COVID-19 Reinfections

The definition of COVID-19 reinfection has evolved since early 2021. Fundamentally, it describes an infected individual who has been fully vaccinated, with or without a booster or boosters, and who becomes infected with COVID-19 again. The CDC more precisely defines it as COVID-19 infection of a given person with 2 different viral strains occurring at least 45 days apart. Alternately, it may represent 2 positive CoV-2 RT-PCR tests with negative tests in between. ^{[1, 2]}  Determining reinfection rates of COVID-19 is essential in determining the effectiveness of current vaccine prophylaxis. Fairly early in the pandemic, it was recognized that reinfection, in both vaccinated and non-vaccinated individuals, most likely is due to a variant. ^{[1, 3]}

(See Coronavirus Disease 2019 [COVID-19].)

Cases of suspected reinfection must be differentiated from reactivation/relapse of the virus, which is seen in a clinically recovered individual within the first 4 weeks of infection. Testing for viral RNA has remained positive. During relapse, a small viral load of dormant virus becomes reactivated, often for unclear reason. The site usually is in the lower respiratory tract. The only way to absolutely establish this state is to demonstrate that there is no difference between genetic samples taken at the beginning and at the time of reactivation. Since it is unusual to do such testing at the beginning of an individual's disease, the estimation of reactivation is based on a small sample size. It may occur in 9–27% of cases. The immune response to reinfection is characterized by a much higher IgG antibody level and an absent level of IgM to the virus.

Symptoms alone and/or any type of organ damage lasting more than 4 weeks is termed post-acute sequelae of COVID-19 infection (PASC). The most common complaints are shortness of breath and fatigue. When this occurs and is associated with viral shedding, it is understandable to consider persistent infection. The nasal discharge of acute infection is greatest in the first week and usually is resolved by 17 days; however, it can last more than 80 days. After 7 days, the shed RNA material becomes more fragmented and less infectious. ^[1]

A very important reason to focus on recurrent infection is to explore the role, if any, that it may play in the pathogenesis of long COVID-19, a condition that may be associated with chronic fatigue symptoms of a myalgic encephalomyelitis, loss of taste and smell, and cardiac arrhythmias.

The replication of RNA viruses such as HIV has been described as being quite "sloppy," or haphazard. End spike proteins may be reproduced in fragments or with changes different from the template. Hundreds of variants were documented within 12 months of COVID-19. These often have no significant effect on the disease; however, they may increase both the severity of the infection and its transmissibility. Diagnostic testing may be affected by such changes, and the most important of these changes probably is that therapies such as monoclonal antibodies, antiviral agents, and vaccines may be mitigated. Those strains with such effects are termed variants of concern (VOC). The long-awaited "herd immunity" may never occur because the profile of the herd is constantly changing. ^{[4, 5]}

The Alpha variant was detected in Great Britain during November 2020. It quickly spread throughout the world and became the primary VOC in the United States.

The Beta VOC surfaced in South Africa, causing a second wave of infection. Individuals with Beta would be more likely than those with the Alpha variant to develop severe disease, with 50% likely to require ICU care and 57% more likely to die. 

The Delta variant first appeared in India during November 2020. ^[6] It rapidly spread throughout the world and eventually displaced the Alpha variant after arriving in the United States in late 2021. Its 12 significant genomic mutations have made it the most infectious and rapidly spreading variant. It was particularly severe in the unvaccinated and caused a higher rate of breakthrough infections; recognition of this led to the recommendation of a booster vaccine.

The Gamma VOC shares a common mutation with the Beta variant. In the United States from January 2021-April 2021, only 28 cases were due to this strain, whereas 75% were caused by the Beta variant. Our inability to explain the significant clinical difference between 2 very similar viruses highlights the incompleteness of our understanding of vaccine failures.

The Omicron variant BA.1 was first reported in the United States in December 2021. By January 2022, this VOC accounted for 95% of all COVID-19 infections. It has replaced the Delta variant as the most common worldwide cause of COVID-19. Overall, it is associated with less severe disease but is much more transmissible, both in the vaccinated and unvaccinated. There is evidence of less syncytial damage to the lung, but increased concentrations in the nasal mucosa. Because Omicron makes use of endosomal fusion, rather than TMPRSS2, to penetrate into the host's cells, it has markedly increased the types of cells it can invade. 

Omicron BA.2 is more transmissible than BA.1 and may lead to less severe infection. Omicron BA.2 has gained 20 mutations of spike proteins compared with BA.1. These may explain its increased transmissibility without any increase in disease severity. It appears that the Omicron BA.2 variant is less sensitive to the protective effects of interferon but does not evade detection by T cells. Omicron appears to be less suppressed in fully vaccinated individuals, and administration of a booster vaccine partially overcomes this. Omicron is resistant to 17 neutralizing antibody treatments. ^[7]

BA.3 is notable for having 13 mutations, none of which would justify it becoming a VOC.

The Omicron variants BA.4 and BA.5.have started multiplying in South Africa ( 50% of isolates). It is not clear whether they will be more pathogenic. There is no data currently whether they will increase the rate of hospitalizations or deaths or just replace earlier versions of Omicron without leading to a rise in serious illness. ^[8]  

Please see COVID-19 Variants. 

The primary purpose of any microorganism, be it viral, fungal, or bacterial, is self-replication. ^[9]  Since viral particles are not alive, these microorganisms need to penetrate the host's cells and co-opt their metabolic pathways. If this is done quickly enough, the intruders may be shielded from detection by the host's immune system.

COVID-19 belongs to the coronavirus family of single-stranded respiratory viruses. RNA viruses have a high rate of mutation during their replication, many of which are end stage, meaning that they have lost their ability to reproduce. However, occasionally such mutations allow the virus to infect other species. It is estimated that a single amino acid change resulted in what we recognize as COVID-19. This variant gained the ability to "jump" from bats to humans.

As do all respiratory viruses, COVID-19 initially seeks out the nasal mucosal cells. These are protected by the overlying mucous barrier that is swept along by the respiratory cilia. Conditions that damage this barrier (eg, smoking) put the underlying mucosal cells at risk for viral invasion. ^[10]  These cells have a high concentration of ACE2 receptors. The emblematic spike proteins of the virus are uniquely designed to efficiently "zero in " on these receptors. They are composed of 3 binding subunits that form the head of the spike. These structures are glycosylated to shield them from the host's immune system. In addition, the stalks of these spikes are composed of a series of hinges to facilitate the binding to the ACE2 receptors. After adherence is established, lysis of the spike proteins occurs. This is necessary for the fusion of the virus and the membrane of the host cell. This is facilitated by transmembrane serine proteases that reside on the cellular membrane.

As the virus ramps up its intracellular replication, the host recognizes the foreign genome of the coronavirus and starts producing interferon and other cytokines that results in "shut down" of all the intracellular metabolic processes. This response leads to the death of the cell. This inflammatory response is meant to limit viral replication. However, COVID-19 possesses mechanisms that effectively thwart these defenses. The persistent inflammatory response leads to impairment of organ functioning and spread of the infection beyond the respiratory tract into the deeper viscera such as the lungs, heart, and deep body adipose tissue. ^[11]  This migration is facilitated by furin and other proteases.

ORF3a is a viral protein unique to COVID-19 that has a significant effect on the entire replication cycle of the virus from entry into the host cell through viral transcription and replication and final release into the bloodstream. It also promotes inflammation and other immune responses that can set off a cytokine storm and cellular death. ^[12]  Severe COVID-19 is characterized by the unchecked inflammatory process (cytokine storm) described above and marked immunosuppression due to dysfunctional monocytes. ^[13]

In addition, the respiratory/nasal tract epithelium interacts with the adjacent endothelium, which may play a significant role in the thrombo-embolic phenomenon of COVID-19. ^[14]  

Most cases are very mild and occur in younger, non-immunosuppressed patients, with few, if any, long-term health consequences. In those who present with, or who develop during medical care, respiratory failure, septic shock, kidney failure, or severe respiratory distress of several etiologies and thromboembolic processes, the "therapeutic sink" is thrown at them in desperation. Therapeutic interventions are based on relatively small numbers often lacking statistical significance. What is required is a development of more valid diagnostic and therapeutic pathways that recognize that disease processes may change dependent on the duration of the illness. The various interventions may need to be altered as the contribution of the pathogenic components evolves. Although it is unusual to have a non-COVID-19 infection playing a role at the time of presentation, as a patient progressively worsens, the likelihood of superinfection with either bacteria, fungus, or virus needs to be considered.

Garcia-Vidal et al have developed a timeline presenting the most likely pathologic process based on symptom duration, findings of the physical examination, and laboratory test results at a given time during the infection. It recognizes 3 major pathogenic processes, co-infection, inflammatory response, and thrombotic events. Although rudimentary, it provides a framework for the clinician to develop rational therapeutic options for the care of these challenging patients. It will need to be updated as more information for each process becomes available, but it provides a significant start. ^{[15, 16]}  

Since the severity of COVID-19 was recognized, a frantic search for effective compounds among pre-existent antivirals or those with antiviral properties has ensued. As more knowledge about the many pathogenic properties of the virus has been gained, development of newer classes of agents has been undertaken. 

Antiviral Therapies 

Remdesivir

Remdesivir (Veklury) is a prodrug that is activated by the host cell to adenosine triphosphate. In vitro, it is active against many RNA viruses (HIV, hepatitis C, SARS-CoV-2, MERS-CoV). The initial good results from small observational studies of hospitalized patients have not been supported by randomized controlled trials. Its best effects seem limited to those with mild disease. Combined studies with anti-inflammatory agents seem to improve its effectiveness. ^[17]  Remdesivir requires IV administration and may be administered in both inpatient (up to 10 consecutive days) and outpatient settings (for 3 consecutive days). It is approved by the FDA for treatment of confirmed COVID-19 in adults and pediatric patients aged 28 days and older who weigh at least 3 kg who have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. As of mid-2022, it is the only antiviral option for young children who are at risk for severe disease. 

Results from the randomized, double-blind, placebo-controlled PINETREE trial supported the expanded indication and EUA. Among 562 outpatients with COVID-19 at high risk for disease progression, those treated with remdesivir demonstrated an 87% lower risk of hospitalization or death compared with those in the placebo group (P = 0.008). Overall, 2 of 279 patients who received remdesivir (0.7%) required COVID-19 related hospitalization compared with 15 of 283 patients who received a placebo (5.3%). The study included patients who tested positive for SARS-CoV-2 with symptom onset within the previous 7 days and at least 1 risk factor for disease progression. Patients received either 3 consecutive days of IV remdesivir (200 mg IV on Day 1, then 100 mg on Days 2 and 3) or placebo. ^[18]  

Nirmatrelvir/ritonavir or Molnupiravir

The oral antivirals, molnupiravir and nirmatrelvir/ritonavir (Paxlovid), have become available via emergency use authorization (EUA). The performance of molnupiravir has been disappointing, and it essentially has no role in current COVID-19 therapy. The role of ritonavir is to maintain therapeutic serum levels of nirmatrelvir by decreasing its hepatic metabolism.

Nirmatrelvir/ritonavir appears to be effective in reducing hospitalization and death by 89%. ^[19]  

The nirmatrelvir/ritonavir EUA is for the treatment of mild to moderate COVID-19 in adults and pediatric patients older than 12 years who are positive for coronavirus and are at high risk for progression to severe COVID-19, including hospitalization or death. It is not authorized for longer than 5 consecutive days; for initiation of treatment in severe or critically ill patients requiring hospitalization; nor for preexposure or postexposure prophylaxis of COVID-19. Treatment should be started within 5 days of symptoms and not extend beyond 5 days. Dosing of nirmatrelvir is 300 mg with 100 mg of ritonavir by mouth twice daily for no longer than 5 days. 

Nirmatrelvir/ritonavir utilization also may need to be restricted because of its potential interaction with greater than 70 commonly used medications. See Medscape Drug Interaction Checker

Rebound/persistent/relapsed infections

There have been anecdotal reports of return of symptoms of COVID-19 shortly after stopping the 5-day antiviral course both in high and lower risk patients. In a retrospective cohort study of medical records during the Omicron variant phase from January through June 2022, the 7-day and 30-day COVID-19 rebound rates after nirmatrelvir/ritonavir were 3.53% and 5.4% for COVID-19 infection, 2.31% and 5.87% for COVID-19 symptoms, and 0.44% and 0.77% for hospitalizations. The 7-day and 30-day COVID-19 rebound rates after molnupiravir treatment were 5.86% and 8.59% for COVID-19 infection, 3.75% and 8.21% for COVID-19 symptoms, and 0.84% and 1.39% for hospitalizations. ^[19] Additional descriptions of relapsed infections have been described, ^[20] and prompted the CDC to issue a health advisory to alert clinicians of rebound cases in May 2022. 

The manufacturer of nirmatrelvir/ritonavir, Pfizer, announced that the drug failed to show a statistically significant effect in preventing active disease in those exposed to active cases. ^[21] In none of these 2 types of patients was there genomic evidence of resistance to the drug. These failures raise concerns about the frequency of failures, risk factors, whether such prophylaxis interferes with the immune response, and whether those who relapse are contagious. ^{[22, 23]}  

The indications for nirmatrelvir/ritonavir use most likely will change. The author believes that everyone who has proven COVID-19, regardless of clinical state, should be started on nirmatrelvir/ritonavir. Continuation of the drug for longer than the recommended duration may be necessary in certain situations and needs to be determined. Preliminary evidence supports this idea that a likely possibility of recrudescence is insufficient drug exposure, particularly if a patient has a high viral load. ^[24]  Additional studies are needed to explore the optimal duration of therapy and explore patient variables that may contribute to rebound infections. 

The current “one dose fits all" approach is based on very limited data. Therapeutic levels were established by indirect computer techniques (eg, SILICO program) and not actual measurements.³⁵ 

Each patient’s therapeutic regimen should be followed by the course of their symptoms, physical findings, and laboratory abnormalities. This may be especially true in developing approaches to the vexing challenge of  Long COVID. Currently, so much of the treatment is based on dealing with mild-to-moderate symptoms (headache, fatigue, depression) and not determining the role of ongoing inflammation, thrombosis, and persistent infection.³⁶ 

Nirmatrelvir/ritonavir may serve as a bridging antiviral because it was developed by techniques not taking into account how quickly VOC can develop resistance. ^[25] Antivirals such as those below are much more likely to retain their efficacy as the virus evolves. 

Other Antivirals

The use of short interfering RNAs (siRNAs) appears to be quite effective in vitro in stopping viral replication. The risk of viral mutation overcoming its effectiveness is low because its targets are in deeply conserved regions of the viral genome. ^[26]  

Sabizabulin (VERU-111) is an oral compound with both antiviral and anti-inflammatory properties. It works by disrupting the cytoskeleton that the virus sets up in the host's cell. In a phase 3 trial involving 204 moderately to severely ill patients, sabizabulin treatment resulted in a 24.9% absolute risk reduction and a 55.2% relative reduction in deaths compared with placebo (P = 0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin compared with 45.1% (23 of 51) for placebo. ^[27]  

For more information, see COVID-19 Treatment: Investigational Drugs and Other Therapies. 

Clinical Worsening During Treatment

If a patient deteriorates during treatment, conduct a systematic analysis of causes. 

Table. Clinical Complication Patterns of COVID-19 Infection ^[28] (Open Table in a new window)

The potential roles of coinfection, inflammation, and thrombosis should be evaluated with the following lab tests: CBC with differential, CRP, LDH, ferritin, and IL-6 should be obtained along with a troponin T for cardiac status. A D-dimer should be measured to detect underlying macro- or micro- thrombi. Appropriate imaging, cultures, and lab tests should be performed to rule out acquired infection.

Replacement of vitamin D has been found useful in terminating a cytokine storm when dexamethasone is given when the CRP is greater than 13.5 mg/dL and JAK level is greater than 3.5 mg/dL. Similar data needs to be generated for therapy of active hypercoagulable states. ^[29]

Long COVID-19 represents prolongation of many of the symptoms of the initial COVID-19 infection, as well as a wide range of newer ones. There is no established treatment for this. Vaccinated and boosted individuals are less likely to develop this condition. However, personalized treatment based on imaging studies, organ function, and laboratory testing as discussed above hopefully will decrease the risk for this entity. ^[30] Additionally, the use of oral antivirals for post-COVID sequelae needs to be explored to determine if this is an appropriate treatment. ^[31]

It is extremely important to keep in mind that the patient has an infection and that the antiviral agent should be continued until it is reasonable that it has been eradicated. If the patient clinically worsens with major complications of inflammation, coinfection, and/or thrombosis, continue medications and advanced treatments until the monitored markers normalize. ^[36]  

Please see Long Coronavirus 2019 (COVID-19).

Appropriate mask use and inside social distancing are extremely protective. This has been demonstrated in the elementary schools in the United States and throughout the world. For a variety of reasons, it has not been well accepted by the general public. Conversely, failure to do so has resulted in many “super spreader“ events.  

A variety of nasal and oral mucosa locally applied sprays and creams has been developed to prevent acquisition of Covid-19 through inhalation and to limit dissemination by nasal droplets. ^[10]

Other types of vaccines, especially those focused on augmenting T cell immunity, are under development. ^[32]

The role of the newly available oral antivirals as prophylaxis is being studied as well. ^[33]

More extensive personalized/precise therapy of COVID-19 hopefully will prove to be effective prophylaxis against long COVID-19.

As discussed in the Pathophysiology section, there are 3 complicating patterns of COVID- 19 infection: co-infection, inflammatory, and thrombotic. They are the result of the failures of the host cell to prevent its defenses from going out of control (cytokine storm or adverse thrombotic events or a variety of superinfections). Provisional timelines for the onset of each have been developed. What is apparent is that for any given time following the onset of illness, 1 or the other may be predominant. Zeroing in on these processes is key to avoiding permanent disabilities or death. We need to develop protocols to promptly recognize each and institute treatment.