The Impact of COVID-19 on Nurses:

COVID-19 Pathophysiology and Disease Process

Mary C. Vrtis, Ph.D., MSN, RN, OCN, NEA-BC, FCN

May 25, 2025

Time to read:

26–39 minutes

COVID-19 Pathophysiology and Disease Process May 25 2025 Download

A Global Effort to Learn About this New Pathogen

Infectious disease specialists, virologists, scientists, and throughout the world immediately collaborated to share anecdotal information regarding single patient successes and treatment failures. Techniques that worked, at least sometimes, for example “proning” (positioning the patient on the abdomen) were shared through the Internet and word of mouth. Preliminary research studies were often posted to prepublication sites to help communicate findings more broadly. Much has been learned, and this chapter summarizes what is now known about the deadliest versions of the SARS-CoV-2 virus and the organ and tissue damage that the COVID-19 disease caused with the early variants.

A Range of Responses to COVID-19

Most patients with COVID-19 infections exhibit mild disease, but severity ranged from totally asymptomatic (patients tested positive for virus but were not sick) to life-threatening critical illness and death.

Signs and symptoms of severe disease with the ancestral SARS-CoV-2 virus included:

Dyspnea (difficulty breathing).
Hypoxemia (decreased blood oxygen levels).
Severe acute pneumonia.
Acute respiratory distress syndrome.
Lung tissue damage (this appears like ground glass on chest x-ray).
Acute respiratory failure with need for mechanical ventilation.
Septic shock.
Metabolic acidosis.
Coagulation dysfunction, peripheral and lung blood clots.
Multiple organ dysfunction syndrome or failure (China CDC, 2020, February 17; Zhu, et al., 2023).
Vascular endothelial inflammation.
Hypercoagulation and hyperfibrinolysis (Valencia, et al., 2024).

The signs and symptoms of less severe illness are sometimes limited to moderate or low-grade fever, myalgia (muscle aches), nasal congestion, runny nose, and dry cough. Gastrointestinal symptoms nausea, vomiting, abdominal pain, and diarrhea may be present, or not (China CDC, 2020, February 17). Asymptomatic transmission with SARS-CoV-2 was identified early in the pandemic and continues to be an issue.

Various factors interact that determine the outcome of the disease process for a single individual, and these may include age, comorbidities, and overall condition of the individual, as well as characteristics and virulence of the infecting variant. Though much is known through worldwide collaborative research, COVID-19 is constantly evolving and a great deal of information about previously circulating variants that have been superseded may never be understood.

Modes of Transmission – SARS-CoV-2 (COVID-19) in 2020

COVID-19 is easily transmitted from one person to another. There are at least four modes of transmission:

Airborne: SARS-CoV-2 microscopic viruses may be released into the air during normal breathing as well as during coughing and sneezing, etc. Very small viral particles can float through the air and accumulate in indoor rooms. Airborne viruses remain suspended for an unknown period and can be inhaled by another person (U.S. EPA, 2024).

When caring for patients, respiratory protective equipment, such as N95 or FFP2 respirators or powered air purifying respirators (PAPR) are recommended to protect against infection (CDC, 2024 March 1; Leung, 2021; Stadnytskyi, et al., 2020).

The Centers for Disease Control and Prevention eventually recommended that the general public wear face masks to protect against this and other viral respiratory infections such as RSV (respiratory syncytial virus) and the flu. The recommendation is to wear the highest level of protection possible that the individual can tolerate for long periods of time and describes the range of different protection from medical surgical masks to N95 respirators (CDC, 2024 March 1).

Engineering controls such as air filtering and increased ventilation with outside air are also needed when near ill people (EPA, 2024).

Droplets of water containing the virus are projected into the air when an infected patient coughs, sneezes, speaks, yells, sings, laughs, etc. and the droplets may be inhaled as they are suspended in the air. Droplets are heavy and usually fall to the ground in less than six feet, so maintaining a distance of more than six feet between people had previously been recommended (CDC, 2021 May 7, Leung, 2021). However, it is now known that the SARS-CoV-2 remains airborne and that the six foot spacing does not provide adequate protection, especially indoors (U.S. EPA, 2024). Physical distancing is still important as the closer one is to an infected person, the greater the likelihood of becoming infected (CDC, 2024 March 1).
Direct (physical) contact may occur when contaminated biological material such as sputum is propelled, and the organism enters the clinician’s unprotected eyes, nose, or mouth. Barrier protections such as face shields (in addition to respirators), gowns, and gloves as well as good hand hygiene are also important (CDC, 2021 May 7, Leung, 2021).
Indirect transmission may occur through physical contact with a contaminated object (fomite), surface, or hands if the infectious organism is subsequently carried to the mouth, nose, or eyes. The recommendations are the same as for direct (CDC, 2021 May 7; Leung, 2021; Ting, et al., 2023; Siegel, et al., 2022 May).

These precautions were to be used for patients with active COVID-19 infection and those who were exposed to and under investigation for the disease (CDC Health Alert Network, 2020 January 17). Unfortunately, the equipment needed was not readily available at all or only in limited supplies in many cases. In February, when the shortages of protective equipment were most severe, the World Health Organization published: World Health Organization (2020, February 27). Rational use of personal protective equipment for coronavirus disease 2019 (COVID-19). Interim guidance. https://apps.who.int/iris/bitstream/handle/10665/331215/WHO-2019-nCov-IPCPPE_use-2020.1-eng.pdf. The goal of this document was to direct inadequate supplies of respiratory protection to where the need was greatest. See the chapter A Global Shortage of Personal Protective Equipment.

COVID-19 Pathophysiology

Infections with SARS-CoV-2 begin with inhalation of airborne virus or respiratory droplets expelled by an infected person. Contact with contaminated objects or surfaces can also result in infection when contaminated hands bring viruses to the mouth, nose or eyes. Direct transmission can occur when the uninfected person comes into contact with infected mucous membranes (CDC, 2024 March 1). For example, one might have direct contact as result of deep kissing. The virus infects nasal and bronchial epithelial cells and the pneumocytes that line the alveoli first.

The SARS-CoV-2 virus enters by attaching to the ACE2, angiotensin converting enzyme 2 receptors on the outside of human cells. ACE2 is an enzyme produced in the lungs and kidneys that is important in control of blood pressure, inflammation, and wound healing. The enzyme is involved in the Renin-Angiotensin-Aldosterone-System (RAAS) that is a feedback loop which is activated to compensate for hypotension and hypovolemia. The process is as follows:

As shown in figure 1, angiotensinogen is produced in the liver. Renin is released from the kidneys where it is produced. Renin decreases renal perfusion in the juxtaglomerular apparatus and that slows production of urine. Renin also converts angiotensinogen to angiotensin I.

Angiotensin I is then converted in the lungs by angiotensin converting enzyme (ACE) to angiotensin II. Aldosterone is produced and secreted by the cortex of the adrenal glands (located above each kidney). This triggers the kidneys to retain sodium and water and to release potassium. Antidiuretic hormone (ADH) is released by the posterior pituitary gland and water is reabsorbed by the kidneys and returned to the vascular system.

Angiotensin II stimulates the sympathetic nervous system to increase blood pressure through vasoconstriction of the arterioles and increase heart rate. Blood pressure elevation cannot be sustained this way for prolonged periods without seriously damaging vascular tissues and increasing cardiac afterload. Elevated heart rates increase myocardial oxygen demands, thus increasing the risk of cardiac complications, especially in a person with pre-existing coronary artery disease or chronic heart failure. The inflammatory process also exacerbates when angiotensin II accumulates.

The result is thirst and a desire to drink fluids. Urine output drops when water is retained by the kidneys, making urine more concentrated – so that it is typically darker yellow. When the blood pressure returns to low normal, dehydration is reversed by oral or parenteral fluid replacement, or blood loss has been stabilized, the human body strives to return to the patient’s baseline status. The role of ACE2, angiotensin converting enzyme 2, is to cleave the angiotensin II hormone. After the angiotensin II molecule is split in two, the RAAS cycle is interrupted, the fast heart rate is slowed, and the tight arteriolar vasoconstriction is relaxed. The sympathetic nervous system returns to homeostasis or balance.

SARS-CoV-2 and the ACE2 Receptors

The SARS-CoV-2 virus attaches to the human cell by binding the S protein to the ACE2 receptors on the outside of the human cells. The S proteins are on the surface of COVID-19 virus, see the depiction of the virus in figures 2 and 3. The U.S. CDC has a now familiar illustration that shows the ultrastructural morphology of the COVID-19 virus. This image is available through the public image library (https://phil.cdc.gov/details.aspx?pid=23312). The S proteins are the red protrusions on the outside of the virus. The SARS-CoV-2 virus can enter and infect a human cell when it is attached to an ACE2 receptor. ACE2 receptors are found on the outside of the cells and in a number of tissues and organs, including lungs, kidneys, heart, blood vessels, eyes, and the gastrointestinal tract. Under normal conditions, the ACE2 enzyme attaches to the ACE2 receptor which starts the process of splitting angiotensin II when it is no longer needed.

The S protein on the SARS-CoV-2 virus attaches to the receptor with a bond that is 10 to 20 times stronger than the bond between the ACE2 enzyme and the ACE2 receptor, so the virus blocks the normal functions of the ACE2 enzyme. When angiotensin II accumulates, the arterioles remain constricted and inflamed, and the heart rate elevation continues even after the low blood pressure or hypovolemia issues that initiated the response are resolved. The end result is a worsening inflammatory response and development of pulmonary fibrosis (Zhu, et al., 2023).

The process of infecting the human cells requires the attachment of the SARS-CoV-2 S protein to the ACE2 receptor (also known as hACE-2 or host receptor angiotensin converting enzyme 2). Then entry into the cell is facilitated by a protease, a protein molecule that breaks up other proteins, called TMPRSS2 (transmembrane serine protease 2). The protease enzyme TMPRSS2 is normally found in the endothelial cells that line the inside of respiratory and gastrointestinal blood vessels. When TMPRSS2 cleaves the SARS-CoV-2 attachment at the S protein, the protease exposes a peptide site on the S protein that fuses with human cell wall. This process allows the virus to enter the cell, (Zuh, et al., 2023) see figure 3.

Once inside the human cell, the virus takes over and creates lots of copies of viral RNA and viral proteins that are used to create new viruses. Production of new viruses continues until the human cell membrane is destroyed by escaping virus and becomes necrotic and bursts open, releasing more viruses that are ready to seek new human cell hosts (Zhu, et al., 2023).

With the wide variety of individual host responses to several different variants that have arrived and disappeared over the last four years in mind, we will discuss some of what is known about COVID-19 pathophysiology.

Viral Mutations

Mutations occur during the viral replication process within the human cells. As discussed in other chapters, each set of mutations that resulted in a variant of concern has had different characteristics that provided a competitive advantage in factors such as transmissibility, immunosuppressive ability, severity of symptoms, and the likelihood of adverse effects.

As discussed above, the S protein (also known as the spike glycoprotein) on the outside of the SARS-CoV-2 protein envelope is the area that bonds to ACE2 receptors on the human cell. There are two other surface proteins on the virus. The M protein and the E protein are involved in “viral budding,” the process by which the newly created virus pushes out through the host cell membrane, taking parts of the lipid human cell membranes to form the viral envelope.

The S, spike protein has two subunits, S1 is the part that attaches to the hACE-2 (human ACE2) surface receptor on the cell being attacked. S2 has a role in attachment of the virus to the host cells and entry into the cells. There are thousands of mutations that have been documented in the GISAID database that affected attachment of the S protein to the host cells.

The receptor binding domain (RBD) is an area of the virus that has had many mutations. This is where the three points on the SARS-CoV-2 virus connect to the ACE2 receptor on the host cell. Mutations that increase the strength of the SARS-CoV-2 bond to the host cell in the RBD are problematic, because the virus competes with vaccine induced antibodies, antibodies induced by the intrinsic immune system during a COVID-19 infection, and some medications used to treat the infection by blocking that location (Chakraborti, et al., 2022; Naqvi, et al., 2020). Medications such as monoclonal antibodies were designed to block the virus, and then bind to the disease-causing viral antigen and kill the virus. With SARS-CoV-2 when a variant arises that creates a stronger bond with the ACE2 receptor than the bond that occurs with the medication, the virus becomes resistant to the drug. Several of the SARS-CoV-2 variants that affected the S protein bond to the ACE2 receptors or to the RBD developed resistance to earlier COVID-19 vaccines and specific monoclonal antibodies that were effective treatments for the ancestral wild type.

Cytokine Storm Post-Acute COVID-19

A cytokine storm is the result of an out of control, unregulated human immune system. When unregulated, the full power of the immune system essentially ends up attacking the ill individual and not just the microorganism or malignancies. Therefore, we will review the complexities of “normal” immune function first.

The Innate and Adaptive Immune Systems

The human immune system has two levels. The INNATE immune system helps to prevent infection and eliminate invading pathogens. It also stimulates the acquired immune system. The innate system is always functioning and includes, but is not limited to:

Physical barriers like skin, hair, mucous membranes, cilia lining airways, etc.
Chemical barriers, such as acid in the stomach and blood coagulation factors.
Normal flora bacteria that compete with pathogens for oxygen and nutrients.
Inflammation related proteins, such as complement and C-reactive protein.
White blood cells including natural killer lymphocyte cells, phagocytic macrophages, dendritic cells, mast cells, neutrophils, basophils, and eosinophils.
Sentinel cells (dendritic cells, macrophages in tissues, and mast cells) that can recognize pathogen-associated molecular patterns (PAMPs) and release pro-inflammatory cytokines.
Phagocytic white blood cells (monocytes, macrophages, and neutrophils) that move to inflamed tissues and kill and ingest pathogens and dead tissue.
Antimicrobial enzymes in blood, and tissues that are secreted by epithelial cells.

Macrophages are large white blood cells that are present in body tissues and engulf and phagocytize dead cellular debris, microorganisms, and dying human cells that are infected or damaged. Macrophages routinely patrol to eliminate debris. Phagocytic macrophages are drawn to the inflammation at the site of injury, and they also initiate the ADAPTIVE immune system.

Dendritic cells are also part of the innate immune system, and they also initiate the ADAPTIVE, specialized immune response. Dendritic cells scavenge for, ingest, and recycle the peptides from the pathogens. They also identify the specific microbial antigens for which antibodies need to be produced by the body in order to eliminate the infection. Dendritic cells “present” or show the antigen to other white blood cells so that the other cells will recognize the antigen and attack the microorganism. Antigen presenting dendritic cells enter the lymphatic system where they activate naïve T cells (Lichtman, A., & Pillai, S., 2024). The complement system is part of the innate immune system that becomes active in response to viral, bacterial, fungal, and protozoal infections. More than 30 complement proteins are involved in an “enzymatic cascade” when activated. It is known that SARS-CoV-2 can trigger complement activation and that complement proteins are associated with higher severity COVID-19 related inflammation. However, more research is needed to determine whether the effect of the complement cascade is protective or destructive (Beirag, et al., 2023).

The innate immune system is always turned on and responds very quickly to microbial invaders or trauma. There is a lot of non-verbal communication going on between specialized cells of the innate immune system all of the time. At least some of that communication is carried on through cytokines.

The ADAPTIVE immune system has to be turned on in order to respond to a specific threat to homeostasis.

The T lymphocytes CD8 and CD4 T are also drawn to the site of injury. Cytotoxic T lymphocytes of the CD8 type are white blood cells that locate and destroy invaders, such as bacteria and viruses. CD4 T lymphocytes help to regulate the immune response, neutralize viral antibodies, kill infected cells by secreting cytotoxic (cell killing) and antiviral cytokines.

Naïve B cell lymphocytes are specialized white blood cells that develop in bone marrow. They are activated with the adaptive immune system and defend against microbial threats by making and deploying antibodies. Antibodies have five different isotypes (also known as immunoglobulin classes), these are IgM, IgG, IgD, IgE, and IgA. The part of the antibody that binds to the antigen is specific to the foreign protein on the pathogen.

Antibodies can prevent infection by:

Binding to and neutralizing the antigen so that the pathogen cannot interact with the host cells.
Facilitating a complement protein bond with the antigen.
Opsonization – coating the pathogen with molecules that allow phagocytic cells to see the microbe and destroy it.

T helper cells activate B cells in the lymphatic system. Once activated, B cells clone over and over, “clonal expansion.” The B cells then differentiate into either mature plasma cells or memory B cells capable of recognizing and remembering specific antigens. Memory B cells have a longer life span and can initiate a rapid response if the body is reinfected with a microbial antigen to which antibodies were previously produced (Cleveland Clinic, 2023, February; Cleveland Clinic, 2022; Lichtman, A., & Pillai, S., 2024).

The Cytokine Storm Inflammatory Process

When a harmful agent enters the body, it initiates an inflammatory reaction. Damaged cells release chemicals including histamine, prostaglandins, and bradykinin. Local blood vessels become more permeable and intravascular fluid leaks into the injured tissues.

There are many different cytokines that help to keep the immune system working to protect the body, and many regulate inflammation. Cytokines are proteins produced by different cells and released as needed. Cytokines that have been implicated in cytokine storm include:

Interleukins are proteins that relay messages between leukocytes (white blood cells) and other cells, there are many interleukins that have been identified.
- Proinflammatory interleukins involved in cytokine storms include IL-6, IL-1α, IL-1β, and IL-17 (Valencia, et al., 2024).
Tumor necrosis factor (TNF) – TNF-alpha.
Interferons (IFN), see table 1.

A cytokine storm occurs when a huge, uncontrolled flood of cytokines is released and causes massive inflammation affecting several of the vital organs occurs as a result of a dysregulated (unrestrained) immune response to the infection.

Table 1 Proinflammatory cytokines

Cytokine	Gene	AKA	Produced by	Role in COVID-19
IL-1α	Interleukin 1α	IL-1, IL-1A, IL1F1, IL1-alpha, IL-1 alpha	Monocytes and macrophages	Released after cell injury and induces apoptosis
IL-1β	Interleukin 1β	IL-1, IL1F2, IL1-β	Activated macrophages	With other cytokines causes severe, acute lung damage due to the inflammatory response
IL-2	Interleukin 2	IL-2, TCGF (T-cell growth factor), lymphokine	Activated CD4+ and CD8+ T lymphocyte cells	Involved in inflammatory cytokine storms
IL-6	Interleukin 6	BSF2, IFNB2, IFN-beta-2	Produced at sits of acute and chronic inflammation by various cells, including monocytes and macrophages	Involved in cytokine induced inflammation, maturation of B cells, the protein is an endogenous pyrogen and induces fever. IL-6 blocking monoclonal antibodies reduced severity of reactions (pre-Omicron)
IL-10 Primarily ant–inflammatory	Interleukin 10	IL-10A, CSIF (cytokine synthesis inhibitory factor), CSIF (cytokine synthesis inhibitory factor)	Monocytes, lymphocytes	Involved in cytokine storm in COVID-19. Has a role as an anti-inflammatory cytokine actions to return to homeostasis BUT can also have immune stimulating effect in other situations (Carlini, et al., 2023).
IL-17	Interleukin 17A	IL-17, ILA17, CTLA-8 (cytotoxic T-lymphocyte associated antigen 8)	Activated T cells	Involved in the COVID-19 cytokine storm inflammatory response, promotes, pro inflammatory cytokine, stimulates production of chemokines by other cells.
IL-18	Interleukin 18	IGIF (interferon gamma inducing factor), IL-1g, IL1F4	Macrophages, keratinocytes	Stimulates production of interferon gamma, regulates T cells, involved in cytokine storm, vital organ injuries, and fatalities
INF-γ	Interferon gamma	IFG, IF1, IMD69	Cells of innate and adaptive immune systems	Involved in cytokine storm
CXCL10/ IP 10	CXCL10, human interferon-inducible protein 10	C7, IFI10, INP10, IP-10, human interferon-inducible protein 10	Lung epithelial cells	Chemokine may be a key in regulation of cytokine storm, stimulates monocytes, natural killer cells, and T cell migration
TNF	TNF tumor necrosis factor	TNFA, TNFSF2, TNLGIF, TNF-alpha	Macrophages	Involved in many diseases. Actively involved in cytokine storm
CSF2	Colony stimulating factor	CSF, GMCSF (granulocyte macrophage colony stimulating factor)	Macrophages, T cells, mast cells, natural killer cells, mast cells, endothelial	Actively involved in cytokine storm
CCL2/ MCP1	CCL2 C-C motif chemokine ligand 2	MCP1, monocyte chemoattractant 1, MCP1, HC11, MCAF	Macrophages, endothelial cells, adipocytes	Chemokine associated with severe COVID-19 cytokine storm

References for table 1

National Library of Medicine, National Center for Biotechnology Information (2024, June 10). IL-1A Interleukin 1 alpha. https://www.ncbi.nlm.nih.gov/gene/3552

National Library of Medicine, National Center for Biotechnology Information (2024, June 10). IL-1B Interleukin 1 beta. https://www.ncbi.nlm.nih.gov/gene/3553

National Library of Medicine, National Center for Biotechnology Information (2024, June 10). IL-2 Interleukin 2. https://www.ncbi.nlm.nih.gov/gene/3558

National Library of Medicine, National Center for Biotechnology Information (2024, June 10). IL6 Interleukin-6. https://www.ncbi.nlm.nih.gov/gene/3569

National Library of Medicine, National Center for Biotechnology Information (2024, May 27). IL-10 Interleukin 10. https://www.ncbi.nlm.nih.gov/gene/3586

National Library of Medicine, National Center for Biotechnology Information (2024, June 10). IL-17A Interleukin 17A. https://www.ncbi.nlm.nih.gov/gene/3605

National Library of Medicine, National Center for Biotechnology Information (2024, June 6). IL-18 Interleukin 18. https://www.ncbi.nlm.nih.gov/gene/3606

National Library of Medicine, National Center for Biotechnology Information (2024, June 10). IFNG Interferon gamma. https://www.ncbi.nlm.nih.gov/gene/3458

National Library of Medicine, National Center for Biotechnology Information (n.d.). CXCL10 C-X-C motif chemokine ligand 10. https://www.ncbi.nlm.nih.gov/gene/3627

National Library of Medicine, National Center for Biotechnology Information (n.d.). TNF tumor necrosis factor. https://www.ncbi.nlm.nih.gov/gene/7124

National Library of Medicine, National Center for Biotechnology Information (n.d.). CSF2 colony stimulating factor 2. https://www.ncbi.nlm.nih.gov/gene/1437National Library of Medicine, National Center for Biotechnology Information (n.d.). CCL2 C-C motif chemokine ligand 2. https://www.ncbi.nlm.nih.gov/gene/6347

Cytokine storms may occur in several disease processes including COVID-19 infections. The uncontrolled inflammatory response is more destructive than the viral infection and can cause irreversible vital organ damage

Inflammatory cells, including phagocytic macrophages, monocytes, and neutrophils are attracted to the areas of inflammation.

When the adaptive immune response kicks in cytotoxic CD8 T cells target the human cells infected with SARS-CoV-2 virus and attack. CD4 helper T cells stimulate the B cells to start production of antibodies that will specifically target the SARS-CoV-2 virus. Swelling isolates the infected and damaged tissues and attracts phagocytes, the white blood cells that ingest dead and dying cells, and foreign matter such as bacteria or viruses. Exudate develops from dead tissues, and live and dead phagocytes. In the lung, exudate and mucous block air exchange in the alveoli (Wong, R., 2021).

Injury to the Vascular Endothelium

The vascular endothelium is comprised of a single cell thickness row of cells that line the inside of all of the blood vessels in the body, including arteries, arterioles, veins, venules, and capillaries. In total, there are more than a trillion endothelial cells that make up the inside layer of about 60,000 miles of blood vessels that are in a human body. The vascular endothelium is considered an endocrine organ that is the interface between the blood vessels and the tissue cells to which the blood vessels supply oxygen and nutrients and also remove carbon dioxide and byproducts of metabolism. The endothelial cells regulate a number of functions, including but not limited to:

Controlling the flowrate of the blood vessels, for example:
- Maintaining normal size under the usual circumstances needed for blood flow and oxygen delivery.
- Vasodilating when the environment is too hot to help cool the body, and during exercise to deliver more oxygen and blood to body tissues.
- Vasoconstricting when blood pressure drops, in stressful situations, and in the arms and legs when it is very cold to send more blood to the core.
Managing vascular permeability, for example:
- Providing an effective barrier to excessive fluid loss from the vascular system.
- Increasing blood vessel permeability to allow flow of fluids and immune cells into the tissues to fight infection.
Protecting blood from toxins and foreign material.
Preventing inappropriate formation of blood clots and thrombi when there is no injury (Cleveland Clinic, 2022).

Endothelial injury and dysfunction during a SARS-CoV-2/ COVID-19 infection may activate the coagulation sequence, resulting in peripheral and pulmonary thrombosis within both veins and arteries as well local angiogenesis (formation of new blood vessels). A great deal of evidence suggests that SARS-CoV-2 virus affects endothelial hyperpermeability, vasoconstriction, inflammation, hypercoagulability, and release of pro-inflammatory cytokines and vasoactive compounds (Valencia, et al., 2024).

Post-Acute Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome is a post-acute infection complication of COVID-19 that affects the entire body. Signs and symptoms manifest two to six weeks after the acute COVID-19 infection is over. It can occur in adults (MIS-A) or children under the age of 21 (MIS-C). The inflammation affects the heart, lungs, brain, kidney, eyes, skin, or gastrointestinal system and is quite severe, but treatable.

Multisystem Inflammatory Syndrome in Children (Under Age 21)

Since May of 2020, the CDC has received health department reports on 9,694 children who met the criteria for MIS-C, and 79 of those children died. Of the 9,164 children for whom race/ethnicity was specified, an estimated 35% were white, 25.2% were Hispanic/Latino, 30.2% were Black, 2.5% were Asian, and 60% were male (CDC, 2024 June).

Children with new onset MIS-C are extremely ill and most will require intensive care admissions. Approximately 1 to 2% of children with MIS-C do not survive. The incidence in April to June of 2020 was estimated at 316 cases per million SARS-CoV-2/ COVID-19 infections in the U.S. Children usually recover well, despite being severely ill initially.

“Defining criteria for children (MIS-C) are:

“Clinical Criteria

An illness characterized by all of the following in the absence of a more likely alternative diagnosis

Subjective or documented fever (temperature => 38 degrees C.
Clinical severity requiring hospitalization or resulting in death.
Evidence of systemic inflammation C-reactive protein => 3.0 mg/dl (30 mg/L).
New onset manifestation in at least TWO of the following categories:
Cardiac involvement indicated by:
- Left ventricular ejection fraction <55% OR
- Coronary artery dilatation, aneurysm, or ectasia, OR
- Troponin elevated above normal range.
Mucocutaneous involvement as indicated by:
- Rash, OR
- Inflammation of the oral mucosa (e.g., mucosal erythema or swelling, drying or fissuring of the lips, strawberry tongue). OR
- Conjunctivitis or conjunctival injection (redness of the eyes). OR
- Extremity findings (e.g., erythema (redness) or edema (swelling) of the hands or feet).
Shock.
Gastrointestinal involvement indicated by:
- Abdominal pain, OR
- Vomiting, OR
- Diarrhea.
Hematological involvement as indicated by:
- Platelet count < 150,000 cells/µL.
- Absolute lymphocyte co (ALC) count less than 1,000 cells/µL”

(Council of State and Territorial Epidemiologists, 2023).

Multisystem Inflammatory Syndrome in Adults (MIS-A)

In adults there is a lot of variation in how MIS-A manifests. Severe, acute, multiple organ dysfunction and/or shock are often involved. The clinical criteria in the case definition is a little different than for children. Dysregulation of the immune response appears to be involved, but the pathophysiology is not well understood, and the prevalence is not known (Zahornacky, O., et al., 2023).

“CDC Case Definition for MIS-A:

This definition was developed in 2021 through expert opinion and is intended to assist in identification and reporting of M/S-A cases to CDC passive surveillance.

A patient aged 22.1 years hospitalized for =>24 hours, or with an illness resulting in death, who meets the following clinical and laboratory criteria.

The patient should not have a more likely alternative diagnosis for the illness (e.g., bacterial sepsis, exacerbation of a chronic medical condition).

l. Clinical Criteria

Subjective fever or documented fever (238.0 C) for 224 hours prior to hospitalization or within the first THREE days of hospitalization* and at least THREE of the following clinical criteria occurring prior to hospitalization or within the first THREE days of hospitalization*. At least ONE must be a primary clinical criterion.

A. Primary clinical criteria

1. Severe cardiac illness Includes myocarditis, pericarditis, coronary artery dilatation/aneurysm, or new-onset right or left ventricular dysfunction (LVEF<50%), 2nd/3rd degree A-V block, or ventricular tachycardia. (Note: cardiac arrest alone does not meet this criterion).

2. Rash AND non-purulent conjunctivitis.

B. Secondary clinical criteria

1. New-onset neurologic signs and symptoms Includes encephalopathy in a patient without prior cognitive impairment, seizures, meningeal signs, or peripheral neuropathy (including Guillain-Barré syndrome).

2. Shock or hypotension not attributable to medical therapy (e.g., sedation, renal replacement therapy).

3. Abdominal pain, vomiting, or diarrhea.

4. Thrombocytopenia (platelet count microliter). Laboratory evidence.

The presence of laboratory evidence of inflammation AND SARS-CoV-2 infection.

C. Elevated levels of at least TWO of the following: C-reactive protein, ferritin, IL-6, erythrocyte sedimentation rate, procalcitonin.

D. A positive SARS-CoV-2 test for current or recent infection by RT-PCR, serology, or antigen detection.NOTE: These criteria must be met by the end of hospital day 3, where the date of hospital admission is hospital day 0” (CDC, 2023).

Post-Acute or Long COVID

After the acute COVID-19 infection is over, many patients have post-COVID symptoms that continue for a long time. There are various names used to describe these conditions, and while some are mild, such as fatigue, others can be serious and even life-threatening.

Cardiac arrythmias and palpitations (Dini, et al., 2023).
Acute myocardial infarction (Zuin, et al., 2023).
Acute to chronic pericarditis (Dini, et al., 2023).
Multisystem inflammatory syndrome (Zahornacky, et al., 2023).
Central nervous system, cognitive deficits, seizures, or stroke (Baig, 2020; Doyle, 2022).
Musculoskeletal issues and pain (Shukla, et al., 2023).

Healthcare workers are not immune to long COVID-19 syndrome. One study of 679 healthcare professionals found that 30.3% had long COVID issues (Shukla, et al., 2023). In January of 2023, up to 10,000 clinicians working in the UK National Health System were off due to long COVID symptoms (Baines, 2023). Up to 200 plus symptoms have been associated with sequelae of COVID-19 infections (Zhu, et al. 2023).

See the chapter Post-COVID/ Long COVID for more information.

A Mini Primer on the Viral Genetics of SARS-CoV-2

New variants of SARS-CoV-2 emerge frequently. Some are the result of substitution of one or more nucleic acids for another. Insertion mutations are due to the addition of genetic material. Deletion mutations occur when nucleic acids are deleted from the viral genome. In most cases, there have been several changes in the genome that make a variant more or less able to compete (Rogozin, I. B., et al., 2024).

In a rare situation, two existing variants of the virus infecting one patient in the same human cell at the same time can share genetic material and create a new recombinant variant during the viral reproduction process. Recombination sometimes causes the virus to be better able to compete. Reversals can occur when a backward mutation returns to viral RNA to an older state.

Mutational hotspots are locations on a gene where mutations occur frequently. Genetic mutations that affect areas in the genome that improve the virus’ ability to evade the host’s immune system generated antibodies occur more frequently due to natural selection of mutations that improve virus survival (Rogozin, I. B., et al., 2024). Figure 5 shows a depiction of the gene encoding for the S-spike glycoprotein, the yellow area on the picture, a location where mutations occur frequently. Proteins are made up of amino acids (the building blocks of proteins). A specific viral gene provides instructions in the form of a single strand of viral RNA that contains the instructions for building proteins needed by the virus to survive. The gene for the S-protein of the ancestral wild type of SARS-CoV-2 is a single strand of 1,273 ribonucleic acids. The RNA template is read, and the SARS-CoV-2 virus uses material within the host cell to build the spike glycoprotein.

The S-protein is needed for the virus to be able to gain entry to and infect the host cells. When mutations occur when copying the gene, they can have:

Have no effect on the protein produced, or
Produce a protein that does not function or blocks entry into the cells, a negative effect for the virus, or
Produce a protein that makes it easier for the SARS-CoV-2 virus to enter into the host cell making it easier to cause infection, a positive effect (Rogozin, I. B., et al., 2024) – for the virus, not for the human.

GISAID.org is a database that allows for comparison of genetic mutations. When the results of whole genetic sequencing for a viral variant is entered into GISAID, the program compares all the numerous gene sequences to the ancestral wild type (the reference sequence) and lists all the existing changes present.

GISAID also checks all the other sequences previously submitted to see if there is a previously submitted clone that has already been identified. The database can also show information about previously submitted family ties to other version of the virus in the same clade, a cluster of versions of the virus with a common ancestor. (CDC, 2023 September 1. SARS-CoV-2 Variant classification and definitions. https://covid.cdc.gov/covid-data-tracker/#variant-summary; https://GISAID.org; Rogozin, I. B., et al., 2024). The second example of a gene important to viral survival is the one that encodes for the membrane that provides shape and protects viral contents, the M protein, circled in red on the diagram. This gene has only 668 ribonucleic acids that provide the instructions for building the membrane proteins. When the whole genome is sequenced and entered into the database, this information is also compared to the submissions that were previously entered. See figure 6.

Summary

SARS-CoV-2, the virus responsible for COVID-19, is airborne and can be transmitted during normal breathing and relaxed conversation from one person to the next. Droplets resulting from coughs, sneezing, yelling, and singing can transmit the virus as does direct contact with oral or nasal secretions and mucous membranes, as well as indirect contact via objects. Social distancing is helpful in that the amount of virus in air decreases with distance away from an infected person, but the 6-foot apart guideline will not protect from infection. Respirators are needed when providing direct care. Masks or respirators with the highest level of protection tolerated is recommended by the CDC.

Pathology is related to the renin-angiotensin-aldosterone, and failure of the angiotensin converting enzyme 2 (ACE2) to cleave and inactivate angiotensin 2. The virus enters through the respiratory system and attaches to and enters human cells by bonding to the ACE2 receptors and that prevents activation of ACE2 as the enzyme if prevented from attaching to the ACE2 receptors on the outside of the host cell.

There is great variation in signs and symptoms that can range from totally asymptomatic to critically ill in a moribund state. Severity depends on many host factors including age, co-morbidities and overall condition. As the virus is constantly mutating, some therapeutic options that worked with previous variants are no longer useful. See chapter Dangerous Mutations, the Continuous Emergence of SARS-CoV-2 Variants for more information. The most severe signs and symptoms are related to attack on respiratory cells combined with a hyperactive immune response, vascular endothelial damage, and a prolonged inflammatory process. Serious and potentially lethal complications include respiratory failure, multi organ failure secondary to thromboembolisms, cytokine storm, and multisystem inflammatory syndrome.

References

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