Covid-19 Research

Research Article

Administration of HeberFERON in Patients with Persistent Oropharyngeal SARS-CoV-2 Wuhan/D614G Strain Viral Shedding

Journal of Biomedical Research & Environmental Sciences article abstract with citation details, DOI, publication dates, subject areas, full text links, and references.

View DOI Submit Manuscript

Article Details

Publication record, authors, dates, abstract, and full text access.

Open Access
Article Type Research Article
Subject Biology Group
OCLC 9385857608
Ivan Campa-Legra, Juan J Lence, Marel Alonso-Valdes, Marisol Diaz-Galvez, Adriana Sin-Mayor, Maura Garcia-Sanchez, Sara Martinez-Martin, Jesus Perez-Escribano, Idelsis Esquivel-Moynelo, Yaquelin Duncan-Roberts, Claudia Martu00ednez-Suarez, Abraham Beato-Canfuk and Iraldo Bello-Rivero
Issue: Volume2-Issue12
Pages: 1253-1266
Received: 2021-12-13
Accepted: 2021-12-27
Published: 2021-12-29

Abstract

Study background: HeberFERON accelerates SARS-CoV-2 clearance in COVID-19 cases. Considering this we evaluated the employment of HeberFERON in patients with more than 14 days of viral shedding.

Methods: This is a case series study of mild or moderate ill patients with laboratory-confirmed SARS-CoV-2 from one hospital in Havana, Cuba. We evaluated the effect and safety of HeberFERON in patients previously treated with Heberon Apha R that resulted with prolonged viral shedding. All patients received lopinavir-ritonavir 200/50 mg every 12 h and chloroquine 250 mg every 12 h. The primary endpoint was the time to negativization of viral RNA in patients with persistent viral shedding. The protocol was approved by the Ethics Committee of the Luis Diaz Soto Hospital.

Results: The characteristics of the individuals included the age ranged from 19-87 years with a mean of 40 years, (Study and Control I groups), while in the Control group II the mean age was 43.8 years. Leukocytes, platelets, neutrophils, and eosinophils, show a significantly lower counts in the groups with viral persistence.

Under IFN treatment the median viral shedding duration from diagnosis were 21 days and 19 days in Study group and Control group II, respectively. The Control group I showed a median viral shedding of 11 days (log-rank p = 0.000). Significant longer median viral negativization time (19 days) of symptomatic than asymptomatic patients (11 days, Long-rank p = 0.004), was observed. In patients under Heberon Alpha R treatment that resulted persistent for viral presence, the median time to viral negativization was 7 days for the period of administration of HeberFERON. Being symptomatic at diagnosis was significantly associated with viral persistence. The HeberFERON showed an adequate safety profile.

Conclusion: HeberFERON showed a safe and rapid negativization of patients with viral persistence, achieving negativization in more than 50% of patients in 7 days.

FullText HTML FullText PDF DOI: 10.37871/jbres1380 Crossmark

Certificate of Publication

Certificate of Publication

Copyright

© 2021 Campa-Legra I, et al. Distributed under Creative Commons CC-BY 4.0 Creative CommonsAttribution

How to cite this article

Campa-Legra I, Lence JJ, Alonso-Valdes M, Diaz-Galvez M, Sin-Mayor A, Garcia-Sanchez M, Martinez-Martin S, Perez-Escribano J, Esquivel-Moynelo I, Duncan-Roberts Y, Martínez-Suarez C, Beato-Canfuk A, Bello-Rivero I. Administration of HeberFERON in Patients with Persistent Oropharyngeal SARS-CoV-2 Wuhan/D614G Strain Viral Shedding. J Biomed Res Environ Sci. 2021 Dec 29; 2(12): 1253-1266. doi: 10.37871/jbres1380, Article ID: JBRES1380, Available at: https://www.jelsciences.com/articles/jbres1380.pdf

Subject area(s)

AntivirologyMicrobiologyBiologyVirology

References

  1. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel Coronavirus diseases (COVID-19)-China, 2020. China CDC Weekly 2020:2:113-122.
  2. Protocolo De Actuación Nacional Para La Covid-19.
  3. https://bit.ly/3uQWRoL
  4. Campbell F, Archer B, Laurenson-Schafer H, Jinnai Y, Konings F, Batra N, Pavlin B, Vandemaele K, Van Kerkhove MD, Jombart T, Morgan O, le Polain de Waroux O. Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021. Euro Surveill. 2021 Jun;26(24):2100509. doi: 10.2807/1560-7917.ES.2021.26.24.2100509. PMID: 34142653; PMCID: PMC8212592.
  5. Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, Ludden C, Reeve R, Rambaut A; COVID-19 Genomics UK (COG-UK) Consortium, Peacock SJ, Robertson DL. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021 Jul;19(7):409-424. doi: 10.1038/s41579-021-00573-0. Epub 2021 Jun 1. PMID: 34075212; PMCID: PMC8167834.
  6. Baton Rouge. Symptoms of the Delta Variant vs. Previous COVID-19 Strains. News & Blog. July 26, 2021.
  7. https://bit.ly/3eoU3t4
  8. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJ, Baillie JK, Semple MG; ISARIC4C investigators. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020 May 22;369:m1985. doi: 10.1136/bmj.m1985. PMID: 32444460; PMCID: PMC7243036.
  9. Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, Ng OT, Marimuthu K, Ang LW, Mak TM, Lau SK, Anderson DE, Chan KS, Tan TY, Ng TY, Cui L, Said Z, Kurupatham L, Chen MI, Chan M, Vasoo S, Wang LF, Tan BH, Lin RTP, Lee VJM, Leo YS, Lye DC; Singapore 2019 Novel Coronavirus Outbreak Research Team. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020 Apr 21;323(15):1488-1494. doi: 10.1001/jama.2020.3204. Erratum in: JAMA. 2020 Apr 21;323(15):1510. PMID: 32125362; PMCID: PMC7054855.
  10. Widders A, Broom A, Broom J. SARS-CoV-2: The viral shedding vs infectivity dilemma. Infect Dis Health. 2020 Aug;25(3):210-215. doi: 10.1016/j.idh.2020.05.002. Epub 2020 May 20. PMID: 32473952; PMCID: PMC7237903.
  11. Long QX, Tang XJ, Shi QL, Li Q, Deng HJ, Yuan J, Hu JL, Xu W, Zhang Y, Lv FJ, Su K, Zhang F, Gong J, Wu B, Liu XM, Li JJ, Qiu JF, Chen J, Huang AL. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020 Aug;26(8):1200-1204. doi: 10.1038/s41591-020-0965-6. Epub 2020 Jun 18. PMID: 32555424.
  12. Zhou B, She J, Wang Y, Ma X. Duration of Viral Shedding of Discharged Patients With Severe COVID-19. Clin Infect Dis. 2020 Nov 19;71(16):2240-2242. doi: 10.1093/cid/ciaa451. PMID: 32302000; PMCID: PMC7184358.
  13. Lee S, Kim T, Lee E, Lee C, Kim H, Rhee H, Park SY, Son HJ, Yu S, Park JW, Choo EJ, Park S, Loeb M, Kim TH. Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea. JAMA Intern Med. 2020 Nov 1;180(11):1447-1452. doi: 10.1001/jamainternmed.2020.3862. PMID: 32780793; PMCID: PMC7411944.
  14. Li J, Zhang L, Liu B, Song D. Case Report: Viral Shedding for 60 Days in a Woman with COVID-19. Am J Trop Med Hyg. 2020 Jun;102(6):1210-1213. doi: 10.4269/ajtmh.20-0275. PMID: 32342849; PMCID: PMC7253087.
  15. Zapor M. Persistent Detection and Infectious Potential of SARS-CoV-2 Virus in Clinical Specimens from COVID-19 Patients. Viruses. 2020 Dec 3;12(12):1384. doi: 10.3390/v12121384. PMID: 33287245; PMCID: PMC7761721.
  16. Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM, Peiris M, Poon LLM, Zhang W. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020 Jun;20(6):656-657. doi: 10.1016/S1473-3099(20)30232-2. Epub 2020 Mar 19. PMID: 32199493; PMCID: PMC7158902.
  17. Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, Niemeyer D, Jones TC, Vollmar P, Rothe C, Hoelscher M, Bleicker T, Brünink S, Schneider J, Ehmann R, Zwirglmaier K, Drosten C, Wendtner C. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020 May;581(7809):465-469. doi: 10.1038/s41586-020-2196-x. Epub 2020 Apr 1. Erratum in: Nature. 2020 Dec;588(7839):E35. PMID: 32235945.
  18. Ling Y, Xu SB, Lin YX, Tian D, Zhu ZQ, Dai FH, Wu F, Song ZG, Huang W, Chen J, Hu BJ, Wang S, Mao EQ, Zhu L, Zhang WH, Lu HZ. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl). 2020 May 5;133(9):1039-1043. doi: 10.1097/CM9.0000000000000774. PMID: 32118639; PMCID: PMC7147278.
  19. Zheng X, Chen J, Deng L, Fang Z, Chen G, Ye D, Xia J, Hong Z. Risk factors for the COVID-19 severity and its correlation with viral shedding: A retrospective cohort study. J Med Virol. 2021 Feb;93(2):952-961. doi: 10.1002/jmv.26367. Epub 2020 Sep 16. PMID: 32725915; PMCID: PMC7821149.
  20. To KK, Tsang OT, Leung WS, Tam AR, Wu TC, Lung DC, Yip CC, Cai JP, Chan JM, Chik TS, Lau DP, Choi CY, Chen LL, Chan WM, Chan KH, Ip JD, Ng AC, Poon RW, Luo CT, Cheng VC, Chan JF, Hung IF, Chen Z, Chen H, Yuen KY. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 May;20(5):565-574. doi: 10.1016/S1473-3099(20)30196-1. Epub 2020 Mar 23. PMID: 32213337; PMCID: PMC7158907.
  21. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, Yin H, Xiao Q, Tang Y, Qu X, Kuang L, Fang X, Mishra N, Lu J, Shan H, Jiang G, Huang X. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020 May;5(5):434-435. doi: 10.1016/S2468-1253(20)30083-2. Epub 2020 Mar 20. PMID: 32199469; PMCID: PMC7158584.
  22. Hossain ME, Lister D, Bartolo C, Kinsella PM, Knox J, Aldrich R, Cowan R, Commons RJ. Prolonged Viral Shedding in Patients with Mild to Moderate COVID-19 Disease: A Regional Perspective. Infect Dis (Auckl). 2021 Apr 13;14:11786337211010428. doi: 10.1177/11786337211010428. PMID: 33911876; PMCID: PMC8047841.
  23. Yoshikawa T, Hill TE, Yoshikawa N, Popov VL, Galindo CL, Garner HR, Peters CJ, Tseng CT. Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection. PLoS One. 2010 Jan 15;5(1):e8729. doi: 10.1371/journal.pone.0008729. PMID: 20090954; PMCID: PMC2806919.
  24. Mosaddeghi P, Shahabinezhad F, Dehghani Z, Farahmandnejad M, Taghipour MJ, Moghadami M, Nezafat N, Masoompour SM, Negahdaripour M. Therapeutic Approaches for COVID-19 Based on the Interferon-mediated Immune Responses. Curre Current Signal Transduction Therapy. 2021;16(3). doi: 10.2174/1574362416666210120104636.
  25. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, Feldt T, Green G, Green ML, Lescure FX, Nicastri E, Oda R, Yo K, Quiros-Roldan E, Studemeister A, Redinski J, Ahmed S, Bernett J, Chelliah D, Chen D, Chihara S, Cohen SH, Cunningham J, D'Arminio Monforte A, Ismail S, Kato H, Lapadula G, L'Her E, Maeno T, Majumder S, Massari M, Mora-Rillo M, Mutoh Y, Nguyen D, Verweij E, Zoufaly A, Osinusi AO, DeZure A, Zhao Y, Zhong L, Chokkalingam A, Elboudwarej E, Telep L, Timbs L, Henne I, Sellers S, Cao H, Tan SK, Winterbourne L, Desai P, Mera R, Gaggar A, Myers RP, Brainard DM, Childs R, Flanigan T. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Jun 11;382(24):2327-2336. doi: 10.1056/NEJMoa2007016. Epub 2020 Apr 10. PMID: 32275812; PMCID: PMC7169476.
  26. Avanzato VA, Matson MJ, Seifert SN, Pryce R, Williamson BN, Anzick SL, Barbian K, Judson SD, Fischer ER, Martens C, Bowden TA, de Wit E, Riedo FX, Munster VJ. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell. 2020 Dec 23;183(7):1901-1912.e9. doi: 10.1016/j.cell.2020.10.049. Epub 2020 Nov 4. PMID: 33248470; PMCID: PMC7640888.
  27. Pickles OJ, Lee LYW, Starkey T, Freeman-Mills L, Olsson-Brown A, Cheng V, Hughes DJ, Lee A, Purshouse K, Middleton G. Immune checkpoint blockade: releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome? Br J Cancer. 2020 Sep;123(5):691-693. doi: 10.1038/s41416-020-0930-7. Epub 2020 Jun 16. PMID: 32546835; PMCID: PMC7296191.
  28. Corti D, Purcell LA, Snell G, Veesler D. Tackling COVID-19 with neutralizing monoclonal antibodies. Cell. 2021 Jun 10;184(12):3086-3108. doi: 10.1016/j.cell.2021.05.005. Epub 2021 May 26. Erratum in: Cell. 2021 Aug 19;184(17):4593-4595. PMID: 34087172; PMCID: PMC8152891.
  29. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020 May 28;181(5):1036-1045.e9. doi: 10.1016/j.cell.2020.04.026. Epub 2020 May 15. PMID: 32416070; PMCID: PMC7227586.
  30. O'Connell P, Aldhamen YA. Systemic innate and adaptive immune responses to SARS-CoV-2 as it relates to other coronaviruses. Hum Vaccin Immunother. 2020 Dec 1;16(12):2980-2991. doi: 10.1080/21645515.2020.1802974. Epub 2020 Sep 2. PMID: 32878546; PMCID: PMC8641610.
  31. Guidotti LG, Chisari FV. Cytokine-mediated control of viral infections. Virology. 2000 Aug 1;273(2):221-7. doi: 10.1006/viro.2000.0442. PMID: 10915592.
  32. Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol. 2016 Jul;38(4):471-82. doi: 10.1007/s00281-016-0558-0. Epub 2016 Mar 10. PMID: 26965109; PMCID: PMC4896975.
  33. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, Ng YY, Lo J, Chan J, Tam AR, Shum HP, Chan V, Wu AK, Sin KM, Leung WS, Law WL, Lung DC, Sin S, Yeung P, Yip CC, Zhang RR, Fung AY, Yan EY, Leung KH, Ip JD, Chu AW, Chan WM, Ng AC, Lee R, Fung K, Yeung A, Wu TC, Chan JW, Yan WW, Chan WM, Chan JF, Lie AK, Tsang OT, Cheng VC, Que TL, Lau CS, Chan KH, To KK, Yuen KY. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-1704. doi: 10.1016/S0140-6736(20)31042-4. Epub 2020 May 10. PMID: 32401715; PMCID: PMC7211500.
  34. Esquivel-Moynelo I, Pérez-Escribano J, Duncan-Roberts Y, Vázquez-Blomquist D, Bequet-Romero M, Báez-Rodríguez L, Castro-Ríos J, Cobas-Cervantes L, Pagé-Calvet E, Travieso-Pérez S, Martinez-Suarez C, Campa-Legra I, Fernandez-Masso J, Camacho- Rodriguez H, Díaz-Gálvez M, Sin-Mayor A, García- Sánchez M, Martínez-Martín S, Alonso-Valdés , Hernández-Bernal F, Nodarse-Cuni H, Bello-Garcia D, Canaan-Haden Ayala C, Gonzáles-Moya I, Beato-Canfuk A, Vizcaino-Cesar T, Guillén-Nieto G,Muzio-González Ve, Fish E and Bello-Rivero I. A combination treatment of IFN-α2b and IFN-γ accelerates viral clearance and control inflammatory response in COVID-19: Preliminary results of a randomized controlled trial. Ann Antivir Antiretrovir. 2021; 5(1):001-014. doi: 10.17352/aaa.000010.
  35. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. Erratum in: JAMA. 2021 Mar 16;325(11):1113. PMID: 32031570; PMCID: PMC7042881.
  36. Griffin DO, Brennan-Rieder D, Ngo B, Kory P, Confalonieri M, Shapiro L, Iglesias J, Dube M, Nanda N, In GK, Arkfeld D, Chaudhary P, Campese VM, Hanna DL, Sawcer D, Ehresmann G, Peng D, Smorgorzewski M, Amstrong A, Vinjevoll EH, Dasgupta R, Sattler FR, Mussini C, Mitjà O, Soriano V, Peschanski N, Hayem G, Piccirillo MC, Lobo-Ferreira A, Rivero IB, Hung IFH, Rendell M, Ditmore S, Varon J, Marik P. The Importance of Understanding the Stages of COVID-19 in Treatment and Trials. AIDS Rev. 2021 Feb 8;23(1):40-47. doi: 10.24875/AIDSRev.200001261. PMID: 33556957.
  37. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. PMID: 32171076; PMCID: PMC7270627.
  38. Li TZ, Cao ZH, Chen Y, Cai MT, Zhang LY, Xu H, Zhang JY, Ma CH, Liu Y, Gao LJ, Duan ZH, Mou DL, Liang LC. Duration of SARS-CoV-2 RNA shedding and factors associated with prolonged viral shedding in patients with COVID-19. J Med Virol. 2021 Jan;93(1):506-512. doi: 10.1002/jmv.26280. Epub 2020 Jul 15. PMID: 32644223; PMCID: PMC7362127.
  39. Yan D, Liu XY, Zhu YN, Huang L, Dan BT, Zhang GJ, Gao YH. Factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalised non-critically ill patients with SARS-CoV-2 infection. Eur Respir J. 2020 Jul 16;56(1):2000799. doi: 10.1183/13993003.00799-2020. PMID: 32430428; PMCID: PMC7241115.
  40. Xu K, Chen Y, Yuan J, Yi P, Ding C, Wu W, Li Y, Ni Q, Zou R, Li X, Xu M, Zhang Y, Zhao H, Zhang X, Yu L, Su J, Lang G, Liu J, Wu X, Guo Y, Tao J, Shi D, Yu L, Cao Q, Ruan B, Liu L, Wang Z, Xu Y, Liu Y, Sheng J, Li L. Factors Associated With Prolonged Viral RNA Shedding in Patients with Coronavirus Disease 2019 (COVID-19). Clin Infect Dis. 2020 Jul 28;71(15):799-806. doi: 10.1093/cid/ciaa351. PMID: 32271376; PMCID: PMC7184421.
  41. van Kampen JJA, van de Vijver DAMC, Fraaij PLA, Haagmans BL, Lamers MM, Okba N, van den Akker JPC, Endeman H, Gommers DAMPJ, Cornelissen JJ, Hoek RAS, van der Eerden MM, Hesselink DA, Metselaar HJ, Verbon A, de Steenwinkel JEM, Aron GI, van Gorp ECM, van Boheemen S, Voermans JC, Boucher CAB, Molenkamp R, Koopmans MPG, Geurtsvankessel C, van der Eijk AA. Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19). Nat Commun. 2021 Jan 11;12(1):267. doi: 10.1038/s41467-020-20568-4. PMID: 33431879; PMCID: PMC7801729.
  42. Zhang W, Du RH, Li B, Zheng XS, Yang XL, Hu B, Wang YY, Xiao GF, Yan B, Shi ZL, Zhou P. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020 Feb 17;9(1):386-389. doi: 10.1080/22221751.2020.1729071. PMID: 32065057; PMCID: PMC7048229.
  43. Li W, Su YY, Zhi SS, Huang J, Zhuang CL, Bai WZ, Wan Y, Meng XR, Zhang L, Zhou YB, Luo YY, Ge SX, Chen YK, Ma Y. Virus shedding dynamics in asymptomatic and mildly symptomatic patients infected with SARS-CoV-2. Clin Microbiol Infect. 2020 Nov;26(11):1556.e1-1556.e6. doi: 10.1016/j.cmi.2020.07.008. Epub 2020 Jul 9. PMID: 32653662; PMCID: PMC7346822.
  44. Fontana LM, Villamagna AH, Sikka MK, McGregor JC. Understanding viral shedding of severe acute respiratory coronavirus virus 2 (SARS-CoV-2): Review of current literature. Infect Control Hosp Epidemiol. 2021 Jun;42(6):659-668. doi: 10.1017/ice.2020.1273. Epub 2020 Oct 20. PMID: 33077007; PMCID: PMC7691645.
  45. Vibholm LK, Nielsen SSF, Pahus MH, Frattari GS, Olesen R, Andersen R, Monrad I, Andersen AHF, Thomsen MM, Konrad CV, Andersen SD, Højen JF, Gunst JD, Østergaard L, Søgaard OS, Schleimann MH, Tolstrup M. SARS-CoV-2 persistence is associated with antigen-specific CD8 T-cell responses. EBioMedicine. 2021 Feb;64:103230. doi: 10.1016/j.ebiom.2021.103230. Epub 2021 Jan 30. PMID: 33530000; PMCID: PMC7847186.
  46. Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med. 2020 Jun 1;217(6):e20200678. doi: 10.1084/jem.20200678. PMID: 32353870; PMCID: PMC7191310.
  47. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020 May 28;181(5):1036-1045.e9. doi: 10.1016/j.cell.2020.04.026. Epub 2020 May 15. PMID: 32416070; PMCID: PMC7227586.
  48. Yang B, Fan J, Huang J, Guo E, Fu Y, Liu S, Xiao R, Liu C, Lu F, Qin T, He C, Wang Z, Qin X, Hu D, You L, Li X, Wang T, Wu P, Chen G, Zhou J, Li K, Sun C. Clinical and molecular characteristics of COVID-19 patients with persistent SARS-CoV-2 infection. Nat Commun. 2021 Jun 9;12(1):3501. doi: 10.1038/s41467-021-23621-y. PMID: 34108465; PMCID: PMC8190301.
  49. Ahmed R, Salmi A, Butler LD, Chiller JM, Oldstone MB. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med. 1984 Aug 1;160(2):521-40. doi: 10.1084/jem.160.2.521. PMID: 6332167; PMCID: PMC2187458.
  50. Anasagasti-Angulo L, Garcia-Vega Y, Barcelona-Perez S, Lopez-Saura P, Bello-Rivero I. Treatment of advanced, recurrent, resistant to previous treatments basal and squamous cell skin carcinomas with a synergistic formulation of interferons. Open, prospective study. BMC Cancer. 2009 Jul 30;9:262. doi: 10.1186/1471-2407-9-262. PMID: 19643007; PMCID: PMC2724551.
  51. Bello-Rivero I, Garcia-Vega Y, Valenzuela-Silva C, Vázquez-Blomquist D. Development of a new formulation of interferons (HEBERPAG) for BCC treatment. Cancer Res Ther. 2013;10:235-243. doi:10.14312/2052-4994.2013-36.
  52. García-García I, Hernández-González I, Díaz-Machado A, González-Delgado CA, Pérez-Rodríguez S, García-Vega Y, Campos-Mojena R, Tuero-Iglesias ÁD, Valenzuela-Silva CM, Cruz-Ramírez A, Martín-Trujillo A, Santana-Milián H, López-Saura PA, Bello-Rivero I; CIGB-128-A Study Group. Pharmacokinetic and pharmacodynamic characterization of a novel formulation containing co-formulated interferons alpha-2b and gamma in healthy male volunteers. BMC Pharmacol Toxicol. 2016 Dec 7;17(1):58. doi: 10.1186/s40360-016-0103-8. PMID: 27923408; PMCID: PMC5142133.
  53. Mazzoni A, Salvati L, Maggi L, Capone M, Vanni A, Spinicci M, Mencarini J, Caporale R, Peruzzi B, Antonelli A, Trotta M, Zammarchi L, Ciani L, Gori L, Lazzeri C, Matucci A, Vultaggio A, Rossi O, Almerigogna F, Parronchi P, Fontanari P, Lavorini F, Peris A, Rossolini GM, Bartoloni A, Romagnani S, Liotta F, Annunziato F, Cosmi L. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J Clin Invest. 2020 Sep 1;130(9):4694-4703. doi: 10.1172/JCI138554. PMID: 32463803; PMCID: PMC7456250.
  54. Choi B, Choudhary MC, Regan J, Sparks JA, Padera RF, Qiu X, Solomon IH, Kuo HH, Boucau J, Bowman K, Adhikari UD, Winkler ML, Mueller AA, Hsu TY, Desjardins M, Baden LR, Chan BT, Walker BD, Lichterfeld M, Brigl M, Kwon DS, Kanjilal S, Richardson ET, Jonsson AH, Alter G, Barczak AK, Hanage WP, Yu XG, Gaiha GD, Seaman MS, Cernadas M, Li JZ. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med. 2020 Dec 3;383(23):2291-2293. doi: 10.1056/NEJMc2031364. Epub 2020 Nov 11. PMID: 33176080; PMCID: PMC7673303.
  55. Baang JH, Smith C, Mirabelli C, Valesano AL, Manthei DM, Bachman MA, Wobus CE, Adams M, Washer L, Martin ET, Lauring AS. Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient. J Infect Dis. 2021 Jan 4;223(1):23-27. doi: 10.1093/infdis/jiaa666. PMID: 33089317; PMCID: PMC7797758.
  56. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30. PMID: 32007143; PMCID: PMC7135076.
  57. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24. Erratum in: Lancet Respir Med. 2020 Apr;8(4):e26. PMID: 32105632; PMCID: PMC7102538.
  58. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, Akdis CA, Gao YD. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 Jul;75(7):1730-1741. doi: 10.1111/all.14238. Epub 2020 Feb 27. PMID: 32077115.
  59. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020 Jul 28;71(15):762-768. doi: 10.1093/cid/ciaa248. PMID: 32161940; PMCID: PMC7108125.
  60. Wilk AJ, Rustagi A, Zhao NQ, Roque J, Martínez-Colón GJ, McKechnie JL, Ivison GT, Ranganath T, Vergara R, Hollis T, Simpson LJ, Grant P, Subramanian A, Rogers AJ, Blish CA. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med. 2020 Jul;26(7):1070-1076. doi: 10.1038/s41591-020-0944-y. Epub 2020 Jun 8. PMID: 32514174; PMCID: PMC7382903.
  61. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011 Jul 25;11(8):519-31. doi: 10.1038/nri3024. PMID: 21785456.
  62. Widegren H, Andersson M, Borgeat P, Flamand L, Johnston S, Greiff L. LTB4 increases nasal neutrophil activity and conditions neutrophils to exert antiviral effects. Respir Med. 2011 Jul;105(7):997-1006. doi: 10.1016/j.rmed.2010.12.021. Epub 2011 Jan 19. PMID: 21251805; PMCID: PMC7127613.
  63. Phipps S, Lam CE, Mahalingam S, Newhouse M, Ramirez R, Rosenberg HF, Foster PS, Matthaei KI. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood. 2007 Sep 1;110(5):1578-86. doi: 10.1182/blood-2007-01-071340. Epub 2007 May 10. PMID: 17495130.
  64. Mansson A, Fransson M, Adner M, Benson M, Uddman R, Björnsson S, Cardell LO. TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis. Int Arch Allergy Immunol. 2010;151(2):118-28. doi: 10.1159/000236001. Epub 2009 Sep 15. PMID: 19752565.
  65. Nagase H, Okugawa S, Ota Y, Yamaguchi M, Tomizawa H, Matsushima K, Ohta K, Yamamoto K, Hirai K. Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol. 2003 Oct 15;171(8):3977-82. doi: 10.4049/jimmunol.171.8.3977. PMID: 14530316.
  66. Wong CK, Cheung PF, Ip WK, Lam CW. Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. Am J Respir Cell Mol Biol. 2007 Jul;37(1):85-96. doi: 10.1165/rcmb.2006-0457OC. Epub 2007 Mar 1. PMID: 17332440.
  67. Drake MG, Bivins-Smith ER, Proskocil BJ, Nie Z, Scott GD, Lee JJ, Lee NA, Fryer AD, Jacoby DB. Human and Mouse Eosinophils Have Antiviral Activity against Parainfluenza Virus. Am J Respir Cell Mol Biol. 2016 Sep;55(3):387-94. doi: 10.1165/rcmb.2015-0405OC. PMID: 27049514; PMCID: PMC5023029.
  68. Davoine F, Lacy P. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front Immunol. 2014 Nov 10;5:570. doi: 10.3389/fimmu.2014.00570. PMID: 25426119; PMCID: PMC4225839.
  69. Du SQ, Yuan W. Mathematical modeling of interaction between innate and adaptive immune responses in COVID-19 and implications for viral pathogenesis. J Med Virol. 2020 Sep;92(9):1615-1628. doi: 10.1002/jmv.25866. Epub 2020 May 13. PMID: 32356908; PMCID: PMC7267673.
  70. Butterfield JH. Treatment of hypereosinophilic syndromes with prednisone, hydroxyurea, and interferon. Immunol Allergy Clin North Am. 2007 Aug;27(3):493-518. doi: 10.1016/j.iac.2007.06.003. PMID: 17868861.
  71. Usul E, Şan İ, Bekgöz B, Şahin A. Role of hematological parameters in COVID-19 patients in the emergency room. Biomark Med. 2020 Sep;14(13):1207-1215. doi: 10.2217/bmm-2020-0317. Epub 2020 Jul 21. PMID: 32692248; PMCID: PMC7372996.
  72. Ruscitti P, Berardicurti O, Di Benedetto P, Cipriani P, Iagnocco A, Shoenfeld Y, Giacomelli R. Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm. Front Immunol. 2020 May 28;11:1130. doi: 10.3389/fimmu.2020.01130. PMID: 32574264; PMCID: PMC7270352.
  73. Gómez-Pastora J, Weigand M, Kim J, Wu X, Strayer J, Palmer AF, Zborowski M, Yazer M, Chalmers JJ. Hyperferritinemia in critically ill COVID-19 patients - Is ferritin the product of inflammation or a pathogenic mediator? Clin Chim Acta. 2020 Oct;509:249-251. doi: 10.1016/j.cca.2020.06.033. Epub 2020 Jun 21; PMID: 32579952; PMCID: PMC7306200.
  74. Vargas-Vargas M, Cortés-Rojo C. Ferritin levels and COVID-19. Rev Panam Salud Publica. 2020 Jun 1;44:e72. doi: 10.26633/RPSP.2020.72. PMID: 32547616; PMCID: PMC7286435.
  75. Rosário C, Zandman-Goddard G, Meyron-Holtz EG, D'Cruz DP, Shoenfeld Y. The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013 Aug 22;11:185. doi: 10.1186/1741-7015-11-185. PMID: 23968282; PMCID: PMC3751883.
  76. Lin Z, Long F, Yang Y, Chen X, Xu L, Yang M. Serum ferritin as an independent risk factor for severity in COVID-19 patients. J Infect. 2020 Oct;81(4):647-679. doi: 10.1016/j.jinf.2020.06.053. Epub 2020 Jun 24. PMID: 32592705; PMCID: PMC7313486.
  77. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, Damoraki G, Gkavogianni T, Adami ME, Katsaounou P, Ntaganou M, Kyriakopoulou M, Dimopoulos G, Koutsodimitropoulos I, Velissaris D, Koufargyris P, Karageorgos A, Katrini K, Lekakis V, Lupse M, Kotsaki A, Renieris G, Theodoulou D, Panou V, Koukaki E, Koulouris N, Gogos C, Koutsoukou A. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3. doi: 10.1016/j.chom.2020.04.009. Epub 2020 Apr 21. PMID: 32320677; PMCID: PMC7172841.
  78. Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, Cheng J, Zhang X, Zhao Y, Xia Z, Zhang L, Wu G, Yi J. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020 Jul 7;12(7):e12421. doi: 10.15252/emmm.202012421. Epub 2020 Jun 5. PMID: 32428990; PMCID: PMC7280589.
  79. Regis G, Bosticardo M, Conti L, De Angelis S, Boselli D, Tomaino B, Bernabei P, Giovarelli M, Novelli F. Iron regulates T-lymphocyte sensitivity to the IFN-gamma/STAT1 signaling pathway in vitro and in vivo. Blood. 2005 Apr 15;105(8):3214-21. doi: 10.1182/blood-2004-07-2686. Epub 2004 Dec 30. PMID: 15626737.
  80. Byrd TF, Horwitz MA. Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma. J Clin Invest. 1993 Mar;91(3):969-76. doi: 10.1172/JCI116318. PMID: 8450071; PMCID: PMC288049.
  81. Han H, Yang L, Liu R, Liu F, Wu KL, Li J, Liu XH, Zhu CL. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020 Jun 25;58(7):1116-1120. doi: 10.1515/cclm-2020-0188. PMID: 32172226.
  82. Tao J, Song Z, Yang L, Huang C, Feng A, Man X. Emergency management for preventing and controlling nosocomial infection of the 2019 novel coronavirus: implications for the dermatology department. Br J Dermatol. 2020 Jun;182(6):1477-1478. doi: 10.1111/bjd.19011. Epub 2020 Apr 20. PMID: 32141058.
  83. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28. PMID: 32109013; PMCID: PMC7092819.
  84. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017 Jan;149:38-44. doi: 10.1016/j.thromres.2016.11.007. Epub 2016 Nov 19. PMID: 27886531.
  85. WHO. Tracking SARS-CoV-2 variants. 2021.
  86. https://bit.ly/3EvQf3N
  87. Riemersma KK, Grogan BE, Kita-Yarbro A, Halfmann PJ, Segaloff HE, Kocharian A, Florek KR, Westergaard R, Bateman A, Jeppson GE, Kawaoka Y, O’Connor DH, Friedrich TC, Grande KM. Shedding of infectious SARS-CoV-2 despite vaccination when the Delta variant is prevalent – Wisconsin. medRxiv preprint. doi: 10.1101/2021.07.31.21261387.
  88. Elliott P, Haw D, Wang H, Eales O, Walters CE, Ainslie KEC, Atchison C, Fronterre C, Diggle PJ, Page AJ, Trotter AJ, Prosolek SJ, The COVID-19 Genomics UK (COG-UK) Consortium, Ashby D,. Donnelly CA, Barclay W, Taylor G, Cooke G, Ward H, Darzi A, Riley S. The COVID-19 Genomics UK Consortium. REACT-1 round 13 final report: exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant in England during May to July.
  89. https://bit.ly/3sBfYpb
  90. Chia PY, Xiang Ong SW, Chiew CJ, Ang LW, Chavatte JM, Mak TM, Cui L, Kalimuddin S, Chia WN, Tan CW, Ann Chai LY, Tan SY, Zheng S, Pin Lin RT, Wang L, Leo YS, Lee VJ, Lye DC, Young BE. Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study. Clin Microbiol Infect. 2021 Nov 23; S1198-743X(21)00638-8. doi: 10.1016/j.cmi.2021.11.010. Epub ahead of print. PMID: 34826623; PMCID: PMC8608661.
  91. Hetemäki I, Kääriäinen S, Alho P, Mikkola J, Savolainen-Kopra C, Ikonen N, Nohynek H, Lyytikäinen O. An outbreak caused by the SARS-CoV-2 Delta variant (B.1.617.2) in a secondary care hospital in Finland, May 2021. Euro Surveill. 2021 Jul;26(30):2100636. doi: 10.2807/1560-7917.ES.2021.26.30.2100636. PMID: 34328076; PMCID: PMC8323455.
Publish with JBRES — Peer-reviewed, multidisciplinary Open Access with rapid review, DOI, and global visibility.
Double-Blind CrossRef DOI Discoverable
Submit Manuscript Membership