COVID-19: What Should the General Practitioner Know?

Figures & data

Table 1 Clinical Symptoms and the Course of SARS-CoV-2 Infection

Frequency of Symptoms and Complications Occurring in the Course of SARS-CoV-2 Infection
Infected patients [%]	60–90%	20–59%	5–19%	<5%
symptoms	fever cough dyspnoea lymphocytopenia	muscle pain or tiredness presence of sputum fatigue smell and taste disorders (loss of smell is often present before fever and can be the dominant symptom of infection)	headache hemoptysis sore throat diarrhea shortness of breath arthralgia chills nausea or vomiting	swelling of the nasal mucosa enlargement of palatine tonsils conjunctival hyperemia lymph nodes enlarged rash
COVID-19 complications	most often pneumonia – present in > 90% of patients (usually a ground-glass shadow on chest CT)		ARDS rarely: septic shock acute kidney failure cardiomyopathy rhabdomyolysis DIC (disseminated intravascular coagulation)
The course of SARS-CoV-2 infection	mild most patients (81%) the mild disease of the upper respiratory tract without clinical complications hospitalization is not required (the exception are the elderly who should be carefully monitored because of the high risk of sudden clinical disease exacerbation)	severe 14% of patients patients require hospitalization and oxygen therapy	critically ill 5% of patients ICU treatment is required critically ill patients frequently with severe pneumonia mechanical ventilation usually is needed

Note: Data based on research from Guan et al,⁵ Zhao et al,⁷ and Chakraborty et al⁸

Table 2 Drugs Currently Used or Under Investigation for COVID-19

Drug	Drug Class: Mechanism of Action	Study: Study Findings	Indication/Standard Dose
Remdesivir (GS-5734)	Antiviral: prodrug of an adenosine C-nucleoside leading to decreased viral RNA production^Citation70	Wang et al 2020. A double-blind study in 236 patients. Intravenous Remdesivir vs placebo: dose tolerated; no statistically significant clinical benefits, however, numerical reduction in time to clinical improvement were observed^Citation71	200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions
		Grein et al 2020. A preliminary prospective compassionate-use cohort study of 61 patients: high incidence of adverse effects; improvement in oxygen-support requirement was observed in 68% of patients, overall mortality of 13% over a median follow-up of 18 days^Citation72	Patients with confirmed SARS-CoV-2 infection (by RT-PCR) and oxygen saturation of ≤ 94% on ambient air or on oxygen support. 200 mg intravenously on day 1, followed by 100 mg daily for the remaining 9 days
Antimalarial drugs: CQ and HCQ	AMD: accumulation of CQ in lysosomes alters the pH thus activating proteases in lysosomes and thus affecting the degradation of proteins and glycosaminoglycan	Liu et al 2020. In Vitro study, Vero E6 cell line: HCQ efficiently inhibits SARS-CoV-2 infection in vitro^Citation73	Vero E6 cells were treated with CQ or HCQ (50 μM) for 1 hour
		inhibits SARS-COV-2 at low-micromolar concentrations^Citation74	Polish recommendations: Chloroquine, orally, 250 mg p.o.(in specific cases 500 mg) every 12 hours, 7–10 days (no more than 10 days)^Citation16
	CQ can inhibit the entry of SARS-CoV-2 and prevent virus-cell fusion by interfering with glycosylation of ACE2 receptor and its binding with spike protein	Gautret et al, 2020. RCT with 36 patients treated with HCQ (± Azithromycin): reduction in viral load by day 6 post-inclusion; synergy observed with the combination of hydroxychloroquine and azithromycin^Citation75 Wang et al, 2020. In vitro study: potent inhibition of coronavirus with CQ^Citation74	600mg of hydroxychloroquine daily + Azithromycin 500mg on day1 then 250mg per day, subsequent 4 days
	HCQ possesses an anti-inflammatory effect on Th17-related cytokines (IL-6, IL-17, and IL-22)	HCQ causes quick viral clearance in combined therapy with azithromycin^Citation75	The oral loading dose of HCQ 400mg bid on the first day, and the maintenance dose of 200mg bid continue to be treated for four days^Citation76.
		Overall, it appears that good results have been seen in vitro, however, robust clinical data to support the use of HCQ in clinical practice is lacking. A systematic review reveals that there is still a lack of clinical studies demonstrating the efficacy of CQ/HCQ in vivo^Citation89
Lopinavir/Ritonavir (LPV/r)	Protease inhibitor	Cao et al, 2020. RCT of 199 patients: no benefit was observed with LPV/r treatment beyond standard care^Citation77	400 mg/100 mg, orally twice daily plus standard of care, or standard of care alone
		Ye et al, 2020. A retrospective cohort study of 47 patients treated with LPV/r plus adjuvant drugs: shorter time to temperature normalization and negative viral RNA^Citation78	5 mL/dose (400/100 mg) for adults, twice a day or 10 mL/dose (800/200 mg) once a day with food plus adjuvant drugs
Biologic anti-cytokine drugs	Immunomodulator: Humanized monoclonal antibody against IL-6	Tocilizumab Xiaoling et al 2020 A retrospective study of 20 patients: radiographic evidence of pulmonary lesion resorption in 90%, temperature normalization after day 1 of treatment^Citation79	400mg intravenous drip Tocilizumab in addition to standard care plus lopinavir, methylprednisolone. No control arm.
		Siltuximab Gritti et al, 2020. Normalization of serum CRP level by day 5, 33% showed a decreased need for O2 support^Citation80	Intravenously at a dose of 11 mg/kg/day over 1 hour; dose ranging from 700 to 1200 mg (median dose = 900 mg) A second dose could be administered per compassionate-use program (Five patients received a second dose of siltuximab)
Ivermectin	Anti-helminthic drug with Anti-viral property: Inhibition of IMPα/β1-mediated nuclear import of viral proteins → inhibition of viral RNA replication	Caly et al, 2020. In vitro study in SARS-CoV-2 infected Vero/hSLAM cell line. Post-infection samples were taken for viral load quantitation (real-time PCR) of cell-associated virus or supernatant: Injected at 2h post-infection, ivermectin affected ~5000-fold reduction in viral RNA at 48 h^Citation81	Serial dilutions of Ivermectin. IC50 ~2 μM
Convalescent Plasma (CP)	Binding of the transfused antibodies to the pathogen, resulting in cellular cytotoxicity, phagocytosis, or direct neutralization of the pathogen	Shen et al, 2020. Case series report of 5 patients: decrease in SOFA score, increase in PAO2/FiO2, ARDS resolution, and negative viral load by day 12. Increase in neutralizing antibodies by day 7^Citation82	Critically ill patients with COVID-19 and ARDS. Pao2/Fio2 of <300 and mechanical ventilation support. 400 mL of convalescent plasma transfused directly.
		Duan et al 2020 A pilot cohort study to evaluate the safety of CP in 10 patients: well tolerated with no adverse effects. Improved oxygen saturation, lymphocyte count, CRP, clinical status and resorption of lung lesions by day 7^Citation83	200 mL of convalescent plasma transfused directly
Corticosteroids	Anti-inflammatory	Villar et al, 2020. Multicenter placebo-controlled RCT of Dexamethasone in 277 patients: no difference in the incidence of adverse effects (hyperglycemia, new infections, barotrauma); a significant decrease in 60-day mortality and increased number of ventilator-free days in Dexamethasone arm^Citation84	An intravenous dose of 20 mg once daily (day 1 to 5), then reduced to 10 mg once daily (day 6 to 10)
		The RECOVERY trial was a randomized control trial in 2108 patients with COVID. It revealed a decrease in 28-day mortality in patients receiving dexamethasone. It decreased incidence of mortality by a third in patients on mechanical ventilation compared to those without^Citation90 Interestingly, patients who receive delayed mechanical ventilation and are tolerating modest to moderate hypoxia have better outcomes than their counterparts. High PEEP ventilation has been linked with higher mortality in COVID-induced lung injury.^Citation91,Citation92
Heparin	Anti-inflammatory action May inhibit viral attachment via conformational changes to the SARS-CoV-2 surface receptor (Spike) S1	Tang et al, 2020. A retrospective cohort study of 449 patients randomized to heparin or LMWH vs placebo: anticoagulation conferred survival benefit in patients meeting SIC criteria or with markedly elevated D‐dimer (at least 6x ULN). Overall no difference in 28-day mortality in heparin users and non-users^Citation85	A 7-day course of 40‐60 mg enoxaparin/day OR 10,000‐15,000 U of UFH/day
Nutritional Supplements	Zinc inhibits SARS-CoV and retrovirus RNA polymerase activity in vitro, and zinc ionophores block the replication of these viruses in cell culture Zinc enhances chloroquine intracellular uptake	No concluded trials	1200 mg/day intravenous infusion plus standard of care
	Lipoic acid induces HO-1 potentially boosting interferon 1 response	Zhong et al 17 patients in Placebo-controlled RCT: lower SOFA score increase and lower 30-day all-cause mortality compared to placebo, albeit statistically insignificant^Citation86 McCarty and DiNicolantonio 2020^Citation87	1200–1800 mg

Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; RT-PCR, reverse transcriptase-polymerase chain reaction; IMPα/β1, importin alpha/beta; CRP-C, reactive protein; RCT, randomized control trial; HO-1, heme oxygenase 1; LMWH, low molecular weight heparin; SIC score, sepsis‐induced coagulopathy score; ULN, upper limit of normal; UFH, unfractionated heparin.

Figure 1 The challenges for GPs to reduce SARS-CoV-2 contagion rates (according to Modenese, Ing E, Li DKT, Hollander, Smith).

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