Clinical Course

Updated by Rohin Gawdi on 5/03/2020

Summary: Clinical Course

• SARS-CoV-2 passes through nasopharyngeal mucosa and enters the lungs

• From the lungs, virus enters the blood and mobilizes to other organs

  • This is the start of the milder viremia phase, indicated by fever and cough

• If immune function can compensate for the viremia, then patients will enter recovery phase

• If patients’ immune system fail to clear the virus, the acute pneumonia phase will begin 7-10 days after symptoms begin

  • ARDS occurs on average, 8 days post-onset

• Severe disease can result from cytokine release syndrome if patient lymphocyte count continues to fall and D-Dimer continues to rise

  • There is clinical evidence that LMWH and IVIg can improve severe disease

• Viral load and viral shedding both worsen as symptom severity worsens

  • This suggests that viral load may be a useful prognostic factor

Literature Review:

While studies that examine pathogenesis of SARS-CoV-2 infection are limited at this time-point, clinical observations and immune changes found in other betacoronavirus infections have painted a preliminary picture of immunologic role in COVID-19 infection. It has been noted clinically that SARS-CoV-2 passes through nasal and larynx mucosal membranes to enter the lungs. Infection of the lungs causes early symptoms of COVID-19: fever and cough (7). The virus enters peripheral blood from the lungs and targets organs that express ACE2, namely the kidneys, GI tract, and heart. Further evidence of these organs being targeted is the presence of SARS-CoV-2 in fecal samples (7) and the increased incidence of myocardial damage from COVID-19 infection (8).

A paper from Lin et al. suggests a clinical phase divided into three phases: the milder viremia phase, the acute pneumonia phase, and recovery phase. If the patient’s immune function is effective and other affected organ systems are largely intact, the acute pneumonia phase is skipped and recovery begins. If patients are immunocompromised or have comorbidities such as heart disease or diabetes, the immune system can fail to effectively limit the viremia phase and patients may enter the acute pneumonia phase 7-10 days after they experience symptoms. Clinical data has shown that on average, ARDS occurs about 8 days after symptom onset in these patients (9). Evidence suggests that worsening disease and ARDS is brought on by cytokine release syndrome (CRS), resulting in IL-6 overproduction (10). According to initial data, IL-6 was significantly elevated in patients who experienced symptom exacerbation and ARDS. It is also notable that non-surviving patients with COVID-19 have higher D-Dimer, neutrophil levels with reduced renal function when compared to surviving patients. Additionally, patients with severe disease presented with low platelet count and high fibrin degradation products, indicating hemorrhage. (23) As stated above, lymphocytopenia is a common CBC finding of severe COVID-19. Thus CRS must be largely mediated by non-T-cell leukocytes. Some early evidence suggests that blockage of IL-6 may show benefit in patients, although other studies have produced data that IL-6 is not elevated significantly in severe cases of COVID-19 (10). Some hospitals in China have attempted to use IFN-gamma-pretreated mesenchymal stem cells (MSCs) in severe cases of COVID-19 infection in order to repair damaged lung tissue (11). Other data suggests that niacin may also prevent lung damage based on bleomycin-induced lung injury animal studies (12). During this phase, if the patient experiences further reduction of T and B cell count with rising viral load and D-Dimer levels, they may progress to more severe disease within 14-21 days after symptoms appear (13). This paper from Ling et al. suggests from clinical data of influenza, SARS-CoV infection and preliminary data from SARS-CoV-2 cases that the administration of IVIg and LMWH during the acute pneumonia phase can increase lymphocyte counts, reduce viral load and D-Dimer count, and may help induce recovery (13-15). However, it is also important to consider the patient’s ability to transmit the virus. Given SARS-CoV-2’s heightened transmissibility, the rate of viral shedding has also been addressed by literature. According to a study by Liu et al., patients with severe cases of COVID-19, on average, expressed a viral load from nasopharyngeal swab of 60 times higher than that of patients with mild infections. Furthermore, mild cases had clearance of the virus to levels undetectable by RT-PCR by day 10 post-onset. A different study showed that in patients with severe disease (mortality of >40%), viral shedding was present at 20 days post-onset (16). These results show that patients with severe symptoms have high viral load and a longer shedding period, and may indicate the utility of SARS-CoV-2 viral load as a useful metric for assessing disease severity and prognosis (17).

Summary and Literature Review written by Rohin Gawdi 3/29/2020