Treatment of Severe COVID-19 Illness

A Pediatric Rheumatologist’s Perspective and Proposed Treatment Protocol

“Human experience, which is constantly contradicting theory, is the greatest test of Truth.”

Samuel Johnson

ABSTRACT:

This article offers an approach to treatment of severe COVID-19 illness that might save lives, prevent organ damage, reduce ICU admissions, minimize need for mechanical ventilation, shorten length of hospital and ICU stays, reduce hospital costs, and, in the process, reduce fears, angst, moral stress, and a sense of powerlessness among patients, families, physicians, nurses, other health care workers, and the public.

In most cases of COVID-19 the immune system safely and efficiently neutralizes the virus, such that the patient is either asymptomatic or experiences only mild-moderate symptoms (which may create misery but are not life-threatening or organ threatening and do not require hospitalization). A minority of patients with COVID-19 experience severe, life-threatening illness. Tragically, 337,419 people in the USA have died from COVID-19, according to the CDC (as of this writing, on 12/30/20). Currently, hospitals and ICUs throughout California and much of the country are being overwhelmed with severely ill patients. Due to shortage of beds, ventilators, personnel, and supplies, rationing of health care is now being seriously contemplated.

In the majority of patients with severe COVID-19 illness the most threatening aspects of the illness appear to be due, not to ongoing active viral infection, but to excessive immune reactions to the virus— hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm.”

These life-threatening abnormal immune reactions are not new or unique to COVID-19 infection. For years it has been known that life-threatening hyperinflammation and cytokine storm occur with many bacterial infections and with many other viral infections, including seasonal influenza infection.

Over the past four decades, pediatric rheumatologists have developed extensive experience with excessive immune reactions (hyperinflammatory, hyperimmune, autoimmune, and cytokine storm reactions), including how to bring them under control. Much of this experience has come from managing systemic onset juvenile idiopathic arthritis that has become complicated by macrophage activation syndrome and “cytokine storm.” The pediatric rheumatology approach to hyperinflammatory states is characterized by early, anticipatory, appropriately compulsive, serial monitoring; prompt and appropriately bold immunosuppression of hyperinflammation, carefully using corticosteroid and anti-cytokine therapies (e.g., anakinra); and careful, anticipatory, tailored adjustments along the way—always balancing concerns about risks versus benefits.

Pediatric rheumatologists have experienced remarkable success with this approach to treatment of hyperinflammatory/hyperimmune reactions. This approach has the capacity to bring life-threatening cytokine storm under control, often within 1-4 days. If applied to management of severe COVID-19 illness, this approach may save many lives, reduce ICU admissions, and shorten hospitalizations. Details of this approach are provided in a Proposed Treatment Protocol for Severe COVID-19 Illness (see APPENDIX).

KEY WORDS: COVID-19, Hyperinflammation, Cytokine Storm, microvascular Endotheliopathy, Corticosteroid, Anti-Cytokine Treatment, Susac syndrome

BACKGROUND:

Normal behavior of Innate and adaptive immunity:

In most cases of COVID-19 infection (perhaps as many as 98% of those infected? [1]) the immune system safely and efficiently neutralizes the virus, such that the patient is either asymptomatic or experiences only mild-moderate symptoms (which may cause considerable misery but are not life-threatening or organ threatening and do not require hospitalization). In these cases, the two main phases of immune reactivity work remarkably well together:

First, the relatively primitive innate immune system quickly senses danger and creates (e.g., via Type 1 interferon) an immediate local anti-viral milieu that thwarts viral replication—thereby diminishing the viral load. Second, the innate immune system (via Type 1 interferon, cytokines, and chemokines) activates the more sophisticated adaptive immune system (e.g., B cells and T cells) which then produces virus-specific antibodies (first IgM, then IgG), activates cytotoxic T cells (which kill virus-infected cells to slow viral propagation to other cells), and creates memory B and T cells for future protection against that virus (and, to a lesser extent, against similar viruses).

For this sequential two-phase process to be safe, efficient, and successful, just the right amount of Type 1 interferon needs to be promptly made available; just the right extent of activation of the adaptive immune system needs to occur; and the timing of these two processes needs to be right. Too little (or too late) or too much Type 1 interferon can be harmful; and too little (or too late) or too much of an adaptive immune response can be harmful. Furthermore, both the innate and adaptive immune systems need to make wise, timely, coordinated adjustments along the way, including shutting down reactions as soon as they are no longer needed. It is all about careful timing, balance, coordination, regulation, and adjustment.

Abnormal behavior of innate and adaptive immunity in COVID-19—hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm”:

A small percentage of patients with COVID-19 experience severe illness, and in most of these cases the most threatening aspects of the illness appear to be due, not to ongoing active viral infection, but to excessive immune reactions triggered by the virus. [2-13] It is possible that in some cases of severe illness the main problem is that the Type 1 interferon reaction is too slow or otherwise inadequate, and/or the initial cytotoxic T cell response is too slow or otherwise dysfunctional, such that the virus is not promptly neutralized and overwhelms the patient. But most often, the main problem in patients with severe COVID-19 illness appears to be that their innate immune system, or their adaptive immune system, or both, have become excessively active, and these excessive immune reactions cause the severe illness. Instead of mounting an appropriate, timely, well-coordinated, well-balanced immune reaction, the immune system appears to excessively activate much of its armamentarium—both the innate armamentarium and the adaptive armamentarium—resulting in hyperinflammatory, hyperimmune reactions, often with “cytokine storm.” [2-13]

Great imbalance, discoordination, dysregulation, dysfunction, and hyperactivity characterize these hyperinflammatory/hyperimmune reactions. The immune system, for example, excessively activates macrophages (a powerful and explosive primitive component of our innate immunity); excessively releases an array of potentially harmful cytokines (resulting in a “cytokine storm”); may excessively activate cytotoxic T cells (which may be dysfunctional, as well, or become exhausted); and excessively triggers complement and coagulation cascades. These activations feed-back on each other, accelerate each other, and create vicious cycles that further escalate and perpetuate the excessive immune reactions. Production of autoantibodies (e.g., anti-phospholipid antibodies and anti-platelet antibodies) may add to these problems. [9, 13] Furthermore, an appropriate immune attack directed against viral proteins may be accompanied by an inappropriate and harmful attack on similar looking human proteins—cross-reactive “molecular mimicry.” [9, 10]

Note: Hereafter, for purposes of brevity, the more inclusive term, “hyperimmune reactions,” will sometimes be used instead of “hyperinflammatory, hyperimmune reactions, often with cytokine storm.” The term “hyperimmune reactions” refers not only to hyperinflammation and cytokine storm, but also to a variety of other immune-mediated phenomena that may occur with COVID-19— e.g., abnormal production of autoantibodies; cross-reactive immune attack directed at human proteins (molecular mimicry); and autoimmune reactions that involve little or no hyperinflammation (such as possible immune-mediated microvascular endotheliopathy).

Harmful consequences of hyperimmune reactions:

Quite soon, these excessive immune reactions start damaging human cells and organs. For example, the storm of cytokines causes fever, clinical and laboratory signs of systemic inflammation, and immune-mediated injury to multiple organs. In addition, it is possible that endothelial cells that line the inner walls of the pulmonary microvasculature may become immunologically injured (my hypothesis, not yet proven) and swell, potentially partially occluding the lumen of these vessels, thereby reducing blood flow to the lung’s air sacs (alveoli). Through a variety of potential mechanisms the alveoli may become both ischemically and immunologically injured, inflamed, and potentially fibrosed. In some patients, activated coagulation cascades result in micro and macro thrombi, potentially throughout all vasculatures. Abnormal production of anti-phospholipid antibodies may add to risk of thrombosis. [9, 13]

All organs, including the brain, can be affected by these unfortunate immune-mediated phenomena. Respiratory failure, multi-organ failure, cardiac failure, strokes, and death often result, particularly if these excessive immune reactions proceed un-treated or inadequately treated, as opposed to being detected early and promptly and adequately suppressed.

Indeed, the leading cause of life-threatening/organ threatening complications of COVID-19 appears to be the above-mentioned hyperimmune reactions. [7] Development of cytokine storm has appeared to be the major determinant of COVID-19 outcome. Clinical and lab features of cytokine storm have correlated well with poor outcome in COVID-19. [2-8] Elevated cytokine levels (e.g., IL-6) have been found in most patients dying of COVID. [7]

[Note: The above discussion represents a simplified and incomplete understanding of the complex immunologic events occurring in severe COVID-19 illness. There is still much to be learned about the immune aberrations that occur in COVID-19, including the possibility that the virus itself might have adverse effects on a person’s immune competency.]

Hyperimmune reactions are not new or unique to COVID-19 infection:

Hyperimmune reactions are certainly not new or unique to COVID-19 infection. For many years it has been known that life-threatening hyperinflammation/cytokine storm occurs with many bacterial infections and with many other viral infections, including seasonal influenza infection. [12, 14-22] In fact, usual seasonal influenza viruses are major triggers of cytokine storm. [2] In one study of patients who died of H1N1 influenza, 81% had features of cytokine storm. [18]

PEDIATRIC RHEUMATOLOGY EXPERIENCE WITH HYPERIMMUNE REACTIONS:

History:

For many years, pediatric rheumatologists have struggled to understand and treat excessive immune reactions, including hyperinflammation and cytokine storm. [23-44] Pediatric rheumatologists have played a leading role in studying hyperimmune reactions, because many childhood autoimmune/autoinflammatory diseases (e.g., systemic onset juvenile idiopathic arthritis) become complicated by excessive macrophage activation (macrophage activation syndrome) and “cytokine storm.” [23-44] Their knowledge of hyperimmune reactions has resulted from extensive individual and collective experience and collaborative international study, including thoughtful development of strict diagnostic and classification criteria and uniform treatment protocols [23, 24, 25, 31, 32], as well as randomized clinical trials. [37-39]

Nearly 40 years ago, when I was a visiting pediatric rheumatologist at Beijing Children’s Hospital, I vividly remember discussing (with Beijing pediatricians) the excessive macrophage activation and massive cytokine release associated with systemic onset juvenile idiopathic arthritis (JIA) and how to treat it (with high dose corticosteroid, at that time). The concept of excessive macrophage activation/excessive release of cytokines was new at that time in the USA and Europe and was largely unknown in China.

Since then, pediatric rheumatologists around the world have been routinely and successfully treating hyperinflammatory/hyperimmune reactions (e.g., macrophage activation syndrome, “cytokine storm,” secondary HLH, and systemic inflammatory response syndrome) with corticosteroid and, more recently, with specific anti-cytokine treatments—either anti-IL-1 treatment (anakinra) or anti-IL-6 treatment (tocilizumab). [37-44] These treatments have been lifesaving and organ-saving, particularly when these hyperinflammatory/hyperimmune reactions are recognized early; treated promptly with appropriately aggressive immunosuppression; and monitored compulsively with serial lab testing, with nuanced adjustments being made along the way. Bold, but careful, use of corticosteroid and anakinra has shown capacity to bring cytokine storm under control, often within a few days.

Pediatric rheumatology’s understanding of hyperimmune reactions and how to best treat them is still a work in progress. Pediatric rheumatologists are still learning. It has been a difficult and humbling 40-year process, and many questions remain unanswered. But the experience of pediatric rheumatologists is relevant to severe COVID-19 illness and worth sharing.

Lessons learned, regarding hyperimmune reactions:

An important lesson that pediatric rheumatologists have learned about cytokine storm is that if the clinician acts too slowly or too timidly, the patient will suffer greatly and may die. Anticipatory thinking, early detection, prompt and appropriately bold immunosuppressive treatment, compulsive serial monitoring, and careful adjustments, have been the keys to success. Failure to anticipate, failure to detect early, failure to promptly treat appropriately aggressively, failure to compulsively monitor, and failure to make wise adjustments can, each by themselves, cause preventable death and damage. Personal experiences, collective clinical observations, carefully studied collaborative case series, and, ultimately, randomized clinical trials [37-39] have documented the value of the pediatric rheumatology approach to hyperimmune reactions associated with childhood rheumatic diseases—diseases which, by the way, are often much more explosively hyperinflammatory and life-threatening than their counterparts in adults.

Application of experience with childhood rheumatic diseases to infection-triggered hyperimmune reactions:

The above experience of pediatric rheumatologists has been applied to the recognition and treatment of hyperimmune reactions triggered by bacterial and viral infection, in adults and children. [12, 45-51] Historically, for many years, Emergency Department physicians, hospitalists, and ICU pediatricians in children’s hospitals have commonly consulted pediatric rheumatologists for help in recognizing and treating infection-triggered hyperimmune reactions. Randomized controlled trials of immunosuppressive treatment of infection-related hyperimmune reactions have been conducted. [45, 46]

In other words, for many years before COVID-19 arrived on the scene, pediatricians and pediatric rheumatologists (and physicians for adults) had developed considerable experience with the diagnosis and treatment of infection-triggered hyperimmune reactions. We learned to test patients serially and proactively for elevated levels of CRP, serum ferritin, D-dimer, PT, PTT, triglycerides, LDH, and liver transaminases; and lowered levels of platelets, lymphocytes, albumin, and fibrinogen—early markers of an evolving hyperinflammation/cytokine storm. And we learned to treat aggressively and promptly, but carefully, with corticosteroid and specific anti-cytokine therapies, such as anakinra—all the while worrying about administering immunosuppression in the context of infection, but not being paralyzed by that worry.

Decision-making in the absence of randomized controlled trials:

In the beginning, we did not have randomized controlled trials that proved that this treatment for infection-related hyperinflammation was effective, safe, and necessary. We quickly learned, though, from individual and collective experience, that these children were likely to die or sustain irreversible multi-organ damage, if not treated promptly and aggressively with immunosuppressive medications. Knowing that these children were faced with a life-threatening and organ-threatening disease process, we (and the child’s parents and grandparents) felt morally and ethically obligated to boldly treat these children, despite absence of randomized controlled trials. The alternative, watching them suffer and die, seemed obviously unacceptable.

It seemed to be unethical and unwise to withhold corticosteroid and anakinra treatment that had worked so well for hyperinflammatory reactions associated with childhood rheumatic diseases, simply because no randomized clinical trials had yet been conducted to prove the safety, efficacy, and necessity of such treatment in the context of infection-triggered hyperinflammation. Yes, of course, randomized double-blind, controlled trials would have been ideal, but they were unavailable and would take much time to complete. In the meantime, it seemed unacceptable to withhold treatments that were likely to be effective, safe, and necessary.

Our careful boldness resulted in the eventual accumulation of increasingly positive clinical evidence of the efficacy, safety, and necessity of such treatment—for both hyperinflammatory reactions associated with childhood rheumatic diseases and hyperinflammatory reactions associated with infection. Prior to onset of the COVID-19 epidemic, ample ideal randomized controlled trials still had not been completed for treatment of viral-triggered hyperinflammatory reactions, but lessons from treatment of hyperinflammatory reactions associated with childhood rheumatic diseases had become well-established and were available for valuable guidance.

For several years now, prompt recognition and careful, bold immunosuppressive treatment have become the “standard of care” for hyperinflammatory reactions in children—both when it occurs in the context of a childhood rheumatic disease and in the context of infection. Many pediatric rheumatologists, particularly those of us who have seen the tragic outcomes of untreated and under-treated children, would not automatically withhold corticosteroid and anakinra from a child suffering from life-threatening viral-triggered cytokine storm/hyperinflammation, and instead, watch them suffer and die, un-treated, or only minimally treated, as if there was nothing we could, or should do, or appropriately try (other than supportive measures).

Immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy—a possible cause of the “silent hypoxia” noted in COVID-19:

Pediatric rheumatologists have also learned how to recognize and treat immune-mediated microvascular endotheliopathies —as occurs in juvenile dermatomyositis and in Susac syndrome. [52-54] In these microvascular endotheliopathies, the endothelial cells that line the inner walls of the small blood vessels become immunologically injured, swell, and partially occlude the lumen of the vessels. This reduces blood flow through these vessels and leads to ischemic injury to the tissues they perfuse.

This is mentioned because one hypothesis is that one of the earliest abnormal immune reactions in COVID-19 might be a virus-triggered, Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy within the pulmonary microvasculature. [52-58] Such an aberration, which may affect the pulmonary vasculature in an uneven fashion, would lead to varying degrees of decreased blood flow to the alveoli, ischemic injury to the alveoli, impaired oxygenation, and ventilation-perfusion mismatch. It is possible that this is a proximal cause of the initial “silent hypoxia” (and subsequent symptomatic hypoxia) in COVID-19. [59}

This hypothesized abnormal immune reaction in the pulmonary microvasculature would be an example of a hyperimmune reaction that is not typically hyperinflammatory. It is different from the hyperinflammatory/cytokine storm reaction that occurs in COVID-19. The latter reaction probably occurs somewhat later than the hypothesized microvascular endotheliopathy, though it could occur simultaneously. The hyperinflammatory/cytokine storm reaction could add inflammatory injury to the alveoli and, possibly, the pulmonary microvasculature.

If the above hypothesis is true, the best treatment for this early hyperimmune reaction in the pulmonary microvasculature would be prompt, effective immunosuppression, which would also serve to blunt any hyperinflammatory/cytokine storm reaction that might be brewing. Such immunosuppression could protect the alveoli from both ischemic and inflammatory injury and decrease the likelihood of development of acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. But to be effective, this treatment would need to be given early after onset of these immune reactions, before it becomes too late. IVIG and pulses of IV methylprednisolone have usually worked quickly (often within 1-4 days) and well to subdue acute episodes of immune-mediated microvascular endotheliopathy in Susac syndrome. [54]

In addition, it needs to be considered that the SARS-CoV-2 virus itself might cause direct damage to the alveoli. Indeed, a theme throughout this article is that severe COVID-19 illness is due to both the virus itself and excessive immunologic reactions to the virus. Both need to be suppressed in as timely and precise a fashion as possible.

It is conceivable that, in COVID-19, a Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy could occur in the microvasculatures of other organs, including the brain. It is conceivable that the “brain fog,” cognitive dysfunction (e.g., short term memory difficulty), and psychosis experienced by some patients with COVID-19 might be due to immune-mediated microvascular endotheliopathy. [60] If so, such pathology could be successfully reversed with appropriate immunosuppression; and, if left untreated, or inadequately suppressed, could result in irreversible damage.

A PEDIATRIC RHEUMATOLOGY APPROACH TO TREATMENT OF SEVERE COVID-19 ILLNESS:

How might a pediatric rheumatologist approach the problem of severe COVID-19 illness? (See APPENDIX for details about a proposed approach.)

Imagine a spectrum of possible clinical scenarios:

When a patient is admitted to the hospital, a first step is to imagine several possible patient characteristics/profiles (clinical situations):

1. In some patients the main problem might be hyperimmune reactions, with little or no problem with ongoing viral infection. That is, by the time of admission the patient’s innate immune system (and subsequent adaptive immune system) has adequately subdued the viral infection, but excessive immune reactions have become the main problem. At least, the threat posed by the hyperimmune reactions is greater than the threat posed by the viral load at the time. In such a patient, immunosuppression would be the patient’s greatest need—greater immunosuppression if the viral infection has already been fully eradicated; lesser, more careful immunosuppression if viral eradication has been less complete.
2. In other patients (a minority, probably), inadequate eradication of the virus might be the main problem, with little or no hyperimmune reaction being present. This would result in potentially overwhelming viral infection that needs augmented anti-viral therapies (treatment with remdesivir, interferon, anti-viral monoclonal antibodies, or convalescent plasma, or a combination of these), not immunosuppression. One would want to be careful, however, if Type 1 interferon is given (to boost viral eradication), lest it unwittingly trigger excessive downstream immunologic reactions.
3. In other patients, the problem might be both an inability to eradicate the virus (resulting in varying degrees of worrisome ongoing viral infection) and an inability to control the immune reaction to the virus. Such patients would benefit from both anti-viral therapies (e.g., remdesivir, interferon, and/or monoclonal antibodies or convalescent plasma) and immunosuppressive therapies—with the anti-viral therapies being given first, followed by immunosuppressive treatment as soon as it was deemed relatively safe. Serial monitoring would guide the making of adjustments along the way.

Early initiation of serial monitoring:

To determine which of the above situations is the case with a given patient, the recommendation is to immediately begin (early in the hospital course) serial documentation of the following:

• The extent of the patient’s viral load on admission and whether it subsequently increases or decreases, and how fast— assessed by following the Ct values at which serial COVID-19 PCR tests are positive. (See section on Ct values below. Also, see companion article on Ct values.)
• The extent to which the patient has developed IgM and IgG antibodies to SARS-CoV-2. This information supplements the Ct information and documents the extent to which the patient has already mounted an appropriate antibody response. (See section on antibody levels, below.)
• The extent to which hyperinflammation/cytokine storm is evolving— assessed by following serial serum ferritin levels, CRP, ESR, D-dimer, PT, PTT, CBC, platelet count, serum albumin, LDH, ALT, AST, triglycerides, IL-6 level (if readily available), etc. (An elevated CRP correlates well with elevated cytokine levels.)
• The extent to which ischemia-producing microvascular endotheliopathy might be evolving in the pulmonary microvasculature—- assessed by constantly monitoring paO2 and/or O2 saturation (the latter with pulse oximetry) and potentially by obtaining lab biomarkers of endothelial dysfunction. (Unfortunately, though, we do not, yet, have excellent, reliable, easily interpretable, readily available biomarkers of endothelial dysfunction.)
• The extent to which inappropriate coagulopathy is developing. Coagulopathy can develop as a consequence of microvascular endothelial injury, systemic hyperinflammation/cytokine storm, anti-phospholipid antibodies, or combinations of these. This can be monitored by following D-dimer, PT, PTT, and obtaining anti-phospholipid antibodies.

Administering immunosuppressive treatment in the context of infection:

If evidence of hyperimmune reactions (e.g., hyperinflammation/cytokine storm) is found, and if these hyperimmune reactions are thought to represent a greater threat than any ongoing active viral infection, one strategy is to carefully, but boldly, treat with immunosuppressive/immunomodulatory medications (e.g., corticosteroid and anakinra), while continuing to compulsively monitor the viral load and being prepared to augment viral eradication.

Please see A Proposed Treatment Protocol for Severe COVID-19 Illness in the APPENDIX for further details about immunosuppressive/immunomodulatory treatment options.

There is certainly valid concern that treating a person with a viral infection with immunosuppressive treatments might adversely interfere with viral eradication and promote viral replication; however, this possibility can be monitored, and necessary adjustments can be made. Alternatively, under-treatment (or no treatment) of a viral-triggered immune over-reaction (e.g., hyperinflammation/cytokine storm) could lead to regrettable (and preventable) organ failure and death and may represent a considerably greater threat than the possibility of the virus becoming unleashed and overwhelming.

Recognition that in severe COVID-19 illness, hyperimmune reactions may be the main problem:

It is possible that in most patients with severe COVID-19 illness the main problem is not ongoing active virus infection, itself, but the excessive immune reaction the virus has provoked in that patient, and that failure to adequately suppress hyperimmune reactions results in high likelihood of death or regrettable organ damage. [2-13] The potential benefits of promptly treating such a patient with immunosuppressive medications may far outweigh the potential risks of adversely affecting viral eradication.

Attentive care is required to serially and quantitatively estimate the patient’s viral load (by following Ct values) before and during any aggressive immunosuppressive treatment—to determine whether immunosuppressive treatment is interfering with viral clearance to any clinically significant degree; to determine whether certain concomitantly administered anti-viral therapies (e.g. interferon, remdesivir, convalescent plasma, or anti-viral monoclonal antibodies, given in combination with the immunosuppression) is wise and (if used) is providing additional benefits; and to make careful adjustments.

Understanding Ct values and estimating viral load:

Although the COVID-19 PCR test is designed as a qualitative test, aspects of it (namely the Ct value at which the patient’s test is positive) can be used to estimate viral load. Ct = Cycle threshold; Ct = the number of amplification cycles needed before the test detects presence of viral material in a specimen. The Ct value is the inverse of the viral load. The higher the Ct needed to detect the viral material, the lower the viral load in the specimen and the less sick and contagious the person is likely to be. [61-69]

If a test is positive at a Ct of 12 (becomes positive after only 12 amplification cycles), the viral load might be 100,000,000 copies per microliter, or more. [61, 62] If the test is positive at a Ct of 22, the viral load might be approximately 2,500,000 copies/mL. [63, 64] If the test becomes positive only at a Ct of 37, 40, or 45, the result most likely represents either a false positive, or a true positive that is detecting a trace amount (less than 100 copies, possibly even just a few copies) of inert, non-contagious, “dead” SARS-CoV-2 viral debris. [61, 62]

Knowing the Ct value at which a severely ill patient’s COVID-19 test is positive, would be immensely helpful to a physician who would like to know how much of a viral load the patient is carrying and whether it is relatively safe (or not) to administer life-saving immunosuppression, if careful monitoring reveals need for the latter. By using serial Ct values for guidance, the precision and timing of treatment of severe COVID-19 illness could be markedly improved. This, in turn, could reduce morbidity, mortality, need for mechanical ventilation, duration of hospital and ICU stays, and cost of care.

Unfortunately, to date, the COVID-19 PCR test has been reported only in a binary fashion, as being either positive or negative, with no indication of how strongly or weakly positive. Although the Ct information has always been available for each result, it has not been routinely reported or used for clinical (or epidemiological) purposes.

Another problem is that there has typically been a delay (often of 3-4 days) in receiving results of the COVID-19 PCR test. COVID-19 PCR results can be made available in a short amount of time, if urgently needed. It takes only 45-60 minutes, or less, to perform the test. Testing could be prioritized so that results on inpatients could be received promptly.

Taking SARS-CoV-2 antibody levels, disease duration, and timing into account:

To supplement information provided by Ct values, it is helpful to document the patient’s SARS-CoV-2 antibody levels (IgM, IgG, or both). Antibodies to SARS-CoV-2 most commonly become detectable 1-3 weeks after onset of symptoms. According to one study, 32% of patients have developed at least low levels of IgG antibody within 4 days after onset of symptoms; by 7 days 48% have developed IgG antibodies; by 14 days 77% have IgG antibodies; and by 17-19 days 100% have IgG antibodies. [70] The antibody levels are lowest during the first week and highest during the third week. [70] If a patient has high IgG antibodies at the time of admission to the hospital or ICU, the clinician can reasonably suspect that the patient has been able to at least mount a good B cell response.

In one study of hospitalized patients, 38/114 patients (33%) had IgG SARS-CoV-2 antibodies at the time of admission. [64] IgG antibody levels correlated inversely with viral loads. High viral loads almost never occurred in the presence of IgG antibody. Incidentally, in that same study, 31.5% of hospitalized patients had a positive COVID-19 PCR test at a Ct <22 on admission; 27% had a positive test at a Ct> 30 on admission; and 9.5% had a positive test at a Ct of 35 or higher on admission. This means that on admission at least 9.5% probably had little or no active infection and an additional 17.5% probably had only mildly active viral infection, at most.

The above study [64] also showed that the viral load decreased as the days since onset of symptoms increased. The vast majority of patients with a Ct less than 22 (low Ct, high viral load) were less than 7 days post onset of symptoms. A minority of those with a Ct less than 22 were 7-10 days post onset of symptoms. Only a rare patient with a Ct less than 22 was 11-14 days post onset of symptoms. No patients who were more than 14 days post onset of symptoms had a Ct less than 22.

It is helpful to realize that the course of the viral load and the course of a hyperinflammatory/cytokine storm reaction are different and opposite. The viral load is highest during the hours before onset of COVID-19 symptoms and during the first few days after onset of symptoms. [62] By 7 days after onset of symptoms, the viral load is usually rapidly decreasing, due to the immune response (assuming an effective immune response). The viral load steadily declines thereafter. In contrast, the hyperinflammatory/cytokine storm reaction begins at some point during the first week and accelerates during the second and third weeks. As the viral load is declining, the hyperinflammatory reaction is accelerating. The viral load peaks early and usually subsides relatively quickly (assuming an effective immune response); hyperinflammatory reactions peak later and usually subside slowly (if untreated).

If a patient is admitted to the ICU on day 12 with a new, unexplained surge of fever and/or other worsening symptoms, the timing alone would suggest (but of course, not prove) a low viral load, presence of protective IgG SARS-CoV-2 antibodies, and presence of a hyperinflammatory/cytokine storm reaction. If such is confirmed, the patient would need immunosuppression, and it would be relatively safe to provide it. So, knowing the date of onset of a patient’s COVID-19 symptoms, the Ct value at which the patient’s admission PCR test was positive, the patient’s SARS-CoV-2 antibody status on admission, and the usual timing of the viral versus hyperinflammatory phases of COVID illness, can help the clinician recognize whether a severely ill patient’s main problem is a hyperinflammatory reaction, or an ongoing high viral load, or both. Bear in mind that sometimes a hyperinflammatory reaction will subside spontaneously; but this cannot be relied upon. Usually, immunosuppressive medication is needed to control a hyperinflammatory reaction.

So, knowing an admitted patient’s Ct value, IgG antibody level, and the number of days post onset of symptoms, helps the clinician to discern how high and threatening the patient’s viral load is apt to be. This information, coupled with lab assessment of the extent to which hyperinflammation/cytokine storm is present, helps the clinician to recognize whether the severely ill patient is suffering primarily from out-of-control active viral infection, excessive immune reactions to the virus, or both. This recognition, in turn, guides the clinician’s decision as to whether the patient primarily needs anti-viral therapies, or primarily needs immunosuppression, or needs both.

Timing, tailoring, and adjusting:

While carefully following the patient, it is essential to place great emphasis on the timing, tailoring, and adjustment of treatment; on knowing exactly where the patient stands and how matters are trending, regarding the extent of viral load and the extent of hyperimmune reactions; and on tailoring treatment to the changing specifics of the individual patient—always balancing concerns about benefits versus risks.

Preventative measures prior to hospitalization:

Although this article focuses on anticipatory monitoring and early treatment of hospitalized patients who have developed (or are in the process of developing) severe COVID-19 illness, anticipatory monitoring of outpatients is also important. Outpatients and their physicians can watch for both “silent” [59] and symptomatic hypoxia, as well as early signs, symptoms, and lab evidence of a developing hyperinflammatory/cytokine storm. Home pulse oximetry and serial lab monitoring would be appropriate for certain outpatients. An important theme of this article is that early detection and prompt treatment is essential for best outcome, both in outpatients and inpatients. Outpatients who might be developing severe COVID-19 illness should be admitted as soon as that becomes apparent—so that they can receive prompt attention before it becomes too late for optimal outcome.

Evidence for and against outpatient anti-viral approaches is beyond the scope of this article.

A pediatric rheumatology approach to severe COVID-19 in a nutshell:

Anticipation, timing, compulsive serial monitoring, tailoring, attention to trends, and prompt informed adjustments are of great importance: If a patient in a threatening hyperinflammatory state is found to have a viral load that has become low, or is waning, more aggressive immunosuppression could be promptly given. If a patient in a hyperinflammatory state is found to have a viral load that is still remarkably high, less aggressive immunosuppression might be given, until the viral load lowers, and anti-viral therapies might be initiated, first, to accelerate viral eradication. Compulsive monitoring, compulsive caring, careful timing, tailoring, constant prompt adjustments, and nuanced clinical judgment are the keys.

Simultaneous clinical care and clinical research:

To maximally learn from the COVID-19 experience, pediatric rheumatologists, starting at the beginning of the epidemic, would make certain that all patients with severe COVID-19 illness are promptly placed on some sort of an appropriately aggressive treatment protocol—consisting of immunosuppressive treatment for those with hyperinflammation, anti-viral treatments for those with poorly controlled viral infection, or both, depending on test results—so that various treatment approaches could ultimately (at least retrospectively) be compared for efficacy, safety, and necessity. For example, please see the Treatment Proposal provided at the end of this article (APPENDIX). Most pediatric rheumatologists would make certain that no patient with a threatening cytokine storm/hyperinflammatory reaction is left untreated—i.e., not given at least some corticosteroid, as early as conditions (benefit/risk ratios) would permit.

Furthermore, for purposes of clinical research and epidemiologic study, it is essential to establish strict, accurate, uniform criteria for what constitutes a “definite COVID-19 death” vs a “probable COVID-19 death” vs a “possible COVID-19 death” vs a “death occurring in the context of either a positive COVID-19 test or exposure to COVID-19, but not due to COVID-19.” This is a basic, fundamental principle of scientifically sound clinical research and is essential for generation of quality data. These categories should not be lumped together, and all counted as “COVID-19 deaths.”

Also, strict criteria must be developed to define gradations of the disease severity of patients upon entry to the hospital and ICU—including characterizing and stratifying (both initially and serially) patients according to the severity of their viral load and the severity of any hyperinflammatory/hyperimmune reactions.

Trust, but verify:

Pediatric rheumatology experience with hyperinflammatory/hyperimmune/cytokine storm reactions suggests that the protocol for treatment of severe COVID illness proposed in this article is worth considering—at least for implementation on a pilot basis. If pilot study at a few academic medical centers reveals statistically significant improvement in outcome in those centers that implement this protocol, compared to centers that practice the current standard of care, then this protocol (at least the successful components of it) could be implemented on a wider basis.

Patient and public education:

Finally, it is important to provide thorough patient and family education (and Public education), including detailed discussion of hyperimmune reactions, Ct values, SARS-CoV-2 antibody levels, the significance of the duration of time since onset of COVID-19 symptoms, and the benefits versus risks of all treatment options. Family concerns should be honored. Advocacy is an important component of comprehensive pediatric care.

]TO WHAT EXTENT HAS A PEDIATRIC RHEUMATOLOGY APPROACH BEEN APPLIED TO THE CHALENGES OF COVID-19?

To what extent has a pediatric rheumatology approach already been applied to the treatment of patients with severe COVID-19 illness? This is an important question, because, if this approach has already been in widespread practice, then, the current and cumulative morbidity and mortality data would suggest that this approach has not worked well. On the other hand, if this approach has not been in widespread practice, then there would be more reason to think it might improve outcomes. If a few hospitals have already implemented a similar approach, it would be helpful to carefully compare the outcomes in those hospitals with outcomes in hospitals that have primarily provided only standard supportive measures.

An important tradition in medicine is the regular scheduling of “Morbidity and Mortality” conferences, which are designed to critically and constructively examine patient care that resulted in disappointing outcome. It is an important form of peer review. The purpose is to determine whether anything could have been done better. The purpose is not to blame, shame, or castigate those who provided the clinical care. The goal is to protect patients by improving care and helping physicians become better clinicians. It is in that spirit that the following questions are asked:

Since the beginning of the COVID-19 epidemic, have patients with severe COVID-19 illness been approached in an anticipatory fashion, starting at the time of admission, with appropriately compulsive serial monitoring of viral load and extent of immune hyperreactivity? For example, has it been routine to serially and proactively follow the Ct values of positive COVID-19 PCR tests; and to serially follow serum ferritin, CRP, and other lab manifestations of a brewing hyperinflammatory state/cytokine storm?

In the beginning of the epidemic (or since), have patients promptly received appropriate anti-viral therapies (if needed), or appropriately aggressive immunosuppression (if needed), or both (if needed)?

In the beginning, were strict, accurate, uniform criteria established to define gradations of disease severity, including gradations of viral load and immune hyperreactivity—to guide individual patient care, facilitate prospective and retrospective clinical research, and collect quality epidemiologic data?

Since the beginning have all patients been placed on one of several appropriate immunosuppressive/anti-viral treatment protocols, either based on the patient’s clinical characteristics or randomly assigned, or a mixture of both—to ensure that each patient could promptly receive appropriate anti-viral and/or immunosuppressive treatment, and to ensure that every clinical experience could be at least retrospectively studied for research purposes?

Since the beginning, have strict, accurate, uniform, classification criteria been established for “definite COVID-19 death,” “probable COVID-19 death,” “possible COVID-19 death,” and “definite or possible COVID-19 exposure was present, but death was not due to COVID,” to ensure quality data for analysis of the number and nature of “COVID-19” deaths? Have such criteria been uniformly used?

Since the beginning, have patients, families, and the general public received adequate education about Ct values, hyperimmune reactions, and treatment options (e.g., bold, but careful use of corticosteroid and anakinra)?

Before going further, it is important to appreciate and emphasize that the physicians who have been on the front lines throughout the COVID-19 epidemic have been placed in an extraordinarily difficult position. They have often been overwhelmed with large numbers of severely ill patients. They have had little time to think, communicate, organize, or study the issues before them. Much of what they have seen has seemed new to them. Most have had little previous background in immunology and rheumatology. They have been encumbered by PPE (personal protective equipment) and worried about their own health. They have been physically and emotionally exhausted and morally stressed. Understaffing has been a problem, as has availability of supplies, beds, ICU space, PPE, and PCR test kits (and timely results of PCR tests}.

Our health care workers have put forth a heroic, selfless effort. Under these difficult circumstances it is a lot to ask physicians to emulate the ideal approach described and advocated in this article. Furthermore, although this ideal approach would save money in the long run, it entails expensive treatments in the short term. Moreover, the supply of many of these treatments (e.g., anakinra, tocilizumab, monoclonal neutralizing antibodies) have been quite limited, and it would have been difficult to quickly produce an adequate supply of them.

Answers to most of the above-listed questions are unclear:

In the beginning, the NIH (the National Institutes of Health, both in the USA and other countries), the CDC, the WHO, the Infection Disease Society of America, and the USA COVID-19 Task force discouraged use of corticosteroid and anti-cytokine therapies for COVID. [71-74] They were understandably hesitant to use immunosuppressive treatments in the context of viral illness. Their guidelines did not recommend corticosteroid therapy or specific anti-cytokine therapies for patients, “unless as part of a clinical trial.”

During the early months of the COVID-19 epidemic, clinical trials were rare, especially in non-academic medical centers. During the early months, most patients with severe COVID-19 illness apparently did not receive corticosteroid or any anti-cytokine therapy. For example, in one of the most widely cited retrospective studies of treatment of severe COVID, only 7.7% of 1806 hospitalized patients had received corticosteroid. [75] In that study, those who had elevated inflammatory markers and were treated with corticosteroid had a better outcome.

To date, it is unclear what percentage of patients with a COVID-related cytokine storm/hyperinflammatory reactions have been recognized and treated with corticosteroid or anti-cytokine therapy, and what percentage of those who have received anti-cytokine treatment (e. g. tocilizumab, an anti-IL-6 therapy) received it before their cytokine storm/hyperinflammatory reaction had become far advanced and already caused severe damage. It is unclear how many of the randomized clinical trials that have been conducted on COVID-19 have paid optimal attention to issues of timing, stratification, tailoring, adjustment, and compulsive monitoring of viral load (with serial Ct values) and extent of hyperimmune reactivity.

Have COVID-19 clinical trials supported the pediatric rheumatology approach?

Have clinical trials of immunosuppressive treatment of severe COVID-19 illness supported the pediatric rheumatology approach described in this article? Yes. [76-92] The clinical trials that have been done, so far, have suggested that corticosteroid treatment and anti-cytokine therapies (anakinra and tocilizumab) have been beneficial, particularly when given in a timely, careful, tailored fashion. Granted, the level of ferritin and cytokine elevation in severe COVID-19 illness has, often, not been as dramatic as in other cytokine storm situations, but this does not mean that COVID-related hyperinflammatory/hyperimmune reactions are not harmful and do not need to be treated with early and appropriately aggressive immunosuppression.

CONCLUSIONS:

In most cases of severe COVID-19 illness the main problem appears to be, not ongoing active viral infection, but excessive immune reactions to the virus—hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm.” An intriguing hypothesis is that initial “silent” and early symptomatic hypoxia might be due to a viral-triggered, Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy in the pulmonary microvasculature.

Over the past 40 years pediatric rheumatologists have developed considerable experience with these kinds of hyperimmune reactions. Pediatric rheumatologists still have much to learn, but what we have learned may be of value to those who are caring for patients with severe COVID-19 illness.

A major reason for the alarming number of COVID-19 deaths and for hospitals and ICUs becoming overwhelmed may be this: If a clinician does not recognize hyperimmune reactions occurring in a brewing case of severe COVID-19 illness and does not promptly treat such reactions with appropriately aggressive immunosuppression, the patient inexorably worsens and ends up in the ICU.  If the clinician continues to withhold appropriate immunosuppression, the patient ends up on a ventilator and with multiorgan failure.  By that time, it is much too late, and the patient remains on a ventilator for days and weeks, often to eventually die.  In the meantime, that patient and many similar patients increasingly occupy bed space in the ICU, for days and weeks—slowing turnover and overwhelming staff. 

On the other hand, if patients with early, brewing severe COVID-19 illness are promptly recognized, accurately interpreted, and promptly treated with appropriately aggressive immunosuppression (when indicated, as per the pediatric rheumatology protocol explained in this article), it is likely that they can be saved, often without need to go to the ICU. [80] Cytokine storm can often be largely shut down within 1-4 days with anakinra [80] and corticosteroid. Implementation of this protocol might result in shortened hospital stays, fewer ICU admissions, fewer patients needing ventilators, shortened ICU stays, and more rapid ICU bed turnover. Hospitals and ICUs might not become overwhelmed.  Most importantly, outcome might be markedly improved.  Lives might be saved, and survivors might be less damaged, often not damaged at all. And even money might be saved in the long run.

The pediatric rheumatology approach to treatment of severe COVID-19 illness described in this article (and summarized in the APPENDIX) has potential to markedly improve the quality of care, and, in the process, reduce fears, angst, moral stress, and a sense of powerlessness among patients, families, physicians, nurses, other health care workers, and the public.

“Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction and skillful execution; it represents the wise choice of many alternatives.” ~ Will A. Foster

Robert M. Rennebohm, MD Email: rmrennebohm@gmail.com Website: notesfromthesocialclinic.org

(Updated January 16, 2021)

APPENDIX:

A Proposed Treatment Protocol for Severe COVID-19 Illness:

Reasons for severe COVID-19 illness:

This proposal begins with an understanding that patients with severe COVID-19 illness may be severely ill because of one or more of the following reasons:

• Unusual difficulty eradicating the SARS-CoV-2 virus:
  • Sluggishly produced, dysfunctional, or inhibited Type 1 interferon
  • Sluggishly activated, dysfunctional, or exhausted NK T-cells (Natural Killer T-cells)
  • Age-related decreased overall immune competence
  • Co-morbidity-related decreased immune competence
  • An unusually large viral load in the first place
  • Unusually low level of cross-reactive coronavirus antibodies or memory T-Cells (that are often provided by past exposure to ordinary non-COVID-19 coronaviruses)
  • Combinations of the above
• Excessive immunologic reactions to the COVID-19 virus—e.g., hyperinflammatory, hyperimmune, cytokine storm reactions—including a variety of autoimmune phenomena and the possibility of Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy in the pulmonary microvasculature (and possibly in other organs).
• A combination of unusual difficulty eradicating the COVID-19 virus AND excessive immunologic reactions to the COVID-19 virus
• In addition, illness in some patients is complicated by microvascular and macrovascular thrombosis, triggered by the hyperinflammation/cytokine storm, endothelial cell injury, anti-phospholipid antibodies, or combinations of these factors

This proposal encourages an understanding that most patients who become severely ill with COVID-19 may do so primarily because of hyperinflammatory, hyperimmune, autoimmune reactions, often with cytokine storm, and they may or may not also be dealing with a worrisome, ongoing viral load at the time of admission. [2-13]

The importance of the date of onset of COVID-19 symptoms:

This proposal also emphasizes the importance of knowing the date of onset of the patient’s COVID-19 symptoms and the usual time course of viral load and development of hyperimmune reactions. This knowledge enables the clinician to view the patient’s clinical details in the context of illness duration, which, in turn, improves the clinician’s ability to accurately determine whether the patient’s main problem is an ongoing high viral load, or a hyperinflammatory/hyperimmune/cytokine storm reaction, or both.

Early initiation of serial monitoring:

A principle of this proposal is that it is incumbent upon the physician to thoroughly study the patient—both upon entry to the hospital and serially thereafter—to document which of the above-mentioned factors are responsible for the patient’s severe illness. Upon admission, serial documentation of the following would be commenced:

• The extent of the patient’s viral load on admission and whether it subsequently increases or decreases, and how fast— assessed by following the Ct values at which serial COVID-19 PCR tests are positive. (See section on Ct values in main text. Also, see companion article on Ct values.)
• The extent to which the patient has developed IgM and IgG antibodies to SARS-CoV-2. This information supplements the Ct information and documents the extent to which the patient has already mounted an appropriate antibody response. (See section on antibody levels in main text.)
• The extent to which hyperinflammation/cytokine storm is evolving— assessed by following serial serum ferritin levels, CRP, ESR, D-dimer, PT, PTT, CBC, platelet count, serum albumin, LDH, ALT, AST, triglycerides, IL-6 level (if readily available), etc.
• The extent to which ischemia-producing microvascular endotheliopathy might be evolving in the pulmonary microvasculature— assessed by constantly monitoring paO2 and/or O2 saturation (the latter with pulse oximetry) and potentially by obtaining lab biomarkers of endothelial dysfunction. (Unfortunately, though, we do not, yet, have excellent, reliable, easily interpretable, readily available biomarkers of endothelial dysfunction.)
• The extent to which inappropriate coagulopathy is developing. Coagulopathy can develop because of microvascular endothelial injury, systemic hyperinflammation/cytokine storm, anti-phospholipid antibodies, or combinations of these. This can be monitored by following d-dimers, PT, PTT, and obtaining anti-phospholipid antibodies.

Tailoring treatment to the individual patient’s characteristics and most pressing needs:

An important principle of this proposal is that treatment should be tailored and adjusted to the specific (often changing) characteristics of the individual patient. If the primary threat to the patient is hyperinflammation/cytokine storm, immunosuppressive treatment is the most urgent and the most important consideration. If excessive ongoing viral infection is the primary problem/threat, augmentation of viral eradication is the most urgent and important treatment. If both problems are equally responsible/present, both need to be equally addressed, and done so in the most careful, timely, and sequenced fashion. If the primary problem is hyperinflammation/cytokine storm and there is little or no problem with ongoing viral infection, then immunosuppression can be provided more quickly, aggressively, and safely than if worrisome ongoing viral infection is also present. Furthermore, serial monitoring may reveal changes in status that permit or require nuanced adjustments.

Options for suppression of viral replication (augmentation of viral eradication):

• Remdesivir (possibly in combination with other anti-viral medications) —to interfere with viral replication. [86]
• Interferon alpha 2b (possibly in combination with anti-viral medications) —to induce an anti-viral state and further inhibit viral replication. [86-88]
• Convalescent plasma (possibly in combination with anti-viral medications and interferon alpha 2b)—to immediately provide high levels of antibody against the SARS-CoV-2 virus.
• Specific monoclonal neutralizing antibody (or combination of antibodies) against the SARS-CoV-2 virus. [93]
• IVIG [10, 84, 89] —to possibly block attachment of virus to receptors on human cells (?); to possibly provide cross-reactive anti-coronavirus antibodies; [89] and to also help subdue an excessive immune response to the virus (which possibly includes an immune-mediated occlusive microvascular endotheliopathy in the pulmonary microvasculature [52-58].)

Options for suppression of COVID19 induced “cytokine storm”/hyperinflammation:

• Corticosteroid (e.g., dexamethasone, methylprednisolone) —to comprehensively subdue immune over-reactivity. [75, 79, 90]. Some patients may adequately respond to a dose in the range of 1 mg/kg/day; others may need initial pulses of IV methylprednisolone.
• IV Anakinra—to selectively block IL-1 and, thereby, shut down “cytokine storm.” [10-12, 80-83, 85, 91,] For some patients high dose IV anakinra might be more appropriate than low dose SQ anakinra. [80] Anakinra may be preferable to tocilizumab because of anakinra’s greater flexibility, shorter half-life, and lower likelihood of predisposing to secondary bacterial infection. Initial and subsequent doses of anakinra can be tailored and quickly adjusted to the apparent evolving needs of the patient—i.e., anakinra may provide more precise and tailored treatment than tocilizumab.
• Tocilizumab, an anti-IL-6 agent, would be an alternative to anakinra, but anakinra has a better over-all safety profile and may be preferable. [10-12, 76-78, 92]
• IVIG [10, 84, 89]. If IVIG is used (e.g., 1-2 gm/kg initial dose), concomitant anticoagulation should be considered.

Options for prevention/treatment of abnormal microvascular and macrovascular coagulation:

• Heparinization/anticoagulation [13, 55]

Simultaneous clinical care and clinical research:

Another principle of this proposal is that it is amenable to both tailored (individualized) treatment and randomized treatment—i.e., parts of the treatment could be tailored to the specific characteristics of the individual patient, while other parts randomized for research purposes. For example, if a patient’s primary problem is hyperinflammation/cytokine storm and that patient, at that time, has little or no problem with ongoing viral infection, then that patient could be randomized to receive either:

• High dose corticosteroid (IV pulses of mega-doses of methylprednisolone, which works faster and better than lower doses), alone
• Lower dose corticosteroid, alone
• Anakinra (high dose vs low dose anakinra— alone, or with corticosteroid
• Tocilizumab, instead of anakinra— alone, or with corticosteroid
• IVIG (particularly if immune-mediated microvascular endotheliopathy is also suspected)
• Combinations of the above
• And there would also be an option to randomize to also receive one or more of the treatments that would augment viral eradication.

A point of emphasis is that every patient deserves access to an approach like that described in this APPENDIX, and every patient’s experience can be viewed as a clinical research opportunity.

The practicality of a pediatric rheumatology approach:

This pediatric rheumatology approach is not just some ideal, “pie-in-the-sky” approach that is “not possible in the real world.” The above immunosuppressive approach has been practiced for decades by pediatric rheumatologists. Pediatric rheumatologists have found this approach to not only be realistic, but to be necessary, to save the patient.

Some further comments:

There may be some confusion regarding what Hippocrates meant when he said, “Do no harm.” One aspect of this admonition is to avoid causing harm by the treatments/interventions you implement. But another aspect is to avoid causing harm by your unwillingness to use a treatment/intervention that, yes, has risks, but can be lifesaving or otherwise reduce suffering/damage. One aspect is “harm from actions taken;” the other is “harm from actions not taken.” Some physicians seem to think that if harm occurs because of their actions, it is their fault; but, if harm occurs because of their inaction, it is the disease’s fault. In my view, undertreatment of severe COVID-19 illness results in “harm from actions not taken.”

It is also important to point out that randomized controlled trials (RCTs), though truly ideal, do not always represent the highest quality of evidence and data. It depends on the quality of the RCT. Sometimes, carefully studied human experience contradicts the prevailing narrative (including the results of some RCTs) and is the better test of Truth.

Finally, it is important for the Public, particularly future patients, to know what options are available for treatment of severe COVID-19 illness. At the very least, for future patients, the pediatric rheumatology approach discussed in this article is an approach to be considered.

 

NOTE 1: This protocol may also be applicable to patients who become severely ill with influenza A, influenza B, and other potentially life-threatening viral respiratory infections, including the four common coronavirus infections (HKU1, NL63, OC43, and 229E).

NOTE 2: This article represents an updated and expanded version of an article that was originally published in the Russian journal, Russia Biomedical Research. [94]

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Treatment of Severe COVID-19 Illness

A Pediatric Rheumatologist’s Perspective and Proposed Treatment Protocol

“Human experience, which is constantly contradicting theory, is the greatest test of Truth.”

Samuel Johnson

ABSTRACT:

This article offers an approach to treatment of severe COVID-19 illness that might save lives, prevent organ damage, reduce ICU admissions, minimize need for mechanical ventilation, shorten length of hospital and ICU stays, reduce hospital costs, and, in the process, reduce fears, angst, moral stress, and a sense of powerlessness among patients, families, physicians, nurses, other health care workers, and the public.

In most cases of COVID-19 the immune system safely and efficiently neutralizes the virus, such that the patient is either asymptomatic or experiences only mild-moderate symptoms (which may create misery but are not life-threatening or organ threatening and do not require hospitalization). A minority of patients with COVID-19 experience severe, life-threatening illness. Tragically, 337,419 people in the USA have died from COVID-19, according to the CDC (as of this writing, on 12/30/20). Currently, hospitals and ICUs throughout California and much of the country are being overwhelmed with severely ill patients. Due to shortage of beds, ventilators, personnel, and supplies, rationing of health care is now being seriously contemplated.

In the majority of patients with severe COVID-19 illness the most threatening aspects of the illness appear to be due, not to ongoing active viral infection, but to excessive immune reactions to the virus— hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm.”

These life-threatening abnormal immune reactions are not new or unique to COVID-19 infection. For years it has been known that life-threatening hyperinflammation and cytokine storm occur with many bacterial infections and with many other viral infections, including seasonal influenza infection.

Over the past four decades, pediatric rheumatologists have developed extensive experience with excessive immune reactions (hyperinflammatory, hyperimmune, autoimmune, and cytokine storm reactions), including how to bring them under control. Much of this experience has come from managing systemic onset juvenile idiopathic arthritis that has become complicated by macrophage activation syndrome and “cytokine storm.” The pediatric rheumatology approach to hyperinflammatory states is characterized by early, anticipatory, appropriately compulsive, serial monitoring; prompt and appropriately bold immunosuppression of hyperinflammation, carefully using corticosteroid and anti-cytokine therapies (e.g., anakinra); and careful, anticipatory, tailored adjustments along the way—always balancing concerns about risks versus benefits.

Pediatric rheumatologists have experienced remarkable success with this approach to treatment of hyperinflammatory/hyperimmune reactions. This approach has the capacity to bring life-threatening cytokine storm under control, often within 1-4 days. If applied to management of severe COVID-19 illness, this approach may save many lives, reduce ICU admissions, and shorten hospitalizations. Details of this approach are provided in a Proposed Treatment Protocol for Severe COVID-19 Illness (see APPENDIX).

KEY WORDS: COVID-19, Hyperinflammation, Cytokine Storm, microvascular Endotheliopathy, Corticosteroid, Anti-Cytokine Treatment, Susac syndrome

BACKGROUND:

Normal behavior of Innate and adaptive immunity:

In most cases of COVID-19 infection (perhaps as many as 98% of those infected? [1]) the immune system safely and efficiently neutralizes the virus, such that the patient is either asymptomatic or experiences only mild-moderate symptoms (which may cause considerable misery but are not life-threatening or organ threatening and do not require hospitalization). In these cases, the two main phases of immune reactivity work remarkably well together:

First, the relatively primitive innate immune system quickly senses danger and creates (e.g., via Type 1 interferon) an immediate local anti-viral milieu that thwarts viral replication—thereby diminishing the viral load. Second, the innate immune system (via Type 1 interferon, cytokines, and chemokines) activates the more sophisticated adaptive immune system (e.g., B cells and T cells) which then produces virus-specific antibodies (first IgM, then IgG), activates cytotoxic T cells (which kill virus-infected cells to slow viral propagation to other cells), and creates memory B and T cells for future protection against that virus (and, to a lesser extent, against similar viruses).

For this sequential two-phase process to be safe, efficient, and successful, just the right amount of Type 1 interferon needs to be promptly made available; just the right extent of activation of the adaptive immune system needs to occur; and the timing of these two processes needs to be right. Too little (or too late) or too much Type 1 interferon can be harmful; and too little (or too late) or too much of an adaptive immune response can be harmful. Furthermore, both the innate and adaptive immune systems need to make wise, timely, coordinated adjustments along the way, including shutting down reactions as soon as they are no longer needed. It is all about careful timing, balance, coordination, regulation, and adjustment.

Abnormal behavior of innate and adaptive immunity in COVID-19—hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm”:

A small percentage of patients with COVID-19 experience severe illness, and in most of these cases the most threatening aspects of the illness appear to be due, not to ongoing active viral infection, but to excessive immune reactions triggered by the virus. [2-13] It is possible that in some cases of severe illness the main problem is that the Type 1 interferon reaction is too slow or otherwise inadequate, and/or the initial cytotoxic T cell response is too slow or otherwise dysfunctional, such that the virus is not promptly neutralized and overwhelms the patient. But most often, the main problem in patients with severe COVID-19 illness appears to be that their innate immune system, or their adaptive immune system, or both, have become excessively active, and these excessive immune reactions cause the severe illness. Instead of mounting an appropriate, timely, well-coordinated, well-balanced immune reaction, the immune system appears to excessively activate much of its armamentarium—both the innate armamentarium and the adaptive armamentarium—resulting in hyperinflammatory, hyperimmune reactions, often with “cytokine storm.” [2-13]

Great imbalance, discoordination, dysregulation, dysfunction, and hyperactivity characterize these hyperinflammatory/hyperimmune reactions. The immune system, for example, excessively activates macrophages (a powerful and explosive primitive component of our innate immunity); excessively releases an array of potentially harmful cytokines (resulting in a “cytokine storm”); may excessively activate cytotoxic T cells (which may be dysfunctional, as well, or become exhausted); and excessively triggers complement and coagulation cascades. These activations feed-back on each other, accelerate each other, and create vicious cycles that further escalate and perpetuate the excessive immune reactions. Production of autoantibodies (e.g., anti-phospholipid antibodies and anti-platelet antibodies) may add to these problems. [9, 13] Furthermore, an appropriate immune attack directed against viral proteins may be accompanied by an inappropriate and harmful attack on similar looking human proteins—cross-reactive “molecular mimicry.” [9, 10]

Note: Hereafter, for purposes of brevity, the more inclusive term, “hyperimmune reactions,” will sometimes be used instead of “hyperinflammatory, hyperimmune reactions, often with cytokine storm.” The term “hyperimmune reactions” refers not only to hyperinflammation and cytokine storm, but also to a variety of other immune-mediated phenomena that may occur with COVID-19— e.g., abnormal production of autoantibodies; cross-reactive immune attack directed at human proteins (molecular mimicry); and autoimmune reactions that involve little or no hyperinflammation (such as possible immune-mediated microvascular endotheliopathy).

Harmful consequences of hyperimmune reactions:

Quite soon, these excessive immune reactions start damaging human cells and organs. For example, the storm of cytokines causes fever, clinical and laboratory signs of systemic inflammation, and immune-mediated injury to multiple organs. In addition, it is possible that endothelial cells that line the inner walls of the pulmonary microvasculature may become immunologically injured (my hypothesis, not yet proven) and swell, potentially partially occluding the lumen of these vessels, thereby reducing blood flow to the lung’s air sacs (alveoli). Through a variety of potential mechanisms the alveoli may become both ischemically and immunologically injured, inflamed, and potentially fibrosed. In some patients, activated coagulation cascades result in micro and macro thrombi, potentially throughout all vasculatures. Abnormal production of anti-phospholipid antibodies may add to risk of thrombosis. [9, 13]

All organs, including the brain, can be affected by these unfortunate immune-mediated phenomena. Respiratory failure, multi-organ failure, cardiac failure, strokes, and death often result, particularly if these excessive immune reactions proceed un-treated or inadequately treated, as opposed to being detected early and promptly and adequately suppressed.

Indeed, the leading cause of life-threatening/organ threatening complications of COVID-19 appears to be the above-mentioned hyperimmune reactions. [7] Development of cytokine storm has appeared to be the major determinant of COVID-19 outcome. Clinical and lab features of cytokine storm have correlated well with poor outcome in COVID-19. [2-8] Elevated cytokine levels (e.g., IL-6) have been found in most patients dying of COVID. [7]

[Note: The above discussion represents a simplified and incomplete understanding of the complex immunologic events occurring in severe COVID-19 illness. There is still much to be learned about the immune aberrations that occur in COVID-19, including the possibility that the virus itself might have adverse effects on a person’s immune competency.]

Hyperimmune reactions are not new or unique to COVID-19 infection:

Hyperimmune reactions are certainly not new or unique to COVID-19 infection. For many years it has been known that life-threatening hyperinflammation/cytokine storm occurs with many bacterial infections and with many other viral infections, including seasonal influenza infection. [12, 14-22] In fact, usual seasonal influenza viruses are major triggers of cytokine storm. [2] In one study of patients who died of H1N1 influenza, 81% had features of cytokine storm. [18]

PEDIATRIC RHEUMATOLOGY EXPERIENCE WITH HYPERIMMUNE REACTIONS:

History:

For many years, pediatric rheumatologists have struggled to understand and treat excessive immune reactions, including hyperinflammation and cytokine storm. [23-44] Pediatric rheumatologists have played a leading role in studying hyperimmune reactions, because many childhood autoimmune/autoinflammatory diseases (e.g., systemic onset juvenile idiopathic arthritis) become complicated by excessive macrophage activation (macrophage activation syndrome) and “cytokine storm.” [23-44] Their knowledge of hyperimmune reactions has resulted from extensive individual and collective experience and collaborative international study, including thoughtful development of strict diagnostic and classification criteria and uniform treatment protocols [23, 24, 25, 31, 32], as well as randomized clinical trials. [37-39]

Nearly 40 years ago, when I was a visiting pediatric rheumatologist at Beijing Children’s Hospital, I vividly remember discussing (with Beijing pediatricians) the excessive macrophage activation and massive cytokine release associated with systemic onset juvenile idiopathic arthritis (JIA) and how to treat it (with high dose corticosteroid, at that time). The concept of excessive macrophage activation/excessive release of cytokines was new at that time in the USA and Europe and was largely unknown in China.

Since then, pediatric rheumatologists around the world have been routinely and successfully treating hyperinflammatory/hyperimmune reactions (e.g., macrophage activation syndrome, “cytokine storm,” secondary HLH, and systemic inflammatory response syndrome) with corticosteroid and, more recently, with specific anti-cytokine treatments—either anti-IL-1 treatment (anakinra) or anti-IL-6 treatment (tocilizumab). [37-44] These treatments have been lifesaving and organ-saving, particularly when these hyperinflammatory/hyperimmune reactions are recognized early; treated promptly with appropriately aggressive immunosuppression; and monitored compulsively with serial lab testing, with nuanced adjustments being made along the way. Bold, but careful, use of corticosteroid and anakinra has shown capacity to bring cytokine storm under control, often within a few days.

Pediatric rheumatology’s understanding of hyperimmune reactions and how to best treat them is still a work in progress. Pediatric rheumatologists are still learning. It has been a difficult and humbling 40-year process, and many questions remain unanswered. But the experience of pediatric rheumatologists is relevant to severe COVID-19 illness and worth sharing.

Lessons learned, regarding hyperimmune reactions:

An important lesson that pediatric rheumatologists have learned about cytokine storm is that if the clinician acts too slowly or too timidly, the patient will suffer greatly and may die. Anticipatory thinking, early detection, prompt and appropriately bold immunosuppressive treatment, compulsive serial monitoring, and careful adjustments, have been the keys to success. Failure to anticipate, failure to detect early, failure to promptly treat appropriately aggressively, failure to compulsively monitor, and failure to make wise adjustments can, each by themselves, cause preventable death and damage. Personal experiences, collective clinical observations, carefully studied collaborative case series, and, ultimately, randomized clinical trials [37-39] have documented the value of the pediatric rheumatology approach to hyperimmune reactions associated with childhood rheumatic diseases—diseases which, by the way, are often much more explosively hyperinflammatory and life-threatening than their counterparts in adults.

Application of experience with childhood rheumatic diseases to infection-triggered hyperimmune reactions:

The above experience of pediatric rheumatologists has been applied to the recognition and treatment of hyperimmune reactions triggered by bacterial and viral infection, in adults and children. [12, 45-51] Historically, for many years, Emergency Department physicians, hospitalists, and ICU pediatricians in children’s hospitals have commonly consulted pediatric rheumatologists for help in recognizing and treating infection-triggered hyperimmune reactions. Randomized controlled trials of immunosuppressive treatment of infection-related hyperimmune reactions have been conducted. [45, 46]

In other words, for many years before COVID-19 arrived on the scene, pediatricians and pediatric rheumatologists (and physicians for adults) had developed considerable experience with the diagnosis and treatment of infection-triggered hyperimmune reactions. We learned to test patients serially and proactively for elevated levels of CRP, serum ferritin, D-dimer, PT, PTT, triglycerides, LDH, and liver transaminases; and lowered levels of platelets, lymphocytes, albumin, and fibrinogen—early markers of an evolving hyperinflammation/cytokine storm. And we learned to treat aggressively and promptly, but carefully, with corticosteroid and specific anti-cytokine therapies, such as anakinra—all the while worrying about administering immunosuppression in the context of infection, but not being paralyzed by that worry.

Decision-making in the absence of randomized controlled trials:

In the beginning, we did not have randomized controlled trials that proved that this treatment for infection-related hyperinflammation was effective, safe, and necessary. We quickly learned, though, from individual and collective experience, that these children were likely to die or sustain irreversible multi-organ damage, if not treated promptly and aggressively with immunosuppressive medications. Knowing that these children were faced with a life-threatening and organ-threatening disease process, we (and the child’s parents and grandparents) felt morally and ethically obligated to boldly treat these children, despite absence of randomized controlled trials. The alternative, watching them suffer and die, seemed obviously unacceptable.

It seemed to be unethical and unwise to withhold corticosteroid and anakinra treatment that had worked so well for hyperinflammatory reactions associated with childhood rheumatic diseases, simply because no randomized clinical trials had yet been conducted to prove the safety, efficacy, and necessity of such treatment in the context of infection-triggered hyperinflammation. Yes, of course, randomized double-blind, controlled trials would have been ideal, but they were unavailable and would take much time to complete. In the meantime, it seemed unacceptable to withhold treatments that were likely to be effective, safe, and necessary.

Our careful boldness resulted in the eventual accumulation of increasingly positive clinical evidence of the efficacy, safety, and necessity of such treatment—for both hyperinflammatory reactions associated with childhood rheumatic diseases and hyperinflammatory reactions associated with infection. Prior to onset of the COVID-19 epidemic, ample ideal randomized controlled trials still had not been completed for treatment of viral-triggered hyperinflammatory reactions, but lessons from treatment of hyperinflammatory reactions associated with childhood rheumatic diseases had become well-established and were available for valuable guidance.

For several years now, prompt recognition and careful, bold immunosuppressive treatment have become the “standard of care” for hyperinflammatory reactions in children—both when it occurs in the context of a childhood rheumatic disease and in the context of infection. Many pediatric rheumatologists, particularly those of us who have seen the tragic outcomes of untreated and under-treated children, would not automatically withhold corticosteroid and anakinra from a child suffering from life-threatening viral-triggered cytokine storm/hyperinflammation, and instead, watch them suffer and die, un-treated, or only minimally treated, as if there was nothing we could, or should do, or appropriately try (other than supportive measures).

Immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy—a possible cause of the “silent hypoxia” noted in COVID-19:

Pediatric rheumatologists have also learned how to recognize and treat immune-mediated microvascular endotheliopathies —as occurs in juvenile dermatomyositis and in Susac syndrome. [52-54] In these microvascular endotheliopathies, the endothelial cells that line the inner walls of the small blood vessels become immunologically injured, swell, and partially occlude the lumen of the vessels. This reduces blood flow through these vessels and leads to ischemic injury to the tissues they perfuse.

This is mentioned because one hypothesis is that one of the earliest abnormal immune reactions in COVID-19 might be a virus-triggered, Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy within the pulmonary microvasculature. [52-58] Such an aberration, which may affect the pulmonary vasculature in an uneven fashion, would lead to varying degrees of decreased blood flow to the alveoli, ischemic injury to the alveoli, impaired oxygenation, and ventilation-perfusion mismatch. It is possible that this is a proximal cause of the initial “silent hypoxia” (and subsequent symptomatic hypoxia) in COVID-19. [59}

This hypothesized abnormal immune reaction in the pulmonary microvasculature would be an example of a hyperimmune reaction that is not typically hyperinflammatory. It is different from the hyperinflammatory/cytokine storm reaction that occurs in COVID-19. The latter reaction probably occurs somewhat later than the hypothesized microvascular endotheliopathy, though it could occur simultaneously. The hyperinflammatory/cytokine storm reaction could add inflammatory injury to the alveoli and, possibly, the pulmonary microvasculature.

If the above hypothesis is true, the best treatment for this early hyperimmune reaction in the pulmonary microvasculature would be prompt, effective immunosuppression, which would also serve to blunt any hyperinflammatory/cytokine storm reaction that might be brewing. Such immunosuppression could protect the alveoli from both ischemic and inflammatory injury and decrease the likelihood of development of acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. But to be effective, this treatment would need to be given early after onset of these immune reactions, before it becomes too late. IVIG and pulses of IV methylprednisolone have usually worked quickly (often within 1-4 days) and well to subdue acute episodes of immune-mediated microvascular endotheliopathy in Susac syndrome. [54]

In addition, it needs to be considered that the SARS-CoV-2 virus itself might cause direct damage to the alveoli. Indeed, a theme throughout this article is that severe COVID-19 illness is due to both the virus itself and excessive immunologic reactions to the virus. Both need to be suppressed in as timely and precise a fashion as possible.

It is conceivable that, in COVID-19, a Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy could occur in the microvasculatures of other organs, including the brain. It is conceivable that the “brain fog,” cognitive dysfunction (e.g., short term memory difficulty), and psychosis experienced by some patients with COVID-19 might be due to immune-mediated microvascular endotheliopathy. [60] If so, such pathology could be successfully reversed with appropriate immunosuppression; and, if left untreated, or inadequately suppressed, could result in irreversible damage.

A PEDIATRIC RHEUMATOLOGY APPROACH TO TREATMENT OF SEVERE COVID-19 ILLNESS:

How might a pediatric rheumatologist approach the problem of severe COVID-19 illness? (See APPENDIX for details about a proposed approach.)

Imagine a spectrum of possible clinical scenarios:

When a patient is admitted to the hospital, a first step is to imagine several possible patient characteristics/profiles (clinical situations):

1. In some patients the main problem might be hyperimmune reactions, with little or no problem with ongoing viral infection. That is, by the time of admission the patient’s innate immune system (and subsequent adaptive immune system) has adequately subdued the viral infection, but excessive immune reactions have become the main problem. At least, the threat posed by the hyperimmune reactions is greater than the threat posed by the viral load at the time. In such a patient, immunosuppression would be the patient’s greatest need—greater immunosuppression if the viral infection has already been fully eradicated; lesser, more careful immunosuppression if viral eradication has been less complete.
2. In other patients (a minority, probably), inadequate eradication of the virus might be the main problem, with little or no hyperimmune reaction being present. This would result in potentially overwhelming viral infection that needs augmented anti-viral therapies (treatment with remdesivir, interferon, anti-viral monoclonal antibodies, or convalescent plasma, or a combination of these), not immunosuppression. One would want to be careful, however, if Type 1 interferon is given (to boost viral eradication), lest it unwittingly trigger excessive downstream immunologic reactions.
3. In other patients, the problem might be both an inability to eradicate the virus (resulting in varying degrees of worrisome ongoing viral infection) and an inability to control the immune reaction to the virus. Such patients would benefit from both anti-viral therapies (e.g., remdesivir, interferon, and/or monoclonal antibodies or convalescent plasma) and immunosuppressive therapies—with the anti-viral therapies being given first, followed by immunosuppressive treatment as soon as it was deemed relatively safe. Serial monitoring would guide the making of adjustments along the way.

Early initiation of serial monitoring:

To determine which of the above situations is the case with a given patient, the recommendation is to immediately begin (early in the hospital course) serial documentation of the following:

• The extent of the patient’s viral load on admission and whether it subsequently increases or decreases, and how fast— assessed by following the Ct values at which serial COVID-19 PCR tests are positive. (See section on Ct values below. Also, see companion article on Ct values.)
• The extent to which the patient has developed IgM and IgG antibodies to SARS-CoV-2. This information supplements the Ct information and documents the extent to which the patient has already mounted an appropriate antibody response. (See section on antibody levels, below.)
• The extent to which hyperinflammation/cytokine storm is evolving— assessed by following serial serum ferritin levels, CRP, ESR, D-dimer, PT, PTT, CBC, platelet count, serum albumin, LDH, ALT, AST, triglycerides, IL-6 level (if readily available), etc. (An elevated CRP correlates well with elevated cytokine levels.)
• The extent to which ischemia-producing microvascular endotheliopathy might be evolving in the pulmonary microvasculature—- assessed by constantly monitoring paO2 and/or O2 saturation (the latter with pulse oximetry) and potentially by obtaining lab biomarkers of endothelial dysfunction. (Unfortunately, though, we do not, yet, have excellent, reliable, easily interpretable, readily available biomarkers of endothelial dysfunction.)
• The extent to which inappropriate coagulopathy is developing. Coagulopathy can develop as a consequence of microvascular endothelial injury, systemic hyperinflammation/cytokine storm, anti-phospholipid antibodies, or combinations of these. This can be monitored by following D-dimer, PT, PTT, and obtaining anti-phospholipid antibodies.

Administering immunosuppressive treatment in the context of infection:

If evidence of hyperimmune reactions (e.g., hyperinflammation/cytokine storm) is found, and if these hyperimmune reactions are thought to represent a greater threat than any ongoing active viral infection, one strategy is to carefully, but boldly, treat with immunosuppressive/immunomodulatory medications (e.g., corticosteroid and anakinra), while continuing to compulsively monitor the viral load and being prepared to augment viral eradication.

Please see A Proposed Treatment Protocol for Severe COVID-19 Illness in the APPENDIX for further details about immunosuppressive/immunomodulatory treatment options.

There is certainly valid concern that treating a person with a viral infection with immunosuppressive treatments might adversely interfere with viral eradication and promote viral replication; however, this possibility can be monitored, and necessary adjustments can be made. Alternatively, under-treatment (or no treatment) of a viral-triggered immune over-reaction (e.g., hyperinflammation/cytokine storm) could lead to regrettable (and preventable) organ failure and death and may represent a considerably greater threat than the possibility of the virus becoming unleashed and overwhelming.

Recognition that in severe COVID-19 illness, hyperimmune reactions may be the main problem:

It is possible that in most patients with severe COVID-19 illness the main problem is not ongoing active virus infection, itself, but the excessive immune reaction the virus has provoked in that patient, and that failure to adequately suppress hyperimmune reactions results in high likelihood of death or regrettable organ damage. [2-13] The potential benefits of promptly treating such a patient with immunosuppressive medications may far outweigh the potential risks of adversely affecting viral eradication.

Attentive care is required to serially and quantitatively estimate the patient’s viral load (by following Ct values) before and during any aggressive immunosuppressive treatment—to determine whether immunosuppressive treatment is interfering with viral clearance to any clinically significant degree; to determine whether certain concomitantly administered anti-viral therapies (e.g. interferon, remdesivir, convalescent plasma, or anti-viral monoclonal antibodies, given in combination with the immunosuppression) is wise and (if used) is providing additional benefits; and to make careful adjustments.

Understanding Ct values and estimating viral load:

Although the COVID-19 PCR test is designed as a qualitative test, aspects of it (namely the Ct value at which the patient’s test is positive) can be used to estimate viral load. Ct = Cycle threshold; Ct = the number of amplification cycles needed before the test detects presence of viral material in a specimen. The Ct value is the inverse of the viral load. The higher the Ct needed to detect the viral material, the lower the viral load in the specimen and the less sick and contagious the person is likely to be. [61-69]

If a test is positive at a Ct of 12 (becomes positive after only 12 amplification cycles), the viral load might be 100,000,000 copies per microliter, or more. [61, 62] If the test is positive at a Ct of 22, the viral load might be approximately 2,500,000 copies/mL. [63, 64] If the test becomes positive only at a Ct of 37, 40, or 45, the result most likely represents either a false positive, or a true positive that is detecting a trace amount (less than 100 copies, possibly even just a few copies) of inert, non-contagious, “dead” SARS-CoV-2 viral debris. [61, 62]

Knowing the Ct value at which a severely ill patient’s COVID-19 test is positive, would be immensely helpful to a physician who would like to know how much of a viral load the patient is carrying and whether it is relatively safe (or not) to administer life-saving immunosuppression, if careful monitoring reveals need for the latter. By using serial Ct values for guidance, the precision and timing of treatment of severe COVID-19 illness could be markedly improved. This, in turn, could reduce morbidity, mortality, need for mechanical ventilation, duration of hospital and ICU stays, and cost of care.

Unfortunately, to date, the COVID-19 PCR test has been reported only in a binary fashion, as being either positive or negative, with no indication of how strongly or weakly positive. Although the Ct information has always been available for each result, it has not been routinely reported or used for clinical (or epidemiological) purposes.

Another problem is that there has typically been a delay (often of 3-4 days) in receiving results of the COVID-19 PCR test. COVID-19 PCR results can be made available in a short amount of time, if urgently needed. It takes only 45-60 minutes, or less, to perform the test. Testing could be prioritized so that results on inpatients could be received promptly.

Taking SARS-CoV-2 antibody levels, disease duration, and timing into account:

To supplement information provided by Ct values, it is helpful to document the patient’s SARS-CoV-2 antibody levels (IgM, IgG, or both). Antibodies to SARS-CoV-2 most commonly become detectable 1-3 weeks after onset of symptoms. According to one study, 32% of patients have developed at least low levels of IgG antibody within 4 days after onset of symptoms; by 7 days 48% have developed IgG antibodies; by 14 days 77% have IgG antibodies; and by 17-19 days 100% have IgG antibodies. [70] The antibody levels are lowest during the first week and highest during the third week. [70] If a patient has high IgG antibodies at the time of admission to the hospital or ICU, the clinician can reasonably suspect that the patient has been able to at least mount a good B cell response.

In one study of hospitalized patients, 38/114 patients (33%) had IgG SARS-CoV-2 antibodies at the time of admission. [64] IgG antibody levels correlated inversely with viral loads. High viral loads almost never occurred in the presence of IgG antibody. Incidentally, in that same study, 31.5% of hospitalized patients had a positive COVID-19 PCR test at a Ct <22 on admission; 27% had a positive test at a Ct> 30 on admission; and 9.5% had a positive test at a Ct of 35 or higher on admission. This means that on admission at least 9.5% probably had little or no active infection and an additional 17.5% probably had only mildly active viral infection, at most.

The above study [64] also showed that the viral load decreased as the days since onset of symptoms increased. The vast majority of patients with a Ct less than 22 (low Ct, high viral load) were less than 7 days post onset of symptoms. A minority of those with a Ct less than 22 were 7-10 days post onset of symptoms. Only a rare patient with a Ct less than 22 was 11-14 days post onset of symptoms. No patients who were more than 14 days post onset of symptoms had a Ct less than 22.

It is helpful to realize that the course of the viral load and the course of a hyperinflammatory/cytokine storm reaction are different and opposite. The viral load is highest during the hours before onset of COVID-19 symptoms and during the first few days after onset of symptoms. [62] By 7 days after onset of symptoms, the viral load is usually rapidly decreasing, due to the immune response (assuming an effective immune response). The viral load steadily declines thereafter. In contrast, the hyperinflammatory/cytokine storm reaction begins at some point during the first week and accelerates during the second and third weeks. As the viral load is declining, the hyperinflammatory reaction is accelerating. The viral load peaks early and usually subsides relatively quickly (assuming an effective immune response); hyperinflammatory reactions peak later and usually subside slowly (if untreated).

If a patient is admitted to the ICU on day 12 with a new, unexplained surge of fever and/or other worsening symptoms, the timing alone would suggest (but of course, not prove) a low viral load, presence of protective IgG SARS-CoV-2 antibodies, and presence of a hyperinflammatory/cytokine storm reaction. If such is confirmed, the patient would need immunosuppression, and it would be relatively safe to provide it. So, knowing the date of onset of a patient’s COVID-19 symptoms, the Ct value at which the patient’s admission PCR test was positive, the patient’s SARS-CoV-2 antibody status on admission, and the usual timing of the viral versus hyperinflammatory phases of COVID illness, can help the clinician recognize whether a severely ill patient’s main problem is a hyperinflammatory reaction, or an ongoing high viral load, or both. Bear in mind that sometimes a hyperinflammatory reaction will subside spontaneously; but this cannot be relied upon. Usually, immunosuppressive medication is needed to control a hyperinflammatory reaction.

So, knowing an admitted patient’s Ct value, IgG antibody level, and the number of days post onset of symptoms, helps the clinician to discern how high and threatening the patient’s viral load is apt to be. This information, coupled with lab assessment of the extent to which hyperinflammation/cytokine storm is present, helps the clinician to recognize whether the severely ill patient is suffering primarily from out-of-control active viral infection, excessive immune reactions to the virus, or both. This recognition, in turn, guides the clinician’s decision as to whether the patient primarily needs anti-viral therapies, or primarily needs immunosuppression, or needs both.

Timing, tailoring, and adjusting:

While carefully following the patient, it is essential to place great emphasis on the timing, tailoring, and adjustment of treatment; on knowing exactly where the patient stands and how matters are trending, regarding the extent of viral load and the extent of hyperimmune reactions; and on tailoring treatment to the changing specifics of the individual patient—always balancing concerns about benefits versus risks.

Preventative measures prior to hospitalization:

Although this article focuses on anticipatory monitoring and early treatment of hospitalized patients who have developed (or are in the process of developing) severe COVID-19 illness, anticipatory monitoring of outpatients is also important. Outpatients and their physicians can watch for both “silent” [59] and symptomatic hypoxia, as well as early signs, symptoms, and lab evidence of a developing hyperinflammatory/cytokine storm. Home pulse oximetry and serial lab monitoring would be appropriate for certain outpatients. An important theme of this article is that early detection and prompt treatment is essential for best outcome, both in outpatients and inpatients. Outpatients who might be developing severe COVID-19 illness should be admitted as soon as that becomes apparent—so that they can receive prompt attention before it becomes too late for optimal outcome.

Evidence for and against outpatient anti-viral approaches is beyond the scope of this article.

A pediatric rheumatology approach to severe COVID-19 in a nutshell:

Anticipation, timing, compulsive serial monitoring, tailoring, attention to trends, and prompt informed adjustments are of great importance: If a patient in a threatening hyperinflammatory state is found to have a viral load that has become low, or is waning, more aggressive immunosuppression could be promptly given. If a patient in a hyperinflammatory state is found to have a viral load that is still remarkably high, less aggressive immunosuppression might be given, until the viral load lowers, and anti-viral therapies might be initiated, first, to accelerate viral eradication. Compulsive monitoring, compulsive caring, careful timing, tailoring, constant prompt adjustments, and nuanced clinical judgment are the keys.

Simultaneous clinical care and clinical research:

To maximally learn from the COVID-19 experience, pediatric rheumatologists, starting at the beginning of the epidemic, would make certain that all patients with severe COVID-19 illness are promptly placed on some sort of an appropriately aggressive treatment protocol—consisting of immunosuppressive treatment for those with hyperinflammation, anti-viral treatments for those with poorly controlled viral infection, or both, depending on test results—so that various treatment approaches could ultimately (at least retrospectively) be compared for efficacy, safety, and necessity. For example, please see the Treatment Proposal provided at the end of this article (APPENDIX). Most pediatric rheumatologists would make certain that no patient with a threatening cytokine storm/hyperinflammatory reaction is left untreated—i.e., not given at least some corticosteroid, as early as conditions (benefit/risk ratios) would permit.

Furthermore, for purposes of clinical research and epidemiologic study, it is essential to establish strict, accurate, uniform criteria for what constitutes a “definite COVID-19 death” vs a “probable COVID-19 death” vs a “possible COVID-19 death” vs a “death occurring in the context of either a positive COVID-19 test or exposure to COVID-19, but not due to COVID-19.” This is a basic, fundamental principle of scientifically sound clinical research and is essential for generation of quality data. These categories should not be lumped together, and all counted as “COVID-19 deaths.”

Also, strict criteria must be developed to define gradations of the disease severity of patients upon entry to the hospital and ICU—including characterizing and stratifying (both initially and serially) patients according to the severity of their viral load and the severity of any hyperinflammatory/hyperimmune reactions.

Trust, but verify:

Pediatric rheumatology experience with hyperinflammatory/hyperimmune/cytokine storm reactions suggests that the protocol for treatment of severe COVID illness proposed in this article is worth considering—at least for implementation on a pilot basis. If pilot study at a few academic medical centers reveals statistically significant improvement in outcome in those centers that implement this protocol, compared to centers that practice the current standard of care, then this protocol (at least the successful components of it) could be implemented on a wider basis.

Patient and public education:

Finally, it is important to provide thorough patient and family education (and Public education), including detailed discussion of hyperimmune reactions, Ct values, SARS-CoV-2 antibody levels, the significance of the duration of time since onset of COVID-19 symptoms, and the benefits versus risks of all treatment options. Family concerns should be honored. Advocacy is an important component of comprehensive pediatric care.

]TO WHAT EXTENT HAS A PEDIATRIC RHEUMATOLOGY APPROACH BEEN APPLIED TO THE CHALENGES OF COVID-19?

To what extent has a pediatric rheumatology approach already been applied to the treatment of patients with severe COVID-19 illness? This is an important question, because, if this approach has already been in widespread practice, then, the current and cumulative morbidity and mortality data would suggest that this approach has not worked well. On the other hand, if this approach has not been in widespread practice, then there would be more reason to think it might improve outcomes. If a few hospitals have already implemented a similar approach, it would be helpful to carefully compare the outcomes in those hospitals with outcomes in hospitals that have primarily provided only standard supportive measures.

An important tradition in medicine is the regular scheduling of “Morbidity and Mortality” conferences, which are designed to critically and constructively examine patient care that resulted in disappointing outcome. It is an important form of peer review. The purpose is to determine whether anything could have been done better. The purpose is not to blame, shame, or castigate those who provided the clinical care. The goal is to protect patients by improving care and helping physicians become better clinicians. It is in that spirit that the following questions are asked:

Since the beginning of the COVID-19 epidemic, have patients with severe COVID-19 illness been approached in an anticipatory fashion, starting at the time of admission, with appropriately compulsive serial monitoring of viral load and extent of immune hyperreactivity? For example, has it been routine to serially and proactively follow the Ct values of positive COVID-19 PCR tests; and to serially follow serum ferritin, CRP, and other lab manifestations of a brewing hyperinflammatory state/cytokine storm?

In the beginning of the epidemic (or since), have patients promptly received appropriate anti-viral therapies (if needed), or appropriately aggressive immunosuppression (if needed), or both (if needed)?

In the beginning, were strict, accurate, uniform criteria established to define gradations of disease severity, including gradations of viral load and immune hyperreactivity—to guide individual patient care, facilitate prospective and retrospective clinical research, and collect quality epidemiologic data?

Since the beginning have all patients been placed on one of several appropriate immunosuppressive/anti-viral treatment protocols, either based on the patient’s clinical characteristics or randomly assigned, or a mixture of both—to ensure that each patient could promptly receive appropriate anti-viral and/or immunosuppressive treatment, and to ensure that every clinical experience could be at least retrospectively studied for research purposes?

Since the beginning, have strict, accurate, uniform, classification criteria been established for “definite COVID-19 death,” “probable COVID-19 death,” “possible COVID-19 death,” and “definite or possible COVID-19 exposure was present, but death was not due to COVID,” to ensure quality data for analysis of the number and nature of “COVID-19” deaths? Have such criteria been uniformly used?

Since the beginning, have patients, families, and the general public received adequate education about Ct values, hyperimmune reactions, and treatment options (e.g., bold, but careful use of corticosteroid and anakinra)?

Before going further, it is important to appreciate and emphasize that the physicians who have been on the front lines throughout the COVID-19 epidemic have been placed in an extraordinarily difficult position. They have often been overwhelmed with large numbers of severely ill patients. They have had little time to think, communicate, organize, or study the issues before them. Much of what they have seen has seemed new to them. Most have had little previous background in immunology and rheumatology. They have been encumbered by PPE (personal protective equipment) and worried about their own health. They have been physically and emotionally exhausted and morally stressed. Understaffing has been a problem, as has availability of supplies, beds, ICU space, PPE, and PCR test kits (and timely results of PCR tests}.

Our health care workers have put forth a heroic, selfless effort. Under these difficult circumstances it is a lot to ask physicians to emulate the ideal approach described and advocated in this article. Furthermore, although this ideal approach would save money in the long run, it entails expensive treatments in the short term. Moreover, the supply of many of these treatments (e.g., anakinra, tocilizumab, monoclonal neutralizing antibodies) have been quite limited, and it would have been difficult to quickly produce an adequate supply of them.

Answers to most of the above-listed questions are unclear:

In the beginning, the NIH (the National Institutes of Health, both in the USA and other countries), the CDC, the WHO, the Infection Disease Society of America, and the USA COVID-19 Task force discouraged use of corticosteroid and anti-cytokine therapies for COVID. [71-74] They were understandably hesitant to use immunosuppressive treatments in the context of viral illness. Their guidelines did not recommend corticosteroid therapy or specific anti-cytokine therapies for patients, “unless as part of a clinical trial.”

During the early months of the COVID-19 epidemic, clinical trials were rare, especially in non-academic medical centers. During the early months, most patients with severe COVID-19 illness apparently did not receive corticosteroid or any anti-cytokine therapy. For example, in one of the most widely cited retrospective studies of treatment of severe COVID, only 7.7% of 1806 hospitalized patients had received corticosteroid. [75] In that study, those who had elevated inflammatory markers and were treated with corticosteroid had a better outcome.

To date, it is unclear what percentage of patients with a COVID-related cytokine storm/hyperinflammatory reactions have been recognized and treated with corticosteroid or anti-cytokine therapy, and what percentage of those who have received anti-cytokine treatment (e. g. tocilizumab, an anti-IL-6 therapy) received it before their cytokine storm/hyperinflammatory reaction had become far advanced and already caused severe damage. It is unclear how many of the randomized clinical trials that have been conducted on COVID-19 have paid optimal attention to issues of timing, stratification, tailoring, adjustment, and compulsive monitoring of viral load (with serial Ct values) and extent of hyperimmune reactivity.

Have COVID-19 clinical trials supported the pediatric rheumatology approach?

Have clinical trials of immunosuppressive treatment of severe COVID-19 illness supported the pediatric rheumatology approach described in this article? Yes. [76-92] The clinical trials that have been done, so far, have suggested that corticosteroid treatment and anti-cytokine therapies (anakinra and tocilizumab) have been beneficial, particularly when given in a timely, careful, tailored fashion. Granted, the level of ferritin and cytokine elevation in severe COVID-19 illness has, often, not been as dramatic as in other cytokine storm situations, but this does not mean that COVID-related hyperinflammatory/hyperimmune reactions are not harmful and do not need to be treated with early and appropriately aggressive immunosuppression.

CONCLUSIONS:

In most cases of severe COVID-19 illness the main problem appears to be, not ongoing active viral infection, but excessive immune reactions to the virus—hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm.” An intriguing hypothesis is that initial “silent” and early symptomatic hypoxia might be due to a viral-triggered, Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy in the pulmonary microvasculature.

Over the past 40 years pediatric rheumatologists have developed considerable experience with these kinds of hyperimmune reactions. Pediatric rheumatologists still have much to learn, but what we have learned may be of value to those who are caring for patients with severe COVID-19 illness.

A major reason for the alarming number of COVID-19 deaths and for hospitals and ICUs becoming overwhelmed may be this: If a clinician does not recognize hyperimmune reactions occurring in a brewing case of severe COVID-19 illness and does not promptly treat such reactions with appropriately aggressive immunosuppression, the patient inexorably worsens and ends up in the ICU.  If the clinician continues to withhold appropriate immunosuppression, the patient ends up on a ventilator and with multiorgan failure.  By that time, it is much too late, and the patient remains on a ventilator for days and weeks, often to eventually die.  In the meantime, that patient and many similar patients increasingly occupy bed space in the ICU, for days and weeks—slowing turnover and overwhelming staff. 

On the other hand, if patients with early, brewing severe COVID-19 illness are promptly recognized, accurately interpreted, and promptly treated with appropriately aggressive immunosuppression (when indicated, as per the pediatric rheumatology protocol explained in this article), it is likely that they can be saved, often without need to go to the ICU. [80] Cytokine storm can often be largely shut down within 1-4 days with anakinra [80] and corticosteroid. Implementation of this protocol might result in shortened hospital stays, fewer ICU admissions, fewer patients needing ventilators, shortened ICU stays, and more rapid ICU bed turnover. Hospitals and ICUs might not become overwhelmed.  Most importantly, outcome might be markedly improved.  Lives might be saved, and survivors might be less damaged, often not damaged at all. And even money might be saved in the long run.

The pediatric rheumatology approach to treatment of severe COVID-19 illness described in this article (and summarized in the APPENDIX) has potential to markedly improve the quality of care, and, in the process, reduce fears, angst, moral stress, and a sense of powerlessness among patients, families, physicians, nurses, other health care workers, and the public.

“Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction and skillful execution; it represents the wise choice of many alternatives.” ~ Will A. Foster

Robert M. Rennebohm, MD Email: rmrennebohm@gmail.com Website: notesfromthesocialclinic.org

(Updated January 16, 2021)

APPENDIX:

A Proposed Treatment Protocol for Severe COVID-19 Illness:

Reasons for severe COVID-19 illness:

This proposal begins with an understanding that patients with severe COVID-19 illness may be severely ill because of one or more of the following reasons:

• Unusual difficulty eradicating the SARS-CoV-2 virus:
  • Sluggishly produced, dysfunctional, or inhibited Type 1 interferon
  • Sluggishly activated, dysfunctional, or exhausted NK T-cells (Natural Killer T-cells)
  • Age-related decreased overall immune competence
  • Co-morbidity-related decreased immune competence
  • An unusually large viral load in the first place
  • Unusually low level of cross-reactive coronavirus antibodies or memory T-Cells (that are often provided by past exposure to ordinary non-COVID-19 coronaviruses)
  • Combinations of the above
• Excessive immunologic reactions to the COVID-19 virus—e.g., hyperinflammatory, hyperimmune, cytokine storm reactions—including a variety of autoimmune phenomena and the possibility of Susac-like, immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy in the pulmonary microvasculature (and possibly in other organs).
• A combination of unusual difficulty eradicating the COVID-19 virus AND excessive immunologic reactions to the COVID-19 virus
• In addition, illness in some patients is complicated by microvascular and macrovascular thrombosis, triggered by the hyperinflammation/cytokine storm, endothelial cell injury, anti-phospholipid antibodies, or combinations of these factors

This proposal encourages an understanding that most patients who become severely ill with COVID-19 may do so primarily because of hyperinflammatory, hyperimmune, autoimmune reactions, often with cytokine storm, and they may or may not also be dealing with a worrisome, ongoing viral load at the time of admission. [2-13]

The importance of the date of onset of COVID-19 symptoms:

This proposal also emphasizes the importance of knowing the date of onset of the patient’s COVID-19 symptoms and the usual time course of viral load and development of hyperimmune reactions. This knowledge enables the clinician to view the patient’s clinical details in the context of illness duration, which, in turn, improves the clinician’s ability to accurately determine whether the patient’s main problem is an ongoing high viral load, or a hyperinflammatory/hyperimmune/cytokine storm reaction, or both.

Early initiation of serial monitoring:

A principle of this proposal is that it is incumbent upon the physician to thoroughly study the patient—both upon entry to the hospital and serially thereafter—to document which of the above-mentioned factors are responsible for the patient’s severe illness. Upon admission, serial documentation of the following would be commenced:

• The extent of the patient’s viral load on admission and whether it subsequently increases or decreases, and how fast— assessed by following the Ct values at which serial COVID-19 PCR tests are positive. (See section on Ct values in main text. Also, see companion article on Ct values.)
• The extent to which the patient has developed IgM and IgG antibodies to SARS-CoV-2. This information supplements the Ct information and documents the extent to which the patient has already mounted an appropriate antibody response. (See section on antibody levels in main text.)
• The extent to which hyperinflammation/cytokine storm is evolving— assessed by following serial serum ferritin levels, CRP, ESR, D-dimer, PT, PTT, CBC, platelet count, serum albumin, LDH, ALT, AST, triglycerides, IL-6 level (if readily available), etc.
• The extent to which ischemia-producing microvascular endotheliopathy might be evolving in the pulmonary microvasculature— assessed by constantly monitoring paO2 and/or O2 saturation (the latter with pulse oximetry) and potentially by obtaining lab biomarkers of endothelial dysfunction. (Unfortunately, though, we do not, yet, have excellent, reliable, easily interpretable, readily available biomarkers of endothelial dysfunction.)
• The extent to which inappropriate coagulopathy is developing. Coagulopathy can develop because of microvascular endothelial injury, systemic hyperinflammation/cytokine storm, anti-phospholipid antibodies, or combinations of these. This can be monitored by following d-dimers, PT, PTT, and obtaining anti-phospholipid antibodies.

Tailoring treatment to the individual patient’s characteristics and most pressing needs:

An important principle of this proposal is that treatment should be tailored and adjusted to the specific (often changing) characteristics of the individual patient. If the primary threat to the patient is hyperinflammation/cytokine storm, immunosuppressive treatment is the most urgent and the most important consideration. If excessive ongoing viral infection is the primary problem/threat, augmentation of viral eradication is the most urgent and important treatment. If both problems are equally responsible/present, both need to be equally addressed, and done so in the most careful, timely, and sequenced fashion. If the primary problem is hyperinflammation/cytokine storm and there is little or no problem with ongoing viral infection, then immunosuppression can be provided more quickly, aggressively, and safely than if worrisome ongoing viral infection is also present. Furthermore, serial monitoring may reveal changes in status that permit or require nuanced adjustments.

Options for suppression of viral replication (augmentation of viral eradication):

• Remdesivir (possibly in combination with other anti-viral medications) —to interfere with viral replication. [86]
• Interferon alpha 2b (possibly in combination with anti-viral medications) —to induce an anti-viral state and further inhibit viral replication. [86-88]
• Convalescent plasma (possibly in combination with anti-viral medications and interferon alpha 2b)—to immediately provide high levels of antibody against the SARS-CoV-2 virus.
• Specific monoclonal neutralizing antibody (or combination of antibodies) against the SARS-CoV-2 virus. [93]
• IVIG [10, 84, 89] —to possibly block attachment of virus to receptors on human cells (?); to possibly provide cross-reactive anti-coronavirus antibodies; [89] and to also help subdue an excessive immune response to the virus (which possibly includes an immune-mediated occlusive microvascular endotheliopathy in the pulmonary microvasculature [52-58].)

Options for suppression of COVID19 induced “cytokine storm”/hyperinflammation:

• Corticosteroid (e.g., dexamethasone, methylprednisolone) —to comprehensively subdue immune over-reactivity. [75, 79, 90]. Some patients may adequately respond to a dose in the range of 1 mg/kg/day; others may need initial pulses of IV methylprednisolone.
• IV Anakinra—to selectively block IL-1 and, thereby, shut down “cytokine storm.” [10-12, 80-83, 85, 91,] For some patients high dose IV anakinra might be more appropriate than low dose SQ anakinra. [80] Anakinra may be preferable to tocilizumab because of anakinra’s greater flexibility, shorter half-life, and lower likelihood of predisposing to secondary bacterial infection. Initial and subsequent doses of anakinra can be tailored and quickly adjusted to the apparent evolving needs of the patient—i.e., anakinra may provide more precise and tailored treatment than tocilizumab.
• Tocilizumab, an anti-IL-6 agent, would be an alternative to anakinra, but anakinra has a better over-all safety profile and may be preferable. [10-12, 76-78, 92]
• IVIG [10, 84, 89]. If IVIG is used (e.g., 1-2 gm/kg initial dose), concomitant anticoagulation should be considered.

Options for prevention/treatment of abnormal microvascular and macrovascular coagulation:

• Heparinization/anticoagulation [13, 55]

Simultaneous clinical care and clinical research:

Another principle of this proposal is that it is amenable to both tailored (individualized) treatment and randomized treatment—i.e., parts of the treatment could be tailored to the specific characteristics of the individual patient, while other parts randomized for research purposes. For example, if a patient’s primary problem is hyperinflammation/cytokine storm and that patient, at that time, has little or no problem with ongoing viral infection, then that patient could be randomized to receive either:

• High dose corticosteroid (IV pulses of mega-doses of methylprednisolone, which works faster and better than lower doses), alone
• Lower dose corticosteroid, alone
• Anakinra (high dose vs low dose anakinra— alone, or with corticosteroid
• Tocilizumab, instead of anakinra— alone, or with corticosteroid
• IVIG (particularly if immune-mediated microvascular endotheliopathy is also suspected)
• Combinations of the above
• And there would also be an option to randomize to also receive one or more of the treatments that would augment viral eradication.

A point of emphasis is that every patient deserves access to an approach like that described in this APPENDIX, and every patient’s experience can be viewed as a clinical research opportunity.

The practicality of a pediatric rheumatology approach:

This pediatric rheumatology approach is not just some ideal, “pie-in-the-sky” approach that is “not possible in the real world.” The above immunosuppressive approach has been practiced for decades by pediatric rheumatologists. Pediatric rheumatologists have found this approach to not only be realistic, but to be necessary, to save the patient.

Some further comments:

There may be some confusion regarding what Hippocrates meant when he said, “Do no harm.” One aspect of this admonition is to avoid causing harm by the treatments/interventions you implement. But another aspect is to avoid causing harm by your unwillingness to use a treatment/intervention that, yes, has risks, but can be lifesaving or otherwise reduce suffering/damage. One aspect is “harm from actions taken;” the other is “harm from actions not taken.” Some physicians seem to think that if harm occurs because of their actions, it is their fault; but, if harm occurs because of their inaction, it is the disease’s fault. In my view, undertreatment of severe COVID-19 illness results in “harm from actions not taken.”

It is also important to point out that randomized controlled trials (RCTs), though truly ideal, do not always represent the highest quality of evidence and data. It depends on the quality of the RCT. Sometimes, carefully studied human experience contradicts the prevailing narrative (including the results of some RCTs) and is the better test of Truth.

Finally, it is important for the Public, particularly future patients, to know what options are available for treatment of severe COVID-19 illness. At the very least, for future patients, the pediatric rheumatology approach discussed in this article is an approach to be considered.

NOTE 1: This protocol may also be applicable to patients who become severely ill with influenza A, influenza B, and other potentially life-threatening viral respiratory infections, including the four common coronavirus infections (HKU1, NL63, OC43, and 229E).

NOTE 2: This article represents an updated and expanded version of an article that was originally published in the Russian journal, Russia Biomedical Research. [94]

REFERENCES:

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