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COVID-19 Long Haulers: The Frontier of Prevention and

Treatment

Kenneth R. Durbin, Raquel S. Markulin, Nicole R. Squatrito, Hayden A. Turk, and Victoria M.

Woods

Centofanti School of Nursing, Youngstown State University

NURS 3749: Nursing Research

Ms.Randi Heasley

April 5, 2021
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Abstract

The purpose of this research was to determine the role of current COVID-19 treatments and how

it plays into determining if a patient will experience symptoms of, and be classified as, a long

COVID patient. This paper aimed to define what long COVID is and symptoms experienced by

these patients. The correlation between pharmacological treatment such as colchicine and

convalescent plasma and improved patient outcomes were explored. This research was drawn

from twelve total sources of both qualitative studies and meta-analyses of literature reviews.

Colchicine was found to be an appropriate treatment for both preventing long COVID and

treating long hauler patients. Convalescent plasma was shown to reduce disease severity and

mortality risk. The impact on COVID-19 vaccinations on long haulers was also explored.

Overall, the research examined showed there are treatments that can prevent COVID patients

from reaching long hauler status and treat those patients who are already there.
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Introduction

Coronavirus disease 19 (COVID-19) is a contagious viral infection caused by the virus

severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified

in Wuhan, China in December of 2019. The virus has spread worldwide infecting 126,697,603

people, including 2,776,175 deaths as of March 25, 2021 (WHO). Symptoms of the COVID-19

disease vary greatly from case to case and range from mild to severe. Mild symptoms include

fever, cough, shortness of breath, fatigue, muscle or body aches, headache, loss of taste or smell,

nasal congestion, nausea or vomiting, and diarrhea. The viral mechanism of action leads to

vascular inflammation, specifically targeted to organs with perfuse vasculature. Because of this,

the lungs, liver, kidneys, and brain are likely to be the site of complications and damage from

COVID-19 infection.There is a four-staged classification system of escalating phases that is

useful when structuring a proper treatment plan to treat COVID-19 (Risk et al., 2020, p.1). Risk

(2020) states the corresponding stages:

Stage I (early infection) begins at the time of viral inoculation and establishment of

infection. Patients may or may not manifest non-specific symptoms (i.e. malaise, fever,

sore throat, dry cough), and treatment is often symptomatic. Stage II is characterized by

hyperresponsiveness of the immune system. Patients develop viral pneumonia and

possibly hypoxia, and markers of systemic inflammation are elevated. The third stage is

characterized by a hypercoagulable state. Patients with hypoxia are likely to progress to

stage IV, the most severe stage, where multi-systems organ failure occurs.(p.1-2)

After initial recovery, patients can experience sequelae that lasts weeks to months. These patients

have come to be identified by terms such as long-COVID or COVID long-haulers. This report
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aims to outline the common symptoms shared by long-haulers, experimental treatments and

medications being used, and scientific understanding of long-COVID to date.

Patients with long-term COVID-19 issues are a very new population of study. A great

deal of interventions such as medications, plasma administration, and nonpharmacologic

treatments have been tried with differing levels of research done. This report looks at studies

showing the comparison of patient outcomes of those started on interventions in hopes to prevent

long-hauler symptoms versus those that were not. The ultimate goal with treatment research is to

prevent long-term complications from diseases such as COVID-19. Therefore, the following

research question was addressed: For COVID-19 patients, does the use of pharmacological

measures reduce the risk of complications and long COVID and improve patient outcomes, and

do these same pharmacologic treatments decrease symptoms of current long COVID patients and

reduce time of sequelae?

Literature Review

Long-haulers

Long COVID is a term used to describe someone who has persistent symptoms of

COVD-19 beyond the acute illness. Persistent symptoms can be classified into acute phases

lasting 3-4 weeks and chronic lasting beyond 12 weeks (Ladds et al., 2020, p.2). Long haulers

continuous symptoms consist of “cough, breathlessness, fever, sore throat, chest pain,

palpitations, cognitive deficits, myalgia, neurological symptoms, skin rashes, and diarrhea. Some

also have persistent or intermittent low oxygen saturations” (Ladds et al., 2020, p 2). In addition

to continuous fluctuating symptoms, long haulers can have complications due to inflammatory

reactions with vasculature. Conditions secondary to COVID-19 consist of myocardial infarction,

heart failure, cardiac arrhythmias, myo- or pericarditis, thromboembolic complications, and/or

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long term respiratory conditions (Ladds et al., 2020, p. 2-4). According to Ladds (2020), long

haulers can be classified into groups:

Individuals with persisting symptoms seem to fall into three broad groups: people who

were initially hospitalised with acute respiratory distress syndrome (ARDS) and now

have long-term respiratory symptoms dominated by breathlessness; people who may not

have been hospitalised initially but who now have a multisystem disease with evidence of

cardiac, respiratory, or neurological end-organ damage manifesting in a variety of ways;

and people who have persisting symptoms, often but not always dominated by fatigue,

with no evidence of organ damage. (p.2)

The puzzling aspect of long haulers is that most patients who are experiencing these

lasting symptoms start with mild to moderate symptoms when initially infected with COVID-19.

The majority of the patients experiencing long-hauler symptoms do not require hospitalization or

intensive care when they are in the hospital. What astounds doctors the most are the lasting

symptoms that are disproportionately affecting those of a younger age (Rubin, 2020, p.1381). It

is suspected that COVID-19 triggers long lasting changes in the immune system and organs,

particularly the lungs that persist beyond the patient being infected with the virus (Rubin, 2020,

p. 1381-1382). Scientists speculate that the dysregulation of the autonomic nervous system is the

reasoning for many of these symptoms like tachycardia, extreme fatigue, and dyspnea. (Rubin,

2020, p. 1383). One of the most challenging issues about longer-haulers is that most never had

confirmation of their COVID-19 diagnosis adding skepticism to the persistent symptoms.

(Rubin, 2020, p. 1383) The modesty of symptoms patients are experiencing can be mistaken for

a cold or even the flu. This misconception results in more spread of infection and longer time

without treatments and therapies for the virus.

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Clinically, COVID-19 seems to be milder in the pediatric population. With that being said

however, a small percentage of children with the disease develop hyperinflammation and

long-term symptoms. Data about long hauler symptoms for children is very limited, but it

appears to follow that of the adult population. In the study done in Sweden by Ludvigsson

(2020), it was shown that the pediatric population experiences very similar long COVID

symptoms that the adult population does. The children in the study had symptoms for six to eight

months after diagnosis with COVID-19 including: fatigue, dyspnea, heart palpitations,

headaches, muscle weakness, dizziness, sore throats, and difficulting concentrating (Ludvigsson,

2020). The subjects in the study also did not fully return to school for at least six months which

is very concerning as the long-term effects of COVID-19 in children may have a severe impact

on the education system.

Treatment: Colchicine

Historically, colchicine has been around since its approval by the US Food and Drug

Administration in 2009, and has been approved to be successful in treating acute gout,

pericarditis and other inflammatory conditions (Reyes et al., 2020. p.3). In regards to other

inflammatory conditions mentioned above, colchicine marks up a reputation of decreasing

c-reactive protein levels (general inflammatory marker), and is associated with thrombus

resolution. The reputation colchicine has in inflammatory diseases set up a platform to be used in

treating COVID-19. The encouragement for the use of colchicine for SARS-CoV-2 helped in

providing cheap, non-immunosuppressive drugs along with the potential to prevent progression

from inflammatory action (Phase 2) to a hyperinflammatory state (Phase 3) (Reyes et al., 2020,

p.5). Early identification of COVID-19 would allow early administration to hospitalized and
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non- hospitalized patients could result as an impact on whether patients are able reduce the

inflammatory phase 2 and 3 to prevent further complications later on.

In the GRECO-19 Trials, the study showed a suppression of D- dimer levels versus the

control group (Reyes et al., 2020, p.6). Deftereos (2019) created a randomized clinical trial with

105 patients hospitalized with COVID-19 to have standard medical treatment and or colchicine

with standard medical treatment, patients were given a loading dose of colchicine (1.5mg of

colchicine followed by 0.5mg given 60 minutes later.) Maintenance dose was 0.5mg twice daily

until the patient was discharged from the hospital or maximum of 21 days (p.3). The results show

a significant decrease in D-dimer, in the colchicine group (0.76) compared to the control group

(0.92) (Table 2 p.7).

Tardif’s (2021) study was performed as a randomized double-blind trial involving

patients who tested positive with COVID-19 through polymerase chain reaction PCR test.

Following the positive PCR patients were randomly selected to be given 0.5 mg of colchicine (3

x daily for 3 days and once a day after) or placebo. Approximately 4488 patients were a part of

the trial and were followed for 30 days. Tardif”s (2021) study found the following, “When the

93% of patients who had a formal diagnosis of COVID-19 are considered, the benefit of

colchicine on the primary efficacy endpoint was more marked (25%)” ( p.11). In better terms,

the study showed a risk reduction for patients with colchicine.

Results further showed, patients who received colchicine compared to placebo showed

4.7% risk reduction in complications to the virus compared to placebo at 5.8%. In addition, the

reduced risk of mechanical ventilation, patients with colchicine 0.5% compared to 1.0% placebo

and lastly the reduction of death, 0.2% colchicine compared to 0.4% placebo (Tardif et al., 2021,

p.10). Overall, colchicine is a cheap and productive medication that can be given to individuals
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who suffer from COVID-19, and provide the individuals a better chance of survival, and reduce

the risk of individuals who suffer from long-term COVID by preventing the later stages that

damage the body.

Use of Plasma

The use of convalescent plasma has been a contributor to the multiple treatment options

for COVID-19. This method of treatment is not new, dating back over one hundred years with

the use of passive antibody transfers using convalescent plasma during the 1918 flu pandemic

(Joyner et al., 2021, p. 1016). Presumably, the plasma from patients who previously were

infected with COVID-19 is rich with antibodies, aiding in potential recovery for the recipients

currently infected (Joyner et al., 2021, p. 1015). This study was based on a U.S. national registry

determining the antibody levels used per transfusion, and each enrolled patient was observed for

death within 30 days of their transfusion (Joyner et al., 2021, p. 1015). The results of the study

looked at the subgroups of antibody levels (high, medium, low) and the recipient’s 30-day

mortality rate after receiving their transfusion. The study also included additional variables like

mechanical ventilation.

The initiation of the COVID-19 Convalescent Plasma Expanded-Access Program began

with the Mayo Clinic in efforts to provide access to the safety profiles of convalescent plasma in

patients with COVID-19 (Joyner et al., 2021, p. 1016). With this access, the study provided was

able to assess the level of antibodies per transfusion and split the study into categories; high

(>18.45), medium (4.62 to 18.45), and low (<4.62) IgG antibody levels (Joyner et al., 2021, p.

1017). 3082 patients were enrolled in the study from 680 acute care facilities in the United States

with 61% of them male, 23% African American, 37% Hispanic, 69% younger than 70 years old

(Joyner et al., 2021, pp. 1019-1020). The primary outcome of the study resulted in 26.9% of all
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patients in the study dying within 30 days of their plasma transfusion (830 of 3082). This event

occurred in all three separate categories of antibodies; 29.6% of the low group, 27.4% in the

middle group, and 22.3% in the high group. The higher level of antibodies the patient received

resulted in the lower relative risk of death within 30 days of transfusion compared to the other

groups (Joyner et al., 2021, p. 1021).

This study identified convalescent plasma being a beneficial treatment to those afflicted

with COVID-19 finding those who are not on mechanical ventilation and received a transfusion

with high antibody levels were associated with a lower mortality risk (Joyner et al., 2021, p.

1025). The study found that patients who had a plasma transfusion within three days of their

COVID-19 diagnosis had a lowered risk of death. (Joyner et al., 2021, p. 1025). This study took

place in acute care facilities where patients were hospitalized, but this therapy could be used

outside of the hospital as treatment for those who have mild to moderate symptoms and were not

hospitalized. This group of people who were not hospitalized end up as COVID-19 long-haulers

with persistent symptoms after the virus had left their body. The concluding data of this study

presents increased probability of surviving COVID-19 with convalescent plasma transfusions

and can be a potential treatment for those who are exhibiting acute and chronic symptoms of

COVID-19.

Effects of Vaccination on Long COVID patients

A potential therapy for long haul patients is to be vaccinated against COVID-19. As greater

portions of the population are vaccinated, vaccinated long haulers are reporting a decrease in

symptoms. Although the vast majority of this evidence is antidotal. A small UK study showed

promising results. The NHS of Bristol surveyed 66 long haul patients who were highly

symptomatic at least eight months post COVID-19 infection (Arnold et al., 2021, p.2). 44 of the
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patients received the vaccine and 22 did not (Arnold et al., 2021, p.2). 32 days post vaccine long

haul patients reported a 23.2% increase in symptom resolution (Arnold et al., 2021, p.2). None of

the vaccinated patients reported a worsening of symptoms post vaccine administration. It is of

note that this study worked with a small sample size and relied purely on patient recall. This

study gives promising results but merely serves as a jumping off point for further, more in depth,

research into the topic.

In one study conducted on Israel's COVID-19 vaccination program, it was found that,

even during a nationwide surge in cases, the number of patients older than 70 years old needing

ventilation due to the severity of symptoms consistently decreased after implementation of the

vaccination campaign. The vaccination program started on December 20, 2020 and was followed

by a rapid rollout of the vaccines and prioritized older age groups (>60 years old). Two groups

were compared in this study, patients 70 years and older who have had both doses of the

Pfizer-BioNTech vaccine and patients younger than 50 who had also received their second dose

of the same vaccine (Lewis, 2020). It was found that, “Since implementation of the second dose

of the vaccination campaign, the ratio of COVID-19 patients requiring mechanical ventilation

aged ≥70 years to those aged <50 years has declined 67%” (Lewis, 2020). While more research

is requiquired, this study provides preliminary evidence of the effectiveness of vaccines in

preventing severe COVID-19 symptoms. And it is surmisable that if vaccines prevent severe

complication, they prevent severe disease progression, which is the hallmark of a Long COVID

infection.

Morbidities and mortality rates

A meta-analysis done in the Journal of Global Health shows how certain patients with

comorbidities underlying their COVID-19 diagnosis can affect the occurence of death. A total of
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forty-one different studies were thoroughly looked over in order to make a connection between

comorbidities and an increased likelihood of death from COVID-19 infection. The comorbidities

were placed into different groups and the likelihood of death was estimated using a

random-effect model. According to Islam et al. (2020), “The likelihood of death was higher

among COVID-19 patients who had comorbidities like cardiovascular diseases, cerebrovascular

diseases, respiratory diseases, renal diseases, immune and metabolic disorders, hepatic diseases,

and cancer.” Studies such as this one can help the healthcare system prioritize care for certain

individuals with an increased chance of mortality in order to improve patient outcomes.

An in-depth look at the numbers from the study show the correlation between the specific

comorbidity and the increased chance of death. Those who had pre-existing cardiovascular

diseases had a 3.42% increased risk of death, immune and metabolic disorders was shown to be

2.46% higher, respiratory diseases 1.94%, cerebrovascular diseases 4.12%, cancers 2.22%, renal

diseases 3.02%, and finally liver diseases with a 2.35% increased risk of mortality (Islam et al.,

2020). Previous cerebrovascular diseases, cardiovascular disease, and renal disease bring the

most risk when it comes to patients infected COVID-19. Using results such as these may allow

the healthcare system to rank patients based on comorbidities to determine who needs the

highest-level care in order to reduce fatalities from this disease.

Conclusion

In conclusion, our literature review found that there are multiple promising avenues for

long haulers treatment and prevention. The pharmacological agent colchicine was found to

prevent COVID-19 patients from progressing into the third stage of the disease,

hyperinflammatory state. By preventing stage 3 of the disease, the risk of complication and

prolonged disease progression was reduced. Thereby reducing the likelihood of patients
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becoming COVID long haulers. Convalescent plasma administration was shown to reduce

mortality risk in COVID-19 patients. Therefore it is a potential treatment to prevent long COVID

symptoms. In several clinical studies, COVID-19 vaccine administration was shown to reduce

disease progression into severe complications and to elevate symptoms for long haul patients.

Both convalescent plasma and COVID-19 vaccine effects on reducing long COVID symptoms or

preventing disease progression into long COVID, require further study. But both treatment types

offer the potential for promising results.

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