How to Treat a Cytokine Storm

Timing is the critical factor in whether steroids help or harm COVID-19 patients with endocrine conditions

With Paul M. Stewart MD, Michael Roth MD, and Michael E. Wechsler MD

During this time of rampant COVID-19 infection, there are a lot of opinions and commentaries hitting the journals regarding treatment for patients. The problem is that the experimental studies that need to be done to determine effective treatments are currently underway and we will have to wait weeks or months for the results. In the intervening period, we are left with expert opinions about how to move forward. This is especially concerning for those with comorbid conditions that put them at greater risk of contracting COVID-19 or who may experience a more severe disease if they become infected.

A recent editorial written by the editors of the Journal of Clinical Endocrinology and Metabolism, Editor-in-Chief Paul M. Stewart, MD, and Deputy Editors Ursula B. Kaiser, MD, and Raghavendra G. Mirmira, MD, PhD, outline a course of action for healthcare providers of endocrine patients during this COVID-19 crisis1.  

Adrenal insufficiency: Addison’s Disease and secondary conditions

Much of the advice focuses on patients with adrenal insufficiency, either primary, as in Addison’s Disease, or secondary, as might be the case in hypopituitarism, but their advice can be extrapolated to other endocrine disorders.

The concern for patients with adrenal insufficiencies revolves around their reliance on exogenous glucocorticoids. Endogenously, glucocorticoids are released from the adrenal gland as part of a stress response, suppressing the immune response and preventing inflammation. Adrenal insufficient patients then do not mount a normal stress response on their own and must take additional glucocorticoid doses to combat stressors.

When asked about how these patients should approach a stressor like the current virus, Dr. Stewart told EndocrineWeb, “Those with known adrenal failure secondary to either adrenal disease itself, commonly called Addison’s Disease, or secondary to a problem in the pituitary gland, take regular steroid replacement therapy and know to ‘double dose’ in the event of any intercurrent illness, which extends to COVID-19.”

The authors caveat this advice with this addition: “Moreover, those patients taking supraphysiologic doses of glucocorticoids may have an increased susceptibility to COVID-19.”

The controversy of glucocorticoids in the time of the Coronavirus

Because glucocorticoids have a powerful anti-inflammatory effect, they were used non-empirically to treat lung inflammation during the SARS and MERS epidemics with little, no, or detrimental effects2,3. The detrimental effects included prolonged viral presence in the short term and increased risk of osteocrenosis, avascular necrosis, and steroid-induced diabetes with prolonged use2-5. As such, the World Health Organization opposes the general use of glucocorticoids in their March 13, 2020 update to “Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected6." WHO states:

“Given the lack of effectiveness and possible harm, routine corticosteroids should be avoided unless they are indicated for another reason. Other reasons may include exacerbation of asthma or COPD, septic shock, and a risk and benefit analysis needs to be conducted for individual patients.”

Adrenal insufficiencies could fall into the category of other reasons. When asked specifically about the controversy between glucocorticoid use in COVID-19 and their use in other disorders, Dr. Stewart stated,

“This isn’t easy. Maybe as high as 5% of the patients we are or will see in hospitals with COVID-19 related illness are patients with prior treatment with pharmacological doses of steroid to treat underlying inflammatory conditions – for example asthma, inflammatory bowel disease, polymyalgia, etc. We know that up to half of these patients cannot mount a normal steroid response to infection and may need intravenous replacement therapy to prevent deterioration and potential death.”

The recommendation by WHO regarding these other conditions is:

“If corticosteroids are prescribed, monitor and treat hyperglycaemia, hypernatraemia and hypokalaemia. Monitor for recurrence of inflammation and signs of adrenal insufficiency after stopping corticosteroids, which may have to be tapered.”6

This controversy seems to be on the minds of many healthcare professionals as they try to maneuver treatment options in patient populations with comorbid disorders. From the University Hospital in Basel, Switzerland, Dr. Michael Roth (Pulmonary Cell Research and Pneumology, Department of Biomedicine and Internal Medicine) tells us that this is something their team is constantly discussing.

Dr. Roth told EndocrineWeb, “We came to the conclusion that the use of medication (glucocorticoids) depends largely on the timing. Steroids are the best anti-inflammatory drugs that we have. As soon as a patient shows signs of a ‘cytokine storm,’ steroids should be used. At other stages the MD in charge must make a decision for each individual patient. The major problem is that there is no treatment that can be applied to all patients.”

COVID-19 and the cytokine storm

A cytokine storm occurs when there is an excessive and uncontrolled release of pro-inflammatory cytokines. It can result in acute respiratory distress syndrome (ARDS), multiple organ failure, and death. Such storms were seen in severe SARS and MERS patients in the past, and COVID-19 can have a similar cytokine profile7.

Clinical reports from China published by Zhang et al. in the journal Clinical Immunology, revealed that, in addition to lymphocytopenia, COVID-19 patients had high inflammatory parameters and proinflammatory cytokines, particularly IL2, IL6, IL7, IL8, IL10, and TNFa. Inflammatory cytokines were further elevated in patients admitted to the ICU7, all suggestive of a COVID-19 induced cytokine storm.

Autopsy reports from COVID-19 patients found atrophy in the spleen and secondary lymphoid tissues. Since these organs do not express ACE2, the receptor for COVID-19 infection8,9, Zhang et al. theorize that damage to the immune system was a result of a cytokine storm7.

Zhang et al. conclude, in agreement with Dr. Roth, that in light of the real possibility of a cytokine storm in critically ill patients, an anti-inflammatory treatment may be necessary, but that “a timely anti-inflammation treatment initiated at the right window of time is of pivotal importance and should be tailored in individual patients to achieve the most favorable effects.”

Treatment recommendations for endocrine patients

In the case of adrenal insufficiencies, it seems the consensus is to continue with standard glucocorticoid treatment including increased dosing during immunological stresses. Further, patients on glucocorticoid treatment, regardless of reason, should be closely monitored. Overall, when treating endocrine patients, the JCEM editors suggest that preventing and treating COVID-19 in endocrine patients should be no different than the general population, but healthcare providers do need to recognize that these patients are at greater risk for a more severe infection1.

Michael E. Wechsler, MD, Director of the Cohen Family Asthma Institute (National Jewish Hospital, Colorado) summarizes this advice best, “Treat the underlying disease and treat COVID-19 as separate entities. If there is an exacerbation of the disorder, treat it with the standard critical care measures even in the context of COVID-19 infection.”

Dr. Stewart and Dr. Roth report no current conflicts with regard to their involvement in conducting or discussing this study.

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