tocilizumab) is available under emergency use authorization(EUA) for the management of COVID-19, the utility of these treatments varies based on the timing and severity of illness and/or certain risk factors.[2] 

The previous epidemics of SARS-CoV and MERS-CoV left individuals who recovered from these viral illnesses with persistent symptoms of severe fatigue, decreased quality of life (QOL), persistent shortness of breath, and behavioral health problems that resulted in a significant burden on local healthcare systems where the epidemics occurred. Similarly, a constellation of various clinical symptoms termed post-acute COVID-19 syndrome has been described in a minor proportion of patients who recovered from SARS-CoV-2 induced COVID-19 despite biochemical evidence that the replication of SARS CoV 2 ceases to exist after four weeks after the initial infection (based on the sampling of viral isolates from the respiratory tract and not the nasopharyngeal/oropharyngeal specimen).

Post-acute COVID-19 is a syndrome characterized by the persistence of clinical symptoms beyond four weeks from the onset of acute symptoms. The Center for Disease Control (CDC) has formulated "post-Covid conditions" to describe health issues that persist more than four weeks after being infected with COVID-19. These include

  • Long Covid (which consists of a wide range of symptoms that can last weeks to months) or persistent post-Covid syndrome (PPCS)
  • Multiorgan effects of COVID-19
  • Effects of COVID-19 treatment/hospitalization

The typical clinical symptoms in "long covid" are tiredness, dyspnea, fatigue, brain fogginess, autonomic dysfunction, headache, persistent loss of smell or taste, cough, depression, low-grade fevers, palpitations, dizziness, muscle pain, and joint pains.

Multiorgan effects of COVID-19 include clinical manifestations pertaining to the cardiovascular, pulmonary, renal, and neuropsychiatric organ systems, although the duration of these multiorgan system effects is unclear.

Long-term "effects of COVID-19 treatment or hospitalization" are similar to other severe infections. They include post-intensive care syndrome(PICS), resulting in extreme weakness and posttraumatic stress disorder. Many of the patients with these complications from COVID-19 are getting better with time. Post COVID-19 care clinics are being opened at multiple medical centers across the USA to address these specific needs.

Based on the chronicity of symptoms post COVID-19 infection, Nalbandian et al. classified post-acute COVID-19 as follows-

  • Subacute or persistent symptomatic COVID-19 symptoms (up to 12 weeks from the initial acute episode).
  • Chronic or post-Covid syndrome, symptoms present beyond 12 weeks. However, it should not be attributable to an alternative diagnosis.[3]

This review article describes the prevalence, system-based manifestations, relevant clinical investigations, treatment, and importance of an interprofessional team approach in the management of patients with post-acute COVID-19 syndrome.

Etiology

Given limited published data on this new clinical entity, the precise pathophysiology of post-acute COVID-19 syndrome is unknown and is likely multifactorial especially considering the involvement of multiple organ systems. Following any severe infection or trauma, the human body reacts with an overwhelming immune response called systemic inflammatory response syndrome (SIRS), followed by a prolonged compensatory, counterbalancing anti-inflammatory cascade called compensatory anti-inflammatory response syndrome (CARS).[4]

A delicate balance between SIRS and CARS determines the immediate clinical outcome and, eventually, the prognosis associated with the infection. SARS CoV 2 infection in patients with underlying comorbidities or immunocompetent settings may lead to excessive cytokine release called "cytokine storm." Persistent cytokine release results in acute respiratory distress syndrome (ARDS), hypercoagulable state, maladaptation of the angiotensin-converting enzyme 2 (ACE2) pathway, hypoperfusion to end-organs, septic shock, multiorgan failure, and eventually death. Immunologic hemostasis between immune activation and immunosuppression will result in either clinical recovery or viral reactivation, secondary infections, and death.[5]

Epidemiology

Based on limited data from multiple studies (observation and prospective cohort) from China, France, Spain, United Kingdom, United States, Italy that evaluated long-term consequences of acute COVID-19, patients with acute COVID-19 who required admission to the ICU and/or ventilatory support were shown to be at increased risk of developing post-acute COVID-19 syndrome.

Patients with pre-existing pulmonary conditions, older age, obesity are considered to be at increased risk of developing post-acute COVID-19 syndrome.[6]

Through the evolution of this global pandemic, it became increasingly clear that patients with pre-existing conditions such as diabetes mellitus, chronic kidney disease(CKD), chronic cardiovascular disease, underlying malignancies, organ transplant recipients, and chronic liver disease are at increased risk for developing severe COVID-19. However, it is unclear if the prevalence of these comorbid conditions as risk factors in post-acute COVID-19 syndrome is yet to be established.[7]

Female patients recovering from COVID-19 were more prone to develop symptoms of post-acute COVID-19 syndrome, especially fatigue, anxiety, and depression at 6-month follow-up.[8] 

Data evaluating racial and ethnic consideration in post-acute COVID-19 syndrome is limited. Halpin et al., in their study evaluating post-COVID-19 symptoms 4 to 8 weeks after hospital discharge, noted that 42.1% of Black Asian and Minority Ethnic (BAME) participants reported moderate to severe breathlessness compared with 25% of white patients.[9]

Histopathology

Post-acute COVID-19 syndrome is a multisystem disorder that commonly affects the respiratory, cardiovascular, and hematopoietic systems. In addition, neuropsychiatric, renal, and endocrine systems are also involved to a lesser extent. Significant organ-specific histopathologic findings are described below.

Lungs

  • COVID-19 lung autopsy has shown all phases of diffuse alveolar damage with focal and organized fibroproliferative diffuse alveolar damage similar to ARDS.[10] Rarely microcystic honeycombing, myofibroblastic proliferation, and mural fibrosis were also noted.
  • Lung tissue analysis (autopsy and explanted lungs of lung transplant recipients) with severe COVID-19 pneumonia showed histopathology like end-stage pulmonary fibrosis without active SARS-CoV-2 infection, suggesting that some people may develop lung fibrosis following resolution of active infection.
  • The severity of endothelial damage, microthrombi seen on lung autopsy is significantly more in SARS-CoV-2 infection compared to ARDS from influenza.[11]

Heart

  • There is much variability in COVID-19 myocardial insult in the histopathologic examination. 62% of Autopsy findings of acute COVID-19 showed the presence of virus genome in the heart tissue.[12]
  • Endomyocardial biopsy is the definitive test in the diagnosis of myocarditis. The presence of lymphocyte infiltration with myocyte injury without ischemia is consistent with viral myocarditis according to 1987 Dallas criteria. However, in post-acute Covid-19 syndrome, only 10% to 20% of myocarditis is diagnosed with endomyocardial biopsy. This low sensitivity is secondary to sampling error.
  • Immunohistochemical analysis of endomyocardial biopsy showed severe intramyocardial inflammation with increased perforin-positive cells. There are increased numbers of macrophages, T lymphocytes, CD45R0 T memory cells. There is an increased number of cell adhesion molecules(CAM) like CD 54/ICAM-1.[13]

Brain

  • A single-center histopathological study of brain specimens obtained from eighteen patients who succumbed to COVID-19 demonstrated acute hypoxic injury in the cerebrum and cerebellum of all patients. Notably, no features of encephalitis or other specific brain changes were seen. Additionally, immunohistochemical analysis of brain tissue did not show cytoplasmic viral staining.[14]

Renal

  • SARS-CoV-2 has been isolated from multiple kidney biopsies, with the most predominant finding being acute tubular necrosis. The presence of collapsing variant focal segmental glomerulosclerosis, acute tubular injury, and global tuft involution is specific for COVID-19 associated nephropathy (COVAN).[15]

History and Physical

The most common reported symptom was dyspnea followed by cough and loss of taste or smell among the 32% of patients who reported persistent symptoms during a 60-day follow-up of 488 patients after hospitalization from acute COVID-19. The results of this observational cohort study also reported a readmission rate of 15% and a mortality rate of 6.7%.[16] In another study that evaluated 110 COVID-19 patients after discharge from hospitalization due to acute COVID-19 for 90 days, fatigue and dyspnea (39%) were the most common symptoms noted, followed by sleep disturbance (24%), chest pain (12%), and cough (11%).[17] 

A 6-month follow-up study by Huang et al. evaluated 1733 patients as follow up after post-COVID-19 hospitalization reported that fatigue (63%) was the most common symptom, followed by sleep disturbances (26%), depression/anxiety (23%), and hair loss (22%). Patients hospitalized with severe acute respiratory failure secondary to COVID-19 are considered to have impaired pulmonary function and abnormal chest imaging at 6-month follow-up. Based on these above studies, fatigue, shortness of breath, psychological stress (anxiety, depression), posttraumatic stress disorder, poor concentration, and sleep abnormalities were observed in at least 25% or more of the study participants. 

Pulmonary Manifestations

  • The severity and long-term complications of COVID-19 infection are yet to be seen. However, data shows that many patients have persistent respiratory symptoms weeks to months after the initial diagnosis of COVID-19.
  • Both viral-dependent and independent mechanisms contribute to endothelial, epithelial damage caused by monocyte and neutrophil invasion resulting in ARDS. A decrease in diffusion capacity is the most reported physiologic derangement in post-acute COVID-19 and directly correlates with the severity of acute illness. The most common high-resolution lung CT findings of post-acute COVID-19 are the persistence of ground-glass opacities.
  • Dyspnea, cough, oxygen dependence, difficulty to wean from mechanical ventilation or NIV, fibrotic lung changes, decreased diffusion capacity, and reduced endurance are the common pulmonary sequelae seen in patients with post-acute COVID-19 syndrome.
  • Dyspnea is the predominant pulmonary symptom (40% to 50% prevalence at 100 days) in post-acute COVID-19. At a 6-month follow-up, the average 6-minute walking distance was significantly lower than the standard reference because of shortness of breath. About 6% of patients continue to require supplemental oxygen at 60-day follow-up.[16] 
  • A study from Spain showed that about 50% of tracheostomy patients were successfully weaned off at 30-day follow-up post-discharge.[18] About 50% of patients are at least one abnormal CT chest finding (ground-glass opacity, fibrotic changes) at a 6-month follow-up. 

Cardiovascular Manifestations

  • Direct virus-mediated cytotoxicity, ACE 2 receptor down-regulation, immune-mediated inflammation affecting the myocardium, and pericardium are the most common mechanisms of cardiovascular damage resulting in clinical symptoms such as dyspnea, fatigue, myocarditis, decreased cardiac reserve, dysregulation of the renin-angiotensin-aldosterone system(RAAS), autonomic dysfunction, and arrhythmias.[19]

Hematologic Manifestations

  • Acute COVID-19 associated thromboembolism is secondary to the hyperinflammatory and hypercoagulable state compared to consumptive coagulopathy from DIC.[20] Hypoxia, endothelial injury, platelet activation, proinflammatory cytokines result in disproportionately high thromboembolism in acute COVID-19. Both the duration and severity of this hyper-inflammatory state contribute to the risk of thrombotic complications in the post-COVID-19 phase. 

Neuropsychiatric Manifestations

  • Microvascular thrombi, systemic inflammation, direct viral-mediated neurotoxicity are hypothesized to be the possible mechanisms contributing to neuropathology in COVID-19. Dysautonomia, deconditioning, and posttraumatic stress disorder can contribute to post COVID-19 brain fog. Prolonged duration of ICU stay, prolonged intubation contribute significantly to long-term cognitive impairment in COVID-19 patients.[21]

Renal Manifestations

  • A significant proportion (20%) of severe COVID-19 patients requiring intubation also required renal replacement therapy(RRT) during hospitalization. The majority of them did not require dialysis near discharge. 

Endocrine Manifestations

  • Viral injury, inflammatory and immunologic damage contribute to post-acute COVID-19 endocrine manifestations. Isolated case reports of DKA, Subacute, and Hashimoto thyroiditis have been reported weeks after resolving acute COVID-19 symptoms.[22][23] Immobilization, steroid use, vitamin D deficiency during acute and post-acute recovery of COVID-19 might contribute to bone demineralization.

Multisystem Inflammatory Syndrome in Children (MIS-C)

  • MIS-C is a new clinical entity characterized by fever, multiorgan dysfunction, increased inflammatory markers seen in individuals less than 21 years old, with recent or current SARS-CoV-2 infection
  • The most likely underlying mechanism is acquired an immune response from complement activation, formation of autoantibodies (viral host mimicry), and excessive cytokines from T-cell stimulation.[24]

Evaluation

A detailed clinical history regarding the onset and duration of current symptoms, underlying medical comorbidities, the severity of COVID-19, and medication history must be obtained by treating providers during the follow-up visit.

Hospitalization records of COVID-19 related admission, if applicable, must be reviewed thoroughly, including the pertinent diagnostic tests performed and duration of hospitalization.

Given post-acute COVID-19 syndrome is an evolving clinical entity, currently, there are no guidelines regarding its management. Nevertheless, until further guidance is available, this novel clinical entity should be considered a diagnosis of exclusion. All other complications associated with COVID-19 and other acute alternative diagnoses must be first ruled out with pertinent laboratory and radiologic assessment.

Multiple case reports have reported reactivation and relapse of SARS-CoV-2 in COVID-19 recovered patients. Hence, reinfection with SARS-CoV-2 needs to be ruled out.[25]

Other postviral secondary bacterial and fungal infections or other viral illnesses also need to be ruled out.

Routine laboratory assessment with complete blood count (CBC), comprehensive metabolic panel (CMP) that includes testing for renal, liver function, and a coagulation panel must be considered in all patients.

Other tests such as C-reactive protein(CRP), fibrinogen, D-dimer, troponin, and ferritin can also be considered if clinically indicated.[26]

Repeat pulmonary imaging, preferably with a high-resolution CT scan (HRCT) or CT Angiogram, can be considered in patients presenting with predominantly respiratory symptoms.[27]

Cardiac function tests such as EKG and echocardiography must also be considered to rule out an underlying cardiopulmonary disease process.

Neuroimaging that includes vascular (CT/MRI) and neuropsychological testing must be performed if clinically indicated in patients presenting with neuropsychiatric manifestations.

Treatment / Management

General Considerations

  • As described earlier, post-acute COVID-19 syndrome can be considered a multi-system disorder manifesting commonly with respiratory, cardiovascular, hematologic, and neuropsychiatry symptoms either alone or in combination. As such, the therapy should be individualized and should incorporate an interprofessional approach directed towards addressing both the clinical and psychological aspects of this disorder.
  • Given the increased clinical awareness of this syndrome, Post-COVID care clinics providing multidisciplinary assessment and resources for patients recovering from COVID-19 are opening at major medical centers across the United States.
  • Treatment for coexisting conditions such as diabetes, chronic kidney disease, hypertension should be optimized.[28][26]
  • Patients should be educated about self-monitoring at home with FDA-approved devices that include a pulse oximeter, blood pressure, and blood glucose monitors.
  • Patients should be encouraged to consume a healthy balanced diet, maintain proper sleep hygiene, limit alcohol use and quit smoking.[26]
  • Simple analgesia with acetaminophen as needed should be considered
  • If tolerated, a structured exercise program consisting of aerobic and resistance components must be advised, provided they are no other contraindications.[29]

Pulmonary

  • Post COVID-19 patients with persistent/residual pulmonary symptoms after recovery should be seen by a pulmonologist as early as possible for evaluation and close follow-up. 
  • Patients with persistent symptoms may benefit from enrollment into a pulmonary rehabilitation program which is key for faster clinical recovery and vaccination against influenza and Streptococcus pneumoniae.
  • Pulmonary function tests (PFTs) and 6MWT should be considered if clinically indicated.
  • The role of steroids in post-acute COVID-19 is unknown, and data evaluating its effectiveness in post-COVID-19 patients is limited. A small study evaluating COVID-19 patients four weeks after discharge demonstrated rapid and significant improvement with early initiation of steroids.[30] Further clinical trials are required to ascertain its benefit in COVID-19 patients.

Cardiovascular

  • Post COVID-19 patients with persistent cardiac symptoms after recovery should be followed closely by a cardiologist.
  • Cardiac function tests such as EKG, echocardiography must be considered to rule out arrhythmias, heart failure, and ischemic heart disease.
  • Additionally, given the increased incidence of myocarditis in patients with COVID-19, an MRI of the heart can be considered to evaluate for myocardial fibrosis or scarring if clinically indicated.

Hematologic

  • Although COVID-19 is associated with a prothrombotic state, there is currently no consensus regarding the benefit of venous thromboembolism (VTE) prophylaxis in the outpatient setting. However, current CHEST guidelines recommend anticoagulation therapy for a minimum duration of 3 months in COVID-19 patients who develop proximal DVT or PE.[31]

Neuropsychiatric

  • Patients should be screened for common psychological issues such as anxiety, depression, insomnia, PTSD and should be referred to behavioral health specialists if indicated.
  • Given the vast neurological symptoms associated with this syndrome, neurology evaluation should be considered early.
  • In addition to routine laboratory workup as described above, additional laboratory tests such as hemoglobin A1C (HbA1c), TSH, thiamine, folate, Vitamin B12, and Vitamin B12 must be checked to evaluate for other contributing metabolic conditions.[32]
  • EEG and EMG be considered if there are concerns for seizures and paresthesias, respectively.

Differential Diagnosis

Understanding of post-acute COVID-19 syndrome at this time is limited, and any organ system can be potentially affected. Hence,post-acute COVID-19 syndrome should be considered a diagnosis of exclusion. All other well-described complications associated with COVID-19 and other acute alternative diagnoses must be first ruled out with pertinent laboratory assessment and imaging. Considering this novel clinical entity manifests with various respiratory, cardiovascular, hematologic, and neuropsychiatry symptoms either alone or in combination, the following commonly occurring conditions can be considered but not limited to in the differential diagnosis of post-acute COVID-19 syndrome.

Respiratory

  • Pulmonary embolism
  • Lung atelectasis/fibrosis
  • Postviral bacterial pneumonia

Cardiovascular

  • Ischemic heart disease
  • Post viral myocarditis
  • Myocardial fibrosis/scarring
  • Congestive Heart Failure
  • Arrhythmias

Hematologic

  • Deep vein thrombosis

Neuropsychiatric

  • Stroke
  • Cerebral vein thrombosis
  • Seizures
  • Anxiety
  • Depression
  • Insomnia
  • Post Traumatic Stress Disorder(PTSD)

Infectious

  • Bacterial and fungal infections
  • Other viral infections that include SARS-CoV-2 reinfection

Prognosis

The prognosis of this new clinical entity is not known and is likely dependent on the severity of clinical symptoms, underlying comorbid conditions, and response to treatment. More clinical studies evaluating post-COVID-19 patients are required to understand the duration and the long-term effects of this new clinical entity.

Complications

Post-acute COVID-19 syndrome itself is an increasingly recognized complication of COVID-19 and secondary complications associated with this syndrome are poorly understood at this time. More clinical data is required to further understand the long-term sequelae of this syndrome.

Deterrence and Patient Education

  • Patients with this syndrome should be educated about the importance of self-monitoring at home and should be followed by a home health aide, if possible, regularly.
  • Patients should be educated and encouraged to seeking emergency care when necessary.
  • Patients should be encouraged to seek behavioral health counseling or be provided with mental health crisis hotline numbers, especially when associated with neuropsychiatric manifestations.
  • Patients require education regarding the efficacy of the available vaccines and the benefits of the vaccination.

Enhancing Healthcare Team Outcomes

  • COVID-19 has wreaked havoc across the world and has overwhelmed many healthcare systems, and will continue to remain a threat to global public health until the majority of the world’s population gets vaccinated against this illness.
  • Close follow-up of all COVID-19 patients during recovery is needed to develop a team approach to understand and manage this complex and evolving health crisis. 
  • Management of post-acute COVID-19 syndrome requires a holistic and interprofessional team approach that includes physicians across specialties (primary care, pulmonology, cardiology, infectious disease), physiatrists, behavioral health experts, physical and occupational therapists, and social workers.
  • The survivors of COVID-19 require rehabilitation focusing on cardiopulmonary sequelae, psychological burden, and fatigue at a much larger level because of the current global pandemic.[33]
  • Primary care providers should recognize this syndrome as early as possible and rule out other potential implicating diagnoses and refer patients to post COVID-19 care clinics if available.
  • Patients with this syndrome should be educated about the importance of self-monitoring at home and, if possible, should be followed by a home health aide on a regular basis.
  • Considering post-acute COVID-19 syndrome is commonly associated with the involvement of multiple organ systems that include neuropsychiatric abnormalities, patients suspected to have this syndrome should be referred to a behavioral health specialist and, if indicated, a neurologist in a timely manner.
  • There should be close communication between the primary care physician, specialist physicians, and behavioral health experts to outline the best possible care individualized to each patient, all coordinating activity and communicating as an interprofessional team.
  • Such an interprofessional team approach enhances improved patient care outcomes and reduces unnecessary hospitalizations, thus preventing exhaustion of healthcare resources that have already been under considerable strain throughout this pandemic.


Article Details

Article Author

Venu Chippa

Article Author

Abdul Aleem

Article Editor:

Fatima Anjum

Updated:

6/19/2022 12:01:22 AM

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