The response to infection by the SARS-CoV-2 virus depends in large part on the health of one’s neuroendocrine immune system. A properly balanced and harmonious human immune system can eliminate the virus after it detects the spike (S) protein or other viral antigens. However, aging and chronic, low-grade inflammation can lead to an imbalanced immune system that can’t eliminate the virus. This is frequently exacerbated by underlying conditions or morbidities. Environmental pollutants and very small particulate matter are especially harmful1. So, the goals of this article are:
- describe the human immune system and show how it’s linked to the nervous and endocrine systems;
- describe how infections and vaccines train the immune system to prevent Covid-19;
- describe that an imbalanced immune system can cause serious illness and death in its pathological response infection by the SARS-CoV-2 virus;
- provide an update on what we know about some lingering effects of Covid-19 in children.
The innate and acquired immune systems are linked to the nervous and endocrine systems
Reductionist thinking looks at the immune system as if were isolated from the neuroendocrine system. This may be useful in many ways, but we should remember that it is actually part of the endocrine and nervous systems. Systems thinkers describe a neuroendocrine immune system. The links between the immune system and central nervous system are evident in the long-term psychological effects it has on many. Infection by the SARS-CoV-2 virus and even just social isolation can impair interactions between the immune, nervous and endocrine systems. When infection leads to severe cases of Covid-19, immune cells secrete high levels of cytokines, which activate the hypothalamic-pituitary-adenocortical (HPA) axis of neuroendocrine system, which produces deadly levels of glucocorticoids2. Even our bones are part of this system. That is, bone marrow produces hematopoietic stem cells that can differentiate into immune cells. This includes myeloid cells (monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, red blood cells, megakaryocytes, platelets and dendritic cells) and lymphoid cells (T-cells, B-cells and natural killer cells, or NK cells). For now, let’s focus on the immune system.
In many people, the innate immune system detects viral infection and stimulates the acquired immune system. Memory cells are produced so our immune system can recognize future infections. When a person is vaccinated, the viral S protein enters the blood. The innate immune system detects it and activates the acquired immune system, producing a long-lasting immunity. So, when an immunized person is exposed to the virus from an infected person, his or her immune system will destroy the virus once it enters the bloodstream. However, while the virus is in the immunized person’s nose, he or she can spread it to others by kissing, coughing, sneezing, talking or singing near them. That is, the SARS-CoV-2 virus is transmitted primarily by respiratory droplets, with a possible, but unproven, fecal–oral transmission route. It binds to the angiotensin-converting enzyme 2 (ACE-2) receptor on the outer portion of cell membranes in the nose, lungs, heart and many other parts of the body. It is crucial for heart and lung health3. Upon infection, the median incubation period is about 4–5 days before the onset of symptoms4. About 97.5 % of symptomatic patients develop symptoms within 11.5 days after being infected. Upon being admitted to the hospital, patients with Covid-19 typically have a fever and dry cough. Some patients also experience difficulty in breathing, muscle and/or joint pain, headache/dizziness, diarrhea, nausea and may cough up of blood. Within 5–6 days of the onset of symptoms, the SARS-CoV-2 viral load reaches its peak. Severe Covid-19 cases progress to acute respiratory distress syndrome (ARDS), on average around 8–9 days after the onset of symptoms4. However, a healthy, balanced immune system can keep viral infections from developing into Covid-19.
How infections and vaccines can train the immune system to prevent Covid-19
The first step in activating the immune system is to for macrophages and dendritic cells (DCs) to detect the infection5. Viral RNA and protein antigens such as the spike (S) protein are detected by these sentinel cells. Macrophages in our tissues activate our innate immune system. There are different types of macrophages: osteoclasts in bone, Kupffer cells in the liver and glial cells in the brain. Macrophages kill infected cells and invading pathogens, such as the SARS-CoV-2 virus that causes Covid-19. They also secrete biochemicals called cytokines that activate other immune cells. Cytokines include tumor necrosis factor (TNF), interleukins (ILs) IL-1, IL-6, IL-8 and IL-12. DCs activate the acquired immune system, also known as the adaptive immune system. Both tissue macrophages and DCs are made from precursors called monocytes. Monocytes are made in the bone marrow, circulate in the blood and enter tissues.
So, the human immune system has a fast initial response to infection that is innate and needs no training. Similar innate immune systems exist in all animals. There is a cell-based innate immunity that consists of white blood cells (also known as leukocytes) and a variety of biochemicals in body fluids, formerly called humors. The three types of leukocytes are granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes (T cells and B cells). Infected cells are killed by phagocytosis using a subgroup of leukocytes that circulate in the bloodstream as monocytes. They are converted into macrophages, which subsequently enter tissues during inflammation.
DCs are a distinct lineage of mononuclear phagocytes. They specialize in presenting antigens to T cells while initiating and controlling immunity. DCs activate and condition virus-specific T cells. They bridge innate and adaptive immunity and have additional roles in shaping the immune response to pathogens, vaccines, and tumors. DCs are cells with many thin, long arms. They are located throughout the body, but are particularly abundant in interfaces between the external and internal environments. This includes the skin and the lining of the nose, lungs and gastrointestinal tract, where they are ideally placed to encounter invading pathogens. DCs can migrate into the bloodstream and reach infected tissues. When they sense a tagged cell that is harmful, they are activated. They ingest and break down the various constituents of the cell. They contain proteasomes, which catalyze the hydrolysis of proteins that are tagged with ubiquitin. The small peptide fragments produced by the hydrolysis are transported to the surface of the DCs, where they are held in place by a human leukocyte antigen (HLA), also called a major histocompatibility complex (MHC) protein. The tagged DCs then migrate to a lymph node where they encounter T-cells that have a matching receptor that binds the HLA-peptide complex. The DCs bind to CD4+ T cells, and become antigen presenting cells (APCs). Note that CD is a type of protein called cluster of differentiation. It functions as a co-receptor for T-cell receptors.
Classical DCs (cDCs) process antigens and present cells. They have high phagocytic activity when they are immature cells and high cytokine-producing capacity when they mature. They can move from tissues to the T cell and B cell zones of lymphoid organs. cDCs regulate T cell responses both in the steady state and during infection. They are generally short-lived and are replaced by blood-borne precursors. Plasmacytoid DCs (PDCs) differ from cDCs in that they live longer and some of them carry characteristic immunoglobulin rearrangements. They are present in the bone marrow and all peripheral organs. PDCs respond to viral infection with a massive production of type I interferons (IFNs). However, they also can act as APCs to control T cell responses.
An important difference between B and T cells is that B cells recognize antigens in their native form, while T cells recognize antigens that have been processed into peptide fragments that are complexed with MHC on the surface of APCs. T cells recognize this complex by using their cognate T cell receptors (TCRs). On the other hand, antigens activate B cell receptor signaling. This results in the internalization, processing, and presentation of antigen to T lymphocytes in the context of cell surface proteins of the MHC class II family. Recognition of such processed antigen by the TCR induces the formation of a stable association, or synapse, between the two cell types, resulting in the transmission of signals required for regulating the B cell response6.
To make so many different types of immunoglobulins, B cells mix and match the variable, diversity and joining segments (V, D and J) that are coded for by different gene segments. When a B-cell encounters an APC, it ingests the antigen. The antigen is displayed together with an HLA II protein which binds to CD4+ cells that secrete cytokines, which stimulate B-cell proliferation. Some B-cells have relatively large nuclei and make many copies of their antibodies. Other B-cells are long-lived memory cells. Another subtype of B-cells produces lower affinity IgM antibodies. They form pentamers and bind to the surfaces of bacteria. This produces aggregates that are attacked and destroyed by macrophages. Most B-cells are distributed in tissues throughout the body, including the lymph nodes, as are T-cells. A smaller fraction of B-cells circulates through the blood vessels. Activated B-cells are cleared in the liver and spleen, so they only survive a few days. Naïve B-cells, which have not been exposed to antigens and memory B-cells are protected and live much longer. When a person with a healthy immune system is infected by a virus, bacteria or pathogenic organism, some of the B cells produce antibodies that may persist for months or years, depending on how long protection against the antigen-producing pathogen is required7. Next, pathogen-specific B cells persist in a resting state. They circulate in the body and can be reactivated to produce more antibodies when a person is infected again. However, these two types of B cells produce different antibodies. The class or isotype usually changes. It is no longer the IgM class that was produced initially. The affinity of the antibody for the pathogenic antigen is much stronger than in the initial immune response. The immune memory includes not just the antibody that is made, but also involves the B and T cells that combine rapidly to make more antibodies. This repeats and magnifies the previously successful immune responses7.
Naïve T and B cells that express IgM and IgD are activated by an antigen in the primary antibody response, either directly or after being processed by a dendritic cell7. Depending on how they are primed, activated T cells become one of several types of helper T cells (Th cells), such as Th1, Th2 or Th17. They each produce a distinct repertoire of cytokines. Th1 cells secrete IFN-γ, Th2 cells secrete IL-4, and Th17 cells secrete TGF-β. In addition, activation of T cells leads to T memory (TM) cells being produced. Signals from T cells induce B cell proliferation and class switching. Activated B and Th cells can also establish the places where the affinity of the antibody for the antigen will increase. Th cells within germinal centers are different than early subsets of Th cells. They secrete IL-21 in addition to other cytokines. Long-lived plasma cells and memory B cells are produced in the germinal centers. They express isotypes of immunoglobulins that reflect the type of Th that was used in the initial priming. Different classes of antibodies appear in the memory compartments. They are specialized in clearing specific types of pathogens. This is based on the initial interactions between dendritic and T cells7.
NK cells are very cytotoxic, so they must be carefully regulated in a healthy immune system. They are crucial components of the innate immune system, but they also influence adaptive immune responses. NK cells interact with many different types of cells to influence their fate. The outer portions of the cell membranes of the cells being targeted contain different types of receptors. Some activate and others deactivate NK cells. Cytokines such as TNF-, viral double-stranded RNA and IFNs can activate them. The granules in NK cells release perforin and proteolytic enzymes, which form pores in the membranes of invading cells. This kills them by catalyzing the hydrolysis of their proteins. NK cells also remove the body’s own cells that become malignant or infected with viruses, or any other cells that are tagged with IgG.
Vertebrates have an acquired immunity that provides a slower, but sustainable response. The innate immune system recognizes RNA in viruses using RNA sensors8. These sensors activate transcription of DNA which increases the production of cytokines, chemokines and type 1 interferon (I IFN), the first line of defense against viruses. The chemokines attract white blood cells to the sites of infections, such as nasal passages and lungs. Type I IFNs activate signaling pathways that lead to the biosynthesis of antiviral proteins which restrict further infection by viruses in many people. However, non-structural proteins in the SARS-CoV-2 virus can interfere with the IFN signaling. Moreover, some people produce high levels of pro-inflammatory cytokines. This attracts various immune cells (neutrophils, macrophages and T cells) from the blood circulation into the infected tissue. This can lead to diffuse alveolar damage, capillary damage, vascular barrier damage, multiorgan damage and ultimately death. So, Covid-19 is like SARS and MERS. They are diseases that are mediated by a cytokine storm8.
A properly balanced innate immune system recruits immune cells to the site of infection, identifies and removes foreign substances and activates the adaptive immune system. It also identifies a characteristic protein on viruses and other pathogenic organisms. This characteristic protein is called an antigen. The S protein is strongly antigenic in the SARS-CoV-2 and other coronaviruses. Antigens are attached it to the surface of specific immune cells, which present it to the adaptive immune system for destruction. The innate immune system does not have a memory and does not offer specific resistance against organisms that have invaded the host in the past. For this, the adaptive immune system is needed. It is activated by the innate immune system and is three major cell types: B cells, CD4+ T cells and CD8+ T cells9.
Macrophages swallow up and digest bacteria as well as dead and dying cells. B-lymphocytes are defensive white blood cells that are made in the bone marrow. They produce antibodies that recognize antigens that are left behind by macrophages and subsequently prime or activate T-lymphocytes that are made in the thymus gland. When a person is first exposed to an antigen, it can take a few days or longer to make enough new T-lymphocytes to destroy all the viruses (or other infectious agents, such as bacteria) that have that antigen. If one has an effective immune system, he or she can usually develop an immunity to many infectious diseases even though they have never been vaccinated. For example, at least 98 % of the people who have been exposed to the SARS-CoV-2 virus in China did not die. They must have had an adequately efficient immune system. In the process of developing immunity, the body retains a few T-lymphocytes that are called memory cells. When the same person is exposed to the same infectious agent again later in life, the memory T-cells identify it and stimulate the B-lymphocytes to produce antibodies to attack and eliminate the virus, bacteria or other infectious agent. However, in people with a compromised immune system, it can be difficult or impossible to develop an immunity to a new virus or other infectious agent. So, elderly men as well as people with cardiovascular disease and/or diabetes have a higher risk of mortality caused by the SARS-CoV-2 virus. Interestingly, the mortality due to SARS-CoV-2 is almost zero for children aged 0 to 4 years, even though the very young do not have a fully developed immune system. In contrast, young children are more vulnerable to the influenza virus than older children and young adults.
The adaptive or acquired immune system acts after it is stimulated by the innate system. Mature DCs in the innate immune system form immunological synapses with T cells that have the CD4 cell surface glycoprotein on them. So, they are called CD4+ T-cells. There are two main types of T cells: CD4+, which oversee the immune response and CD8+ cells which do much of the actual killing. The adaptive immune response is initiated by specific interactions between antigen-loaded, mature dendritic cells and naïve CD4+ T cells in the lymph nodes. Dendritic cells link the innate and adaptive immune systems. They engulf exogenous pathogens and toxins, chop them into pieces and present them to T-cells. To do this properly, they must be able to distinguish between self and non-self. So, while our brains help establish our personal identities to the outside world, the immune system establishes our internal identities. Adaptive immunity uses cytokine-producing Th cells. Naïve Th cells are stimulated by antigen presenting cells (APCs) that have cognate antigens on their surface. The naïve cells differentiate into two different types of Th cells, Th 1 and Th2. The Th1 cells secrete interferon-γ (IfN-γ) and promote cellular immunity. The CD4+ Th2 cells produce the cytokines IL-4, IL-5, IL-10 and IL-13, while producing humoral immunity. A small percentage of the cells acquire and retain a memory of one or more antigens from the invading viruses and micro-organisms. This enables us to mount rapid, effective responses to them after being exposed to them once before.
The adaptive immune system uses white blood cells called lymphocytes. The adult human body has about 2 trillion lymphocytes, constituting 20-40 % of all white blood cells. The peripheral blood contains 20–50 % of them as circulating lymphocytes. The rest of them move within the lymphatic system. Natural killer (NK) cells are large and granular. Smaller lymphocytes are T and B cells. There are three general classifications of CD8+ cytotoxic T cells: naïve cells, central memory cells and effector memory cells. Naïve T-cells have not yet been exposed to their cognate antigen, but memory cells have. Memory T cells can recognize bacteria, viruses and cancer cells. Central memory cells express the cytokine CCR7 and IL-2. Effector memory T cells (TEM) express the effector cytokines IFNγ and IL-4. They can reside permanently, or with low turnover rates in peripheral tissues and migratory cells that can move from the periphery and into the blood. Moreover, TEM cells rapidly recognize and kill infected target cells, thus containing new infections. There is also a network of antibodies in the immune system. They are connected to other antibodies and antigens. Antibodies are always being made, even in the absence of infection. They help define self. Every day, about 100 precursors of immune cells enter the thymus and undergo several cell divisions to make about 107 – 108 T-cells.
T-cells make cell surface proteins called immunoglobulins, or Igs. They have two heavy chains and two light chains that are joined by disulfide bonds. Each chain is made up of structural domains called Ig domains. These domains of 70-100 amino acid residues are classified as variable, joining or constant. They are made from three types of genes, which code for the constant, diversity and joining regions. That is, part of an Ig molecule has a structure that is very similar to other Igs in its class. This is called the constant region. There are five types of mammalian heavy chains: α, δ, ε, γ and μ. They make the IgA, IgD, IgE, IgG and IgM antibodies. The constant region is joined with the variable, or diversity region of the Ig, which is on the outer part of the Y-shaped arm. It has a unique structure that gives the antibody molecule its antigenic individuality and is coded for by diverse genes. These unique regions are called complementarity determining regions (CDRs). They define the idiotypes, or antigen binding specificity of the antibodies. More than a million idiotypes are made. Those that bind to self antigens are marked for destruction. Those that bind foreign antigens survive and make memory B and T cells. Only about 5 % of the T cells survive the selection process that eliminates the cells that recognize self-antigens and bind them tightly. There is a selection-driven tolerance (self-tolerance) that helps establish a type of balance or homeostasis. If the elimination process becomes too lenient, some of the T-cells that recognize self survive and kill some of the body’s own cells, causing an autoimmune disease. If the elimination process becomes too severe, some of the T-cells that recognize invading pathogens would be killed and the body could succumb to disease. This homeostasis is controlled, in part, by regulatory T cells (Treg cells), whose development and maturation is controlled by transforming growth factor-β (TGF-β). So, altered TGF-β signaling can predispose people to allergic responses to antigens that may be present in the environment and foods.
Throughout our lives, our immune systems go through different states of homeostasis. When we are in our mother’s womb, we have an underdeveloped immune system that mostly uses Th2 cells instead of the Th1 cells that we use as adults. We are born with a set of immune cells, which make many antibodies and antigens. After we are born and are exposed to different antigens from the environment, our adaptive (acquired) immune systems adapt by making different repertoires of antibodies. Chemical messengers communicate between cells and tissues, to help make necessary changes, in response to changes in our internal environments. So, there is a network in which antigens make antibodies, which make more antibodies. The adaptive immune system does this, but it takes some time. So, as mentioned earlier, the innate immune system responds faster and activates appropriate changes in the adaptive immune system. Toll-like receptors (TLRs), NOD-like receptors (NLRs) and dendritic cells link the two together. So, the immune network consists of nodes (cells and tissues) connected by chemical messengers (chemokines, cytokines and receptors). The reductionist thinking of the 20th century identified the nodes and the chemical messengers. Systems thinking of the 21st century added an emphasis on the relationships between the components, how they communicate and how they are organized. A person’s immune response must be kept in balance to maintain health. This is done through a network of co-signaling molecules. It is coordinated by a network of ligand–receptor interactions on the cell surface, with both co-stimulatory and co-inhibitory capacities. The direction and outcome of immune responses are decided by the interplay of these complicated and often counterbalancing network interactions. When the immune system is unbalanced, viral infection can cause Covid-19.
Ways that an unbalanced immune system can cause serious illness and death in its pathological response infection by the SARS-CoV-2 virus
When the SARS-CoV-2 virus infects cells that express ACE2 and transmembrane protease, serine 2 (TMPRSS2), many copies of it are made in the host cells4. Then, the virus is released, causing the host cell to undergo die by a highly inflammatory form of cell death called pyroptosis. Damage-associated molecular patterns (DAMPs), such as ATP, nucleic acids and ASC oligomers are released. ASC is also known as apoptosis-associated speck-like protein containing CARD (caspase recruitment domain) and PYCARD (pyrin plus CARD domains) structural motifs. It is the key inflammasome adaptor protein in the innate immune response10. DAMPs are recognized by neighboring epithelial cells, endothelial cells and alveolar macrophages that produce pro-inflammatory cytokines and chemokines (including IL-6, IL-10, macrophage inflammatory protein 1α (MIP1α), MIP1β and MCP1). These proteins attract monocytes, macrophages and T cells to the site of infection. This leads to more inflammation and a pro-inflammatory feedback loop. In a defective immune response immune cells accumulate in the lungs, causing overproduction of pro-inflammatory cytokines, which eventually damages the lung infrastructure. The resulting cytokine storm circulates to other organs, leading to multi-organ damage. It’s also possible that non-neutralizing antibodies produced by B cells could enhance SARS-CoV-2 infection by antibody-dependent enhancement. On the other hand, a healthy immune system attracts virus-specific T cells to the site of infection shortly after the initial inflammation. The T cells eliminate the infected cells before the virus spreads. Neutralizing antibodies in a balanced and harmonious immune system can block viral infections. Alveolar macrophages recognize neutralized viruses and dying cells and clear them by phagocytosis. The virus infection is cleared with little or no lung damage, and Covid-19 is prevented10.
However, we are not machines. Not all people are alike. Some people are immunocompromised or have an autoimmune disease, in which their immune system is overactive. Some have such a severe autoimmune condition that they have to take rituximab to kill all the circulating B cells in their body. They are at high risk of infectious diseases. It’s not known if they would be helped by a Covid-19 vaccine. Moreover, we go through many changes throughout our own lives11. Interestingly, children are not as vulnerable to the potentially deadly effects of infection by the SARS-CoV-2 virus. As of April 7, 2021 only 0.0167 % of all Covid-19 deaths in the USA were in the age group of 0 – 4 years, despite being about 6 % of the total population12,13. Still, there are lingering effects in some.
Ways that an imbalanced immune system can cause death in its pathological response to the viral infection
Even though they are less susceptible to Covid-19, young children and elderly people are more susceptible to serious illnesses caused by infections than another age group 11. Infants (under one-year-old) have an immune system biased towards tolerance after being protected in their mothers’ wombs. Their immune system consists of cells with mostly naive phenotypes that begin to mature after being exposed to the environment. The immune systems of very old individuals are characterized by loss of immune cells and reduced diversity of variable receptor genes on B cells and T cells. Also, many elderly people in the USA and many other developed countries suffer from chronic low-grade inflammation due to obesity and other factors14.
Children under 5 years of age tend to be asymptomatic or have just mild symptoms when infected by the SARS-CoV-2 virus15. So, many of them are not identified or diagnosed as being infected by the virus. They tend to have a powerful innate immune response and rarely have underlying conditions or obesity. The average incubation period in children appears to be longer than in adults. Children have lower rates of hospitalization. Among children, infants have the highest percentage of hospitalization. Life‐threatening and fatal cases are seen mostly in patients with underlying diseases. In a study of 48 children, 83 % had comorbidities, all were admitted to intensive care units and the case fatality rate was 4.2 %15.
Still, the World Health Organization (WHO) has recognized that Covid-19 can sometimes cause prolonged illness, even in young adults and children without underlying chronic medical conditions. As described in my previous article, some also suffer from a rare, but serious disease called multisystem inflammatory syndrome in children, or MIS-C16. In addition, some children have been diagnosed with long lasting Covid. One theory is that long Covid may be similar or related to chronic fatigue syndrome, a condition characterized by extreme and persistent tiredness that cannot be explained by another medical condition. Some children experience difficulty with thinking, remembering, processing new information or paying attention. Others report orthostatic intolerance, meaning they might develop worsening symptoms when they change positions, such as sitting up or standing down. So, even though the vast majority of children are in little or no danger of developing Covid-19, some are. The only clinical trials of Covid-19 vaccines that have been completed were done on people 16 years of age and older. So, younger children are not yet being vaccinated, unless they are part of a recently started clinical trial.
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