Current Understanding of COVID-19 Clinical Course and Investigational Treatments

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, this systemic review presents 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). The 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). 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 other information, including guidelines from hospitals and clinics instructing their staff on procedures to follow. In addition, we based some decisions on data collected by organizations such as the CDC, FDA, IHME, IDSA, and Worldometer. None of the case studies or cohort studies used a large number of participants. The largest group of participants numbered <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 along with diagnostic testing, we have also created a treatment algorithm that 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.


INTRODUCTION
The coronavirus disease 2019 (COVID-19) pandemic has spread throughout the globe. According to the Centers for Disease Control and Prevention (CDC), in the United States alone there were 5,460,429 cases along with 171,012 deaths, as of August 19, 2020 (2). A mathematical model created by The Institute for Health Metrics and Evaluation (IHME) predicts that in the United States the number of deaths may climb to over 295,000 by December 1, 2020 (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. To place this in context, Figure 1 provides a comparison of the reproduction rate and case-fatality rates for major respiratory virus pandemics (4)(5)(6). In the general population, casefatality rates for COVID-19 are about 1.4% (7). Data strongly emphasizes early intervention to reduce case-fatality and inhibit reproductive rates.
To date, a number of articles have been published on the clinical course and treatment of the disease (8)(9)(10). The majority of patients present with more than one symptom on admission, FIGURE 1 | Reproduction rate and case-fatality rates for major respiratory virus pandemics (4,5). Rectangle donates case fatality range from multiple publications.
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, there is viral multiplication and localized inflammation in the lungs. Stage 3 is marked by extra-pulmonary systemic hyperinflammation syndrome. The prognosis and recovery from Stage 3 is generally poor. Rapid recognition of which stage the FIGURE 2 | COVID-19 clinical stages and management strategy (15)(16)(17). *Initially mild in stage I (fever, cough, myalgia, other non-specific). May progress in stage II-III to severe dyspnea and respiratory distress (16,(18)(19)(20). **As with all treatment options, risks, and benefits should be carefully reviewed with the patient. ***No treatments are currently FDA approved for COVID-19 treatment. The FDA has approved remdesivir and convalescent plasma for inpatient use. patient is in and the deployment of appropriate therapy may have the greatest yield.
Common correlating factors that tend to lead to 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 suggests 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 that rates of morbidity and mortality are increasing, 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: PubMed (1809 to present); Google Scholar (1900 to present); MEDLINE (1946 to present), CINAHL (1937 to present); and Embase (1980 to present). The keywords used in this search 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  (21,22). ***Symptoms Mild: Fever, cough, fatigue, myalgia, headache, anosmia. Rarely, patients may also present with diarrhea, nausea, and vomiting (8,21,23). Moderate: Symptomatic viral pneumonia with possible hypoxemia (PaO2/FiO2 < 300). Confirmed by chest imaging (CXR or CT) which demonstrate bilateral infiltrates or ground glass opacities (21). Severe symptoms: Systemic (extra-pulmonary) hyperinflammation with one of the following: respiratory rate > 30 or SpO 2 < 92% on room air (11,17). Will also include abnormal chest imaging (CXR, CT scan, or lung ultrasound) characterized by bilateral opacities that are not primarily due to volume overload or lung collapse (partial or full). Echocardiogram can be used rule out of primary cardiac causes (24,25). ****See Table 1 for appropriate Rx for stage. Treatment must be individualized to the patient by considering risks, benefits, and contraindications of the particular Rx. Note: there may be a potential for combining multiple agents if no drug interaction exists, as there are pleural mechanisms of actions. *****Convalescent plasma can be used during any stage, though likely more beneficial earlier in the disease course (63).
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 that 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 (15,64).

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 >65, with hypertension, diabetes, and/or coronary heart disease were at greatest risk (66). 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 (21). 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 despite 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 et al. published in The Journal of Infection (37). Their research found that sepsis and ARDS in hospitalized patients start at around days 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. 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) (16).

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 disease). Stage I symptoms include fever, cough, fatigue, and body aches. In a minority of cases, symptoms may also include headache, abdominal symptoms, anosmia, as well as others. The duration of initial symptoms is 5-7 days, correlating with a peak in viral load (21). 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 antiviral medication. Nevertheless, treatment must be individualized, based on a patient's age, comorbidities, presenting symptoms, and drug interactions (see Figure 3 and Table 1).

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 (16,67). As in Stage II, treatment may include antivirals (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.
It should be noted that many ongoing clinical trials will more clearly define COVID-19 specific treatment risks and benefits.

Pre-exposure and Post-exposure Prophylaxis
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, anti-parasitics, and convalescent plasma have been proposed. Antivirals, like Remdesivir, may prove beneficial at any stage of disease (26,27). Convalescent plasma provides the antibody support needed to envelop and destroy the virus while preventing the exuberant immune response or cytokine release that leads to significant pathology, particularly in Stages IIb and III (46).

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 this 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.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
MH and RA revised the project, the main conceptual ideas and proof outline. BM, DS, JP, JPM, JD, YS, AC, and LA worked out almost all of the technical details with MH and RA assistance. PH, KH performed the numerical calculations and verified the numerical results. All authors contributed to writing and editing the manuscript.