The Clinical Sequelae of Post-acute COVID-19 Syndrome (PASC)

Studies and clinical surveys on disease conditions affecting a large portion of the global population constitute an objective appeal in modern medicine. In recent years, the trend and scope of these studies have been enlarged to accommodate post-treatment surveillance and the long-term effects of therapy methods in treated patients. With the COVID-19 pandemic, studies examining the long-term effects of therapy methods and the sequelae of this virus have become popular over the last few years. There is emerging evidence of long-term sequelae in a significant portion of people clinically treated and certified 'recovered.' Long-term sequelae of COVID-19 as observed clinically present as a spectrum of symptoms with variable severity and duration in formerly healthy adults (Nalbandian et al., 2021).

Early systematic reviews of this spectrum of symptoms suggest different underlying biological factors driving the symptoms reported. Recent clinical trials also demonstrate the pathologic cycle of these biological factors, none of which are mutually exclusive (Nasserie et al., 2021). In the medical community, the symptoms accompanying these biological factors are studied and documented under the umbrella term 'Post-acute COVID-19 Syndrome (PASC).' Patients presenting symptoms consistent with long-term Post-acute COVID-19 symptoms are referred to as 'Long Haulers.' To eliminate controversial results on the clinical information about PASC, host-controlled factors influencing the outcome of viral infections were first studied and reviewed in adult patients. Early consensus based on the available body of evidence on PASC includes the following summary points (Lopez-Leon et al., 2021);

• PASC incidence in the population is linked to host-controlled factors, including age, sex, genetic susceptibility, route of infection, past exposure to a cross-reactive agent, and presence of underlying medical conditions.
• PASC in long haulers is related to biological injuries caused by SARS-CoV-2, dysfunctions in the inflammatory response to COVID-19 infection, and impaired clotting.
• Approximately 80% of individuals with a confirmed COVID-19 diagnosis present with long-term symptoms following recovery from acute infection.
• In children, rare cases of Multisystem Inflammatory Syndrome can precipitate long-term COVID-19 symptoms. Severity and incidence and with an active multi-organ lesion.
• PASC symptoms are individualized in each patient, requiring a dynamic therapeutic approach including periodic evaluations, risk factor identifications, and a personalized clinical care plan.

Mayowa Lopez lived a healthy, happy life, charting a professional course as a Fintech UX designer in her early 30s. She is an African immigrant in Britain who adjusted quickly to the bustling sphere in London and made friends while traveling the United Kingdom to pitch ideas to potential investors and Fortune 500 CEOs. In April 2020, Mayowa tested positive for COVID-19 and presented to the clinic with symptoms of exhaustion, partial loss of taste, migraines, and mildly irregular episodes of cardiac arrhythmias.

As of April 2020, Mayowa's case was another on a long list of patients with a diagnosed case of COVID-19 infection. The symptoms got worse after hospitalization, with the severity level changing consistently.

"At some points, I cried to express the pains I felt. At some points, I developed a dry cough, mild fever, and shortness of breath that required the Matron's attention for emergency care," she recalled in an interview.

Based on available evidence on the treatment regimen at the time, Mayowa was placed on symptomatic treatment with a special regimen to modify and improve immunologic response to the virus. Four months, 12 emergency department visits, and four short hospitalizations later, Mayowa was certified 'recovered' from the virus and discharged. Initially, nothing was unique about Mayowa's case as she joined a poll of other Millions to have globally recovered from the virus.

Two months later, a post-treatment surveillance study conducted by a group of researchers examining race-dependent factors in widely-reported cases of Post-acute COVID-19 Syndrome (PASC) recruited Mayowa into its respondent pool.

Responding to the questions on her recovery history, Mayowa remarked;

"It's been weird lately at work. Sometimes, I barely remember my presentation points. I struggle to keep track of my medications, and sometimes I get an occasional feeling of late-night depression and mild fever. I think my brain feels like a fog sometimes too. It feels empty up there."

The researchers published her symptoms score and response in a systematic study and classified her as a 'Long-Hauler.' This group of healthy adults with a positive history of COVID-19 infections still feel the symptoms months after recovery. As the pandemic dragged on, more and more people identified with this group and presented with different symptoms of varying severity. Local hospitals and Community care groups have since created special campaign programs targeting individuals with post-viral syndromes. 

In a recently published JAMA Research Letter, researchers assessed the persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19. The study included 143 participants with an age range of 19-84 years. The study found that 87.4% (125 of 143 patients) reported persistent cases of at least one symptom, particularly dyspnea and unexplained bouts of fatigue. Only 12.6% (18 of 143) were completely free from any recognized symptoms of COVID-19 (Carfi et al., 2020).

Understanding the complex pathogenesis of delayed symptoms in PASC requires a review of acute syndromes arising from acute COVID-19 infection. Many patients with acute infections are asymptomatic or exhibit mild to moderate symptoms. In approximately 15 % of cases, patients might experience bouts of severe pneumonia, with a few eventually developing acute respiratory distress syndrome (ARDS). Septic shock and multi-systemic organ failure were also documented in a few cases (Huang et al., 2020). In a larger population of infected individuals, the most common symptoms documented include fever, cough, fatigue, diarrhea, sore throat, shortness of breath, and difficulty breathing. A cross-section of patients develops acute neurological complications, seizures, cerebrovascular diseases, encephalitis, anosmia, and the Guillain–Barré syndrome.

Extrapulmonary complications are also well-reported in acute COVID-19. Kidney injury, hyperglycemia, myocardial infarction, arrhythmia, hepatocellular injury, and acute coronary syndromes sum up the symptomatology profile in acute COVID-19 infection. The wide range of symptoms documented in COVID-19 patients reflects how the virus affects multiple organ systems in humans. Human ACE2 receptors required for the attachment and penetration of the virion into host cells are prominently expressed in the brain endothelium, vascular smooth muscle cells, and the respiratory system. In a 2020 publication, Puelles et al. described the expression of ACE2 and TMPRSS2 in a wide range of cells, including pancreatic b-cells, esophageal keratinocytes, and proximal renal tubules. Viral cell entry additionally requires priming of the spike protein by cellular serine proteases such as TMPRSS2 and TMPRSS4.

In acute COVID-19 infections, SARS-CoV-2 employs a different mechanism to evade the host immune systems and impair the basic biological functions and many organ systems. The virion's double-membrane vesicles are not detectable by the host-pathogen pattern recognition receptors. The maturing virions replicate within these vesicles and evade the host immune response smartly. Some genomic studies examining the interplay between SARS-CoV-2 and the type 1 interferon have provided multiple evidence on how the virion also dysregulates the host interferon response (Taefehshokr et al., 2020; Ribero et al., 2020). The active virion expresses protein fragments that counteract the induction of the interferon's antiviral activity, rendering the host immune response ineffective using an adaptive survival mechanism.

To ensure pathogenic survival, SARS-CoV-2 can also stimulate the biological process of clotting by inducing multisystem injuries. The process is complemented with thrombo-inflammation, endothelial cell damage, and the dysregulation of the angiotensin-aldosterone system. Endothelial injuries of infection origins, in turn, trigger excess thrombin formation and inhibit fibrinolysis. In all, this cycle leads to microvascular dysfunction and worsens symptoms associated with the vascular system.

The research interest in COVID-19 infection globally has tilted massively toward vaccine development, drug candidate research, and post-acute symptoms. Primarily, this course is designed to research and examine the pathological basis for the persistence of symptoms after acute COVID-19 infection. This post-acute phase of COVID-19 infection is now widely known in the medical community as 'Long COVID' or 'Post-acute COVID-19 Syndrome (PASC).' Patients who report these symptoms are classified as 'Long Haulers.' For a better perspective on diagnosis and classification, Nalbandian et al. (2021) define PASC as persistent symptoms and or delayed complications presented beyond four weeks after the onset of symptoms.

The delayed symptoms, complications, and biological drivers of long COVID in Long Haulers are subjects of research interest in Europe. In February 2021, the US National Institute of Health announced a $1.15 billion campaign to study the causes, biological drivers, prevention strategies, and therapy options for long COVID. In addition to acute illness, SARS-CoV-2 appears to cause long-term symptoms after the recovery period. This post-acute phase of COVID-19 infection has been reported in the special population, children and adults initially hospitalized after presenting with mild symptoms. Since the virus affects multi-organ systems in the body, the symptoms reported are similar to acute infection but with higher severities. The risk of symptoms persistence after recovery and severity of symptoms later reported increases in patients with underlying medical conditions, especially respiratory system diseases.

Studies on the epidemiological data on a global scale are currently limited for Post-acute COVID-19 Syndrome (PASC). Since the mechanisms underlying the pathophysiology of these conditions are still largely unknown, Scientists reckon it will be premature to label all post-COVID viral infections as PASC. As it stands, the prevalence of Long COVID is still uncertain, although there is enough evidence suggesting it is common among patients initially hospitalized for COVID-19. The prevalence, incidence, and mortality rate on a global scale remain largely unknown. Studies conducted in regions with high cases of long COVID give only regional rates of incidence and prevalence while providing valuable insights on the incidence of each long-COVID feature reported.

In a Technical Article published in 2021, the UK's Office for National Statistics (ONS) provided updated estimates of the prevalence of post-acute symptoms among people with COVID-19 in the United Kingdom. Using three different approaches, the Data Sheet estimated the percentage of COVID-19 patients and those who reported symptoms at least four more weeks after infection. The rates reported using data from Coronavirus Infection Survey (CSI) participants with post-acute symptoms include;

• Approach 1 (Prevalence of any symptoms at a point in time after infection): Among the study participants, 5% reported at last one of the common symptoms. However, the prevalence of these symptoms was 3.4% in a control group of non-COVID participants.
• Approach 2 (Prevalence of continuous symptoms after infection): Among the study population, 3% reported at least one of the common symptoms for a continuous period of at least 12 weeks after infection. Using the same approach, the prevalence in a population of participants who presented with at least one symptom during the acute phase of infection was calculated as 6.7%.
• Approach 3 (Prevalence of self-reported long-COVID): In the study population, about 11.7% of participants self-classify themselves as experiencing long-COVID. When considering PASC, which limits normal living, this normal increases to 17.7% and 11.8% in participants who reported at least one symptom at the acute phase of COVID-19 infection.

Based on prevalence rates from these approaches, it was evidence that post-acute symptoms were reported more in females, patients with underlying disease conditions, adults aged 59-69 years, and those with a high viral load on the infection (ONS, 2021).

Studying the pathological sequelae of Long COVID presents with a slight problem - PASC symptoms were hard to classify and identify. This difficulty in identifying symptoms called for a consensus on what criteria a post-acute COVID symptom must pass to be classed as PASC. As a proposed guideline, the National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners describe Post-acute COVID-19 Syndrome (PASC) as “signs and symptoms consistent with COVID-19 that are present for more than 12 weeks after infection and not attributed to alternative diagnosis” (Shah et al., 2021).

However, the US Center for Disease Control and Prevention describes 'post-COVID conditions' as a wide range of health consequences presented as ≥ four weeks after an acute infection phase with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The pathological sequelae and symptoms presentation in patients with COVID appears to be more pronounced in patients with severe diseases and those with a preexisting medical condition. In many documented cases, the pathological sequelae also directly depend on the host's immune response. Immune response to SARS-CoV-2 also impacts the biological drivers of PASC symptomatology. In long COVID, the continued replication of SARS-CoV-2 increases the risk of host immune system evasion, with proinflammatory responses consequently pronounced. Although the pathophysiological bridge between acute-COVID and long-COVID remains largely unclear, a careful annotation of the clinical symptomatology of PASC helps this switch. The most common symptoms reported in study reviews for PASC include systemic, neuropsychiatric, respiratory, and cardiovascular impairments. However, these symptoms do not present with a definite sequence in PASC patients. Their presentation and severity seem to depend on myriads of factors that vary significantly within the human population.

Lung involvement in severe COVID is a huge interest in the medical community. Pulmonary symptoms corresponding with the onset of long-COVID include cough and shortness of breath. Other symptoms of respiratory concern, as documented in Long Haulers, include difficulty weaning off ventilators, prolonged oxygen requirement, and abnormal lung functions (Chopra et al., 2021). In addition to the commonly reported neuropsychiatric symptoms in acute COVID, long haulers also present with protracted psychiatric symptomatology. Neuropsychiatric manifestations consistent with these patients include psychoses, gustatory impairments, sleep abnormalities, and chronic headaches. Other psychiatric disorders reported in Long Haulers include depression, anxiety, and post-traumatic disorder (PTSD).

In acute COVID, patients present with symptoms indicative of chest pain, chest tightness, and unexplained palpitations. These symptoms were also documented in Long Haulers and myocarditis, acute heart failure, and myocardial injury. Moody et al. (2021) demonstrated evidence of ventricular remodeling in patients initially hospitalized with COVID-19-associated pneumonia. This study and similar others created evidence for cardiac sequelae in long-COVID. The high concentration of Angiotensin-converting enzyme 2 (ACE2) on the brush border of the small intestinal mucosa explains the gastrointestinal-associated symptoms of acute COVID. In addition to nausea and vomiting, abdominal pains, and diarrhea, Long Haulers have also presented with loss of appetite, weight loss, and irritable bowel syndrome. Endocrine manifestations consistent with PASC include significantly high fasting insulin and C-peptide levels. As a direct impact, the endocrine abnormalities in long-COVID include subacute thyrotoxicosis, Graves' disease, altered bowel motility patterns, and Hashimoto's thyroiditis (Montefusco et al., 2021; Brancatella et al., 2020; Tee et al., 2020).

Fig 2: Timeline and Symptom Profile of Long COVID

Source: (Nalbandian et al., 2021)

The biological factors driving the persistence of symptoms in Long Haulers appear to be multidimensional. Different reviews on neuroscience, microbiology, and genomes have been proposed to explore the range of biological systems contributing to the development of chronic symptoms after the acute phase of COVID-19 infection. Currently, the most widely studied probable causes of long-COVID include the following.

Based on available scientific evidence, the pathophysiology of Post-acute COVID-19 Syndrome (PASC) remains largely unknown. This makes it hard to develop a common diagnosis plan for the assessment of Long Haulers. No laboratory assessment has been developed to differentiate long-COVID from acute COVID or detect the immunological bridge between both conditions. This diagnostic difficulty is, in part, due to the heterogeneity of symptoms documented in Long Haulers. Although RT-PCR and antigen tests can detect SARS-CoV-2 reservoirs, these tests do not provide a definite diagnosis of long-COVID. Laboratory investigations and physical examinations might be considered to determine the severity and compare symptoms sequelae if long-COVID is suspected. Where symptoms have persisted for more than 12 weeks, a comprehensive rehabilitation plan involving a multidisciplinary care approach can be initiated. Any adopted care plan must be supportive and designed to resolve ongoing symptoms and designed as a complementary plan for the depletion of SARS-CoV-2 reservoirs.

As a rough guide, the Center for Disease Control and Prevention produced a guideline for basic diagnostic laboratory testing for post-COVID conditions. 

There are more specific tests prescribed for a more specialized diagnostic laboratory for patients with post-COVID conditions. Please see table two in this same section. 

CDC also produced an assessment guideline for selected functional tools for evaluating PASC in Long Haulers.

As it stands, there are different diagnostic guidelines adopted by medical professionals for the evaluation of Long Haulers. The most common evaluation tools used by healthcare providers include the pulmonary function test, the Hospital Anxiety, and Depression Scale, the Montreal Cognitive Assessment, and the Screening for Rehabilitation Needs. In a 2020 publication of the European Respiratory Journal, Klok et al. published a post-COVID 19 Functional Status Scale grading the severity of symptoms reported.

Fig 3: Patient self-report methods for the Post-COVID-19 functional status (PCFS) scale.

(3a)  Flowchart

(3b) Patient Questionnaire

Source (for 3a & 3b): (Klok et al., 2020)

With Post-acute COVID-19 Syndrome (PASC), the goal of therapy is focused on improving quality of life, managing symptoms, and reducing the risk of complications. A multidisciplinary clinical care approach should be developed based on the presenting symptoms, the severity of post-COVID conditions, underlying medical conditions, and the patient's psychiatric conditions. However, it is advisable to share therapy goals and the processes of decision-making with the patient. Since there are no definitive care strategies for PASC yet, any adopted care plan is expected to be progressive, with objective changes made as the patient responds to therapy. Depending on the presenting symptoms, already established management approaches such as breathing exercises can be included in the management plan.

Some patients might benefit from comprehensive rehabilitation care, including speech and language therapy, vocational therapy, and physical and occupational therapy. Rehabilitation care has been documented to be specifically beneficial in patients presenting with neurologic symptoms. For patients with preexisting medical conditions, lifestyle modifications on stress reduction, sleep, and nutrition might also complement therapy. Keeping track of symptoms severity and therapy progress provides invaluable insights into the effectiveness of the care plan. In some patients, over-the-counter medication, vitamins, and supplements may be helpful for electrolyte recalibration and in improving immune response to SARS-CoV-2. Pharmaceutical interventions in Long Haulers should, however, be well monitored. If required, follow-up visits and routine clinic visits can be scheduled for responsible patient care.

In 2020, the British Thoracic Society published a care algorithm recommended for patients with a clinic-radiological diagnosis of COVID-19 pneumonia. Although the specific needs of individual patients might be different, this algorithm provides a follow-up evaluation plan for Long Haulers with respiratory complications.

Fig 4: Care algorithm for patients with post-acute sequelae of SARS-CoV-2

a) Screening tools to consider: Post-COVID-19 Functional Status Scale, COVID-19 Yorkshire Rehabilitation Screen, University of Pennsylvania Post-COVID Screening Measure.
b) Available psychiatric screen tools: General Anxiety Disorder-7 (GAD-7). Patient Health Questionnaire-9 (PHQ-9; for depression screening), PTSD Checklist for DSM-5 (PCL-5), Impact of Event Scale-6 (IES-R; for PTSD screening), Hospital Anxiety and Depression Score (HADS).
c) Available neurocognitive screening tools: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Cognitive Assessment Tool Rapid Version (CAT-rapid).

Source: (Vehar et al., 2021)

Public opinions on COVID-19 are varied and have largely been controversial. It is expected that medical information about post-COVID conditions might be received with skepticism. However, publications on post-COVID conditions are required for public health surveillance and awareness. Public education on long-COVID should be designed to inform the public of the available information about symptomatology, severity, health complications, and supportive care. Depending on existing healthcare directives, vaccinations and masking can also be recommended. Personal hygiene practices such as hand washing and preventive measures such as social distancing should also be advised. Avoiding crowds and poorly ventilated spaces should also be included as a general recommendation.

Based on data from the British Office of National Statistics, about 64% of Long Haulers in large population surveys reported at least a form of limitation in their daily life. About 19% reported different forms of significant limitations. In minors, the limitations reported were lesser compared to that reported by the 50 to 69 age range population (Ayoubkhani., 2021). Studies on the Care Dependency rate using the Care Dependency Scale tool have been conducted to document how people with long-COVID cope with persistent symptoms. The need for dependency and day-to-day assistance increased significantly compared to life before the infection. Vaes et al. reported how 41.1% of independent patients before the inflection now require at least a form of support to survive daily. The level of support required by Long Haulers seems to increase proportionately with the severity and range of symptoms reported. Neurological impairments, if present, make it harder for some Long Haulers to remember medication, hold a conversation, drive, make decisions, and stay focused on a task. The need for assistance increases significantly in this population (Davies et al., 2021).

In addition to primary impacts on daily living, patients with long-COVID have also reported forms of administrative burdens, psychological burdens, and negative impacts on professional life. Some find it hard to fit in perfectly when returning to work. Public support for Long Haulers is recommended in the form of social care and dependency assistance. Healthcare professionals have the responsibility to deliver patient-oriented care with the patient aware of the care plans and goals. Nurses and Care Assistants should prioritize listening to the needs and experiences of long-COVID patients. All members of the healthcare team are expected to supply the needed expertise for patient care based on the care needs document. Proper care for Long Haulers involves drafting and executing an interdisciplinary, holistic, and coordinated care plan with a focus on an integrated diagnostic work-up, treatment, and rehabilitation.

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