Current Understanding of COVID-19 Clinical Course and Investigational Treatments

medRxiv preprint doi: https://doi.org/10.1101/2020.04.19.20071548.this version posted April 24, 2020.
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Current Understanding of COVID-19 Clinical Course and

Investigational Treatments
Richard B. Aguilar, MD1, Patrick Hardigan, PhD2, Bindu Mayi, PhD3, Darby Sider, MD4, Jared
Piotrkowski, MD5, Jinesh P. Mehta, MD6, Jenankan Dev, MD7, Yelenis Seijo, MD7, Antonio Lewis
Camargo, MD7, Luis Andux, MD8, Kathleen Hagen. EdD9, Marlow B. Hernandez, DO, MPH10
1
Chief Clinical Officer, Cano Health, Miami, FL
2
Executive Associate Dean of Research, Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern
University
3
Professor of Microbiology, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University
(NSU), Fort Lauderdale, FL
4
Program Director, Internal Medicine, Cleveland Clinic Florida, Weston, FL
5
Hospitalist, Cleveland Clinic Florida, Weston, FL
6
Director of Intensive Care Unit Operations, Cleveland Clinic Florida, Weston, FL
7
Resident, Internal Medicine, Cleveland Clinic Florida
8
Medical Director, Cano Health
9
Executive Director for Assessment, Health Professions Division, Nova Southeastern University (NSU), Fort
Lauderdale, FL
10
Chief Executive Officer, Cano Health, Miami, FL
Corresponding Author:
Patrick Hardigan, PhD
3200 South University Dr., Health Professions Division
Ft. Lauderdale, Fl 33328
[email protected]
Word Count
1757
i
medRxiv preprint doi: https://doi.org/10.1101/2020.04.19.20071548.this version posted April 24, 2020. The copyright holder for this preprint
Key Points
Question: What are the most effective treatment recommendations for COVID-19?
Findings: COVID-19 can be divided into three distinct Stages, beginning at the time of infection
(Stage I), sometimes progressing to pulmonary involvement (Stage II, with or without
hypoxemia) and less frequently to systemic inflammation (Stage III). In addition to modeling the
stages of disease progression, we also created a treatment algorithm which considers age,
comorbidities, clinical presentation, and disease progression to suggest drug classes or
treatment modalities.
Meaning: This paper presents the first evidence-based recommendations for individualized
treatment for COVID-19.
ii
ABSTRACT:
Importance: Currently, there is no unified framework linking disease progression to established
viral levels, clinical tests, inflammatory markers, and investigational treatment options.
Objective: It may take many weeks or months to establish a standard treatment approach.
Given the growing morbidity and mortality with respect to COVID-19, we present a treatment
approach based on a thorough review of scholarly articles and clinical reports. Our focus is on
staged progression, clinical algorithms, and individualized treatment.
Evidence Review: We followed the protocol for a quality review article proposed by Heyn et.
al.1 A literature search was conducted to find all relevant studies related to COVID-19. The
search was conducted between April 1, 2020 and April 13, 2020 using the following electronic
databases: PubMed (1809 to present), Google Scholar (1900 to present), MEDLINE (1946 to
present), CINAHL (1937 to present), and Embase (1980 to present). Keywords used included
COVID-19, 2019-nCov, SARS-CoV-2, SARS-CoV, and MERS-CoV, with terms such as efficacy,
seroconversion, microbiology, pathophysiology, viral levels, inflammation, survivability, and
treatment and pharmacology. No language restriction was placed on the search. Reference lists
were manually scanned for additional studies.
Findings: Of the articles found in the literature search, 70 were selected for inclusion in this
study (67 cited in the body of the manuscript and 3 additional unique references in the Figures).
iii
The articles represent work from China, Japan, Taiwan, Vietnam, Rwanda, Israel, France, the
United Kingdom, the Netherlands, Canada, and the United States. Most of the articles were
cohort or case studies, but we also drew upon information found in guidelines from hospitals
and clinics instructing their staff on procedures to follow. In addition, we based some decisions
on data collected by agencies such as the CDC, FDA, IHME, ISDA, and Worldometer. None of the
case studies or cohort studies used a large number of participants. The largest group of
participants numbered less than 500 and some case studies had fewer than 30 patients.
However, the review of the literature revealed the need for individualized treatment protocols
due to the variability of patient clinical presentation and survivability. A number of factors
appear to influence mortality: the stage at which the patient first presented for care, pre-
existing health conditions, age, and the viral load the patient carried.
Conclusion and Relevance: COVID-19 can be divided into three distinct Stages, beginning at the
time of infection (Stage I), sometimes progressing to pulmonary involvement (Stage II, with or
without hypoxemia) and less frequently to systemic inflammation (Stage III). In addition to
modeling the stages of disease progression, we have also created a treatment algorithm which
considers age, comorbidities, clinical presentation, and disease progression to suggest drug
classes or treatment modalities. This paper presents the first evidence-based recommendations
for individualized treatment for COVID-19.
iv
Introduction
The coronavirus disease 2019 (COVID-19) pandemic is raging throughout the globe. In
the United States alone, as of April 10, 2020, there were 560,933 cases along with 22,127
deaths (Centers for Disease Control and Prevention, CDC).2 A mathematical model created by
The Institute for Health Metrics and Evaluation (IHME) predicts that in the United States,
assuming continued full social distancing, the number of new cases will peak in late April, and
related deaths will peak by mid-to-late May.3 This creates a critical and immediate need for
medical treatment and resources.
Preliminary data in the US suggests that COVID-19 may be more infectious and lethal
than Influenza H1N1. In the general population, current case-fatality rates for COVID-19 are
about 3.9%, and infection rates are about 2.5 under normal conditions.4 To place this in
context, Figure 1 provides a comparison of the reproduction rate and case-fatality rates for
major respiratory virus pandemics.5-7 Data strongly emphasizes early intervention to reduce
case-fatality and inhibit reproductive rates.
A number of articles have been published on the clinical course and treatment of the
disease.8-10 The majority of patients present with more than one symptom on admission,
although the combination of fever, cough, and shortness of breath is rare. Siddiqi and Mehra
proposed a staged progression model based on observed clinical courses in published studies.11
In Stage 1, or the mild phase, the virus multiplies and establishes residence in the host,
predominantly in the respiratory tract. In Stage 2, we see that viral multiplication and localized
inflammation in the lungs is common. Stage 3 is marked by extra-pulmonary systemic
hyperinflammation syndrome. The prognosis and recovery from Stage 3 is generally poor. Rapid
1
recognition of what stage the patient is in and deployment of appropriate therapy may have
the greatest yield.
Common correlates with poorer outcomes include age, hypertension, diabetes,
coronary artery disease, chronic lung disease, and malignancies.12 Research also finds variations
in outcomes due to a dysregulated and exuberant immune response. Patients requiring
intensive care have significantly higher levels of IL-6, CRP, ferritin, and D-Dimer. An important
therapeutic modality may be to downregulate the cytokine storm, particularly in severe
illness.13 The literature also suggest that disease progression can be predicted. During the
severe acute respiratory syndrome (SARS) pandemic, a retrospective analysis revealed that 2-
week cumulative case data could help estimate the total case numbers with accuracy – well
before the date of the last reported case.14
As we have found, there is no unified framework linking disease progression to
established viral levels, clinical tests, inflammatory markers, and investigational treatment
options. Given that it may take many weeks or months to establish a standard treatment
approach and there is a growing morbidity and mortality, we present an initial treatment
approach based on a thorough review of currently available scholarly articles and clinical
reports. Our focus is on staged progression, clinical algorithms, and individualized treatment.
Methods
We followed the protocol for a quality review article proposed by Heyn et al.1 A
literature search was conducted to find all relevant studies related to COVID-19. The search was
conducted between April 1, 2020 and April 13, 2020 using the following electronic databases:
2
PubMed (1809 to present), Google Scholar (1900 to present), MEDLINE (1946 to present),
CINAHL (1937 to present), and Embase (1980 to present). Keywords used included COVID-19,
2019-nCov, SARS-CoV-2, SARS-CoV, and MERS-CoV, with terms such as efficacy, seroconversion,
microbiology, pathophysiology, viral levels, inflammation, survivability, and treatment and
pharmacology. No language restriction was placed on the search. Reference lists were manually
scanned for additional studies. From this systematic review a model was created that
incorporated clinical course, diagnostics, disease management, and treatment.
Our results focus on recommendations for individualized treatment, by selecting the
most appropriate drug or modality for the patient, carefully weighing risks and benefits.
Clinicians and patients should understand the staged progression of COVID-19 (Figure 2). As
such, we present a treatment algorithm that recommends no treatment for some and specific
treatment for others, depending on age, comorbidities, and symptom severity (Figure 3).
Results
Based on our thorough review of the literature, we correlated the disease course to
COVID-19 testing, diagnostic options, and treatment strategies (see Figure 2). COVID-19 can be
divided into three distinct Stages, beginning at the time of infection (Stage I), sometimes
progressing to pulmonary involvement (Stage II, with or without hypoxemia) and less
frequently to systemic inflammation (Stage III). We also created a treatment algorithm which
considers age, comorbidities, clinical presentation, and disease progression to suggest drug
classes or treatment modalities (see Figure 3). The specific treatments are summarized in Table
1.20-64
3
Comorbidity
Data exists for early identification of cases at high risk of progression to severe COVID-
19. One promising model created in China found that patients who developed severe COVID-19
possessed one of the following diseases: hypertension, diabetes, coronary heart disease,
chronic respiratory disease, or tuberculosis. The same model cited age and various serological
indicators (such as C-reactive protein (CRP), lactate dehydrogenase (LDH), bilirubin, and others)
as factors associated with worse outcomes.65 Additional research confirmed, in a case-control
study, that subjects with high Sequential Organ Failure Assessment (SOFA) scores, with age
greater than 65, with hypertension, diabetes, and/or coronary heart disease were at greatest
risk.15 Lastly, Research focusing on viral load and survival found that higher initial viral load is
independently associated with worse prognosis.2
Disease Progression
The most common presenting symptoms are fever and cough, followed by myalgia and
fatigue. Less commonly, patients may present with sputum production, headache, or
abdominal symptoms like diarrhea.26 In terms of disease progression, a case study of the first
five patients diagnosed with COVID-19 in Europe points the way to two different clinical
evolutions of the disease: 1. Presenting few symptoms, but showing high viral load from the
respiratory tract; 2. A two-step disease process, with worsening of symptoms around 10 days of
symptom onset in spite of decreased viral load in respiratory samples. In our model we plot the
disease progression as a function of infection, survivability, and inflammation (Figure 2). We
identify the inflection point where survival decreases as inflammation increases—
approximately day 10 from symptom onset. Support for this is found in research by Chen J, Qi T,
4
Liu L, et al. published in The Journal of Infection.31 Their research found that sepsis and ARDS in
hospitalized patients starts around day 10 and 11, respectively. They also found temporal
changes in inflammatory laboratory markers beginning at day 4 of illness onset. These included
temporal changes in D-dimer, IL-6, serum ferritin, high-sensitivity cardiac troponin I, and lactate
dehydrogenase. The differences were statistically significant between survivors and non-
survivors for all time points. Figure 4 provides the percent change between survivors and non-
survivors from day 4. In addition, Yang et al.66 found that the patients admitted to the ICU with
severe hypoxemia had a 50% probability of survival at day 7 of ICU admission (corresponding to
Day ~17 in Figure 2).
Stage I
The incubation period is on average 5 days. In most patients, initial presenting
symptoms are mild (though a small number of patients can be asymptomatic throughout the
course of the disease). Stage I symptoms include fever, cough, fatigue, and body aches, but, in a
minority of cases can include headache, GI symptoms, anosmia, as well as others. Duration of
initial symptoms is 5-7 days, correlating with a peak in viral load.26 During this time, the
appropriate diagnostic test is a nasopharyngeal PCR. Laboratory studies may include an
elevated D-Dimer and prothrombin time, as well as lymphopenia (see Figure 2). Given that
symptoms in this stage are mild, and correlated with viremia, the appropriate treatment
modality is supportive care or an antiviral. Nevertheless, treatment must be individualized,
based on a patient’s age, comorbidities, presenting symptoms, and drug interactions (see
Figure 3 and Table 1).
5
Stage II
Some patients progress into Stage II, which is characterized by a decrease in viral levels
and an increase in inflammation that initially localizes to the lungs. Infiltrates are typically seen
on chest x-ray (CXR) or computed tomography (CT). Similar to symptom duration in Stage I, the
typical symptom course in Stage II is also 5-7 days. Treatment with antivirals is still indicated,
but given an average decrease in viral levels during this stage, that treatment is theoretically
less effective than in Stage I. Moreover, Stage II is divided into two sub-stages (IIA and IIB),
depending on whether a patient is hypoxemic or not. This distinction is important for
management (see Figure 2). In Stage IIB, the patient is significantly dyspneic and may benefit,
depending on age and comorbidities, from the use of corticosteroids or other anti-
inflammatory treatments (see Figure 3).
Stage III
Although only a minority of patients (estimated at 10-15%) progress to Stage III,
mortality within this stage is considerable (estimated at 20-30%). The morbidity and mortality
are generally due to uncontrolled inflammation, which at this point is systemic. The most
important symptom is respiratory distress (correlating in a typical patient to a Pulse Ox < 92%).
Laboratory markers include significantly increased CRP and IL-6 levels.66-67 As in Stage II,
treatment may include anti-virals (if the patient is still viremic), but agents to counteract
inflammation and its effects (such as microthrombi) must be considered (see Figure 2). A
summary of investigational therapies can be found in Table 1.
Pre-Exposure and Post-Exposure Prophylaxis
6
A number of clinical trials are exploring pre-exposure and post-exposure prophylaxis.
There is no definitive evidence that any particular treatment modality is effective but antivirals,
hydroxychloroquine, and convalescent plasma are being proposed. Anti-virals, like Remdesivir,
may proof beneficial at any stage of disease.39-40 Hydroxychloroquine is postulated to have anti-
viral properties, and it has been definitively proven as an immunomodulator.32 Convalescent
plasma provides the antibody support needed to envelope and destroy the virus while
preventing the exuberant immune response or cytokine release that leads to significant
pathology, particularly in Stages IIb and III.23
Limitations
This review has several limitations. First, the incredible volume and speed at which data
is published about the treatment of COVID-19 indicates that research findings and
recommendations may change. Second, the research used to create the review came from
small studies, often-times with very few controls. Third, the articles were limited to English-
language publications or translations, so relevant international data could be lacking.
Conclusion
This paper presents the first evidence-based recommendations for individualized
treatment for COVID-19. Based upon the observed transmission and mortality rates, health
professionals urgently need to align patient baseline risk to disease stage and investigational
treatment options. The COVID-19 pandemic represents the greatest public health crisis in three
generations; the need for comprehensive management cannot be overstated.
7
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12
Figure 1. Reproduction Rate and Case-Fatality Rates for Major Respiratory Virus Pandemics
13
Table 1. Summary of Investigational Treatments by COVD-19 Effect
AGENT EFFECT DOSING STAGE MECHANISM COMMENTARY
Remdesivir AV • 200 mg IV x1, followed by 100mg I-III • RNA polymerase inhibitor39 • Adverse effects include elevated ALT and AST, phlebitis, constipation, headache,
qd for 5-10 days nausea.
• Theoretical risk of renal injury.
• Should not be used in pregnancy due to lack of data.
• Has limited drug-drug interactions (no significant CYP effect)
• Clinical trials underway in the US, UK, and China
• Showed efficacy in COVID-19 treatment40
Lopinavir/Ritonavir AV • 200 mg/50 mg/capsule, 2 I-III • Protease inhibitor.41 • Nearly 14% of patients cannot complete a course due to GI side effects.36
capsules PO bid for no more than • Ritonavir is a potent CYP3A4 inhibitor (interacting with Rx such as apixaban,
10-14 days tacrolimus, and amiodarone).
• In rare cases, Lopinavir/Ritonavir can cause liver injury, pancreatitis and cardiac
toxicity.
• Treatment in mostly Stage II-III patients was not found to be superior to
standard of care. Subgroup analysis suggestive that earlier treatment (Stage I)
might be beneficial.41
Favipiravir AV • 1600mg PO bid x1d, then 600mg I-III • Broad spectrum inhibitor of RNA- • Increases liver function parameters (AST, ALT and total bilirubin)
PO bid for up to 14 days dependent RNA polymerase42-43 • Testis toxicity and has a risk for teratogenicity and embryotoxicity
• Was found to be superior to Lopinavir/Ritonavir in a small controlled study.44
Umifenovir AV • 200mg q8h for up to 14 days I-III • S protein / ACE-2 membrane fusion • Metabolism by CYP3A4. Caution with strong inhibitors or inducers.
inhibitor45 • Hypersensitivity risk increases in children under 2 years of age
• Limited clinical evidence shows promise in COVID-19.46
Hydroxychloroquine AV • Stage I-II—400mg PO bid for first I-III • AV: replication-neutralization of the • Adverse effects include: rash, nausea, and diarrhea. GI symptoms can be
A-IN day followed by 200mg bid daily pH cellular organelles for gene mitigated by taking with water; use with caution in diabetic patients may cause
for 5 days20 replication hypoglycemia.34
• Stage III—May consider • A-IN: inhibition of macrophage • Increased risk of retinopathy with a recommended maximal daily dose of
extending treatment (200mg bid) activation and reducing release of 5.0 mg/kg. Avoid if history of retinal disease, macular degeneration, or previous
for up to 14 days.21,20 tissue TNF-a, IL-1, IL-631-33 treatment with tamoxifen.35
• A-IN: interfere with lysosomal • Caution in patient at risk for QT prolongation. EKG at baseline and following
activity and autophagy, disrupt initiation is generally advised, particularly in critically ill patients.
membrane stability, alter signaling • Contraindicated with Epilepsy, Porphyria, G6PD, and Myasthenia Gravis
and transcriptional activity, which • Ideally used for patients hospitalized with Pneumonia36
can then inhibit immune activation • Consider for patients at high risk for disease progression.
and cytokine production32 • Pre-Exposure/Post-Exposure prophylaxis is being studied
Chloroquine AV • Stage I-II – 500 mg bid for 5 days I-III • A-IN: decrease secretion and/or • Has greater adverse event profile than Hydroxychloroquine and possibly less
A-IN • Stage III—may consider receptor expression of cytokines efficacy.
extending treatment for up to 10 such as TNF-a33,37 • Most common symptoms include abdominal cramps, nausea, anorexia.
days • Interfere with lysosomal activity and • Can increase QTc and result in hematologic effects (including hemolysis with
autophagy, similar to G6PD deficiency). Can cause retinal toxicity and hypoglycemia.
Hydroxychrloroquine32 • As with Hydroxychloroquine, additional clinical trial data is necessary to
determine efficacy and safety in COVID-19 patients.38
14
Ivermectin AV • 45 - 64 kg: 9 mg orally single dose I-II broad-spectrum anti-viral activity in vitro • Possible considerations as adjunct therapy or replacement when other agents
• 65 - 84 kg: 12 mg single dose through inhibition of nuclear import of contraindicated
• 85 kg or more: 0.15 mg/kg orally host and RNA viral proteins47 • Contraindicated in Pregnancy
single dose
Ribavirin AV • IV 500 mg each time, bid or tid, II-III • inhibits viral RNA dependent RNA • Can cause birth defects or death in an unborn baby48
no more than 10 days polymerase • Hematologic toxicity is observed in dose-dependent fashion.
• Caution when used with azathioprine or HIV/AIDS medicines
• Ribavirin is likely not effective when used alone and must be used in
combination with IFN-α or lopinavir/ritonavir
Convalescent plasma AV • 200- 250 mL of ABO-compatible I-III • Neutralizing activity against SARS- • Allergic transfusion reactions
donor containing SARS- A-IN convalescent plasma x 2 CoV-2 • Likely most beneficial in early disease course (e.g. Stage I or Stage II), as its
CoV-2– specific antibody (achieving 400 mL in total) on the mechanism of action is to neutralize viral particles.23
(IgG) same day it was obtained from
the donor
Azithromycin A-IN • 500mg qd x 1, then 250mg bid II-III • Inhibits RNA-dependent protein • Previous studies have shown some efficacy against viruses such as Influenza,
for 4 days synthesis Ebola, RSV and Rhinovirus.50
• Multiple immunomodulatory • May confer benefit when added to Hydroxychloroquine.21-22
effects49 • Should be used if superimposed bacterial Pneumonia.
• Does increase QT interval, especially when added to Hydroxychloroquine. An
EKG is recommended prior to start (and EKG or telemetry monitoring while on
Tx is recommended)51
Doxycycline and other A-IN • 200mg qd x 1, then 100mg qd for II-III • Downregulation of NFkB pathway as • May confer benefit when added to Hydroxychloroquine.
Tetracyclines 4 days. May consider extending well as TNFa, IL-1B and IL-6 • Should be used if superimposed bacterial Pneumonia.
treatment for up to 14 days. • Possible inhibition of RNA
replication52
Prednisone CS • 40mg-60mg prednisone PO or II-III • Multiple immunomodulatory • Should not be used in Stage I (unless another indication) as it may increase viral
Methylprednisolone 30mg-60mg methylprednisolone effects, including suppression of load.54
Dexamethasone IV, or 5-10mg dexamethasone IV PMN migration and reversal of • Indicated for asthma or COPD exacerbation or any shock with a history of
Hydrocortisone qd for up to 7 days increased capillary permeability53 chronic steroid use in excess of 10mg prednisone daily. Also used for
• 50mg hydrocortisone IV q6H until multipressor (>2 pressor) shock.
improvement in shock. • Use in patients with hypoxemia may confer a mortality benefit. If ARDS, higher
doses may be required.55,56
Tocilizumab and other IL- A-IN • 4-8mg/kg IV (usually 400mg) x 1 IIb-III • Inhibits inflammatory cytokine • Side effects include upper respiratory tract infections, mild stomach cramps.
6 inhibitors dose. If inadequate response, storm • Black box warning for a risk of serious infections, including tuberculosis and
may repeat one time after 12 • inhibits IL-6 and signal transduction other opportunistic infections. Patients treated with this medication should be
hrs.57 of RNA viruses but not of DNA tested for latent tuberculosis prior to discharge from the hospital
viruses58 • Caution in neutropenia or thrombocytopenia
• May interact with cholesterol-lowering medications, seizure medications, heart
rhythm medications
• May be beneficial for use in Cytokine Activation Syndrome25
IFN-α and other Type 1 AV • 5 million U or equivalent dose IIb-III • Interfere with viral replication • Inhalation pharmacodynamics and pharmacokinetics have never been assessed.
Interferons A-IN each time, 2 times/day for Vapor • Slowdown of cell metabolism and • IV and SC modes of administration are well-described and proven safe in several
inhalation secretion of cytokines clinical trials (under expert use), with similar pharmacodynamics and
pharmacokinetics.59
15
Prazosin and other alpha- A-IN • 1mg bid or tid, titrating up as I-III • Reduces catecholamine and • Contraindicated if hypotension.
1 adrenergic receptor tolerated cytokine response through alpha-1 • No current evidence for starting the Rx if patient is not already on it. A recent
(AR) antagonists AR antagonism retrospective review found that patients previously treated with alpha-1AR
antagonists had improved end points.60
Atorvastatin and other A-IN • Atorvastatin 40mg qhs I-III • Pleiotropic effects, anti- • If there is an indication for a statin, the statin should be started or continued.61
Statins inflammatory
Baricitinib A-IN • Eli Lilly and National Institute for IIb-III • JAK1/JAK2 inhibitor • FDA approved for treatment of rheumatoid arthritis.
AV? Allergies and Infectious Diseases • Theoretic (but unproven) anti-viral • Side effects include upper respiratory tract infection and reactive of herpes
(NIAID) announced that the drug properties simplex and herpes zoster.
will begin its first large • Black box warning for serious infections including TB. Patients must be tested for
randomized trial in COVID-19 TB prior to starting treatment.
patients, in late April in the U.S., • Increase risk of malignancy (including Lymphoma), and thromboembolism.63
and additional sites in Asia /
Europe.63
Heparin, Enoxaparin, and AC • DVT Prophylaxis Dosing (e.g. II-III • Tissue factor pathway inhibition62 • Indicated as DVT prophylaxis for all hospitalized patients (Stage II) without
other Anticoagulants Enoxaparin 40mg SC qd, or contraindication for anticoagulation.
Heparin 5000 SC tid) • Full anticoagulation may be beneficial in Stage III, as it has shown benefit for
• Full anticoagulation— those suffering from sepsis associated coagulopathy, ARDS, or D-Dimer levels
individualize to patient greater than 6-fold the upper limit of normal.62
AV: Antiviral, A-IN: Anti-inflammatory, CS: Corticosteroid, AC:Anti-coagulant
*None of these Rx are considered standard of care for treatment of COVID-19, and ideally should be used as part of a clinical trial. Moreover, this table is not
meant to be a comprehensive review of adverse effects and drug-drug interactions. Treatment must be individualized to the patient, considering the patient’s
age, comorbidities, clinical course, drug interactions, and hypersensitivities. Lastly, this table is meant to be updated as new evidence (and perhaps new agents
or classes of agents) is presented.
16
Figure 2. COVID-19 Clinical Stages and Management Strategy
17
Figure 3. Treatment Algorithm for COVID-19+ Patients Based on Clinical Presentation and
Therapeutic Staging
18
Figure 4. Percent Change in Clinical Measures between Survivors and Non-Survivors
Source: Chen J, Qi T, Liu L, et al. Clinical progression of patients with COVID-19 in Shanghai, China. [published
online March 19, 2020]. J Infect. 2020;S0163-4453(20)30119-5. doi:10.1016/j.jinf.2020.03.004.
19

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medRxiv preprint doi: https://doi.org/10.1101/2020.04.19.20071548.this version posted April 24, 2020.

The copyright holder for this preprint

Current Understanding of COVID-19 Clinical Course and

comorbidities, clinical presentation, and disease progression to suggest drug classes or

treatment for COVID-19.

Importance: Currently, there is no unified framework linking disease progression to established

staged progression, clinical algorithms, and individualized treatment.

seroconversion, microbiology, pathophysiology, viral levels, inflammation, survivability, and

were manually scanned for additional studies.

for individualized treatment for COVID-19.

medical treatment and resources.

case-fatality and inhibit reproductive rates.

inflammation in the lungs is common. Stage 3 is marked by extra-pulmonary systemic

the greatest yield.

Common correlates with poorer outcomes include age, hypertension, diabetes,

in outcomes due to a dysregulated and exuberant immune response. Patients requiring

therapeutic modality may be to downregulate the cytokine storm, particularly in severe

before the date of the last reported case.14

As we have found, there is no unified framework linking disease progression to

microbiology, pathophysiology, viral levels, inflammation, survivability, and treatment and

incorporated clinical course, diagnostics, disease management, and treatment.

Our results focus on recommendations for individualized treatment, by selecting the

as factors associated with worse outcomes.65 Additional research confirmed, in a case-control

independently associated with worse prognosis.2

disease progression as a function of infection, survivability, and inflammation (Figure 2). We

identify the inflection point where survival decreases as inflammation increases—

Day ~17 in Figure 2).

The incubation period is on average 5 days. In most patients, initial presenting

appropriate diagnostic test is a nasopharyngeal PCR. Laboratory studies may include an

modality is supportive care or an antiviral. Nevertheless, treatment must be individualized,

Figure 3 and Table 1).

depending on whether a patient is hypoxemic or not. This distinction is important for

inflammatory treatments (see Figure 3).

Although only a minority of patients (estimated at 10-15%) progress to Stage III,

summary of investigational therapies can be found in Table 1.

Pre-Exposure and Post-Exposure Prophylaxis

A number of clinical trials are exploring pre-exposure and post-exposure prophylaxis.

viral properties, and it has been definitively proven as an immunomodulator.32 Convalescent

pathology, particularly in Stages IIb and III.23

language publications or translations, so relevant international data could be lacking.

This paper presents the first evidence-based recommendations for individualized

generations; the need for comprehensive management cannot be overstated.

AGENT EFFECT DOSING STAGE MECHANISM COMMENTARY

AV: Antiviral, A-IN: Anti-inflammatory, CS: Corticosteroid, AC:Anti-coagulant

Figure 2. COVID-19 Clinical Stages and Management Strategy

Figure 4. Percent Change in Clinical Measures between Survivors and Non-Survivors

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