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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.

Post Acute Coronavirus (COVID-19) Syndrome

Venu Chippa; Abdul Aleem; Fatima Anjum.

Author Information
Last Update: October 1, 2021.

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.

Access free multiple choice questions on this topic.

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
(remdesevir), monoclonal antibodies (e.g., bamlanivimab/etesevimab, casirivimab/imdevimab),
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 and 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.

Review Questions

Access free multiple choice questions on this topic.

 Comment on this article.

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