Balancing immunity and inflammation in lung disease
Key clinical considerations for COVID-19 disease are (1) prevent serious infection by supporting the components of the immune system that are primary in fighting the SARS-CoV-2 virus and (2) prevent the surge in inflammation that entails from damaging the lungs.
Th1 and innate immunity that do the 'heavy lifting' to fight viruses decline with age and are diminished in a variety of chronic conditions but can be supported.
Numerous conditions such as cardiovascular disease, diabetes, obesity, autoimmune and other disorders are characterized by high levels of non-purposeful inflammation. This increases the risk for fatality from severe lung damage (ARDS = acute respiratory distress syndrome) due to the surge of inflammation aroused to fight the virus. Methods that calm the NLRP3 inflammasome, a key mechanism for this inflammation, can help prevent this.
Some considerations for fostering immune system resilience, by way of example, are at the bottom.
The authors of a perspective published in the journal Science note:
The balance between immunity and inflammation
Lungs execute two critical functions that can be at odds with one another: eliminating harmful toxins, particulates, and microbes; and exchanging gas through uninflamed structures—alveoli—to collect oxygen and discharge carbon dioxide. Lungs have a multilayered response to unwanted invaders, offering physical barriers as well as arranging immune cells at airway surfaces. Yet, lungs have the “Goldilocks” challenge of deploying this armory with just the right amount of inflammation. Consequently, lung immunity must be choreographed so that invaders are purged quickly, inflammation tempered, and homeostasis preserved.
Calming the storm of inflammation
In a paper published in Molecular Medicine concerning mechanisms of immune suppression that resolve inflammation to prevent damage after a virus or other pathogen has been cleared, the authors state:
The immune system contains a vast array of cell types and effector molecules specialized to detect and destroy pathogenic microorganisms and the cells and tissues that harbor them. With this highly toxic protective function comes the need for tight regulation so that once the danger of infection has passed, the system can return to relative calm and further damage can be avoided. This regulation is mediated by subsets of cells and immunosuppressive molecules that are specialized to actively suppress the immune response (1–7). Ideally, immune suppression balances the destructive forces of inflammation while allowing clearance of pathogenic infectious agents (Figure 1A) (8). Failures of immune suppression may manifest themselves clinically in the form of severe acute inflammation and cytokine storms that, if improperly controlled, ultimately result in death (Figure 1B) (9). In other cases, poor immune regulation may contribute to chronic or aberrant inflammation including allergies, asthma and autoimmune diseases (10,11). Reciprocally, over-suppression of the immune system may lead to poor clearance of pathogens, leading to persistent infections (Figure 1C) (12) or ineffective tumor surveillance leading to cancer (13)...This delicate balance between inflammation and immune suppression depends on all of the components of the immune response working in concert and requires complex mechanisms of communication between all of the effector and regulatory cell populations (15).
They illustrate balanced (A), overzealous (B), and weak (C) immune responses to infection in these graphs:
Immune responses to infection
In the center (B), severe acute inflammation exceeds the level necessary to fight the infection and fails to properly resolve. The level and duration of non-purposeful inflammation, more likely to occur when the baseline level (before infection) is high, is responsible for severe lung damage in COVID-19.
Immune suppression, like other important biological processes, involves an integrated network of cells and molecules that work together to balance the potentially deleterious effects of uncontrolled inflammation.
Viral titers go down but inflammation stays high
In a review entitled 'Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology' published in Seminars in Immunopathology, the authors state:
...studies from humans who died of SARS and more recent studies in animal models suggested that a dysregulated immune response occurred, resulting in an exuberant inflammation and lethal disease.
The initial phase was characterized by robust virus replication accompanied by fever, cough, and other symptoms, all of which subsided in a few days. The second clinical phase was associated with high fever, hypoxemia, and progression to pneumonia-like symptoms, despite a progressive decline in virus titers towards the end of this phase [28]. During the third phase, ∼20% of patients progressed to ARDS, which often resulted in death [29, 30]. Because of a progressive decline in virus titers, the third phase is thought to have resulted from exuberant host inflammatory responses.
Cytokines and chemokines are immune system signaling molecules that coordinate cellular immune responses and stimulate the movement of cells towards sites of inflammation that play a major role in SARS (severe acute respiratory syndrome).
High serum levels of pro-inflammatory cytokines (IFN-γ, IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) were found in SARS patients with severe disease compared to individuals with uncomplicated SARS [44–47]. Conversely, SARS patients with severe disease had very low levels of the anti-inflammatory cytokine, IL-10 [44]. In addition to pro-inflammatory cytokines and chemokines, individuals with lethal SARS showed elevated levels of IFN...Thus, it appears from these studies that dysregulated and/or exaggerated cytokine and chemokine responses by SARS-CoV-infected AECs, DCs, and macrophages could play an important role in SARS pathogenesis.
Another important point made by these authors is that catastrophic outcomes are associated with an impaired innate immune response with aberrant IFN (interferon) signaling and a suboptimal T cell response. Innate and Th1 immune impairment, common in the aged and those with co-morbidities, is permissive both of more severe infection and progression to a dysregulated, excessive level of damaging inflammation.
Our results showed that rapid SARS-CoV replication in BALB/c mice induced a delayed IFN-α/β response accompanied by an excessive influx of pathogenic inflammatory monocyte-macrophages (IMMs) [38]...CoV-specific T cells are crucial for virus clearance and limit further damage to host [64, 104]. Additionally, T cell responses also dampen overactive innate immune responses [105, 106]. Exuberant inflammatory responses caused by pathogenic hCoV diminish the T cell response, in the case of SARS-CoV infection via TNF-mediated T cell apoptosis, thus resulting in uncontrolled inflammatory response.
Protective versus pathogenic inflammatory responses to pathogenic hCoV infections
Immune dysregulation with COVID-19 in Wuhan, China
In a study published recently in Clinical Infectious Diseases, researchers analyzed clinical data for all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, comparing laboratory data between patients with severe and non-severe outcomes. Their results are illustrative:
Of the 452 patients with COVID-19 recruited, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough and myalgia. Severe cases tend to have lower lymphocytes counts, higher leukocytes counts and neutrophil-lymphocyte-ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels, and lower level of helper T cells in severe group. The percentage of naïve helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 also have lower level of regulatory T cells, and more obviously damaged in severe cases.
T cells should be doing the 'heavy lifting' in fighting a virus; when they are deficient, the maladaptive compensatory immune response tips toward a surge of inflammation enlisting inflammatory cytokines such as IL-6 (interleukin-6) that entail more tissue damage. Lower levels of T reg (regulatory T) cells diminish the capacity to 'rein in' inflammation. Also of practical clinical interest is the high NLR (neutrophil-lymphocyte-ratio) they observed, a prognosticator of dysregulated inflammation for a wide range of disorders.
Another study examining data from 85 fatal cases with COVID-19 in two hospitals in Wuhan published in the American Journal of Respiratory and Critical Care Medicine reports the association of pre-existing conditions that entail a high level of inflammation prior to infection.
In this depictive study of 85 fatal cases of COVID-19, most cases were male aged over 50 years old with noncommunicable chronic diseases...Hypertension, diabetes and coronary heart disease were the most common comorbidities...The majority of the patients died of multiple organ failure.
In accordance with the observation that a dysfunctional inflammatory response to the infection (rather than the virus itself) causes fatality they note:
Most patients received antibiotic (77 [90.6%]), antiviral (78 [91.8%])...treatments. The combination of anti-microbial drugs did not offer considerable benefit to the outcome of this group of patients.
A paper just published in the Journal of Infection further confirms that the NLR (neutrophil-to-lymphocyte ratio) is an independent risk factor for mortality. They found that patients in the highest third of the range for NLR had fifteen times the risk for a fatal outcome compared with those in the lowest third.
Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality
245 COVID-19 patients were included in the final analyses, and the in-hospital mortality was 13.47%. Multivariate analysis demonstrated that there was 8% higher risk of in-hospital mortality for each unit increase in NLR (Odds ratio [OR] = 1.08; 95% confidence interval [95% CI], 1.01 to 1.14; P = 0.0147). Compared with patients in the lowest tertile, the NLR of patients in the highest tertile had a 15.04-fold higher risk of death (OR = 16.04; 95% CI, 1.14 to 224.95; P = 0.0395) after adjustment for potential confounders. Notably, the fully adjusted OR for mortality was 1.10 in males for each unit increase of NLR (OR = 1.10; 95% CI, 1.02 to 1.19; P = 0.016).
The authors conclude:
We found that higher NLR significantly associated with an increased risk of all-cause death during hospitalization...Since NLR could be quickly calculated based on a blood routine test on admission, clinicians may identify high risk COVID-19 patients at an early stage. Thus, treatments can be modified accordingly to reduce the in-hospital death.
Baseline immunological features can predict outcomes
A very interesting study published in the Journal of Infectious Diseases offers a view of immune phenotypes, consistent with the foregoing, that can identify those at the highest risk of the worst outcomes for viral infections and gives insight into how these patients can be helped. Their key findings include:
An increased fraction of activated T cells poised to respond confers a survival advantage after virus infections.
Increased frequencies of regulatory T cells at steady-state Is associated with Protection from death after infection.
Enhanced T-Cell production of proinflammatory cytokines at baseline Is associated with increased risk of death after virus infection.
In their discussion they highlight the role of T reg cells, which can notably be supported by agents commonly deployed in a functional medicine model. It also brings up the important consideration of averting autoimmune conditions from developing in those who recover from the acute infection.
We found that an increased frequency of Tregs with a unique suppressive profile correlated with protection (Figure 2), which supports the notion that balance between active immunity and suppression is likely critical to spare the host from severe disease after infection. We have previously found that Tregs can play a role in protection from human immunodeficiency virus infection through analysis of a case-control cohort [39], and, in addition, there is precedent for Tregs playing a role in protection from immunopathology after infection [40–42]. Furthermore, it has previously been shown that Treg activity is required during viral infections to allow for appropriate generation and migration of immune effector cells to the site of infection [43–45]. Thus, it is possible that this increased Treg abundance and expression of the suppressive marker GITR play a role in coordinating effective antiviral immunity. Alternatively, it is also possible that Tregs could assist in attenuating antiviral immunity upon viral clearance, thereby sparing the host additional collateral damage that could be associated with a prolonged active immune response.
The authors conclude:
Overall, our results define distinct baseline T-cell correlates associated with survival after viral challenge. This study not only identifies specific basal immune characteristics that are associated with protection from mortality upon virus infections, but it also underscores the need for a protective immune response to be balanced to protect the host not only from uncontrolled virus replication but also from disease associated with robust immunity...Likewise, the T-cell profile can inform methods by which to screen for individuals at increased risk of severe clinical disease upon virus infections.
Supporting the fundamental character of these observations, patterns of tolerance versus lethality were also reported in a study of Ebola virus disease (EVD) published in Cell Reports.
...splenic inflammatory responses were highly activated at earlier time points in tolerant animals and diminished by day 5 p.i. [post-infection], while in lethal infection, these pathways became more activated over time, suggesting that tolerance is associated with a tightly regulated host response in immune cells, and lethality is characterized by a deficient host response at earlier time points followed by largely unregulated immune activation...Lethal EVD is likewise associated with increased inflammatory activity at day 5 p.i. in the liver...Taken together, these data indicate that lethal disease is associated with a loss of inflammatory regulation...
Additional observations regarding antioxidant status and glutathione have great practical significance:
Although tolerant animals do show increased vascular injury at day 5 p.i., they do not include an accompanying loss of vascular function, nor do they show sustained vascular activation...In lethal EVD...Antioxidant responses such as glutathionesynthesis and nuclear factor, erythroid-like 2 (NRF2) were suppressed, while oxidative pathways such as inducible or endothelial nitric oxide synthase (iNOS/eNOS) associated with the production of reactive oxygen species (ROS) were activated. Oxidative stress triggers multiple hematological responses, including aberrant platelet activation, coagulation induction, endothelial inflammation, and increased vascular permeability...genetic background and downstream host responses play a critical role in determining severity...
The vascular damage is especially relevant in that the severe lung pathology of COVID-19 not turning out to be the same as typical ARDS but rather involves injury with loss of function to the delicate vascular components of the respiratory epithelial barrier tissue. The above gives some insight into why very high-dose vitamin C infusions may be helpful in critical cases.
In a paper on immune responses to COVID-19 and potential vaccines just published in the Asian Pacific Journal of Allergy and Immunology, the authors highlight the importance of the innate and Th1 immune responses in resisting infection.
Immune responses during SARS-CoV-2 infection
Effective innate immune response against viral infection relies heavily on the interferon (IFN) type I responses and its downstream cascade that culminates in controlling viral replication and induction of effective adaptive immune response...In the nuclei...transcription factors induce expression of type I IFN and other pro-inflammatory cytokines and this initial responses comprise the first line defense against viral infection at the entry site. A successful mounting of this type I IFN response should be able to suppress viral replication and dissemination at an early stage.
In general, the Th1 type immune response plays a dominant role in an adaptive immunity to viral infections. Cytokine microenvironment generated by antigen presenting cells dictate the direction of T cell responses. Helper T cells orchestrate the overall adaptive response, while cytotoxic T cells are essential in killing of viral infected cells...Current evidences strongly indicated that Th1 type response is a key for successful control of SARS-CoV and MERSCoV and probably true for SARS-CoV-2 as well. CD8+ T cell response, even though crucial, needs to be well controlled in order not to cause lung pathology.
They also note that it is the dysregulated immune inflammatory response that is responsible for lethal outcomes and highlight the importance of the NLR (neutrophil-to-lymphocyte) ratio.
Immune responses during SARS-CoV-2 infection
In the severe or lethal cases of SARS-CoV or MERS-CoV infection, increased neutrophil and monocyte-macrophages influx are consistently observed. In a mouse model of SARSCoV infection, dysregulated type I IFN and inflammatory monocyte-macrophages are the main cause of lethal pneumonia. Therefore, excessive type I IFN with the infiltrated myeloid cells are the main cause of lung dysfunction and negatively impact the outcome of the infection.
Pre-existing conditions with inflammation strongly affect outcome
Inflammation is purposeful when it acts to clear an infection, malignant cell, foreign body, or as part of the repair response to trauma. When the job is complete it winds back down to the baseline level and normalcy returns. Non-purposeful inflammation persists in excess of what is required to ensure infection control and tissue repair, or attacks self-tissue in chronic autoimmune and autoinflammatory disorders. These include cardiovascular and metabolic-inflammatory diseases such as diabetes and obesity. When fighting a virus, the immune system must activate a crescendo of inflammation to combat infection. When a person's baseline (before infection) level of non-purposeful inflammation is already high, there is less ability to accommodate the anti-viral surge in inflammation. This risks the loss of regulation that is supposed to prevent an overzealous reaction resulting in the lung damage of ARDS (acute respiratory distress syndrome).
Authors of a systematic review and meta-analysis just published in Archives of Academic Emergency Medicine report on the prevalence of underlying diseases in patients hospitalized for COVID-19. They examined data of data of 76,993 patients for their study.
According to the findings of the present study, hypertension, cardiovascular diseases, diabetes mellitus, smoking, chronic obstructive pulmonary disease (COPD), malignancy, and chronic kidney disease were among the most prevalent underlying diseases among hospitalized COVID-19 patients, respectively.
All the above common conditions are characterized by a systemic burden of inflammation.
In a paper just published in Clinical Immunology, the authors review these principles from the perspective of clinical immunologists and rheumatologists as they discuss the use of anti-inflammatory drugs in the treatment of severe COVID-19. Highlights of their study include:
Inflammatory cytokine storm was very common in patients with severe COVID-19.
The immune system was impaired in critical COVID-19 patients.
A timely anti-inflammation treatment at the right window time is of pivotal importance.
Features common to critical COVID-19 patients include:
1) sudden deterioration of disease around one to two weeks after onset; 2) much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; 3) extremely high inflammatory parameters, including C reactive protein (CRP) and pro-inflammatory cytokines (IL-6, TNFα, IL-8, et al); 4) destroyed immune system revealed by atrophy of spleen and lymph nodes, along with reduced lymphocytes in lymphoid organs; 5) the majority of infiltrated immune cells in lung lesion are monocytes and macrophages, but minimal lymphocytes infiltration; 6) mimicry of vasculitis, hypercoagulability and multiple organs damage.
In addition to the inflammatory component, these spotlight the diminished Th1 and innate immunity noted at the beginning of this post.
They also comment on the phenomenon referred to as 'cytokine storm':
Cytokine storm (CS) refers to excessive and uncontrolled release of pro-inflammatory cytokines. Cytokine storm syndrome can be caused by a variety of diseases, including infectious diseases, rheumatic diseases and tumor immunotherapy. Clinically, it commonly presents as systemic inflammation, multiple organ failure, and high inflammatory parameters.
Consistent with others, most of severe COVID-19 patients in our ICU ward had persistent very high level of erythrocyte sedimentation rate (ESR), CRP, and high level of IL-6, TNFα, IL-1β, IL-8, IL2R, etc., and were associated with ARDS, hypercoagulation and disseminated intravascular coagulation (DIC), manifested as thrombosis, thrombocytopenia, gangrene of extremities...More strikingly, the autopsy findings revealed that the secondary lymphoid tissues had been destroyed in COVID-19 patients...we speculate that lymphocytes were probably destroyed by CS.
A small proportion of COVID-19 patients would transit into the third and most severe stage of illness, which manifested as an extra-pulmonary systemic hyperinflammation syndrome. In this stage, markers of systemic inflammation appeared to be extremely elevated. Therefore, how to block the CS and when to initiate anti-inflammation therapy is critical for reducing death rate of COVID-19.
Here again we see that damage to the vascular components of the respiratory lining tissues is characteristic of COVID-19 but not typical ARDS.This has been necessitating changes in the usual respiratory ventilator tactics. It further emphasizes the importance of inhibiting the inflammatory process to prevent excessive migration of neutrophils to the area because they trigger mechanisms that are pro-thrombotic.
In considering vascular damage associated with severe COVID-19, these investigators also observed the appearance of autoimmune phenomena, something that is likely to become a major health issue for the survivors of COVID-19 and a future topic in this blog.
Another prominent clinical manifestation in severe COVID-19 patients is endothelium damage. Mimicry of vasculitis could be seen in severe COVID-19 patients. Clinically, many critical ill patients have vasculitis-like manifestations, or even gangrene at their extremities; Pathology examination revealed the blood vessels of alveolar septum were congested and edematous, with modest infiltration of monocytes and lymphocytes within and around blood vessels...
Intriguingly, some patients were tested positive with high titer antiphospholipid antibodies, including anticardiolipin antibodies and anti-β2 glycoprotein antibodies, and were associated with severe thrombosis (unpublished data). The underlying mechanism of vascular damage may be due to the direct injury of endothelial cells by virus, leading to DIC, anti-phospholipid syndrome (APS) and mimicry of vasculitis. The pathological autoimmune responses involved in the anti-virus immunity are worth to be emphasized.
The authors conclude:
...a timely anti-inflammation treatment initiated at the right window time is of pivotal importance and should be tailored in individual patient to achieve the most favorable effects.
In another paper concerned with the induction of pro-inflammatory cytokines IL-1 and IL-6, lung inflammation, and anti-inflammatory strategies for COVID-19, just published in the Journal of Biological Regulators and Homeostatic Agents, the authors concisely review some key features.
Inflammation is mediated by pro-inflammatory cytokines including IL-1, IL-6, TNF and IL-8. IL-1 is the most studied cytokine with properties that are relevant to several inflammatory diseases including viral infections (20-21). The complex synthesis and release of inflammatory IL-1 occurs after the binding of CoV-19 to the Toll Like Receptor (TLR). Activation of this receptor causes a biochemical cascade that begins with the formation of pro-IL-1 cleaved by caspase-1, and followed by activation of inflammasome (22). High levels of adenosinetriphosphate (ATP) (over 100 pM) are correlated with...autoinflammatory mediation. The P2X7 receptor causes the activation of the inflammasome with the production of mature interleukins. Through pro-caspase-1 and Ca++ flow, there is the synthesis of IL-lb in the lysosome (23). IL-lb is then secreted outside the macrophage, mediating lung inflammation, fever and fibrosis, and provoking severe respiratory problems. Immune cells are attracted to the place of infection by IL-8, a chemokine that is generated at the inflammatory site. Pro-inflammatory cytokine levels are correlated with CoV-19 replication and disease. It is intuitive to think that anti-inflammatory cytokines, such as IL-IRa, IL-37 or IL-38, can provide relief in both systemic inflammation and fever that occur after infection.
Inflammation occurs to restore the homeostasis after CoV-19 infection and can be very harmful if not controlled. IL-l generated during inflammation by immune cells, fibroblasts and endothelial cells is a response to the pathogenic virus and plays an important role in the pathogenesis of both acute and chronic obstructive respiratory disease and in the progression of pulmonary fibrosis...
Note that the ATP referred to above, released by damaged and dying cells, is a very powerful stimulus of the immune inflammatory response. Many who survive ARDS may require remediation for pulmonary fibrosis from over-exuberant fibroblasts and excessive TGF-beta production.
Data collected by the newly created COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) presented in Medscape Medical News today almost 90% of those admitted to hospital for COVID-19 have the common co-morbidities referred to above. It's of particular interest that while most are age 65 or older, the percentage in the 18-49 years age group have a pre-existing elevation of inflammation due to either obesity or chronic lung disease.
Some considerations for prevention and outpatient support
In the functional medicine domain there are a number of resources that can be deployed to address concerns illustrated above and foster immune system resilience. Key points to address are reversing the impairment of Th1 and innate immunity that resist infection; deficiency of these is notable in the elderly and those with pre-existing conditions, whose immune systems are polarized for non-purposeful inflammation. And reducing the baseline level of inflammation that when high markedly increases the risk for ARDS and as inflammation increases in response to the virus is crucial. There is validation for a number of available agents in the scientific literature (this is a huge topic). However, their safe and effective use requires study and experience; vaguely selecting from a 'menu' or a 'one-size-fits-all' approach for the general public is not recommended. Individuals vary greatly in overall condition, genetics, immune bias, metabolic and endocrine status, etc.--all aspects that have to be evaluated in order to understand the vulnerability a person may have to viral infection, the phase they may be in if infected; how to effectively target their needs, understand their response, and re-calibrate accordingly. Moreover, there are crucial differences in application depending on whether someone is in the prevention, infection, or an excessive inflammation stage. Dampening inflammation inappropriately may impair the ability to fight infection. Promoting antiviral immunity inappropriately may ramp up inflammation excessively. Laboratory tests for key biomarkers are fundamental. All the components of case management for chronic inflammatory disorders come into play with the intent to reduce the baseline level of inflammation and promote effective immunity. By way of on example, some immediate considerations include:
Ensuring the upper range of normal for potassium, vitamins D, A, and gamma E is widely applicable.
ROS (reactive oxygen species) and oxidative damage should be well-controlled (check F2-isoprostane, myeloperoxidase).
Astragalus, andrographis, and reishi mushroom support NK (natural killer) cells (innate immunity).
Berberine, baicalin (Scutellaria baicalensis), echinacea, and goldenseal support Th1 immunity.
Quercetin and vitamin C dampen Th2 thus promoting Th1 immunity.
Melatonin, which supports Th1 immunity in addition to sleep, should be ample.
Glutathione is an extremely important regulator of the immune response, inflammation, oxidative stress, and may be critical in the ELF (epithelial lung fluid); it can be supported by NAC (N-acetyl-cysteine).
Curcumin, berberine, and resveratrol also regulate inflammation and reduce fibrosis.
High insulin levels are pro-inflammatory; berberine and resveratrol also support insulin receptor and AMPK function. Naturally, a diet that does not over-stimulate the release of insulin or trigger inflammation, along with good sleep and stress management are fundamental for health.
Stress chemistry is pro-inflammatory; there are a number of natural adaptogens that can be combined to ameliorate its effect.
High (ventral) parasympathetic tone opposes the pro-inflammatory effect of excess sympathetic nervous system arousal. Transcutaneous vagus nerve stimulation (vTNS) can be simply and inexpensively applied at home.
The neural substrate for healthy physiology in general as well as immune regulation is healthy ventral vagus nerve function (see polyvagal theory), the is experienced as the non-cognitive ('neuroceptive') experience of feeling safe. SSP (the Safe & Sound Protocol of sound stimulation) is designed for this purpose.
The gut and oral microbiome should be attended to for immune system health, a large topic in itself.
Low-dose cytokine therapy is an under-utilized resource.
A PubMed literature search will yield background on these items, including studies that elaborate on their effects regarding the effects on cytokines and other details described in the papers referred to above. This list is merely a limited example; there are more interventions worthy of consideration but, like these, they must be deployed according to informed clinical judgment.
For implications concerning the immune dysregulation characteristic of serious COVID-19 cases and an aftermath of mental health disorders see COVID-19 and immune effects on mental health.
For concerns about autoimmunity triggered by infection see Induction of autoimmunity by infection.