inland empire and covid 19 · 5/6/2020 · • ramiz fargo, md, associate professor of medicine,...

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Inland Empire and COVID‐19:Experience, Adjustment, and Reflections

Department of Medicine

Loma Linda University School of MedicineGrand Rounds

May 6, 2020

Program Outline

Epidemiology of COVID‐19, James Pappas

Riverside County & RUMC, Ramiz Fargo

LLUMC, Ara Chrissian

Thrombosis and Therapeutic Possibilities, Gary E Gilbert

Remdesivir, Jennifer Veltman

Cytokine Storm and Therapeutic Possibilities, Karina Torralba & Vaneet Sandhu

Reflections, Bryant Nguyen

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Panel Participants

• James Pappas, MD, MBA, Associate Professor of Medicine and Pathology, Associate Chief Medical Officer for Patient Safety, Associate Dean for Quality and Patient Safety, Medical Director Epidemiology

• Ramiz Fargo, MD, Associate Professor of Medicine, Program Director, Pulmonary/Critical Fellowship, Chief, Pulmonary and Critical Care, Riverside University Health

• Ara Chrissian, MD, Associate Professor of Medicine and Medical Director of Adult Bronchoscopy and Interventional Pulmonology

• Gary E Gilbert, MD, Associate Professor of Medicine, Harvard School of Medicine, Chief of Hematology & Oncology VA Boston Healthcare System

• Karina Torralba, MD, MACM, Professor of Medicine, Head Division of Rheumatology and Program Director Rheumatology Fellowship

• Vaneet Sandhu, MD, Associate Professor of Medicine, Division of Rheumatology

• Jennifer Veltman, MD, Associate Professor of Medicine, Division of Infectious Disease

• H Bryant Nguyen, MD, MS, Professor of Medicine and Basic Sciences, Executive Vice Chair Department of Medicine, Head Division of Pulmonary and Critical Care Medicine

Panelists

James Pappas, MD Ramiz Fargo, MD Ara Chrissian, MD Gary E Gilbert, MD

Jennifer Veltman, MD Karina Torralba, MD Vaneet Sandhu, MD Bryant Nguyen, MD

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Disclosures

Gary E Gilbert• Little Sparrows Technologies Stocks Co‐founder, stockholder

• Bayer Pharmaceuticals Research grant support Principal investigator

• Takeda Pharmaceuticals Research grant support Principal investigator

Other Participants• No disclosures

Objectives

• Know how this pandemic illness has manifested to frontline doctors in our community

• Know 3 ways COVID‐19 is “different” from other illnesses

• Know 3 evolving treatments

• Respect how the experience of working and living with COVID‐19 has affected physicians and care givers

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Epidemiology of COVID‐19

James Pappas, MD, MBA

Associate Professor of Medicine and Pathology

Associate Chief Medical Officer, Patient Safety

Associate Dean for Quality and Patient Safety

Medical Director Epidemiology

Introduction

Bottom Line: Understanding of COVID‐19 is evolving.

• End of 2019:

– A novel Coronavirus was identified as the cause of a cluster of pneumonia outbreaks in Wuhan, a city in the Hubei province of China.

• This virus spread rapidly:

– First throughout China, resulting in an epidemic

– Followed by increasing cases in the rest of the world

The virus causing COVID‐19 is designated SARS‐CoV‐2

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The COVID‐19 Riddle: “Why Does the Virus Wallop Some Places and Spare Others?”

https://www.ecdc.europa.eu/en/geographical‐distribution‐2019‐ncov‐cases

https://www.nytimes.com/2020/05/03/world/asia/coronavirus‐spread‐where‐why.html

“Experts are trying to figure out why the coronavirus is so capricious.” (NYT)

“The coronavirus has killed so many people inIran that the country has resorted to massburials,…”

“…but in neighboring Iraq, the body count isfewer than 100.”

“The Dominican Republic has reported nearly 7,600 cases ofthe virus. Just across the border, Haiti has recorded about 85.”


“The coronavirus has touched almost every country onearth, but its impact has seemed capricious.”

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Four Main Factors

Demographics: The power of youth

• Many countries that have escaped mass epidemics have arelatively younger population– Case‐in‐point: Africa, the world’s youngest population (> 60% under

the age of 25), 45,000 reported cases in 1.3 billion

– In contrast, Italy (one of the hardest hit) has a national median age ofmore than 45. Average age of those dying of COVID‐19 – 80 years.

• A notable caveat: Japan, with the world’s oldest averagepopulation, has recorded fewer than 520 deaths.


Four Main Factors

Cultural Distance

• Social distancing is built into certain societies– Thailand and India – where virus numbers are relatively low – people

greet at a distance, with palms joined as in prayer.

– In Japan and S. Korea, people bow

• A notable caveat: “In many parts of the Middle East, such asIraq and the Persian Gulf countries, men often embrace orshake hands on meeting, yet most are not getting sick.”


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Four Main Factors

Heat and Light

• The geography of the outbreak seemed to suggest the virusdid not do well in heat.– The virus spread quickly during the winter in temperate zone

countries like Italy and the US and was virtually unseen in warmercountries such as Chad or Guyana.

• A notable caveat: Some of the worst outbreaks in thedeveloping world have been in places like the Amazonasregion of Brazil – as tropical a place as any.


Four Main Factors

Early Strict Lockdown

• Countries that locked down early (e.g., Vietnam and Greece)have been able to avoid out‐of‐control contagions.– Of note: Countries in Africa that learned hard lessons from killers like

Ebola, drug‐resistant TB and HIV, reacted quickly (e.g., Sierra Leoneand Uganda)

• Counter‐intuitively: Some countries where authorities reactedlate or inefficiently appear to have been spared – e.g.,Cambodia and Laos.


Lockdowns and a safety net: “When people are forced to choose between social distancing and feeding their families, they are choosing the latter.”

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So, really…

Nobody knows. It is unlikely that any single reason accounts forcountries being affected so variably. It is likely a combination ofthe above four factors AND luck…


An infected person attends a crowded social event –

Super Spreader Event

1. A passenger infects 634 people on the Diamond Princess cruise ship offthe coast of Japan

2. An infected guest attends a large funeral in Albany, Ga.

3. A 61 year‐old woman goes to church in Daegu, S. Korea, spreading thevirus to hundreds of congregants.

Transmission

The exact mechanism of person‐to‐person spread of SARS‐CoV‐2 is controversial.

Droplet vs. airborne – a quick summary

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Droplet vs. Airborne Transmission

As of May 6, 2020, droplet transmission is

still thought to be the main mode of spread.

• Airborne transmission is controversial:– March 17, 2020 letter to NEJM: SARS‐CoV‐2 viable in aerosols

for at least three hours

– Some studies have identified viral RNA in ventilation systems and in air samples of hospital rooms of patients with COVID‐19.

• However, cultures for viable organisms not performed.

– High speed visualization of respiratory exhalations suggest droplets may be carried beyond six feet.

Direct relevance of these findings to the epidemiology of COVID‐19 is simply not clear.

Some Numbers

COVID‐19 Numbers as of May 4, 2020

United States California San Bernardino County

Cases Death Cases Deaths Cases Deaths

1,152,372 67,456 52,197 2,172 2182 97

Bottom Line: Understanding of COVID‐19 is evolving.

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Ramiz Fargo, MD

Associate Professor of Medicine

Program Director, Pulmonary and Critical Care Fellowship

Chief, Pulmonary and Critical Care, Riverside University Health

Riverside County COVID‐19 Data (April 28th, 2020)

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RUHS Medical Center

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LLUMC COVID Stats Update

Ara Chrissian, MD, FCCP, DAABIP

Associate Professor of Medicine

Division of Pulmonary, Critical Care, Hyperbaric, Allergy and Sleep Medicine

Medical Director of Adult Bronchoscopy and Interventional Pulmonology

Associate Program Director of Pulmonary/Critical Care Fellowship

LLUMC COVID Stats

• Total # patients screened SARS‐CoV‐2 PCR (any test, as of 5/4/20): 2088

• 96 positive (4.9%) – 93 symptomatic (97%)– 73 hospitalized (76%)

• 27 ICU (28%)– 21 mechanical ventilation (22%)

• 74 patients (77%) with resolved status– 67 recovered/discharged (91%)– 7 deceased (9%)

61 yof seen in LLUMC ED for 4 days of fever, dyspnea, fatigue: SARS‐CoV‐2+

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1 3

25

38

55

76

91

1 2

2213

1721

15

0

10

20

30

40

50

60

70

80

90

100

3/16‐22 3/23‐29 3/30‐4/5 4/6‐12 4/13‐19 4/20‐26 4/27‐5/3

LLUMC Total Positive and New COVID‐19 Cases, by week

Total at week's end New during week

12

6.4

9.6

12.6

8.9

6.4

0 0.1

5.3

7.36.2 6

7.7

0

2

4

6

8

10

12

14

3/16‐22 3/23‐29 3/30‐4/5 4/6‐12 4/13‐19 4/20‐26 4/27‐5/3

LLUMC Average Daily COVID‐19 Inpatient Case Census, by Location

Non‐ICU ICU

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200

150140

25 20 15 10

0

50

100

150

200

250Average daily ICU census, per USA hospitals circa 4/15‐25/2020

Additional stats of interest: clinical factors

• Median time from symptom onset to presentation =4 days (1‐14)

• Anosmia, ageusia, headache are common

• Two patients presented in cardiac arrest, two with PE, two with GI bleed

• No viral coinfections identified thus far (0/73)*

• Likely occupational transmission has occurred

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Factors associated with hospitalization (unadjusted)

Outcome variable Hospitalization (n=73) ED/outpatient (n=23) P value

Comorbid conditions

Age, median (range)Age > 65yo, n (%)

57 (20‐89)22 (30)

42 (23‐70)2 (9)

0.0030.05

CV disease, n (%) 43 (59) 5 (22) 0.004

Neurologic disease 19 (26) 1 (4) 0.04

Clinical factors

Nosocomial infection 23 (32) 0 0.001

Abnormal chest imaging 63 (86) 7 (30) <0.0001

GI complaints 24 (33) 16 (70) 0.003

Fatigue and myalgias 31 (42) 17 (74) 0.02

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Characteristics of deceased vs recovered patients

Outcome variable Deceased (n=7) Recovered after hospitalization (n=44)

Recovered, all (n= 67)

Comorbid conditions

Age, median (range)Age > 65yo, n (%)

61 (47‐87)3 (43)

56 (25‐89)13 (30)

55 (23‐80)15 (22)

CV disease, n (%) 6 (86) 21 (48) 26 (39)

Obesity 4 (57) 17 (39) 27 (40)

> 3 comorbidities 4 (57) 5 (11) 5 (7)

Clinical factors

Nosocomial infection 6 (86) 11 (25) 11 (16)

Abnormal chest imaging 7 (100) 44 (100) 51 (76)

Additional stats of interest: testing factors

• SARS‐CoV‐2 PCR has turned positive before symptoms

• PCR has turned positive during hospitalization after initial screen was negative

• PCR has remained positive >2 weeks in several patients, regardless of hospital setting

• Antibody tests have been negative in early portion of clinical disease

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Additional stats of interest: ICU management factors

• Multiple likely etiologies of hypoxemic respiratory failure

• Ideal management approach unknown

• ICU patients have been treated with a variety of modalities: HCQ, steroids, Toci, Anakinra, CP, PLEX, HBOT, AC

• Our first ICU patient, protracted course (ARDS, eventual trach) has been discharged after 38 day hospitalization, without need for MV

COVID‐19 and Thrombosis: Venous thromboembolism, large and small vessel occlusionMay 6, 2020

Gary E Gilbert, MD

Chief of Hematology & Oncology VA Boston Healthcare System

Associate Professor of Medicine, Harvard School of Medicine

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Reports of COVID‐19

coagulopathy

Progressive abnormalities in

coagulation parameters in non‐survivors vs.

survivors

Tang, JTH 2020

Venous thromboembolism

in COVID‐19 patients

Klok RefX

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Arterial and small vessel thrombosis

• Small vessel thrombosis in the lungs of COVID‐19 autopsy cases (Magro 2020 Transl Res)

• Stoke frequency of ~5%, including strokes in asymptomatic young individuals who later test positive for SARS‐CoV‐2 (Li 2020 Lanet preprintes; Oxley 2020 NEJM)

• Myocardial injury in ~15%, generally in the absence of myocarditis or or STEMI

• “COVID‐19 toe” – chilblain‐like red toes as first presenting symptom or developing in the course of COVID‐19 (Piccolo 2020, Landa 2020 J Eur AcadDerm Vener)

• Small vessel thrombosis in skin biopsies of patients with COVID‐19 purpuric lesions

Magro et al Transl Res. 2020 Apr 15

Small Vessel Thrombo‐inflammation in COVID‐19

…The pattern of COVID‐19 pneumonitis was predominantly a pauci‐inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the inter‐alveolar septa by neutrophils… These pulmonary findings were accompanied by significant deposits of terminal complement components C5b‐9 (membrane attack complex), C4d, and mannose binding lectin (MBL)‐associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the alternative and lectin‐based complement pathways… In conclusion, at least a subset of sustained, severe COVID‐19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state….

Magro et al Transl Res. 2020 Apr 15

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Presumed pathogenesis of thrombosis

Cytokines/complement/SARS‐CoV‐2 infectionendothelial inflammationperi‐endothelial fibrin depositionplatelet adhesion & activationactivation of intrinsic coagulation pathway fibrin generationlarge vein thrombosis

Cytokines/complement/ SARS‐CoV‐2 infectionendothelial inflammationperi‐endothelial fibrin deposition vWf secretion/adhesionplatelet adhesion & activationneutrophil adhesion & activation reactive oxides, NETs, proteasesaggregation of platelets, RBCs, neutrophils

Large Veins

Arteries, Capillaries & Venules

heparin

Clinical Implications:

• D‐Dimer is the best parameter to monitor DIC ‐ a composite of small vessel and large vessel coagulation activity (Fibrinogen, aPTT, and PT are probably not useful monitoring DIC for individual patients)

• Decreasing platelet values likely to reflect small vessel DIC, not large vessel thrombosis

• Heparin prophylaxis for VTE recommended ‐ at usual or enhanced doses, unlikely to effect arterial or small vessel thrombosis

• Only off‐label treatment options of small vessel thrombotic disease but current COVID‐19 data doesn’t establish best option

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Off‐label treatment possibilities for small vessel thrombotic disorder: based on efficacy in other small vessel thrombotic disorders

Hemolytic Uremic Syndrome (complement‐mediated vasculopathy)Eculizumab (Soliris) in COVID-19 Infected Patients (SOLID-C19) (clinical trials.gov available on expanded access basis)

Microangiopathy of transplantSingle Patient Expanded Access Treatment Plan For The Investigational Product Product Narsoplimab (clinical trials.gov) – mAb against MASP2, an activator in the activator in the alternative complement activation pathway

Anti‐platelet agents – Aspirin (effective in mouse model of bacterial DIC)

Sickle Cell vaso‐occlusionN‐acetyl cysteine (anti‐oxidant, anti‐von Willebrand factor)Crizanlizumab - Anti‐P‐selectin (inhibits neutrophils binding platelets and endothelial cells; also VWF binding endothelial cells)

TTPCaplacizumab (ant‐vWf)N‐acetyl cysteine (anti‐oxidant, anti‐von Willebrand factor)

Prophylaxis for VTE

Hospitalized COVID‐19 patients

enoxaparin 30 mg q 12 h (40 mg if wt >100 kg)

heparin 5000 u tid if CrCl <30 ml/min

fondaparinux 2.5 mg q 24 h if HIT

COVID‐19 patients with progressive coagulopathy (D‐dimer >4x and increased 2x since starting anticoagulation)

enoxaparin 0.5 mg/kg q 12 h

heparin 7500 u tid if CrCl <30 ml/min

fondaparinux 5 mg q 24 h if HIT

COVID‐19 patients with suspected or proven VTE

enoxaparin 1 mg/kg q 12 h

heparin infusion for aPTT 1.5 – 2.5x ULN

fondaparinux or argatroban if HIT

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Remdesivir & COVID‐19

Jennifer Veltman, MDAssociate Professor of Medicine

Division of Infectious Disease

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Remdesivir (GS‐5734)

● ClassAdenosine nucleotide analogue prodrug (Monophosphate prodrug that undergoes metabolism to an active C-adenosine nucleoside triphosphate analogue)

● Approval StatusInvestigational

● Mechanism Competes for incorporation with adenosine triphosphate (ATP)Does not act as classic chain terminatorPossible delayed chain termination (similar to entecavir)

● Dose (Intravenous): Per Study Protocol200 mg on day 1, followed by 100 mg daily for various time courses (5vs10d)

● Adverse Events: Elevated LFTs (typically 2-3x normal), unclear significanceGI symptoms (nausea, vomiting, gastroparesis, rectal bleeding)

Source: Tchesnokov EP, et al. Viruses 2019;11(4). pii: E326

Antiviral Effective Concentration (EC50)

EC50= The concentration of an antiviral agent at which virus replication is inhibited by 50% in a cell‐based assay. Conceptually similar to the MIC for an antibacterial agent

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Remdesevir EC50 and SARS‐COV2

Source: Wang TP, et al. Cell Res. 2020;30:269‐71.

Remdesivir in Adults with Severe COVID-19: A Randomized, Double-blind Trial (China)

● Background: A randomized, double-blind, placebo-controlled, multicenter trial of remdesivir in adults with severe COVID-19

conducted between February 6, 2020 and March 12, 2020

● Location: 10 hospitals in Hubei, China

● Inclusion Criteria (intended n = 453; actual n = 237)

a. Age ≥18 years

b. PCR positive test for SARS-CoV-2 infection

c. Pneumonia on chest imaging

d. SpO2 ≤94% on room air or PaO2:FiO2 <300mmHg

e. Symptom onset ≤12 days prior to enrollment

● Exclusion Criteria

a. Pregnant or breastfeeding

b. Cirrhosis or AST/ALT > 5x upper limit of normal

c. GFR <30mL/min per 1.73 m² or renal replacement therapy

d. Treatment with another investigational drug in the 30 days before screening

● Duration of follow up: 28 days or until discharge

Source: Wang Y, et al. Lancet. April 29, 2020 [Epub ahead of print]

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Baseline Characteristics* Remdesivir

200mg IV (d1), 100mg iv (d2‐10)

(n = 158)

Placebo

Equivalent volume given d1‐10

(n = 78)

Age, years, median (IQR) 66.0 (57.0–73.0) 64.0 (53.0–70.0)

Male, n (%) 89 (56%) 51 (65%)

Comorbidities, n (%) 112 (71%) 55 (71%)

Hypertension 72 (46%) 30 (38%)

Diabetes 40 (25%) 16 (21%)

Coronary Heart Disease 15 (9%) 2 (3%)

Adjunctive Therapies

Receiving interferon alfa‐2b 29 (18%) 15 (19%)

Receiving lopinavir–ritonavir 27 (17%) 15 (19%)

Antibiotic treatment 121 (77%) 63 (81%)

Corticosteroids therapy 60 (38%) 31 (40%)

Remdesivir in Adults with Severe COVID-19: A Randomized, Double-blind Trial (China):Results

Outcome Remdesivir

(n = 158)

Placebo

(n = 78)

Difference

(95% CI)

Time to clinical

improvement, days

21.0 (13.0 to 28.0) 23.0 (15.0 to 28.0) 1.23 (0.87 to 1.75)

Day 28 mortality 22 (14%) 10 (13%) 1.1% (–8.1 to 10.3)

Duration of invasive

mechanical

ventilation, days

7.0 (4.0 to 16.0) 15.5 (6.0 to 21.0) –4.0 (–14.0 to 2.0)

Duration of oxygen

support, days

19.0 (11.0 to 30.0) 21.0 (14.0 to 30.5) –2.0 (–6.0 to 1.0)

Duration of

hospital stay, days

25.0 (16.0 to 38.0) 24.0 (18.0 to 36.0) 0.0 (–4.0 to 4.0)


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Interpretation: “In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.”

Authors were unable to enroll nearly half the planned number of participants due to resolution of the COVID-19 outbreak in Hubei, China

There were no differences in the rates of

Time to clearance of virusClinical benefitsMortality


1,000+ patients at 68 sites in the United States and around the world

Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).

“Fauci said the drug will now be tested in combination with anti-inflammatory drugs in an NIH-sponsored trial. He likened the advance on Wednesday to the use of AZT in the mid-1980s to treat AIDS, the disease caused by HIV. Remdesivir likely will serve as a basis for drug cocktails and better antivirals.”

Adaptive COVID‐19 Treatment Trial

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Timing is everything, but did we get it right?

Siddiqu HK et al. Journal of Heart and Lung Transplantation. doi: 10.1016/j.healun.2020.03.012

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Where do we go from here?

Repurposed drug cocktails to see if they have synergistic effects

Hydroxychloroquine, lopinavir/ritonivir, favipiravir

Monoclonal Ab (first patients will be dosed in June)

Acknowledgements

University of Washington’s ‘IDEA’ teaching resource for providing several slides used in the development of this presentation

Dan Rogstad, ‘king of learning objectives’ for writing mine:)

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Cytokine Release Syndrome/Macrophage Activation Syndrome‐related to COVID19

Karina Torralba, MDVaneet Sandhu, MD

Objectives : Learners are expected to

1. Explain the pathophysiology of CRS/MAS

2. Recognize CRS/MAS

Schulert, Grant S., and Alexei A. Grom. “Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine‐Directed Therapies.” Annual Review of Medicine 66 (2015): 145–59. ;

Image from: Baker, R., Liew, J.W., Simonson, P.D. et al. Clin Rheumatol 38, 603–608 (2019).

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CRS/MAS: Mortality rates

The overall mortality associated with CRS/MAS : 30–60%

Condition Mortality Rate

Factors associated with mortality

Autoimmune diseases, in general

38.5% Absence of lymphadenopathyThrombocytopenia

sJIA 23 % DIC, PAH, hemorrhage

SLE 35% Active disease*

Rheumatic diseases + CRS/MAS

• Systemic Juvenile Idiopathic Arthritis

• Kawasaki Disease (KD)

• Systemic Lupus Erythematosus

• Rheumatoid arthritis

• Dermatomyositis

• Systemic Sclerosis/Scleroderma

• Mixed Connective Tissue Disease

• Antiphospholipid Syndrome

• Sjogren’s Syndrome

• Ankylosing Spondylitis

• Sarcoidosis

.

Clinical Features of MAS

• Febrile illness + MOF• Mimics:

• infections • other causes of fever of unknown origin• hepatitis• EncephalitisMain Features:

FeverLymphadenopathy, HepatosplenomegalyHemorrhagic manifestationsSepsis like condition

Fukaya S, Yasuda S, Hashimoto T, et al. Rheumatology (Oxford) 2008; 47:1686.; Lerkvaleekul B,e tl al. Open Access Rheumatol 2018; 10:117‐28.

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Juvenile Idiopathic Arthritis, systemic type(Formerly known as juvenile RA) Ravelli Criteria

Cytokine Release Syndrome/Macrophage Activation Syndrome CriteriaIn Rheumatic Diseases

Systemic Lupus Erythematosus Kawasaki Disease

Falls in line with sJIA RavelliCriteria

Parodi A, Davì S, Pringe AB, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty‐eight patients. Arthritis & Rheumatism. 2009;60(11):3388‐3399. doi:10.1002/art.24883Ravelli A, Magni‐Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. The Journal of Pediatrics. 2005;146(5):598‐604. doi:10.1016/j.jpeds.2004.12.016Sharma P, Shreshtha S, Kumar P, Sharma R, Mahapatra T. A Review on Macrophage Activation Syndrome.2019;13(1):183‐191. doi:10.22207/jpam.13.1.19

ACR/EULAR/PRINTO Approved MAS Criteria

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Schulert, Grant S., and Alexei A. Grom. “Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine‐Directed Therapies.” Annual Review of Medicine 66 (2015): 145–59. ;

Image from: Baker, R., Liew, J.W., Simonson, P.D. et al. Clin Rheumatol 38, 603–608 (2019).

Rheumatic disease biologics for MAS/CRS

IL6 inhibitors: Tocilizumab, Sarilumab

Effective Treatment of Severe COVID‐19 Patients with Tocilizumab. http://www.chinaxiv.org/abs/202003.00026. Published 2020. [Accessed] 10 March 2020.

World Health Organization (WHO). Report of the WHO‐China Joint Mission on Coronavirus Disease 2019 (COVID‐19). https://www.who.int/docs/default‐source/coronaviruse/who‐ chinajoint‐mission‐on‐covid‐19‐final‐report.pdf. Published 2020. [Accessed] 10 March 2020.

Clinicaltrials.gov. Evaluation of the efficacy and safety of sarilumab in hospitalized patients with COVID‐19. Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT04315298. Accessed March 20, 2020.

IL1 inhibitors Anakinra, Canakinumab

Nigrovic, et al Arthritis Rheum. 2011;63(2):545–555. Grom AA et al .Arthritis Rheumatol. 2016;68(1):218–228. Palvi M… Cron R et al. Rheumatology (50)2:2011. Bruck N, J Clin Rheumatol. 2011;17(1):23–27.

Anti‐TNF (Infliximab, Etanercept, Adalimumab)

Aeberli D, Oertle S, Mauron H, et al. Swiss Med Wkly 2002;132:414–422. Baker R, et al. Clin Rheumatol:2019: 308‐603‐608. Sawar H, Espinoza RL, Gedalia A. J Rheumatol 2004;31:623. Ramanan AV, Schneider R. J Rheumatol 2003;30:401–403. Prahalad S, Bove KE, Dickens D, et al. J Rheumatol2001;28:2120– 2124. Makay R, et al. Pediatr Blooc Cancer. 2008: 50, 419.

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Richardson P et al. Lancet. Feb 2020.

‐ Baricitinib –‐ Theory: reduces the ability of the virus to infect lung cells‐ By disrupting AAK1, virus endocytosis through ACE2 receptor is inhibited

Fig. 1. Hypothetical timing of some anti‐rheumatic drugs in COVID‐19 infection. *hypothetical viral load reduction.HCQ: hydroxycloroquine; TCZ: tocilizumab; IVIg: intravenous immunoglobulin.

Ferro F, et al. COVID19: The new challenge for rheumatologists.Clin Exp Rheumatol 2020; 38:175‐80/

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LLUMC/RUHS Rheumatology Observations: COVID‐related MAS/CRS management in Adult MAS/CRS‐COVID19

• Subsets – Classic MAS – Lab+Clinical– Classic MAS by lab – but clinically

ok– Catastrophic APS– SLE‐like, low C3, C4

• MAS/CRS onset varies• Ability to mount MAS/CRS labs

dependent on prior comorbidity

• Suspect prior undiagnosed rheumatic diseases

• Have not* noted rheumatic disease patients prone to developing COVID, or COVID‐MAS/CRS

• #rheumcovid registry –rheum dse (eg SLE, RA) patients can still develop COVID

• Referrals • Biologic utilization• Majority have survived

COVID‐19 at LLUMC Professional and Personal

H Bryant Nguyen, MD, MS

John E Petersen Professor of Medicine and Basic Sciences

Executive Vice Chair Department of Medicine

Head Division of Pulmonary and Critical Care Medicine

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COVID‐19 ICU at LLUMC

• MICU is the designated COVID‐19 ICU

– ARDS is our bread‐and‐butter

– 24 single‐patient rooms, including 4 rooms with negative pressure

• House‐wide intensivists pulling together

– Medical‐, surgical‐, and neuro‐

– Daily Zoom meetings with Chief of Patient Safety and Reliability

– 7‐phase model, > 100 patients

– We kept at Phase 1‐2

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We Have Used Unproven Therapies

• Not able to secure remdesivir

• Hydroxychloroquine

• High‐dose corticosteroid

• Tocilizumab

• Anakinra

• Anticoagulation

• Plasma exchange

• Convalescent plasma

• Hyperbaric oxygen

• What if the dying patient was my own family member and there was no other choice?

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It was our time! We met our challenge, and we keep making a difference

• PCCM Division prepared to shut down other operations

• Nobody got ill, nobody complained

• We took care of all patients– Trauma, OBGYN, cardiac

surgery, neurosurgical

• We bonded with each other and with all our critical care colleagues

inland empire and covid 19 · 5/6/2020 · • ramiz fargo, md, associate professor of medicine,...

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