key: cord-0682005-c6byrfla
authors: Mortaz, Esmaeil; Bassir, Ali; Dalil Roofchayee, Neda; Dezfuli, Neda K.; Jamaati, Hamidreza; Tabarsi, Payam; Moniri, Afshin; Rezaei, Mitra; Mehryan, Payam; Varahram, Mohammad; Marjani, Majid; Mumby, Sharon; Adcock, Ian M.
title: Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra
date: 2021-01-22
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2021.107407
sha: aafec0d1104f4f271627d658fed3a56604e27937
doc_id: 682005
cord_uid: c6byrfla

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected 86,4M patients and resulted in 1,86M deaths worldwide. Severe COVID-19 patients have elevated blood levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)α, CXCL8 and interferon (IFN)γ. Objective To investigate the effect of antiviral treatment serum cytokines in severe COVID-19 patients. Methods Blood was obtained from 29 patients (aged 32-79yr) with laboratory-confirmed COVID-19 upon admission and 7 days after antiviral (Favipiravir or Lopinavir/Ritonavir) treatment. Patients also received standard supportive treatment in this retrospective observational study. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations of COVID-19. Serum was also obtained and cytokines levels were evaluated. 19 age- and gender-matched healthy controls were studied. Results Anti-viral therapy significantly reduced CT scan scores and the elevated serum levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In contrast, sserum levels of IL-6, CXCL8 and IFNγ were elevated at baseline in COVID-19 subjects compared to healthy subjects with IL-6 (p=0.002) and CXCL8 (p=0.023) levels being further elevated after antiviral therapy. IL-1β (p=0.002) and TNFα (p=0.023) levels were also enhanced after treatment but baseline levels were similar to those of healthy controls. These changes occurred irrespective of whether patients were admitted to the intensive care unit. Conclusion Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. There was limited evidence for a viral-mediated cytokine storm in these COVID-19 subjects.

and each lobe was assigned a score: Score 0, 0% involvement, score 1, <5% 133 involvement, score 2, 5% to <25% involvement, score 3, 25% to <50% involvement, score 134 4, 50% to <75% involvement and score 5, 75% or greater involvement. The total CT score 135 was evaluated from all 5 lobes and sum plotted for each patient before and after CPK (p<0.0153), but not troponin (p=0.9), were significantly reduced after antiviral 160 therapy compared to before treatment ( Table 1) . 161 CT scores improved with treatment (p<0.05) irrespective of anti-viral therapy used or Table   169 2). Serum IL-6 levels were significantly elevated after anti-viral therapy compared with 170 levels before therapy (p<0.01) (Fig 1A, Table 2 ). 171 The levels of serum IL-8 were also elevated at baseline in patients [0.2 (0.015 -6.4) pg/ml] 172 compared to healthy controls [0.1 (0.1-0.1) pg/ml, p=0.023] and were further raised after 173 7 days of anti-viral therapy [0.6 (0.052-27.42) pg/ml, p<0.0001] (Fig.1B, Table 2 ). Serum 174 IL-8 levels were significantly elevated after anti-viral therapy compared with levels before 175 therapy (p<0.05) (Fig 1B, Table 2 (Fig 1D, Table 2 ). Table 2 ).

Effect of ICU treatment on serum cytokine levels 189 Since some patients progressed to ICU whilst others did not, we assessed whether there 190 were differences at baseline and after therapy according to ICU status. There was no 191 significant difference in the baseline serum IL-6 level before and after therapy in non-ICU 192 patients (Table 3) Table 3) . 195 Similarly, there were no differences between serum CXCL8 levels in ICU patients and 196 non-ICU patients at baseline and after anti-viral therapy ( Table 3 ). In addition, anti-viral 197 therapy did not significantly affect serum CXCL8 levels in patients in ICU but there was a 198 small but significant increase in serum CXCL8 levels in non-ICU subjects [0.1 (0.02-199 12.36) vs 0.45 (0.03-3.6) pg/ml, p<0.05] ( Table 3) . 200 Serum IFN concentrations did not differ at baseline between patients in ICU or not in 201 ICU and anti-viral therapy had no effect on serum levels of IFN (Table 3) Table 3) . 205 There were no significant differences at baseline between ICU and non-ICU patients in 206 the serum levels of IL-1 (Table 3) . Anti-viral therapy significantly enhanced serum IL-1 greater in ICU patients compared to non-ICU patients after treatment (p<0.05) ( Table 3) . 210 Serum TNF levels before therapy were similar between subjects in ICU and those not 211 in ICU (Table 3) . Anti-viral therapy resulted in a small, but significant increase in serum Table 3) .

Antiviral treatment on serum cytokine levels 216 We evaluated the effect of the two different anti-viral therapies on serum cytokine levels. (Table 4) . 226 Serum IL-8 levels were significantly lower in non-ICU patients treated with Kaletra (0.3 227 (0.1-0.5) pg/ml) compared with those treated with Favipiravir (0.7(0.03-3.6) pg/ml) 228 (p=0.0303) (Table 4B. Fig. 2B) . This difference was not observed in ICU patients. There 229 were no significant differences in post-treatment levels of IL-6 ( Fig. 2A) , IFN- (Fig. 2C) , 230 IL-1 (Fig. 2D) or TNF (Fig. 2E ) between patients treated with Kaletra or Favipirivir.

Serum IL-6 levels were higher in Favipiravir-treated patients in ICU compared to non-232 ICU patients (p=0.0044) whilst IFN- levels were higher in Kaltera-treated patients in the 233 ICU compared to non-ICU patients (p=0.007) (Table 4, Fig. 2) . No other effects of anti-234 viral therapy was seen on serum cytokine expression.

Antiviral therapy resulted in improvements in lung CT scores after 7 days irrespective of 237 whether subjects were in ICU or not. In addition, the raised blood levels of ESR, CRP, 238 LDH and CPK seen in COVID-19 patients compared to those in healthy control subjects 

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