Cytokines storm

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Pathophysiology & Pathogenesis Cytokine Storm & Pathological Changes

Biomarkers & Clinical Correlations

Protocols & Clinical Trails

Cytokine Storm and

Clinical Laboratory

Features of COVID-19

Michael Samoszuk, M.D. April 14, 2020

Biosketch

Graduate of Harvard College and Harvard Medical School.

Residency and fellowships at Brigham and Women’s Hospital; University of California, San Francisco, and University of Southern California

Associate Professor of Pathology and Radiology, University of California, Irvine

Medical and Scientific Director, Quest Diagnostics

Chief Medical Officer at Roche Diagnostics, Ortho- Clinical Diagnostics, Beckman Coulter, Cytovale, and Nihon-Kohden

Multiple grants from NIH; author of more than 75 peer reviewed publications

Overview of

COVID-19

Virus and Disease

Terminology

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2: The virus)

The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2) on human respiratory cells

Coronavirus Disease-19 (COVID-19: The disease)

• Fever
• Cough
• Fatigue
• Bodyaches
• Shortness of breath

Pathologic features: Acute Respiratory Distress Syndrome

Radiologic features

Autopsy findings

Macroscopic features:

• Pleurisy, pericarditis, lung consolidation and pulmonary oedema.

• Lung weight increased

• A secondary infection may be superimposed on the viral infection that can lead to purulent inflammation more typical of bacterial infection.

Microscopic features

• Edema, pneumocyte hyperplasia, focal inflammation and multinucleated giant cell formation

• Hyaline membranes not seen in early or less severe disease

• Diffuse alveolar damage with exudates

• Predominantly lymphocytic infiltrate, and multinucleated giant cells alongside large atypical pneumocytes,

• No definitive viral inclusions

• Hepatic steatosis with mild inflammation but unclear whether this was related to the virus or iatrogenic

• Features are very similar to those seen in SARS and MERS-coronavirus infection

Pathophysiology of

infection

Cytokine storm

• Much remains unknown

• Belief by some experts that hyperactive immune response, rather than the
virus, is what ultimately kills many Covid-19 patients

• Hypoxia and hypoxemia: viral damage to hemoglobin? Lung injury?

• Role of vitamin D deficiency? Race and ethnicity? Socioeconomic status?

Current State of Knowledge

Cytokine Storm:
An immune system gone haywire

• May do more damage than coronavirus itself in patients with the severest forms of Covid-19

• May explain variations in the clinical course

• May point the way to potential new treatments

Cytokines

PROTEINS THAT ARE PART OF THE IMMUNE SYSTEM ARSENAL FOR FIGHTING DISEASES SUCH AS BACTERIAL AND VIRAL INFECTIONS

EXAMPLES: INTERLEUKINS 2, 6, 10

WHEN RELEASED TOO FAST OR TOO MUCH, CAN CAUSE DISASTROUS EFFECTS INCLUDING ORGAN FAILURE AND DEATH

HAVE POTENT EFFECTS ON OTHER INFLAMMATORY CELLS, BLOOD VESSELS, AND COAGULATION SYSTEM

• Unknown why some, but not all, COVID-19 patients experience it

• Genetics?

• Unknown how or why or if predisposing factors (obesity; sleep; cardiovascular disease; diabetes; hypertension; smoking; old age; immune suppression) or initial viral dose impact cytokine storms

• Two stages: A failure to respond quickly or effectively to the virus, followed by an overly aggressive immune response that floods the body with cytokines

• Damage blood vessels, allowing fluid to seep into the lungs and fill them like water balloons

Cytokine Storms

”…Not only capable of causing pneumonia, COVID-19 may also cause damage to other organs such as the heart, the liver, and the kidneys, as well as to organ systems such as the blood and the immune
system.3, 4, 5 Patients eventually die of multiple organ failure, shock, acute respiratory distress syndrome, heart failure, arrhythmias, and renal failure.5, 6 “

Pathologic changes in lungs

Underlying mechanism and multi-organ dysfunction syndrome (MODS)

• Eventually causes patients’ lungs to stop delivering oxygen to blood

• Leads to respiratory failure

• May drive rapid decline in lung function experienced by some patients, including younger and relatively healthy ones

• By poorly understood mechanisms, causes vasodilation, hyper- or hypocoagulability, hypotension, hepatorenal failure

Out-of-Control Immune Response

Biomarkers

Role in management of COVID-19

Laboratory Features of COVID-19

CRP in COVID- 19

Relationship of lung lesions to CRP

Diagnostic Tests

Nucleic acid based Serologic

• rtqPCR to detect viral RNA in nasopharyngeal swabs

• High throughput (Roche Molecular Diagnostics) and point of care rapid versions (Cepheid)

• High rate of ”false” negatives

• Frequently positive in
asymptomatic persons @ 2020 Samoszuk Consulting. All rights reserved.

• Rapid

• IgM for acute infection

• IgG for previous (cleared?) infection

• Useful for epidemiologic studies • Easy to perform, but not yet

cleared for general use • ”False” positives?

Management of patients

Pulse oximetry to measure oxygen saturation of blood

Vital signs (temperature, respiratory rate, heart rate, blood pressure)

Routine clinical lab tests of marginal value in most patients except for MODS

Current protocols

Screening, monitoring, and managing (treating) the infection

Screening and monitoring

• No screening test available
• Diagnostic tests helpful but not

essential for management

• Chest x ray and pulse oximetry in some cases

• Monitoring by vital signs and pulse oximetry

“Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections3 and occurs in 3.7–4.3% of sepsis cases.4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients…. A cytokine profile resembling sHLH is associated with COVID-19 disease
severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte colony
stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant
protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α.6”

• Used to dampen immune response

• Often suggested when there are no alternatives

• Mixed effectiveness: Higher risk of death when treated with steroids

Corticosteroids: Any role in managing the infection?

• Partneringwithhospitalstoexplorewhether or not drugs that are proven to tamp down an out-of-control immune system could help the sickest Covid-19 patients

• “You remove one piece of the storm, and it can quiet the whole thing”—Kevin Tracey, President of the Feinstein Institutes for Medical Research at Northwell Health (which is testing Kevzara, an anti-inflammatory drug from Regeneron Pharmaceuticals)

Pharma Companies

• Tocilizumab (Roche: marketed under brand name Actemra): Cleared by USFDA to treat cytokine storm caused by certain cancer treatments

• US NIH committing $25 million to accelerate late stage study in Covid-19 patients

• Used last month at Seattle’s Swedish Health Services to treat a 45-year old emergency room doctor infected while caring for patients from a nursing home

• Patient on life-support with CRP 200x normal. Responded within two days; taken off life support and discharged within seven days.

Clinical Trials: Promising targeted treatment

Clinical trials

• Losartan (University of Minnesota): Angiotensin II receptor antagonist

• Ruxolitinib (Novartis and Incyte): Inhibits cytokine storm and treats rare blood cancers

• Kineret (Swedish Orphan Biovitrum AB): Expects results by July from a clinical trial in Italy

• Leronlimab (CytoDyn): Ten severely ill Covid-19 patients recovered three days after being infused with this anti-HIV drug which also may block production of inflammatory cytokines

QUESTIONS

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