Updated April 6, 2020 at 10:00 AM Pacific Time

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COVID-19 Cytokine Storm Syndrome: Identification and Treatment

S. Thomas Yadegar, M.D., Shahin Delkhah, M.D., Katherine G. Jacobson

IMPORTANT POINT: THE VAST MAJORITY OF PATIENTS DIAGNOSED WITH COVID-19 WHO ARE ON
MECHANICAL VENTILATION IN THE ICU ARE IN A STAGE OF CYTOKINE STORM SYNDROME; IF THIS
SYNDROME IS NOT RECOGNIZED AND TREATED EARLY AND AGGRESSIVELY, MANY OF THESE PATIENTS
WILL PERISH.

ABSTRACT

The novel coronavirus, SARS-CoV-2, was first reported in Wuhan, China in December 2019, and has
subsequently developed into a global pandemic causing the new illness known as COVID-19 that may
manifest as an upper or lower respiratory tract disease. The lower respiratory tract disease associated
with COVID-19 can be further classified as mild, severe or critical. Cytokine storm syndrome is an elusive
disease that may occur in this patient population. Cytokine storm syndrome is difficult to diagnose, as
patients present at different stages of the storm. In this report, we identify Case 1 as a patient with
COVID-19 pneumonia without cytokine storm syndrome. The patient remained stable and based on
serum ferritin, C-reactive protein (CRP) and D-dimer, was deemed to be low risk for developing cytokine
storm syndrome. Next, Case 2 was a patient with severe disease that progressed to critical status during
hospitalization due to cytokine storm syndrome. The patient’s status improved to mild after escalation
of therapy with an immunosuppressive agent, based on monitoring and evaluation of serum
inflammatory markers and the patient’s clinical status. Based on the patient’s serum markers, it can be
determined that the patient’s clinical deterioration and progressive respiratory failure was due to
cytokine storm syndrome. Without intervention, the patient may have required intubation and
mechanical ventilation. Lastly, we also report Case 3 who was not diagnosed properly and not treated
early enough, which subsequently led to progressive respiratory failure requiring intubation and
mechanical ventilation. This patient was subsequently treated with IL-6 inhibitor without improvement
in clinical status and has now required an additional immunosuppressive agent. Based on these cases,
clinicians should evaluate all COVID-19 patients for cytokine storm syndrome at all varying degrees of
clinical presentation and should treat all COVID-19 patients with cytokine storm syndrome of varying
clinical presentations with early and aggressive immunosuppressive agents, and therefore limit
systematic need for mechanical ventilation, utilization of intensive care unit in an effort to decrease
mortality due to SARS-CoV-2.

INTRODUCTION

Since being declared a global pandemic by the World Health Organization, as of April 4, 2020, COVID-19
has killed over 50,000 people and infected over 1 million people worldwide (Johns Hopkins University).
COVID-19 causes an asymptomatic carrier state as well as upper respiratory tract disease or lower
respiratory tract disease. Further classification of lower respiratory tract disease is based on clinical
presentation. Every patient with suspected COVID-19 should also be evaluated for cytokine storm
syndrome with serological markers in the emergency room and in the outpatient setting. If the markers
are consistent with cytokine storm syndrome, even if the patient is deemed to be clinically stable, such
patient should be admitted and undergo serial testing for progression of cytokine storm syndrome
and/or clinical deterioration. While there is a percentage of patients that are admitted to the hospital
in a critical state, a larger subset of patients are admitted in a mild or severe state. During

1 S. THOMAS YADEGAR, M.D. © 2020

hospitalization, this subset of patients may progress to critical status as a result of cytokine storm
syndrome requiring intubation, mechanical ventilation and intensive care unit utilization if not
identified early in their hospitalization course. It is also imperative that clinicians evaluate for cytokine
storm syndrome in patients who present at critical status and require mechanical ventilation. Clinicians
should rule out other etiologies causing need for mechanical ventilation, such as infection, pulmonary
embolus or cardiac disease. Once clinicians confirm that the cause of mechanical ventilation is cytokine
storm syndrome, clinicians should be aware that this presentation is later in the disease course and
these patients present with a variety of clinical manifestations. Acute respiratory failure or a
hypercoagulable state with widespread thromboembolic disease are common clinical manifestations.
The current trend in treatment is to treat patients that require hospitalization with combination of
hydroxychloroquine and azithromycin, but based on our findings based on the cases below, this trend in
treatment should be immediately discontinued and replaced with the treatments described in this case
report. Patients with cytokine storm syndrome require early and aggressive therapy with
immunosuppressive agents to prevent (a) the exponential increase in cytokines and pro-inflammatory
markers that ultimately result in (b) multi-system organ failure.

In our treatment, the choice of the specific immunosuppressive agents that we used was based on their
availability at our institution. Clinicians should not necessarily use the specific immunosuppressive
agents used by us but should refer to the treatment protocols below and use the immunosuppressive
agents available at their respective institutions.

While we fully support controlled trials being conducted prior to effectuating the treatments described
in this case report, due to the dire nature of Covid-19 and the exponential deaths caused by it, we
believe that withholding the treatments described below is unethical and immoral.

CASE 1

An 83-year-old female with a history of asthma, hypertension and stroke was brought into the
emergency department in Los Angeles, California on March 25, 2020 with chief complaints of
shortness of breath and diarrhea. She was brought in by her family members in a wheelchair from an
assisted living facility. The patient’s initial temperature was 37.1 C, pulse 74 bpm, blood pressure
163/81 mmHg and oxygen saturation of 94% on room air. Chest x-ray on presentation was interpreted
as congestive heart failure. The patient also underwent CT chest, which revealed mild scattered
bilateral ground glass opacification of the lungs without evidence of pleural effusion. The patient
underwent nasopharyngeal swab testing for SARS-CoV-2 by PCR, yielding positive result on March 27,
2020.

The patient was admitted to a medical/surgical floor with droplet and contact isolation. She was placed
on oxygen supplementation on 2 liters per minute (LPM) via nasal cannula and was treated with
acetaminophen and albuterol inhaler, as well as continued treatment with her maintenance inhalers of
budesonide formoterol 160/4.5 mcg and tiotropium 1.25 mcg. On March 27, the patient was initially
weaned off oxygen, but developed abdominal pain and shortness of breath and was subsequently
placed on oxygen supplementation. The patient remained stable but continued to remain weak.
However, since her SARS- CoV-2 PCR test was positive, she was initiated on hydroxychloroquine (initial
dose 400 mg orally twice daily x 1 day; continuing dose 200 mg orally twice daily x 4 days) and
azithromycin (initial dose 500 mg once orally; continuing dose 250 mg orally once daily x 4 days). She
remained afebrile throughout her hospitalization. She underwent serial repeat serum markers of
ferritin, CRP and D-dimer, with results are shown in Table 1. Her hospitalization was significant for
generalized lethargy and weakness, which has prolonged her hospital stay. She has remained on oxygen
supplementation throughout her hospitalization but has never required more than 3 LPM. She has now
2 S. THOMAS YADEGAR, M.D. © 2020
been weaned off oxygen and is currently on room air of a saturation of 93%. She is currently being
evaluated for discharge.

CASE 2

A 62-year-old male with a history of coronary artery disease, hypertension and chronic obstructive
pulmonary disease (COPD) presented to the emergency department in Los Angeles, California on
March 28, 2020 with symptoms of heartburn, shortness of breath and 5 day history of cough. He
initially called the paramedics but was not brought to the hospital, so he decided to walk in. His initial
temperature was 36.8 C, pulse 108 bpm, blood pressure 140/80 mmHg and oxygen saturation 93% on
room air. Chest x-ray on presentation showed ill-defined patchy bilateral pulmonary infiltrates.
Laboratory testing, with values provided in Table 2, revealed evidence of an acute inflammatory
process based on elevated levels of ferritin, CRP and D-Dimer. The patient underwent nasopharyngeal
swab testing for SARS-CoV-2 by PCR yielding a positive result on April 1 , 2020. He was given 1 L normal
saline IV bolus, as well as ceftriaxone 2 g IV and azithromycin 500 mg IV.

He was admitted into the telemetry unit with droplet and contact isolation. He received supplemental
oxygen at 2 LPM via nasal cannula. As the patient was monitored over the next 48 hours, his oxygen
requirements increased from 2 LPM to 6 LPM. On March 30, 2020, CRP significantly increased to 17.71
mg/dL. On March 31, 2020 as a result of clinical decompensation and CRP elevation, the patient was
suspected to be COVID-19 positive and was initiated on hydroxychloroquine (initial dose 400 mg orally
twice daily x 1 day; continuing dose 200 mg orally twice daily x 4 days) and azithromycin (initial dose
500 mg once orally; continuing dose 250 mg orally once daily x 4 days). Despite the above treatment,
the patient continued to decompensate with increasing tachypnea and no improvement in oxygenation.
The rapid response team was contacted on the telemetry floor and patient subsequently was
transferred to the intensive care unit. He continued to decompensate and was given one subcutaneous
injection of sarilumab 200 mg on April 1, 2020 at 10:43 am. At approximately 12:20pm, the patient’s
CRP level decreased to 13.85 mg/dL. The patient’s oxygenation improved at 3:00 pm to 94% on 2 LPM
and his overall clinical status improved significantly. On April 2, 2020 at 7 AM, the patient was on room
air at 94% saturation and his clinical status continued to improve. On April 3, his CRP had decreased to
4.51 mg/dL. He continued to remain stable and has subsequently been discharged home.

CASE 3

A 50-year-old man with no past medical history walked into the emergency department in Los
Angeles, California on March 22, 2020 with chief complaints of fever and shortness of breath. The
patient’s initial temperature was 37.3 C, pulse 118 bpm, blood pressure of 125/78 mmHg, oxygen
saturation on room air was 91%. Chest x-ray on presentation revealed bilateral diffuse patchy
interstitial infiltrates. The patient underwent nasopharyngeal swab testing for SARS-CoV-2 by PCR,
yielding positive result on March 25, 2020. He was treated with ceftriaxone 2 g IV and azithromycin
500 mg IV.

The patient was admitted to the telemetry floor with droplet and contact isolation. The patient was
continued on ceftriaxone 1 g IV and azithromycin 500 mg IV. On March 26, 2020, the patient was
started on hydroxychloroquine (initial dose 400 mg orally twice daily x 1 day; continuing dose 200 mg
orally twice daily x 4 days) and azithromycin (initial dose 500 mg once orally; continuing dose 250 mg
orally once daily x 4 days). During his hospitalization, patient continued to have fever and shortness of
breath and his oxygen requirements varied from 2 LPM to 4 LPM. On March 28, 2020, patient
developed respiratory distress and progressive hypoxemia. The rapid response team was contacted
on the telemetry floor and patient was intubated and transferred to the intensive care unit. At the
time of intubation, he was placed on 100% oxygen. Within 12 hours, the patient’s FiO2 was titrated to
3 S. THOMAS YADEGAR, M.D. © 2020
40%. However, on March 29, 2020, the patient required initiation of IV norepinephrine drip to
maintain his blood pressure. As a result of deterioration in clinical status requiring vasopressor
support, the patient was given one subcutaneous injection of sarilumab 200 mg on March 30, 2020.
Despite sarilumab injection, the patient developed progressive hypoxemia with FiO2 of 70% on April
1, 2020. The patient has continued to require mechanical ventilation. His IV norepinephrine has been
decreased, however, his FiO2 concentration remains at 50%. On April 4, 2020, the patient’s serum
CRP improved as expected (see Table 3); however, his clinical status did not change significantly.
Subsequent, the patient was initiated on mycophenolate mofetil 1000 mg twice daily via nasogastric
tube. At this time, mycophenolate mofetil is the only other immunosuppressive agent available at our
institution.

DISCUSSION

We report Case 1 of SARS-CoV-2 with confirmed COVID-19 which caused pneumonia; however, based
on initial and subsequent low inflammatory markers, she was deemed not at risk for cytokine storm
syndrome and subsequently did not develop cytokine storm syndrome during her hospitalization. We
also report Case 2 of SARS- CoV-2 with confirmed COVID-19 that responded well to IL-6 inhibitor
treatment after failure to improve on hydroxychloroquine-azithromycin therapy. We also report Case 3
of SARS-CoV-2 with confirmed COVID-19 who was not diagnosed properly nor treated early enough,
which subsequently led to progressive respiratory failure requiring intubation and mechanical
ventilation. This patient was subsequently treated with IL-6 inhibitor without improvement in clinical
status and has now required an additional immunosuppressive agent. We postulate based on early
trends in serum markers of ferritin, CRP and D-dimer, clinicians may be able to identify which patients
may progress to critical status. We also postulate that if the diagnosis and subsequent treatment is not
made early enough, then the patient will require a combination of at least two immunosuppressive
agents.

By initially screening for these inflammatory markers and subsequently repeating and trending these
markers during the course of hospitalization, clinicians may ascertain which patients are at risk for
developing cytokine storm syndrome and subsequent progression to critical status. The goal is to
initiate early and aggressive immunosuppressive therapy to prevent this progression. Clinicians should
rule out other etiologies that may cause a combination of clinical deterioration and elevation of
inflammatory markers such as a secondary infection, pulmonary emboli or COPD exacerbation. The
serum ferritin level is of initial diagnostic value for identification of patients who may develop cytokine
storm syndrome. Serum ferritin levels above 500 ng/mL should raise suspicion for active and ongoing
inflammation; however, it does not appear to have any utility in following progression of disease. There
is a subset of patients who present with low ferritin levels, and these patients should not automatically
be ruled low risk for development of cytokine storm syndrome, as they need to be evaluated for iron
deficiency with or without anemia, commonly noted in patients with intravenous drug abuse.
Conversely, the presence of a high ferritin level does not automatically indicate cytokine storm
syndrome in COVID-19 patients. Clinicians should evaluate for other etiologies such as a secondary
infection, Hepatitis B, Hepatitis C, hemachromatosis or other liver diseases. The trend for serum CRP is
important as the marker for progression of disease state. An elevation in CRP, as well as any clinical
deterioration should cause clinicians to initiate therapy with immunosuppressive therapy. After initial
therapy, clinical status needs to be monitored, as CRP will no longer have utility as a marker to follow
progression. D-dimer has been found to be an independent predicator of mortality in Zhou et. al (March
2020); however, its utility in initial diagnosis and following disease progression appears to be limited but
requires further investigation.

Based on trends in inflammatory markers correlated with the patient’s clinical status, we postulate the

4 S. THOMAS YADEGAR, M.D. © 2020

original pathophysiology of patients with COVID-19 who either (1) decompensate to critical status after
admission, or (2) present at critical status without alternate etiology to be cytokine storm syndrome.
This inflammatory response is a delayed response mediated by Type 1 T helper cells, causing activation
of IL- 6 and other pro-inflammatory cytokines. The exact mechanism of this reaction is unclear at this
time and warrants further investigation. Cytokine storm syndrome explains the patient’s progressive
shortness of breath and hypoxemia, which if left untreated, progresses to acute lung injury and
respiratory failure that requires intubation, mechanical ventilation and intensive care unit utilization.
Understanding that patients with cytokine storm syndrome can present at various stages with various
clinical manifestations, this theory also explains why COVID-19 patients presenting at critical status
require mechanical ventilation, assuming clinicians have ruled out alternative etiologies. Therefore, all
COVID-19 patients who have been found to have cytokine storm syndrome may present with different
clinical presentations.

Patients admitted to the hospital who have an insignificant elevation of serum markers should not
automatically be started on treatment with hydroxychloroquine and azithromycin, as seen with Case 1,
as this may cause deleterious side effects. Overall, clinicians should evaluate trends in the above serum
markers as well as deterioration of clinical status to evaluate for initial or escalation of therapy with
immunosuppressive agents. Possible agents include IL-6 inhibitors, IL-1 inhibitors or JAK inhibitors;
however, this is dependent upon individual availability in institutions, as well as further investigation
with well-controlled, randomized trials into the best course of treatment.
CONCLUSION

Clinical data on the role of treating cytokine storm syndrome in relation to COVID-19 patients continues
to remain limited. While there is a plethora of inflammatory markers, clinical testing is limited to
availability at each individual institution, as well as result time. However, central to diagnosing cytokine
storm syndrome in COVID-19 patients is the evaluation of ferritin levels. Once patients with cytokine
storm syndrome have been diagnosed, CRP levels and clinical status are used in following disease
progression. This disorder remains elusive to clinicians, as most clinicians routinely examine white blood
cell count, procalcitonin and other markers upon patient presentation, and these do not correlate with
the cytokine storm syndrome that occurs in COVID-19 patients. Instead, clinicians who suspect cytokine
storm syndrome in COVID-19 patients should evaluate ferritin, CRP, and D-dimer levels in patients
presenting to emergency departments. Ferritin, CRP and D- dimer were chosen as the study markers, as
they are readily available in hospital laboratories and yield results within a few hours. Monitoring IL-6,
IL-1, and other inflammatory markers may be useful in further understanding our proposed immune-
mediated treatment, as well to aid in selection of immunosuppressive agent. With early identification of
cytokine storm syndrome via serum markers of ferritin and CRP, along with the patient’s clinical status,
clinicians should now be able to treat and prevent the underlying cause of decompensation in patients
with COVID-19 cytokine storm syndrome. Clinicians are advised to follow the recommended treatment
protocols at the end of this report. We believe that cytokine storm syndrome may be the leading cause
of mortality in patients with COVID-19. It is imperative that clinicians evaluate and initiate early and
aggressive therapy with immunosuppressive agents in patients with COVID-19 cytokine storm
syndrome, which should lead to decrease in morbidity and mortality.

5 S. THOMAS YADEGAR, M.D. © 2020

Table 1: Laboratory Values for Case 1

Lab 3/25/2020 3/27/2020 3/30/2020 4/3/2020

WBC (K/uL) 5.5 7.8 -- 7.9

Hemoglobin (g/dL) 13.0 12.9 -- 14.0

Platelet count (K/uL 161 149 -- 225

Creatinine (mg/dL) 0.79 0.71 0.66 0.57

AST (U/L) 18 -- -- --

ALT (U/L) 13 --- -- --

Alkaline-phosphatase 78 -- -- --
(U/L)

Total Bilirubin (mg/dL) 0.3 -- -- --

Procalcitonin (mg/mL) <0.10 -- -- --

D-dimer (ug/mL FEU) -- -- 0.39 0.92

CRP (mg/dL) -- 0.15 3.3 3.65

Ferritin (ng/mL) --- 38 92 228

6 S. THOMAS YADEGAR, M.D. © 2020

Table 2: Laboratory Values for Case 2

Lab 3/28/2020 3/30/2020 4/1/2020 4/3/2020

WBC (K/uL) 10.6 10.1 8.6 7.2

Hemoglobin (g/dL) 14.6 13.1 12.3 12.4

Platelet count (K/uL 515 372 489 496

Creatinine (mg/dL) 1.1 0.91 0.94 1.05

AST (U/L) 41 48 62 --

ALT (U/L) 27 36 56 --

Alkaline-phosphatase 59 72 98 --
(U/L)

Total Bilirubin (mg/dL) 0.4 0.2 0.3 --

Procalcitonin (mg/mL) 0.11 -- -- --

D-dimer (ug/mL FEU) 3.50 1.94 1.37 1.20

CRP (mg/dL) 7.16 17.71 13.85 4.51

Ferritin (ng/mL) 1,191 1,181 1,212 1,219

Quantiferon TB Gold -- -- Negative --

7 S. THOMAS YADEGAR, M.D. © 2020

 Table 3: Laboratory Values for Case 3

Lab 3/22/2020 3/25/2020 3/28/2020 3/30/2020 3/31/2020 4/1/2020 4/3/2020

WBC (K/uL) 8.1 6.6 5.3 -- -- 9.1 7.7

Hemoglobin (g/dL) 14.5 13.6 13.5 -- -- 11.9 12.6

Platelet count (K/uL 148 228 472 -- -- 555 449

Creatinine (mg/dL) 0.62 0.55 0.59 0.69 -- 0.53 0.58

AST (U/L) 39 63 48 37 -- 30 45

ALT (U/L) 49 98 105 60 -- 42 56

Alkaline- 87 128 162 169 -- 169 151

phosphatase (U/L)

Total Bilirubin (mg/dL) 0.5 0.4 0.5 1.2 -- 0.4 0.4

Procalcitonin (mg/mL) <0.10 <0.10 -- -- -- --- --

D-dimer (ug/mL FEU) -- -- -- 2.26 -- 8.72 16.44

CRP (mg/dL) -- -- -- 35 -- 16.06 3.59

Ferritin (ng/mL) -- -- -- 1,229 -- 1,337 970

Quantiferon TB Gold -- -- -- -- Negative -- --

8 S. THOMAS YADEGAR, M.D. © 2020

 COVID-19 Cytokine Storm Syndrome Treatment Protocol for Patients Not On Mechanical Ventilation

This treatment protocol is to diagnose and treat cytokine storm syndrome in COVID-19 patients infected with SARS-
CoV-2 not on mechanical ventilation.

Every patient who is diagnosed with COVID-19 disease should undergo serological evaluation for cytokine storm
syndrome. This disease is extremely silent, increases exponentially and the consequences without treatment are
dire. In addition to normal laboratory evaluation at initial presentation in the emergency room, the patient should
undergo serum ferritin, CRP, and D-dimer. The ferritin and CRP are of paramount significance, as they will alert
clinicians to the presence of intense inflammation and possible progression to cytokine storm syndrome, leading
to acute respiratory failure and possible multi-system organ failure. Based on the initial level of ferritin, there will
be serial testing of each inflammatory marker performed throughout the patient’s hospitalization course. There is
a subset of patients who initially present with low ferritin levels, and these patients should not automatically be
ruled low risk for development of cytokine storm syndrome, as they need to be evaluated for iron deficiency with
or without anemia. This is commonly seen in patients with intravenous drug abuse. Conversely, the presence of a
high ferritin level does not automatically indicate cytokine storm syndrome in COVID-19 patients. Clinicians should
evaluate for other etiologies such as a secondary infection, Hepatitis B, Hepatitis C, hemachromatosis or other
liver diseases.

Prior to treatment initiation, all patients should undergo laboratory evaluation to evaluate for active tuberculosis
disease or invasive fungal disease. This can be performed with serum Quantiferon TB Gold, as well as 1,3 Beta-D-
Glucan upon admission. However, treatment should not be delayed if the patient is clinically deteriorating.

The use of hydroxychloroquine-azithromycin should no longer be used as treatment of patients presenting with
COVID-19.

Timely initiation of treatment is of the utmost importance in treating COVID-19 patients with cytokine storm
syndrome, as early and aggressive treatment prevents progressive deterioration.

Informed consent must be obtained PRIOR TO initiation of ANY therapy contained within the below treatment
protocols.

Clinicians should also consider consultation with a rheumatologist and/or hematologist who may be more familiar
with the use of the immunosuppressive medications described below.

Treatment with an IL-6 inhibitor is the first line therapy. The adverse effects include, but are not limited to, the
following:
• Myelosuppression
• Worsening or unmasking of infection which may be severe (particularly tuberculosis, invasive fungal
infections, and other opportunistic infections)
• Gastrointestinal perforation
• Hypertension
• Headache
• Injection site reactions
• LFT abnormalities

Treatment

Ferritin level less than 500 ng/mL

Assuming clinicians have ruled out iron deficiency with or without anemia, these patients are at low likelihood to
develop cytokine storm syndrome. They should undergo repeat ferritin, CRP, and D-dimer at 48 hours intervals. If
the patient’s CRP becomes elevated and the patient’s clinical status deteriorates, clinicians should initiate
immunosuppressive therapy with an IL-6 inhibitor and follow the below treatment protocol.

9 S. THOMAS YADEGAR, M.D. © 2020

Ferritin level greater than 500 ng/mL

Assuming clinicians have ruled out alternative etiology for elevated ferritin, these patients should be considered
high risk to develop cytokine storm syndrome with possible progression and should be followed very closely. The
patient that presents with elevated CRP and is clinically unstable should immediately receive therapy with IL-6
inhibitor and follow the treatment protocol below. If the patient has elevated CRP upon presentation but is
clinically stable, such patient may be considered for immediate initiation of IL-6 inhibitor or be closely monitored
with daily CRP levels at the discretion of clinician. If the patient clinically deteriorates with progressive hypoxemia,
clinicians should immediately initiate therapy with IL-6 inhibitor and follow the below treatment protocol.

Upon initiation of IL-6 inhibitor, if the patient’s clinical status does not improve within 6-12 hours, the patient
should be treated with additional immunosuppressive therapy such as IL-1 inhibitor, JAK inhibitor or
mycophenolate mofetil based on institutional availability. Combination therapy of IL-6 and IL-1 inhibitors may
have lower efficacy. Clinicians should also be advised that upon initiation of IL-6 inhibitor, CRP levels alone are no
longer useful to track the patient’s clinical status, and each patient must be individually evaluated. If the patient’s
clinical status continues to deteriorate despite therapy with 2 immunosuppressive agents, clinicians should add a
third rescue immunosuppressive agent.

All of the above patients should be monitored for other causes of clinical deterioration. These include but are not
limited to:
• Secondary infection
• Cardiac disease such as congestive heart failure or acute myocardial infarction with pulmonary edema
• Asthma or COPD exacerbation
• Pulmonary embolus, which is often a silent disease, and this case, D-dimer may not be useful, as it is
commonly elevated in patients with cytokine storm syndrome. Clinicians should evaluate the patient and
utilize radiological imaging to diagnose pulmonary embolus.

10 S. THOMAS YADEGAR, M.D. © 2020

 COVID-19 Cytokine Storm Syndrome Treatment Protocol for Patients On Mechanical Ventilation

This treatment protocol is to diagnose and treat cytokine storm syndrome in COVID-19 patients infected with
SARS-CoV-2 on mechanical ventilation.

Clinicians should understand that patients on mechanical ventilation are presenting at a later and more intense
stage of cytokine storm syndrome. Upon admission, clinicians should evaluate patients on mechanical ventilation
with serum ferritin, CRP and D-dimer, in addition to routine serologies to rule out other etiologies. However,
clinicians should understand that since these patients are presenting at a later stage of the cytokine storm
syndrome, these inflammatory markers may not necessarily be depended upon for tracking the patient’s clinical
status. Clinicians should continue to monitor each patient’s individual clinical status to track disease progression.
These patients should also undergo laboratory evaluation to evaluate for active tuberculosis disease, invasive
fungal disease or an opportunistic infection as part of the monitoring of such patients’ status during treatment. This
can be performed with serum Quantiferon TB Gold, as well as 1,3 Beta-D-Glucan.

Prior to initiation of this protocol for COVID-19 patients on mechanical ventilation, clinicians should rule out other
etiologies that may require mechanical ventilation, such as a secondary infection, or pulmonary or cardiac disease.
Once clinicians confirm that the cause of mechanical ventilation is cytokine storm syndrome, clinicians should be
aware that this presentation is later in the disease course and these patients present with a variety of clinical
manifestations.

The use of hydroxychloroquine-azithromycin should no longer be used as treatment of patients presenting with
COVID-19.

Timely initiation of treatment is of the utmost importance in treating COVID-19 patients with cytokine storm
syndrome, as early and aggressive treatment prevents progressive deterioration.

Informed consent must be obtained PRIOR TO initiation of ANY therapy contained within the below treatment
protocols.

Clinicians should also consider consultation with a rheumatologist and/or hematologist who may be more familiar
with the use of the immunosuppressive medications described below.

Treatment with an IL-6 inhibitor is the first line therapy. The adverse effects include, but are not limited to, the
following:
• Myelosuppression
• Worsening or unmasking of infection which may be severe (particularly tuberculosis, invasive fungal
infections, and other opportunistic infections)
• Gastrointestinal perforation
• Hypertension
• Headache
• Injection site reactions
• LFT abnormalities

Treatment

After clinicians have ruled out other etiology for COVID-19 patients on mechanical ventilation, clinicians should
initiate combination therapy with 2 immunosuppressive agents, such as IL-1 inhibitor, IL-6 inhibitor, JAK inhibitor
or mycophenolate mofetil. Combination therapy of IL-6 and IL-1 inhibitors may have lower efficacy. There may be
a small subset of patients who do not improve, despite the above therapy. If there is sign of clinical deterioration
or no improvement in clinical status, then clinicians should initiate a third immunosuppressive agent. The choice
of the therapy given will depend upon the patient’s co-morbidities, as well as medication availability at clinicians’
institution(s).

11 S. THOMAS YADEGAR, M.D. © 2020

All of the above patients should be monitored for other causes of clinical deterioration. These include but are not
limited to:
• Secondary infection
• Cardiac disease such as congestive heart failure or acute myocardial infarction with pulmonary edema
• Asthma or COPD exacerbation
• Pulmonary embolus, which is often a silent disease, and this case, D-dimer may not be useful, as it is
commonly elevated in patients with cytokine storm syndrome. Clinicians should evaluate the patient and
utilize radiological imaging to diagnose pulmonary embolus.

12 S. THOMAS YADEGAR, M.D. © 2020

References

“Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) at Johns

Hopkins University (JHU).” Johns Hopkins University,

gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e 9ecf6.

Mehta, Puja, et al. “COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression.” The

Lancet, vol. 395, no. 10229, 16 Mar. 2020, pp. 1033–1034., https://doi.org/10.1016/S0140-

6736(20)30628-0.

Zhou, Fei, et. al Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in

Wuhan, China: a Retrospective Cohort Study. 12 Mar. 2020,

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13 S. THOMAS YADEGAR, M.D. © 2020