by Atmaram Yarlagadda, MD; Samuel L. Preston, DO;  Rachel P. Jeyadhas, MD; Adam Edward Lang, PharmD;  Rasha Hammamieh, PhD; And Anita H. Clayton, MD

Dr. Yarlagadda is the Installation Director of Psychological Health at McDonald Army Health Center in Fort Eustis, Virginia. Dr. Preston is with Uniformed Services University of Health Sciences in Bethesda, Maryland. Dr. Jeyadhas is with the Hampton VA Medical Center in Hampton, Virginia. Dr. Lang is with McDonald Army Health Center in Fort Eustis, Virginia. Dr. Hammamieh is with the Walter Reed Army Institute of Research in Silver Spring, Maryland. Dr. Clayton is with the University of Virginia in Charlottesville, Virginia.

FUNDING: No funding was provided for this study. 

DISCLOSURES: Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense.

ABSTRACT: Neuropsychiatric manifestations of COVID-19 have become increasingly common in published literature as the COVID-19 pandemic continues to devastate the world. Morbidity and mortality associated with COVID-19 infection is driving recognition of the need for potential research in prevention, effective treatment, and reducing fatalities. In this article, we highlighted discussions and proposals previously reported in our series of articles on the subject of the blood–brain barrier to prevent both neurological and psychiatric manifestations of viral infection. The time for a rapid translational approach to bring point-of-care diagnostics and early prevention/treatment tools to practice is now, and it deserves immediate attention. 

Keywords: Cytokine Norms, cytokine signature, pandemics, COVID-19,  blood-brain barrier 

Innov Clin Neurosci. 2021;18(1–3):xx–xx

Identification, isolation, and contact tracing is the algorithm that resonates during any pandemic, particularly with COVID-19-related infection. The triad of allergy, immunology, and infectious diseases are familiar words to clinicians and medical researchers. However, the common element of allergies and infectious diseases is immunology; that is, mounting an immune response to the allergen, (be it chemical or viral in origin). The ability to launch an immune response, and the level of that response in an individual, is seldom known or quantified. Immune responses vary from person to person with mild, moderate, and severe manifestations of the same infection in different individuals. One possible target for assessment is cytokines that circulate peripherally and have the capability to freely cross the blood–brain barrier (BBB).


We will begin with an introductory quote related to the concept of a compromised BBB resulting from and leading to “cytokine-induced sickness behavior, comprised of increased sleep, reduced appetite, decreased sexual drive, and overwhelming fatigue frequently combined with fever” by Michael Maes.1 Over time, this concept has been extended beyond Maes’s observations to several areas of clinical practice correlating vegetative symptoms of depression to manifestations of cytokine induced sickness. Cytokines have unique pleiotropic immunomodulatory mechanisms; one cytokine gene can influence multiple different responses to a given immune reaction.2 Because of high reactivity, standardized collection, storage, and measurement are required. Complicating this response are genetic polymorphisms of various cytokines in association with different disease entities.3 In other words, modifications in genetic expression (epigenetics) amplify rapid phenotypical changes leading to marked changes in protein synthesis.

Relevance to BBB. Cytokines can cross the BBB with ease, whereas the COVID-19 enters through nasal infection and reaches the central nervous system (CNS) through the olfactory bulb, causing neuroinflammation and demyelination of neuronal cells.4 Cytokines activate free calcium, and by potentially disrupting the compartmental model of brain calcium homeostasis, compromise the integrity of the BBB. It has also been reported that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show encephalopathy and neuroinflammation resulting from a cytokine storm.5 The impact of cytokines, whether exogenous or endogenous, in the brain might result in lasting neuropsychiatric effects if left unchecked. This is partly due the limited lymphatic drainage capability of the brain, of which we theorized the presence in 2009 and was confirmed by a team of researchers at University of Virginia in 2015.6,7 Therefore, identification of genetic and epigenetic factors leading to increased cytokines crossing the BBB is crucial, as early interventions, such as treatment with anti-inflammatory agents, administration of antibodies to cytokines (monoclonal), or injection of certain anti-inflammatory cytokines directly, might prevent the development of chronic neuropsychiatric complications inflicted by a “cytokine storm.”6,8 Progressive loss of lymphatic drainage might contribute to the increased age-related morbidities and fatalities seen now with COVID-19 infections, with additional risk associated with dementias and other viral and autoimmune conditions of the CNS.

COVID-19-Related Neurological Manifestations

To better understand the depth and extent of neurological involvement in COVID-19, Motalvan et al analyzed data from 214 patients with COVID-19 from 67 studies, concluding that 36.4 percent of patients diagnosed with COVID-19 had neurological manifestations. Neurological symptoms reflect central infection (e.g., headaches, dizziness, impaired consciousness, acute cerebrovascular disease, ataxia, seizures, special senses), peripheral manifestations (e.g., hypogeusia, hyposmia), and musculoskeletal signs (i.e., ischemic or hemorrhagic effects). Of note, (severe) fatigue was the most common symptom (69.6%), followed by myalgia (34.8%), and headaches (6.5%). High fever, lower oxygen saturation levels, shortness of breath, congestion, runny nose, nausea, and diarrhea (not highlighted by this group) are centrally originated, and thus have systemic manifestations.4 Experimental models have shown that other coronaviruses also compromise the CNS by directly targeting neurons at the cardiorespiratory and olfactory centers, which might explain other CNS SARS-CoV-2 symptoms.9 

Measuring cytokines. COVID-19 has suddenly raised the awareness of cytokines and their mechanisms of action, cytokine storms, and more interestingly, the existence of ongoing treatments with monoclonal antibodies targeting specific cytokines, such as tumor necrosis factor (TNF) α, interleukin (IL), and interferon (IFN) γ.10,11 Ironically, there are few, if any, studies that actually address the meaning of levels of these cytokines, in other words, a system to assess risk and to monitor or compare change/progression compared with baseline numbers. It has now become increasingly clear that interventions to fight COVID-19-related severe pathological manifestations complicated by cytokines must be rapidly developed. Literature is surfacing on high levels of IL-13, in patients placed on ventilators versus those who did not require mechanical ventilation, for example.12 Another recent study that evaluated factors contributing to COVID-19 severity found abnormally high levels of pro-inflammatory cytokines IL-6 and IL-8 and associated lymphocytopenia caused by depletion of CD3+T cells.13 The case for increased monitoring of cytokine levels is becoming stronger and more relevant, not just for COVID-19, but also in other conditions described above, e.g., allergy and infectious diseases, and might overlap or be additive. 

Cytokines can be classified into three groups: 1) pro-inflammatory or those that help launch the immune response (IL-1, IL-6, and TNF); 2) anti-inflammatory or those that block or dampen the immune response (IL-4, IL-10, and IL-3); and 3) hematopoietic or those involved in stimulating the differentiation of hematologic progenitor cells into red and white blood cells (IL-3, IL-5, and G-CSF). This variability in effects points to the need to better understand baseline values of key cytokine levels in normal controls.6

Early versus late manifestations/symptoms are important factors to be considered when cytokine-related end-organ damage is involved. Positive COVID-19 testing followed by comparison of levels of viral load and the respondent release of cytokines, due to the “storm” peripherally, can hypothetically provide the ranges from which a ratio can be derived. Initial levels could be compared to measurable control values (most likely targets of pro-inflammatory cytokines: IL-1, IL-6, TNF, and anti-inflammatory cytokines: IL-4 and IL-10) with reasonable expectations for the development of an algorithm for treatment guidance and monitoring to avoid irreversible end-organ damage. Emerging literature on the natural course of the disease with no intervention points to fibrosis of the lung parenchyma, neuronal invasion followed by neuronal death, paresthesias, seizures, other serious conditions, such as Guillain-Barré syndrome (GBS) and acute disseminated encephalomyelitis (ADEM), stroke, cardiovascular disease, and all too frequently, death.4,14–20

Treatment options under study and currently available have different mechanisms of action: 1) remdesivir, which is directed at decreasing the virulence or viral activity; 2) hydroxychloroquine, which can block acidification, and thus inhibit the attachment of the virus to the cell surface receptor; and 3) dexamethasone, which reduces the inflammatory response, e.g., decreases swelling.21–23 The fundamentals of the inflammatory response stated in Latin, i.e., calor (heat or temperature), dolor (pain or extreme fatigue), rubor (redness or appearance like conjunctivitis), and tumor (swelling) are classic cytokine storm-related stages seen in SARS-CoV-2 pathophysiology. 

In our opinion, the following medications currently available and in clinical trials could potentially be repurposed for the prevention of cytokine storm-related morbidity and mortalities in patients with COVID-19:

Antibodies directed at pro-inflammatory cytokines, such as IL-1, IL-6, and TNF alpha, include 1) the IL-6 blockers, tocilizumab approved to treat rheumatoid arthritis, siltuximab investigated as a cancer therapy, and several others in the same class of drugs; 2) adalimumab, a TNF-blocker approved for the treatment of rheumatoid arthritis; and 3) the IL-1 blocker, anakinra also used in the treatment of rheumatoid arthritis.24,25

Anti-inflammatory cytokines IL-4, IL-10, IL-11, and IL-13 administered as an injection, which could potentially be lifesaving in select patients with COVID-19

Hematopoietic cytokines (erythropoietin, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor) that might promote cell differentiation and reduce morbidity

However, potential adverse effects to these treatments might negatively impact outcomes, e.g., systemic lupus erythematosus-like symptoms with anti-TNFα therapy in patients with rheumatoid arthritis due to accumulation of another cytokine, IFN-α, and cytokine-mediated hippocampal damage due to weakened BBB in patients with acute respiratory distress syndrome (ARDS).26,27

Translational Medicine

Cytokine norms are needed going forward to address treatment of cytokine storms. Cytokine norms would be derived by profiling peripheral cytokine levels in controls and patients positive for COVID-19, leading to an algorithm for appropriate treatment plans for patients with COVID-19 and those with other related viral, bacterial, and allergic conditions. 

Efforts to promote cytokine norms require standardized assays to establish norms of cytokine levels in healthy individuals and cytokine levels in patients with COVID-19 with and without systemic symptoms evaluated across all age groups. The pleiotropic complexities of cytokines will challenge both clinicians and researchers alike to develop a system for treatments and monitoring of response based on levels of specific cytokines across the course of the infection associated with specific morbidities. 

Meanwhile, we propose a fast-track immune status approach to establish appropriate levels of anti-inflammatory cytokine norms, which might vary with age and at initial presentation with COVID-19, to include IL-4, IL-10, IL-11, and IL-13, as they are well studied and less complex. Standardizing and establishing an acceptable normal range for anti-inflammatory cytokines in controls might inform the immune status similar to the range of other lab values used in daily clinical practice. In other words, pro-inflammatory versus anti-inflammatory cytokine ratios and interactions can be established and possibly corrected by infusion of anti-inflammatory cytokines along with hematopoietic cytokines to stimulate the launch of progenitor cells in seriously ill patients with COVID-19.

Limitations. Individual immune response to COVID-19 varies widely; therefore, developing timelines, tracking individual responses over time, and establishing a “core” COVID cytokine signature are all challenges that remain to be investigated. 


Views of the BBB have changed significantly over time; the concept of a “barrier” is now theorized as a highly segregated neuroimmune partition between brain parenchyma and meningeal spaces. Cytokine distribution in the brain is not well defined in contrast to circulating peripheral levels. The final question of interest is whether it is cytokine storm or cytokine pleomorphism that makes COVID-19 more fatal.


This article is dedicated to healthcare workers placing their lives in danger treating patients with COVID-19 on a daily basis.


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