Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:

1. Identify the features of COVID that distinguish it from acute disease.

2. Outline the means to decrease the incidence of long-term effects of COVID.

3. Provide a plan for management of symptoms associated with long COVID.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known at the time as the novel coronavirus, began to spread globally in late 2019 and early 2020, causing the disease that came to be known as novel coronavirus disease, or COVID-19. And as it extended into 2021 and 2022, the disease is now commonly called COVID. Early on, clinicians noted that although some patients recovered from COVID quickly, others suffered protracted effects including cardiovascular, pulmonary, and neurologic problems. Metabolic sequelae also occurred in many patients. These protracted effects came to be called long COVID.

A review of citations in the Library of Congress indicated 2252 studies related to long COVID, with 59 published in 2020, 941 in 2021, and 1426 so far this year (October 2022). The severity of the recurring symptoms often did not seem to be related to the initial degree of illness and was found in children and adults of all ages. Just as there is heterogeneity in the acute infectious phase, there is heterogeneity in the long-term complications seen after COVID-19 illness.1 This marked a change from the respiratory illnesses that had plagued Asia a few years earlier, although milder long-term symptoms had been seen occasionally after influenza. The syndrome was given several names in addition to long COVID, such as post-COVID symptoms and post-acute COVID-19. Patients who had these protracted symptoms came to be referred to as long-haulers.

Now, more than 2 years later, it has become apparent that these sequelae pose a significant threat throughout the world as patients are unable to return to work and require extensive medical care over what may be months or even years.

Incidence

Determining an exact incidence of long COVID has been difficult. One retrospective cohort study based on linked electronic health records collected data from 81 million patients, including 273,618 COVID-19 survivors.2 The incidence and co-occurrence within 6 months and in the 3 to 6 months after COVID-19 diagnosis were calculated for 9 factors of long COVID; these 9 factors were: breathing difficulties/breathlessness; fatigue/malaise; chest/throat pain; headache; abdominal symptoms; myalgia; other pain; cognitive symptoms; and anxiety/depression.

Comparison with a propensity score-matched cohort of patients diagnosed with influenza during the same time was also made. Among COVID-19 survivors [mean +/- standard deviation (SD) age: 46.3 +/- 19.8, 55.6% female], 57% had one or more long COVID symptoms during the 1- to 180-day 6-month period (ie, including the acute phase), and 36.55% had one or more long COVID symptoms between 3 and 6 months (the 90- to 180-day period).

The incidence of each feature was as follows:

* Abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to 180-day period);

* Fatigue/malaise (12.82%; 5.87%);

* Chest/throat pain (12.60%; 5.71%);

* Headache (8.67%; 4.63%);

* Other pain (11.60%; 7.19%);

* Abdominal symptoms (15.58%; 8.29%);

* Myalgia (3.24%; 1.54%);

* Cognitive symptoms (7.88%; 3.95%); and

* Anxiety/depression (22.82%; 15.49%).

All features were more frequently reported after COVID-19 than after influenza [with an overall excess incidence of 16.6% and hazard ratios (HR) between 1.44 and 2.04, P < 0.001]. Significant differences in incidence and co-occurrence were associated with sex, age, and illness severity.

Yet another recent study included 23 reviews and 102 primary studies. Prevalence estimates ranged from 7.5% to 41% in nonhospitalized adults, 2.3% to 53% in mixed adult samples, 37.6% in hospitalized adults, and 2% to 3.5% in primarily nonhospitalized children. Evidence suggested, as in the other study, that female sex, age, comorbid conditions, the severity of acute disease, and obesity are associated with long COVID. Almost 50% of primary studies reported some degree of long COVID-related social and family life impairment, long absence periods off work, adjusted workloads, and loss of employment.3

Yet another online survey in the United Kingdom looked at the duration of symptoms.4 The study included adults who reported laboratory-confirmed (polymerase chain reaction or antibody) or suspected COVID-19 who were not hospitalized in the first 2 weeks of illness. The analysis was restricted to those with self-reported long COVID. Data from 2550 participants with a median duration of illness of 7.6 months (interquartile range [IQR] 7.1-7.9) were determined; 26.5% reported laboratory confirmation of infection. The mean age was 46.5 years (SD 11 years) with 82.8% females; 89.5% described their health as good, very good, or excellent before COVID-19.

The most common initial symptoms that persisted were exhaustion, chest pressure or tightness, shortness of breath and headache. Cognitive dysfunction and palpitations became more prevalent later. Fluctuating (57.7%) or relapsing symptoms (17.6%) were common. Physical activity, stress, and sleep disturbance commonly triggered symptoms. One-third (32%) reported they were unable to live alone without any assistance at 6 weeks from start of illness. Also, 16.9% were unable to work solely due to COVID-19 illness, 37.0% reported loss of income due to illness, and 64.4% said they were unable to perform usual activities and duties.

Acute symptoms clustered broadly into 2 groups: a majority cluster (n = 2235, 88%) with cardiopulmonary predominant symptoms and a minority cluster (n = 305, 12%) with multisystem symptoms.

Ongoing symptoms clustered into 2 groups: a majority cluster (n = 2243, 88.8%) exhibiting mainly cardiopulmonary, cognitive symptoms, and exhaustion, and a minority cluster (n = 283, 11.2%) exhibiting more multisystem symptoms. The more severe multisystem cluster was associated with more severe functional impact, lower income, younger age, female sex, worse baseline health, and inadequate rest in the first 2 weeks of the illness.

A combined UK/US survey collected data from September 6, 2020, to November 25, 2020.5 Responses were from 3762 participants with confirmed (diagnostic/antibody positive; 1020) or suspected (diagnostic/antibody negative or untested; 2742) COVID-19, from 56 countries, with illness lasting over 28 days and onset before June 2020. The prevalence of 203 symptoms in 10 organ systems was estimated and 66 symptoms traced over 7 months.

For most respondents (>91%), the time to recovery exceeded 35 weeks. Participants experienced an average of 55.9 +/- 25.5 (mean +/- SD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, postexertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time; 85.9% of participants [95% confidence interval (CI), 84.8%-87.0%] experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. A total of 1700 respondents (45.2%) required a reduced work schedule compared with pre-illness, and an additional 839 respondents (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%).

Pathophysiology

COVID-19 seems first to target the respiratory system. However, severe long COVID syndrome is associated primarily with cognitive dysfunction and fatigue symptoms, like those experienced by patients receiving chemotherapy for cancer, as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome or mast cell activation syndrome.6 The pathogenesis of cognitive dysfunction in these illnesses is currently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus.

Other researchers have profiled SARS-CoV-2 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19.7 No molecular traces of SARS-CoV-2 were found in the brain, but there were cellular changes indicating that barrier cells of the choroid plexus can sense and relay peripheral inflammation into the brain. Peripheral T cells seem to be able to infiltrate the parenchyma. Moreover, microglia and astrocyte subpopulations associated with COVID-19 were found to share features with pathologic cell states that have been reported in human neurodegenerative disease.8-10 Synaptic signaling of upper-layer excitatory neurons is linked to cognitive function and is preferentially affected in COVID-19.11 Across cell types, alterations associated with COVID-19 overlap those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression.12

Another finding based on laboratory research is that SARS-CoV-2 infects cells via its spike protein binding to its surface receptor on target cells, and this infection results in acute symptoms involving especially the lungs.13 Most of the vaccines for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies.14

Recent publications provide new findings that may help decipher the pathogenesis of long COVID.15,16 One article reported perivascular inflammation in brains of deceased patients with COVID-19, whereas others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB, resulting in perivascular inflammation.15 The spike protein may share antigenic epitopes with human molecular chaperons causing autoimmunity, leading to release of inflammatory cytokines. Researchers are considering potential interventions to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin.

Further implicating the spike protein, a retrospective study measured 3 SARS-CoV-2 antigens in blood samples from 63 individuals diagnosed with COVID-19, of whom 37 had post-acute sequelae of COVID-19 (PASC) identified.17 SARS-CoV-2 spike antigen was detected several months post-infection in 60% of PASC and in none with COVID-19 only. Blood samples were available in 12 individuals (group 1) with continued symptoms and in 6 with COVID-19 only (group 2). Serial blood samples in group 1 showed sustained or fluctuating spike antigen levels, whereas in group 2, high antigen levels dropped rapidly immediately after diagnosis. The authors suggest that these results support the hypothesis that a reservoir of active virus persists within the body in those with long COVID. Ten cytokines were also measured and did not differ between the groups, which speaks against a purely inflammatory action.

Some animal models have been developed to determine the development of neuropathologic findings of autopsied brain tissue from patients who died from COVID. In infected nonhuman primates, researchers have identified neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology consistent with hypoxic-ischemic injury in SARS-CoV-2, including neuron degeneration and apoptosis.18 These symptoms may be found among infected animals that do not develop severe respiratory disease. Sparse virus was detected in brain endothelial cells but did not relate to the severity of central nervous system injury. There was no evidence that SARS-CoV-2 infected neuronal cells, but evidence indicates the involvement of neuroinflammation that may damage brain blood vessels, and brain cells, possibly via activation of microglia and mast cells.19-21 In fact, long COVID could be considered a state of "brain autoimmunity."

Management

COVID-19 is a relatively new disease. More information is added daily on a dynamic basis about the natural history of the disease, especially in terms of postrecovery events and recurring symptoms. Because the definitive cause of long COVID is unknown, there is no single cure.22 It has been recognized that up to 80% of patients experience prolonged illness after COVID-19, including, among other ailments, prolonged malaise, headaches, generalized fatigue, sleep difficulties, hair loss, smell disorder, decreased appetite, painful joints, dyspnea, fibromyalgia, chest pain, and cognitive dysfunction.

Long COVID often persists for months and even years after acute infection. It seems that patients who do not receive adequate treatment during the symptomatic phase are much more likely to develop long COVID. However, treatment should be individualized to clinical signs and symptoms.

No definitive effective antiviral treatment for COVID-19 has been identified. Many drugs have been evaluated and used despite preliminary or conflicting results of the clinical trials.23 Two main drug groups have been identified: agents that target proteins or RNA of the virus, and agents that interfere with proteins or biological processes in the host that support the virus. These groups include:

* Inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, miniproteins, human soluble angiotensin converting enzyme-2, camostat, dutasteride, proxalutamide, bromhexine, hydroxychloroquine (HCQS), umifenovir, nitazoxanide, niclosamide, and lactoferrin);

* Inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, and GC376);

* Inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, and PTC299);

* Inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, and ivermectin); and

* Agents supporting host natural immunity (interferons).

Of these groups and agents, monoclonal antibodies seem to be the most effective. Lopinavir/ritonavir, HCQS, merimepodib, and umifenovir were found to be ineffective in randomized controlled clinical trials. More studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxalutamide, fluvoxamine, bromhexine, nitazoxanide, and niclosamide in the treatment of COVID-19 and prevention of long-term illness. Phased trials of newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin, and AT-527 are ongoing.

A group of critical care specialists (8 medics and 2 former journalists) formed the FLCCC (Front Line COVID-19 Critical Care Alliance) in March 2020, at the beginning of the coronavirus pandemic in an attempt to develop treatment protocols not only to prevent the transmission of COVID-19 but to better understand and improve long-term outcomes.24 The FLCCC is designated as a 501c3 organization that produces weekly updates and seminars on the latest findings for management of COVID. The goal is divided into several specific goals:

* Review emerging published medical literature on COVID-19 from in vitro, animal, clinical, and epidemiologic studies;

* Develop effective treatment protocols for COVID-19 that evolve by incorporating newly identified, applicable therapeutic and pathophysiologic insights;

* Educate health care workers on safe and effective treatment approaches to all phases of COVID-19, from disease prevention strategies to the use of combination-based therapy protocols in both early-stage (I-PREVENT) and hospitalized patients (MATH+);

* Improve outcomes for people impacted by COVID-19 disorders through preventive and treatment strategies designed to optimize health;

* Teach the public how to prevent transmission of the virus and to advocate for the best possible care; and

* Coordinate and accelerate the formation of research studies that will support effective prevention and therapeutic treatments for all impacted by COVID-19.

These goals are accomplished by reviewing medical education for both the public and health care providers, via the publication of scientific manuscripts, media interviews, and medical lectures for medical providers and the public.

One of the treatment protocols recommended by the FLCCC is I-Recover. Although the goals of the FLCCC are admirable, many of the recommendations have been questioned as ineffective, including ivermectin, an FDA-approved antiparasite drug used to treat onchocerciasis (also known as river blindness) and other parasitic diseases. However, some studies have raised questions as to ivermectin's ability to inhibit SARS-CoV-2 replication and to suppress inflammation and subsequent illness.

A recent meta-analysis by Bryant et al25 demonstrated that ivermectin reduced the risk of death by an average of 62% [risk ratio (RR) 0.38, 95% CI, 0.19-0.73] compared with no ivermectin in hospitalized patients. In a Cochrane Review, the identical set of trials found only 4 of the 15 included in Bryant's meta-analysis on mortality met predefined eligibility criteria.26,27 The conclusion drawn was that incorporating careful grading of the certainty of evidence demonstrated uncertainty whether ivermectin compared with placebo or standard of care reduced or increased mortality in moderately ill hospitalized patients (RR 0.60, 95% CI, 0.14-2.51; 2 studies) and mildly ill outpatients (RR 0.33, 95% CI, 0.01-8.05; 2 studies), due to serious risk of bias and imprecision.

The use of prednisone has also been questioned, as a recent study looked at the relative risk of diabetes developing during long COVID in patients receiving corticosteroids.28 In a cohort study, using the national databases of the US Department of Veterans Affairs, 181,280 participants who had a positive COVID-19 test between March 1, 2020, and September 30, 2021, and who survived the first 30 days of COVID-19 were matched to a contemporary control (n = 4,118,441) of participants at the same period, and with a historical control (n = 4,286,911) between March 1, 2018, and September 30, 2019. Both control groups had no evidence of SARS-CoV-2 infection. Participants in all 3 comparison groups were free of diabetes before cohort entry and were followed up for a median of 352 days (IQR 245-406).

The authors reported 2 measures of risk: HR and burden per 1000 people at 12 months. In the postacute phase of the disease, compared with the contemporary control group, people with COVID-19 exhibited an increased risk (HR 1.40, 95% CI, 1.36-1.44) and excess burden (13.46, 95% CI, 12.11-14.84, per 1000 people at 12 months) of incident diabetes; and an increased risk (1.85, 1.78-1.92) and excess burden (12.35, 11.36-13.38) of incident antihyperglycemia. Risks and burdens of postacute outcomes increased in a graded fashion according to the severity of the acute phase of COVID-19 (whether patients were nonhospitalized, hospitalized, or admitted to intensive care).

Low-dose naltrexone, also recommended by the FLCCC, requires more study. In a single small trial of 36 patients with long COVID, improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (P <= 0.001), and improvement in mood approached but was not significant (P = 0.054).29

Other recommendations from the FLCCC include vitamins and HCQS, the latter drug now having been banned from use for COVID treatment. Both HCQS, chloroquine, and azithromycin (AZ) have been used based on in vitro studies favoring antiviral effects against the COVID-19 virus. There is evidence both in favor and against the use of HCQS and AZ combination therapy to manage the COVID-19 infection.30 However, the combination of HCQS and AZ was significantly associated with increased adverse events. It is doubtful that further studies will be carried out.

The White House issued a Presidential Memorandum divided into 4 sections in April 2022, directing the Secretary of Health and Human Services to develop and coordinate an interagency research plan for long COVID.31,32

US President Joe Biden emphasized that "many continue to experience negative long-term effects of COVID-19 ... reporting debilitating, long-lasting effects of having been infected with COVID-19 ... symptoms that can happen to anyone. These symptoms can persist long after the acute COVID-19 infection has resolved, affecting the ability to work, conduct daily activities, engage in educational activities, and participate in communities. Too many have felt the effects of social isolation, sickness, economic insecurity, increased caregiver burdens, and grief. My administration has made significant investments in mental health as well as substance use disorder prevention, treatment, and recovery support for the American public, including by expanding access to community-based behavioral health services. We are committed to advancing behavioral health efforts to better identify the effects of the pandemic on mental health, substance use, and well-being, and to take steps to address these effects."

Summarizing the recommendations from the President:

1. Raise awareness of long COVID;

2. Protection from discrimination;

3. Increased support for mental health issues, including the effects of depression, isolation, and substance abuse;

4. Translational research from the laboratory to the clinical arena;

5. Connecting people with appropriate resources;

6. Strengthening support for affected people, especially in the workplace;

7. Establishment of a coordinated federal efforts program;

8. Increase funding for long COVID research; and

9. Enrollment in the RECOVERY initiative to "enhance the understand of and ability to predict, treat and prevent long COVID"

As of now, management of long COVID starts with prevention or mitigation of the disease with vaccination protocols. During the acute phase, useful agents include antivirals such as remdesivir, a broad-spectrum antiviral medication that has been shown to shorten recovery time and is approved or authorized for emergency use to treat COVID-19. Other measures include early and effective cardiovascular support. Long COVID is also managed with symptom-specific therapy including antidepressants, analgesics, anti-inflammatories, sleep aids, increased social contact, and avoidance of stress. Cognitive dysfunction requires expert consultation and the assurance that it will usually improve.

Going Forward

Almost 3 years into this pandemic, there is still much to learn regarding modification or prevention of long COVID. Worldwide vaccination is important, as those who were vaccinated required less hospitalization and generally had milder disease. Much can be done with animal research and exploration and development of more SARS-CoV-2-specific antiviral drugs. Further education of the public, especially as it relates to understanding in the workplace, is essential. Recognition of diabetes in a COVID-19 patient requires immediate therapy. Prompt access to medical care can initiate appropriate pain therapy and decrease the risk of the development of chronic pain conditions.

References