Post-Acute COVID-19 Syndrome and the Lung Pulmonary …

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Post-Acute COVID-19 Syndrome and the

Lung

Pulmonary Symposium

Robert G. Penn, M.D., FACP, FSHEA, FIDSA

Healthcare Epidemiologist and ID Specialist

Medical Director of Healthcare Epidemiology and Infection Prevention

Methodist Hospital

Infectious Diseases Associates, PC

[email protected]

March 12, 2021

There are no conflicts of interest relevant to this

presentation to report.

Slides presented are my own and those modified

and referenced from various experts.

The content in this presentation is being made available for

informational and educational purposes only. This content is

provided on the understanding that it does not constitute

medical or other professional advice or services. Always work

with a qualified healthcare practitioner when making changes

to your medication, diet or overall healthcare plan.

mailto:[email protected]

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The Story…

The Story…

The Story…

CHARACTERS

SETTING

PLOT

CONFLICT

RESOLUTION

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The Story…

CHARACTERS

SETTING

PLOT

CONFLICT

RESOLUTION

The Story…

CHARACTERS

SETTING

PLOT

CONFLICT

RESOLUTION

The Story…

CHARACTERS

SETTING

PLOT

CONFLICT

RESOLUTION

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The Story…

CHARACTERS

SETTING

PLOT

CONFLICT

RESOLUTION

Objectives and Outline

What do we now understand about acute

COVID-19?

What do we understand about the late

sequelae of post-acute COVID-19?

What can be done to manage post-COVID-19

late sequelae?

Create awareness of a Post-COVID-19 study

for healthcare personnel in the NMHS.

THE FOREWORD

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--Paul Garner, professor of infectious diseases at Liverpool School of Tropical Medicine

https://blogs.bmj.com/bmj/2020/05/05/paul-garner-people-who-have-a-more-protracted-illness-need-help-to-understand-and-cope-with-the-constantly-shifting-bizarre-symptoms/



“A roller coaster of ill health, extreme emotions, and

utter exhaustion. Although not hospitalized, it has

been frightening and long. The illness ebbs and

flows, but never goes away.”



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“Riding the coronacoaster of uncertainty”

Lancet Infect Dis. 2020 Jun; 20(6): 629.

THIS STORY BEGINS IN

DECEMBER 2019…

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THE PROLOGUE

“THE SETUP”

Timeline of the reconstruction and recovery of rSARS-CoV-2

in relation to key events of the COVID-19 pandemic

Modified from Hayden M. SHEA COVID-19 Town Hall, Round 37, January 10, 2021




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virological.org/t/novel-2019-coronavirus-genome/319




AND THEN…

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Emma visits the

Women’s Hospital ED

5 Mar

THE BODY

“THE CONFRONTATION”

Case Report

36-year old female presents to the ED with a progressive

illness of nasal congestion, dry cough, headache, and

fever on Day 10 of illness, onset in London (1-2 weeks

before) on March 5, 2020

Medical conditions – include but not limited to

hypothyroidism, hypertension, diabetes mellitus, chronic

obstructive pulmonary disease, and anxiety

Exam shows vital signs -- temperature 101.1°F, pulse

102, respiratory rate 25, BP 139/79, and oxygen

saturation of 80% on room air, rising to 93% on 3L by

nasal cannula, wt 249 lbs, BMI 42.5

Chest X-ray performed

10

Case Report

Admission arranged and Infection Prevention and

Control contacted

Informed that the Health Department declined COVID-19

testing

EMR reviewed

Chest CT scan recommended and performed

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Case Report

Nasopharyngeal specimen collected for COVID-19 PCR

test

Admitted to acute care with special droplet and contact

precautions

Transport via Isolation Pod….

Sunday Omaha World-Herald. May 17, 2020.




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COVID-19 Dashboard by the Center for Systems

Science and Engineering at Johns Hopkins University

U.S. total 28,895,975 - U.S. deaths 522,872 - NE total 202,310; NE deaths 2,112

Global Cases 116,192,227 – Global Deaths 2,582,259

As of March 6, 2021, 8:22 AM

COVID-19 Dashboard by the Center for Systems

Science and Engineering at Johns Hopkins University

U.S. Case Fatality Rate = 1.8% -- NE Case Fatality Rate = 1.0%

Global Case Fatality Rate = 2.2%

As of March 6, 2021, 8:22 AM

WHAT DO WE UNDERSTAND

ABOUT THE VIRUS?

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2019-Novel Coronavirus – The Basics(2019-nCoV)

What? COVID-19 caused by SARS-CoV-2

Pandemic

Potential to cause severe illness especially in vulnerable patients

2019-Novel Coronavirus – The Basics


Pandemic


How spread?

Droplets (≥5 µ)

Close contact (<6ft >10 min.)

Aerosols (<5 µ)

Fomite

Asymptomatic/presymptomatic

2019-Novel Coronavirus – The Basics


Pandemic


How spread?

Droplets (>5 µ)

Close contact (<6ft >10 min.)

Aerosols (<5 µ)

Fomite

Asymptomatic/presymptomatic

Incubation Period? 2-14 days (median 4 to 5 days)

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Teaching Points

COVID-19 is unprecedented, unpredictable, and highly

transmissible.

https://timesofindia.indiatimes.com/life-style/spotlight/beer-brand-corona-is-willing-to-pay-15-million-to-change-the-name-of-coronavirus/articleshow/73928431.cms

Copyrights apply

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Spike (S) protein binds with high affinity to the angiotensin-converting

enzyme 2 (ACE2) receptor

ACE2 is expressed in type II alveolar cells and in most organs

Protease activation is required for entry into the human host cell

https://www.genetex.com/Research/Overview/infectious_diseases/SARS-CoV-2

Receptors for SARS-CoV-2 Present in

Wide Variety of Human Cells

Baraniuk C. TheScientist. April 29, 2020.

Human cell types within corresponding organs that express the genes for both ACE2

and CTSL (green dot) or both ACE2 and TMPRSS2 (orange dot).ANNA HUPALOWSKA

Kevin J. Clerkin. Circulation. COVID-19 and Cardiovascular Disease,

Volume: 141, Issue: 20, Pages: 1648-1655, DOI:

(10.1161/CIRCULATIONAHA.120.046941) © 2020 American Heart Association, Inc.

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WHAT IS THE CLINICAL

PRESENTATION OF COVID-19?

WHAT IS THE CLINICAL

PRESENTATION OF COVID-19?

a.k.a. “The Body Snatcher with Spectrum of Illness”

Course of COVID-19 Infection

Seheult R. MedCram COVID19 #66 Webcast. May 1, 2020.

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20 to 30% Asymptomatic

Johansson, M, et al. JAMA Network. 2021.

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Clinical Spectrum of SARS-CoV-2 Infection

Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-

CoV-2 using a virologic test (i.e., a nucleic acid amplification test or an antigen test)

but who have no symptoms that are consistent with COVID-19.

Mild Illness: Individuals who have any of the various signs and symptoms of COVID-

19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea,

vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath,

dyspnea, or abnormal chest imaging.

Moderate Illness: Individuals who show evidence of lower respiratory disease during

clinical assessment or imaging and who have saturation of oxygen (SpO2) ≥94% on

room air at sea level.

Severe Illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of

arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300

mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%.

Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple

organ dysfunction.

https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/

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Datta SD, et al. JAMA. December 8, 2020.

What are the symptoms of acute COVID-19?

Fever

Shortness of breath

Cough

Other

Symptoms Associated with COVID-19¹

Fever

Cough

Dyspnea

¹https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html

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Symptoms Associated with COVID-19¹

Fever

Cough

Dyspnea

Anosmia

Ageusia

Sore throat

Myalgias

Chills/rigors

Headache

Rhinorrhea

Nausea/vomiting

Diarrhea

Fatigue

Confusion

Chest pain/pressure

¹https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html

Signs of COVID-19

Typical and Atypical Clinical Features of COVID-19

Source -- Goyal P, et al. N Engl J Med. June 11, 2020.

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Teaching Points


transmissible.

COVID-19 causes multi-system disease.

BEWARE OF THE

VULNERABLE

Underlying conditions among adults

hospitalized with COVID-19

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Underlying conditions among adults

hospitalized with COVID-19

Prevalence of underlying conditions = 89.3%

Older Adults at Risk for COVID-19

https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/older-adults.html

Copyrights apply

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Teaching Points

COVID-19 is unprecedented, unpredictable,

and highly transmissible.


Age and certain pre-existing medical

conditions make patients more vulnerable to

severe COVID-19 and a fatal outcome.

PATIENTS WITH PERSISTENT

SYMPTOMS

Patients with persistent symptoms…Various terms used…

Long-COVID

Post-COVID syndrome

Post-acute COVID-19 syndrome

Late sequelae of COVID-19

COVID Long haulers

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Patients with persistent symptoms…Various terms used…and [PUBMED]

Long-COVID [2020-50; 2021-64]

Post-COVID syndrome [-94; -55]

Post-acute COVID-19 syndrome [-8; -16]

Late sequelae of COVID-19 [-263; -63]

COVID Long-haulers [-8; -4]

Chronic COVID syndrome [-10, -17]

[Range: 8 to 263 in 2020 and 4 to 64 in 2021]

March 7, 2021

Criteria for Post-COVID

Currently, there is no consensus on the case

definition for post-acute COVID-19 syndrome,

and no specific time frame has been established

to define late sequelae of COVID-19

However, the Centers for Disease Control and

Prevention (CDC) has proposed Post-COVID as

sequelae that extend beyond 4 weeks after

initial infection

https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/

Criteria for Long-COVID per NICE

Acute COVID-19: symptoms of COVID-19 for up

to 4 weeks following the onset of illness

Ongoing symptomatic COVID-19: symptoms

of COVID-19 from 4 to 12 weeks following the

onset of illness

Post-COVID-19: symptoms that develop during

or after COVID-19, continue for ≥ 12 weeks, not

explained by an alternative diagnosis

https://www.nice.org.uk/guidance/ng188

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Biomedical and life sciences journal literature citations/abstracts*

*March 7, 2021

2020 - 2,627

- 686

2019-4

3,050 results

Biomedical and life sciences journal literature citations/abstracts*

*March 7, 2021

2020 - 5

- 2

7 results

Post-acute COVID-19 Pulmonary Complications

idsociety.org/covid-19-real-time-learning-network/disease-manifestations-complications/pulmonary-manifestations/

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COVID-19 LungOverview

PulmonaryAdvisor 3/10/2020

“The extent and severity of the long term respiratory

complications of COVID-19 infection remain to be seen,

but emerging data indicate that many patients

experience persistent respiratory symptoms months

after their initial illness…

To summarize, persistent respiratory complications

following COVID-19 may cause substantial population

morbidity, and optimal management remains unclear.

Prospective studies are under way to evaluate these

complications further and to identify people at greatest

risk….”

Fraser E. BMJ. August 3, 2020.

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Patient population: 172 former COVID-19 patients at a Shenzen, China, hospital who underwent high

resolution computed tomography of the thorax and pulmonary function tests at a follow-

up clinic visit 3 months after hospital discharge.

The median patient age was 47.5 (IQR 28-67) years.

The median duration from hospital discharge to radiological and pulmonary function test

was 90 (IQR 88-95) days.

Patient population: 172 former COVID-19 patients at a Shenzen, China, hospital who underwent high

resolution computed tomography of the thorax and pulmonary function tests at a follow-up

clinic visit 3 months after hospital discharge.

The median patient age was 47.5 (IQR 28-67) years.

The median duration from hospital discharge to radiological and pulmonary function test

was 90 (IQR 88-95) days.

Conclusion:

Of the COVID-19 survivors, 6.4% still present pulmonary function abnormality

three month after discharge, which did not vary by disease severity during

hospitalization. 85.9% patients had abnormalities on chest CT, with fibrous

stripes and ground glass opacity as the most common pattern.

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Teaching Points


transmissible.


Age and certain pre-existing medical conditions make

patients more vulnerable to severe COVID-19 and a fatal

outcome.

There is a high prevalence of residual chest CT

abnormalities in post COVID patients and this might

progress to pulmonary fibrosis, especially in severe cases.

Copyrights apply

Case Study Presentation

29-year-old female admitted with a progressive cough and fever on

January 31, 2021

History of developing fatigue and body aches the week of Christmas

Diagnosed with COVID-19 (so now ~6 weeks after onset)

Treated with monoclonal antibody (bamlanivimab) on approximately

day 3 or 4 of her illness

She stays in bed for the most part of ~10 days

Back to work -- city mail carrier, ambulating up to 6 miles a day

Subsequently develops a progressive cough, visits the ED, and is

diagnosed with pneumonia January 15, and treated with a 5-day

course of oral Levaquin

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She had no significant improvement, & developed diarrhea

Started having fever, and started taking acetaminophen regularly,

followed by sweats

Cough was progressive and dyspnea with coughing on exertion

Developed ongoing headache

Seen in the emergency room on January 29, into the early morning

hours of January 30, for further evaluation of her ongoing cough

CTA of the chest and pulmonary arteries performed (“no acute

process”)

Notes her symptoms-fever and post-occipital headache-associated

with her autoimmune cholangitisGI consulted for

recommendationsrecommend a course of oral ciprofloxacin and

metronidazoledischarged from the emergency room

What was "the clue everyone missed"?

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CTA Chest Pulmonary Arteries-1/29

FINDINGS:

There is no filling defect in the main, segmental or subsegmental pulmonary

arteries to suggest a pulmonary embolus. There is no thoracic aortic

aneurysm or dissection. There is no pleural or pericardial effusion.

There is groundglass opacity scattered in the right upper lobe to a lesser

degree left upper lobe as well as the lingula and right middle lobe. Findings

suggest multifocal pneumonia/COVID. There is no hilar, mediastinal or

axillary lymphadenopathy. Images to the upper abdomen show

pneumobilia.

IMPRESSION:

No CT evidence for pulmonary embolus.

Scattered areas of bilateral groundglass opacity from multifocal

pneumonia/COVID.

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CTA Chest Pulmonary Arteries-1/29

FINDINGS:

There is no filling defect in the main, segmental or subsegmental pulmonary

arteries to suggest a pulmonary embolus. There is no thoracic aortic

aneurysm or dissection. There is no pleural or pericardial effusion.

There is groundglass opacity scattered in the right upper lobe to a lesser

degree left upper lobe as well as the lingula and right middle lobe. Findings

suggest multifocal pneumonia/COVID. There is no hilar, mediastinal or

axillary lymphadenopathy. Images to the upper abdomen show

pneumobilia.

IMPRESSION:

No CT evidence for pulmonary embolus.

Scattered areas of bilateral groundglass opacity from multifocal

pneumonia/COVID.

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What is ground-glass opacity (GGO)?

Descriptive term referring to an area of increased attenuation in

the lung on computed tomography (CT) with preserved bronchial

and vascular markings





It is a non-specific sign with a wide etiology including infection,

chronic interstitial disease and acute alveolar disease







Ground glass opacification is also used in chest radiography to

refer to a region of hazy lung radiopacity, often fairly diffuse, in

which the edges of the pulmonary vessels may be difficult to

appreciate

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Ground glass opacification is also used in chest radiography to

refer to a region of hazy lung radiopacity, often fairly diffuse, in

which the edges of the pulmonary vessels may be difficult to

appreciate

The use of the term ground glass derives from the industrial

technique in glassmaking whereby the surface of normal glass is

roughened by grinding it

Copyrights apply

Copyrights apply

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Symptoms continued to progress and, on January 31, she felt very

chilled and had significant facial flushing and checked her temperature

= 103 F°

Presented to the emergency room again late that evening

Laboratory tests showed mildly elevated inflammatory markers and

LFTs

CT scan of the abdomen and pelvis with contrast is completed

Rx IV levofloxacin in the emergency room, and admitted for treatment

of community-acquired pneumonia and Rx doxycycline

Continues to have fevers with temperatures up to 102.2 F° and

increased watery diarrhea, with episodes each time she is up to urinate

On day #3 of hospitalization an Infectious Disease Consultation is

requested


PAST MEDICAL HISTORY

MEDICAL ILLNESSES: Antiphospholipid antibody syndrome,

autoimmune cholangitis, depression, history recurrent HSV-1

labialis

OPERATIONS: Laparoscopic cholecystectomy, multiple

ERCPs, tonsillectomy and adenoidectomy

MEDICATIONS: Hydroxychloroquine, mycophenolate mofetil,

mirtazapine, risperidone

ALLERGIES: AUGMENTIN causes rash, fever. CEFEPIME

causes rash. SULFA causes rash. ERTAPENEM causes

anaphylaxis


FAMILY HISTORY

Mother has asthma

SOCIAL HISTORY

Married to her spouse who is her wife

Works as a mail carrier, doing a lot of physical activity, often

outdoors

She denies any significant travel history, and denies ever being out

of the Midwest region; no unusual hobbies

3 dogs at home that sleep in bed at night, a French Bulldog, a

Chihuahua/Terrier mix, and a Labrador/Doberman mix

Denies any tobacco or alcohol use

No illicit drug use

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Double quotidian fever pattern noted


Frequent dry cough, exacerbated by deep breathing,

talking, and activity

Appetite is diminished and some nausea with

posttussive vomiting episodes

Diarrhea associated with antibiotics and denies

abdominal pain or cramping

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Case Study PresentationPhysical Exam

29-year-old Caucasian female who is well-developed, well-nourished, and in

no acute distress

VITAL SIGNS: At 12:23 today, temperature 102.2 F°, pulse 104,

respirations 18, blood pressure 110/69, oxygen saturations 96% on room air

Height is 65.1 cm, weight is 100 kg (BMI = 36.7 kg/m²)

HEENT: Herpetic lesions on the upper and lower lips

RESPIRATORY: Lungs with diminished bibasilar breath sounds, right

greater than left. Breathing appeared nonlabored

CARDIOVASCULAR: Heart sounds have a regular rate and rhythm,

without murmur, rub or gallop

ABDOMEN: Soft, nondistended, nontender, with positive bowel sounds and

no palpable mass or hepatosplenomegaly

EXTREMITIES: Without edema or synovitis


Laboratory tests:

WBC 4,800

Lymphocytes 800

Hemoglobin 12.7

Platelets 156,000

Chemistry: Glucose 96, sodium 134, potassium 4.2, BUN 3,

creatinine 0.63, calcium 8.5, total protein 5.8, albumin 3.3,

globulin 2.5, total bili 0.3, alk phos 200, ALT 54, AST 20, LD 262

Lactate 1.7

hsCRP 19.1

ESR 22

Procalcitonin 0.18

CT of Abdomen/Pelvis with contrast

IMPRESSION:

Progressive infiltrate in the lingula and right

middle lobe since chest CT of 01/29/2021.

No focal inflammatory process or acute

finding in the abdomen or pelvis.

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IV levofloxacin readded and PO doxycycline continued

Fever and dry, hacky cough persists

Case Study Presentation Diagnostic Test/Procedure?

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Sutton’s Law

Sutton’s Law


OPERATIVE PROCEDURE

Exploratory left video-assisted thoracoscopy

with diagnostic left lower lobe wedge biopsies

x2.

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Histopathology

Diagnosis

Parts A and B "Lung, left lower lobe, wedge biopsies

Acute fibrinous and organizing pneumonia (AFOP).

Organizing and recanalized thrombi/thromboemboli in

multiple muscular pulmonary arteries.

HistopathologyReview by Dr. Tao Huang at University of Michigan

Sections of both lung wedge biopsies are similar in showing a

patchy air-space-filling process. The air space exudate comprises a

combination of abundant fibrin, variably scant amount of organizing

spindle cells and a few chronic inflammatory cells, features

diagnostic of acute fibrinous and organizing pneumonia (AFOP).

The accompanying alveolar interstitium is slightly thickened by a

mild chronic inflammatory infiltrate composed of many mononuclear

inflammatory cells. The degree of the interstitial changes fall short

of a definitive diagnosis of chronic interstitial pneumonia based on

this sample alone and at least part of the interstitial changes can be

explained by the affiliated AFOP. Fibrin thrombi are noted in

multiple small pulmonary muscular arteries, some of which are also

associated with recannulization.

Diagnoses

Post-acute COVID-19 late sequelae with acute fibrinous and

organizing pneumonia (AFOP)

History of COVID-19 infection December 2020

Recurrent herpes simplex virus labialis

Immunocompromised host with autoimmune cholangitis

Antiphospholipid antibody syndrome. Contributing to above findings

of recanalized thrombi/thromboemboli in multiple muscular

pulmonary arteries.

Multiple antibiotic allergy syndrome, with ERTAPENEM,

AUGMENTIN, CEFEPIME, and SULFONAMIDES

History of depression

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Treatment

Course of Valtrex completed

Levofloxacin and doxycycline discontinued

Rx IV methylprednisolone and transitioned to

oral Prednisone and discharged

ORGANIZING PNEUMONIA

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509945/pdf/bmjresp-2020-000724.pdf

ABSTRACTReviews of COVID-19 CT imaging along with postmortem lung biopsies and autopsies indicate that the majority of patients with COVID-19 pulmonary involvement have secondary organising

pneumonia (OP) or its histological variant, acute fibrinous and organising pneumonia, both well-

known complications of viral infections. Further, many publications on COVID-19 have debated

the puzzling clinical characteristics of ‘silent hypoxemia’, ‘happy hypoxemics’ and ‘atypical ARDS’, all features consistent with OP. The recent announcement that RECOVERY, a

randomised controlled trial comparing dexamethasone to placebo in COVID-19, was terminated

early due to excess deaths in the control group further suggests patients present with OP given

that corticosteroid therapy is the first-line treatment. Although RECOVERY along with othercohort studies report positive effects with corticosteroids on morbidity and mortality of COVID-19,

treatment approaches could be made more effective given that secondary OP often requires

prolonged duration and/or careful and monitored tapering of corticosteroid dose, with ‘pulse’

doses needed for the well-described fulminant subtype. Increasing recognition of this diagnosis

will thus lead to more appropriate and effective treatment strategies in COVID-19, which may lead to a further reduction of need for ventilatory support and improved survival.

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ABSTRACTReviews of COVID-19 CT imaging along with postmortem lung biopsies and autopsies indicate that the majority of patients with COVID-19 pulmonary involvement have secondary organising

pneumonia (OP) or its histological variant, acute fibrinous and organising pneumonia, both well-

known complications of viral infections. Further, many publications on COVID-19 have debated

the puzzling clinical characteristics of ‘silent hypoxemia’, ‘happy hypoxemics’ and ‘atypical ARDS’, all features consistent with OP. The recent announcement that RECOVERY, a

randomised controlled trial comparing dexamethasone to placebo in COVID-19, was terminated

early due to excess deaths in the control group further suggests patients present with OP given

that corticosteroid therapy is the first-line treatment. Although RECOVERY along with othercohort studies report positive effects with corticosteroids on morbidity and mortality of COVID-19,

treatment approaches could be made more effective given that secondary OP often requires

prolonged duration and/or careful and monitored tapering of corticosteroid dose, with ‘pulse’

doses needed for the well-described fulminant subtype. Increasing recognition of this diagnosis

will thus lead to more appropriate and effective treatment strategies in COVID-19, which may lead to a further reduction of need for ventilatory support and improved survival.


CONCLUSION

It is our view that, based on the similar clinical presentations, radiographic abnormalities, overlapping yet supportive histopathological patterns on autopsy in conjunction with studies

reporting that patients are ‘steroid-responsive’, early COVID-19 respiratory disease is better

understood primarily as ‘SARS-CoV-2 induced secondary OP’. Given this likely high prevalence

of OP, AFOP or both in early COVID-19, a concern is that the increasingly adoptedRECOVERY trial protocol (6mg dexamethasone daily for up to 10 days) may be insufficient

given that treatment of secondary OP often requires higher doses, prolonged duration of

treatment, and a careful and monitored tapering. Thus, additional studies comparing

corticosteroid type, dosing and duration should be conducted along with the use of other

immunosuppressive agents. Initial and maintenance corticosteroid dosing should be similar to that recommended to treat COP, although patients with secondary OP typically require a shorter

duration. Clinicians should also be aware of the higher ‘pulse’ doses required in the successful

treatment of fulminant cases of OP or AFOP. Although chronic macrolide therapy has

demonstrated efficacy as a steroid-sparing agent in the treatment of COP, there are insufficient data to support a recommendation for use in COVID-19 secondary OP.


CONCLUSION

It is our view that, based on the similar clinical presentations, radiographic abnormalities, overlapping yet supportive histopathological patterns on autopsy in conjunction with studies

reporting that patients are ‘steroid-responsive’, early COVID-19 respiratory disease is better

understood primarily as ‘SARS-CoV-2 induced secondary OP’. Given this likely high prevalence

of OP, AFOP or both in early COVID-19, a concern is that the increasingly adoptedRECOVERY trial protocol (6mg dexamethasone daily for up to 10 days) may be insufficient

given that treatment of secondary OP often requires higher doses, prolonged duration of

treatment, and a careful and monitored tapering. Thus, additional studies comparing

corticosteroid type, dosing and duration should be conducted along with the use of other

immunosuppressive agents. Initial and maintenance corticosteroid dosing should be similar to that recommended to treat COP, although patients with secondary OP typically require a shorter

duration. Clinicians should also be aware of the higher ‘pulse’ doses required in the successful

treatment of fulminant cases of OP or AFOP. Although chronic macrolide therapy has

demonstrated efficacy as a steroid-sparing agent in the treatment of COP, there are insufficient data to support a recommendation for use in COVID-19 secondary OP.

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Histological response to acute lung injury

Diffuse alveolar damage (DAD)

Organizing pneumonia (OP)

Acute fibrinous organizing pneumonia (AFOP)

Eosinophilic pneumonia (EP)

Not yet described in COVID19

OP¹ versus AFOP²

Alveolar epithelial injury causes leakage of

coagulative proteins, which accumulate fibrin

due to diminished fibrinolytic activity

¹Organizing pneumonia

²Acute fibrinous organizing pneumonia

OP versus AFOP




In OP, fibroblast activation and proliferation

then follow, producing a connective tissue

matrix in the alveolus and ducts

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OP versus AFOP




In OP, fibroblast activation and proliferation

then follow, producing a connective tissue

matrix in the alveolus and ducts

In AFOP, although similar ‘organization’

occurs, a high degree of accumulated ‘fibrin

balls’ are the dominant histological finding

Photomicrograph shows immature collagen plugs or Masson bodies

filling the airspaces.

Pierre Kory, and Jeffrey P Kanne BMJ Open Resp Res 2020;7:e000724

©2020 by British Thoracic Society

Photomicrograph shows immature collagen plugs or Masson bodies

(arrows) filling the airspaces.



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37-year-old woman with COVID-19 requiring FiO2

of 1.0 delivered via heated humidified

high-flow nasal cannula for 8 days.



6 days after onset of symptomsPulse Steroids D82 weeks after discharge

Copin C-M, et al. Intensive Care Med. 2020.

Copin C-M, et al. Intensive Care Med. 2020.

45

Teaching Points


transmissible.


Age and certain pre-existing medical conditions make

patients more vulnerable to severe COVID-19 and a fatal

outcome.

There is a high prevalence of residual chest CT

abnormalities in post COVID patients and this might

progress to pulmonary fibrosis, especially in severe cases.

‘Steroid-responsive’ severe COVID-19 respiratory disease

may be better understood primarily as ‘SARS-CoV-2

induced secondary organizing pneumonia.

RESOURCES AND

ADDITIONAL

MANIFESTATIONS OF

LONG-COVID

Long-COVID Syndrome

It’s estimated that 10–30% of cases will

turn into long-COVID, where symptoms

such as dyspnea (shortness of breath),

fatigue, cognitive problems, joint pain,

myalgia, and gastrointestinal and cardiac

issues persist for a month or more

Can happen to anyone who got infected

by SARS-CoV-2, even children, students,

and those who only had mild-to-moderate

Covid-19

It’s 3–6 months and counting, so how

many more months?

The current data is insufficient to

make conclusions

Shin Jie Yong. https://medium.com/microbial-instincts/we-shouldnt-be-surprised-if-long-covid-will-last-for-years-d0c4dd4a3bf

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Most commonly reported symptoms…

Fatigue

Dyspnea

Cough

Arthralgia

Chest pain

https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html

Other reported symptoms include…

Cognitive impairment

Depression

Myalgia

Headache

Fever

Palpitations

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Less common more serious complications…

Cardiovascular: myocardial inflammation, ventricular

dysfunction

Respiratory: pulmonary function abnormalities

Renal: acute kidney injury

Dermatologic: rash, alopecia

Neurological: olfactory and gustatory dysfunction,

sleep dysregulation, altered cognition, memory

impairment

Psychiatric: depression, anxiety, changes in mood

Datta SD, et al. JAMA. December 8, 2020.

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https://www.covid19treatmentguidelines.nih.gov/

49

idsociety.org/covid-19-real-time-learning-network/disease-manifestations-complications/post-covid-syndrome/

50

Huang C, et al. The Lancet. January 16, 2021.

Overall, in this large cohort study of 1,733 patients

with COVID-19 assessed 6 months after discharge,

most patients exhibited at least one symptom,

particularly fatigue or muscle weakness, sleep

difficulties, and anxiety or depression. More severely

ill patients had increased risk of pulmonary diffusion

abnormality, fatigue or muscle weakness, and

anxiety or depression. The seropositivity and titers

of the neutralizing antibodies were significantly lower

than at acute phase.

Huang C, et al. The Lancet. January 16, 2021.

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Overall, in this study of patients with COVID-19 discharged

from the hospital with SARS-CoV-2 RNA clearance

by RT-PCR and interviewed approximately 2 months after

diagnosis, the majority of patients experienced continued

symptoms, with the most common symptoms

being fatigue and dyspnea.

COVID-19 Related Symptoms

The percentages of patients presenting with specific coronavirus disease 2019

(COVID-19)–related symptoms during the acute phase of the disease (left) and at the time of the follow-up visit (right).

Carfi A, et al. JAMA. 2020.

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Copyrights apply

WHAT CAUSES LONG-COVID

AND HOW SHOULD WE

MANAGE?

Overview of the pathophysiology, symptoms, and

potential treatments involved in long-COVID-19

Shin Jie Yong. https://medium.com/microbial-instincts/we-shouldnt-be-surprised-if-long-covid-will-last-for-years-d0c4dd4a3bf

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https://www.nice.org.uk/guidance/ng188

https://www.blf.org.uk/support-for-you/long-covid

General Evaluation of Long-COVID

Comprehensive history of the patient's COVID-19 illness

Illness timeline, duration and severity of symptoms

Types and severity of complications

COVID-19 testing results

Any management strategies

Identify modifiable personal lifestyle factors

Laboratory testing is determined by illness severity, prior

abnormal testing during their illness, and current symptoms

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Focus on Cardiopulmonary Long-COVID Evaluation

Comprehensive history and physical examination

Cardiopulmonary Long-COVID Evaluation


?ongoing dyspnea (at rest and exertion)

?cough, chest discomfort, pleuritic pain, and wheezing,

orthopnea, chest pain (exertional, positional), peripheral

edema, palpitations, dizziness, orthostasis, and pre-

syncope or syncope







syncope or syncope

Health screening tools, 6-minute walking test, & Borg

Scale

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Copyrights apply

Copyrights apply

Copyrights apply

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syncope or syncope


Scale

Cardiopulmonary Exercise Test

Copyrights apply

Copyrights apply

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syncope or syncope


Scale


Breathing exercises

Copyrights apply

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Breath…the creation of human life

Genesis 2:7

-- then the Lord God formed the man of dust from

the ground and breathed into his nostrils the

breath of life, and the man became a living

creature.

Mechanism of Action of Halotherapy*

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syncope or syncope


Scale


Breathing exercises

Sleep hygiene

Copyrights apply

Teaching Points

The COVID-19 pandemic has resulted in a growing

population of individuals with a wide range of persistent

symptoms after acute SARS-CoV-2 infection.

This comprises patients with symptoms that develop during or

after COVID-19, continue for ≥ 12 weeks, and are not explained

by an alternative diagnosis.

Whether the constellation of symptoms represents a new

syndrome unique to COVID-19, or if there is overlap with the

recovery from similar illnesses has not been determined.

There is a growing need for a multi-disciplinary approach to

management of Long-COVID.

60

Upcoming COVID-19 Study

Natural History of Post-Acute COVID-19 Convalescence

Among Healthcare Personnel at NMHS

Invitation to participate will be sent via email and Employee

Connections

Voluntary completion of an 8 to 10 minute anonymous

survey

For those who were diagnosed with COVID-19, addresses

physical/emotional experience of COVID-19 & health

behaviors

For those who were not diagnosed with COVID-19,

addresses emotional response to pandemic & health

behaviors

THE EPILOGUE

“THE RESOLUTION”

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References Kory P, Kanne JP. SARS-CoV-2 organizing pneumonia: ‘Has there been a

widespread failure to identify and treat this prevalent condition in COVID-

19?’. BMJ Open Resp Res 2020;7:e000724. doi:10.1136/bmjresp-2020-

000724

Copin M-C, Parmentier E, Duburcq T, et al. Time to consider histologic

pattern of lung injury to treat critically ill patients with COVID-19 infection.

Intensive Care Med 2020;46:1124–6.

Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD. Acute fibrinous

and organizing pneumonia: a histological pattern of lung injury and possible

variant of diffuse alveolar damage. Arch Pathol Lab Med. 2002

Sep;126(9):1064-70. doi: 10.1043/0003-

9985(2002)126<1064:AFAOP>2.0.CO;2. PMID: 12204055.

https://www.idsociety.org/covid-19-real-time-learning-network/disease-

manifestations--complications/post-covid-syndrome/

https://www.idsociety.org/covid-19-real-time-learning-network/disease-

manifestations--complications/pulmonary-manifestations/

References Goyal P, Choi JJ, Pinheiro LC, et al. Clinical Characteristics of Covid-19 in New York

City. N Engl J Med 2020;382(24):2372–2374.

Liu Y, Yan LM, Wan L, et al. Viral dynamics in mild and severe cases of COVID-19.

Lancet Infect Dis 2020;20(6):656–657.

Revzin MV, et al. Multisystem Imaging Manifestations of COVID-19, Part 1: Viral

Pathogenesis and Pulmonary and Vascular System Complications. RadioGraphics

2020; 40:1574-1599.

Carfì A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study

Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA.

2020;324(6):603-605. doi:10.1001/jama.2020.12603

McIntosh, K. Coronavirus disease 2019 (COVID-19): Clinical features. In: UpToDate,

Post, TW (Ed), UpToDate, Waltham, MA, 2021.

Mikkelsen, ME, Abramoff, B. Coronavirus disease 2019 (COVID-19): Evaluation and

management of adults following acute viral illness. In: UpToDate, Post, TW (Ed),

UpToDate, Waltham, MA, 2021.

Yong, S.J. Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and

Treatments. Preprints 2020, 2020120242 (doi: 10.20944/preprints202012.0242.v1).

References Baraniuk, C. Receptors for SARS-CoV-2 Present in Wide Variety of Human

Cells. TheScientist; April 29, 2020.

Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 Transmission

From People Without COVID-19 Symptoms. JAMA Netw Open.

2021;4(1):e2035057. doi:10.1001/jamanetworkopen.2020.35057

Brooks JT, Beezhold DH, Noti JD, et al. Maximizing Fit for Cloth and

Medical Procedure Masks to Improve Performance and Reduce SARS-

CoV-2 Transmission and Exposure, 2021. MMWR Morb Mortal Wkly Rep

2021;70:254–257. DOI:

http://dx.doi.org/10.15585/mmwr.mm7007e1external icon

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THANK YOU FOR YOUR

ATTENTION

Questions or Comments?

https://virologydownunder.com/the-swiss-cheese-infographic-that-went-viral/

63

Defending against COVID-19

This means masks are key. According to a

recent MMWR, if everyone wears a snug-fitting

mask, spread of the virus that causes COVID-19

can be reduced by up to 95%. The fit and

filtration of the mask is also key to preventing the

spread of COVID-19. Wear a mask that fits

snugly over your nose and mouth when in public

settings, stay 6 feet away from others, and avoid

crowds and poorly ventilated indoor spaces.

64

Defending against COVID-19

Documents

Post-Acute COVID-19 Syndrome and the Lung Pulmonary …