The underlying theoretical concepts of the pathophysiology of Long COVID are as complex as the clinical syndrome itself. Determining how to make the diagnosis of Long COVID provides a different set of complexities itself, as it presents with a wide range of clinical syndromes. Recent publications and several meta-analyses have shed light on many general pathophysiologic mechanisms. This article discusses the most commonly described mechanisms behind COVID-19 and the Long COVID syndromes.
Long COVID Mechanisms
Looking at the greater mass of the scientific publications available, and applying at least a small amount of historic and clinical filtering, researchers can arrive at several basic mechanisms that are likely the driving forces in COVID-19 and its long-term impact. One may look at COVID-19 from the perspective of the following: Thrombosis Cascades, Inflammatory Cascades, Immune Dysregulation, Persistent Virus, Viral Damage and Remodeling and Genetic Factors. Each of the preceding headings are known to take part individually or collectively in Long COVID syndromes.
State of Vaccination in the US
There are two mRNA vaccines that are either fully approved for adults or approved under Emergency Use Authorizations down to age six months – the Pfizer Comirnaty® and the Moderna Spikevax®. Both of these vaccines continue to be safe and effective and should continue to be used and recommended.
The Janssen COVID-19 product based on an adenovirus vector is also available in the US but is not primarily recommended in most settings. Although the Novavax product is used widely in other nations, the antigen carried by this vaccine makes it much less effective than the currently used mRNA products. So, full approval for use in the US remains unclear.
A General SARS-CoV-2 Infection: Initial Response
The SARS-CoV-2 virus attaches to Alveolar Type II cells by using its ACE-II surface receptors. After fusing and entering the cell, it initiates viral replication. Its viral mRNA overcomes the protein replication mechanism of the infected cell to its own purposes. This not only results in new viral particles, but it eventually causes direct damage, dysfunction or death of the alveolar cell.
The initial response of the body to the viral attack is through elements of the innate immune system. As the new viral particles are produced, the infected cell releases immune factors. At first, there is an accumulation of various immune cells including dendritic cells, pulmonary macrophages and others at the areas with infected cells. This then initiates the adaptive immune responses.
Polymorphonuclear leukocytes, mast cells, various T-Cells and B-Cell lines are activated by the inflammatory and immune response mediators as well. Of note, dendritic cells are the most powerful antigen-presenting cells of the immune system. Genetic defects or inhibition of dendritic cell function can markedly reduce host defenses against the infection.
This combined inflammatory and immune response causes cellular components to be activated. The result is a killing of both Type –II and Type-I alveolar cells – both infected and non-infected. This proliferation of immune cells and onslaught of cellular killing helps prevent viral replication, but can also create significant Alveolar/Capillary Interface (ACI) damage and debris accumulation. The death of alveolar cells, if significant, results in severe damage to the ACI, starting on the pulmonary side of the barrier.
A General SARS-CoV-2 Infection: Progression to Long COVID
In later phases of the infection, the system attempts to repair the ACI with a regrowth of some Type I and Type II alveolar cells; however, most of the ACI is simply replaced with fibroblasts that lay down a repair matrix of fibrous and muscular non-pulmonary cells. This results in permanent ACI damage, reduced pulmonary perfusion, decreased compliance, reduced effective volume and radically reduced O2/CO2 gas exchange.
The virus also assaults the vascular endothelium side of the ACI. This results in an enhanced release of additional inflammatory cytokines that spread to and activate the vascular side of the ACI. The ACI becomes more permeable due to the damage and altered function, allowing blood components and fluid to enter the alveoli. This can result in non-cardiac pulmonary edema. The degree of ACI damage and pulmonary edema is manifest in the clinical severity of the acute phase of the pulmonary infection with COVID-19.
As recovery COVID-19 begins, high levels of thrombin and endothelial cell biomarkers develop in some patients. This, along with the overall ACI damage often result in the activation of vascular coagulation process. In most cases, there is only a limited level of microvascular thrombosis; however, in some patients, more extensive thrombosis can develop and propagate. This can cause substantial vascular injury at the ACI as well as large scale pulmonary thrombosis and emboli.
In some settings, the immune and inflammatory responses are unable to completely clear the virus from cells. This may result in a low grade continual level of viral replication, release, reinfection and viral shedding for periods of time. There is also a chronic low-level inflammatory and immune response to the continued presence of the virus in the body.
Although genetics are not generally considered a discrete pathophysiologic cause of COVID-19-related problems, genomic functions obviously underlie the entire panoply of this disease process. Recent studies strongly suggest that there are associations with some chromosomes and specific alleles for increased or decreased risks of SARS-CoV-2 infections and the severity of those infections. For example, polymorphisms (mutations) of allele types rs11385942 on chromosome 3p21.31 and rs657152 on 9q34.2 confer a high risk for severe infections and hospitalizations from COVID-19.
Both of these alleles are known to be involved in the structure and function of the ACE-II receptors. In addition, these genes are also involved in resident T-Cell function (CD-8 lines) that provide immune activity against viruses such as influenza. Other studies have looked at the complex genes governing the ABO blood groups. Associations have been identified that implicate Blood Group O with lower risk of SARS-CoV-2 infections and complications. Conversely, Blood Group A seems to be associated with a higher risk. Although these associations have no strong clinical utility at this time, they are opening windows through which the pathophysiology of COVID-19 and Long COVID may be more clearly defined.
Pathophysiology of Long COVID
The presumed pathophysiology of Long COVID is a highly complex and evolving topic. We have outlined the basics as we know them, but this is far from presenting a comprehensive review of our current knowledge; however, this information can serve as a starting point for further study. See a full reference list for data and studies. Find more COVID-19 resources.