Current Understanding of COVID-19 Clinical Course and Investigational Treatments

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, 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.

Keywords: COVID 19; clinical course; cover-19 testing; directed treatment; disease management; infectious disease.

Figure 1

Reproduction rate and case-fatality rates for major respiratory virus pandemics (4, 5). Rectangle donates case fatality range from multiple publications.

Figure 2

COVID-19 clinical stages and management strategy (–17). *Initially mild in stage I (fever, cough, myalgia, other non-specific). May progress in stage II-III to severe dyspnea and respiratory distress (, –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.

Figure 3

Treatment algorithm for COVID-19+ patients based on clinical presentation and therapeutic staging. *High risk patient: Anyone that is ≥65 y/o or meets comorbidities criteria as defined below. **Comorbidities: Defined as any two of the following: HTN, DM, CVD, CKD, Pre-existing lung disease, CHF, diabetes >7.6%, use of biologicals, HIV+, history of transplant, morbid obesity (BMI ≥ 40) (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 SpO₂ < 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).

Figure 4

Percent change in clinical measures between survivors and non-survivors. Source: (21).