After COVID-19 emerged, a multitude of both novel and repurposed therapeutic agents were used empirically and studied in controlled clinical trialsFil: Chalha, Rossana E.. Ministerio de Salud de la Nación; ArgentinaFil: Medina Ruiz, Luis Antonio. Sistema Provincial de Salud; ArgentinaFil: Ortega, Eugenia Silvana. Ministerio de Salud de la Nación; ArgentinaFil: Morales, Marcelo F.. Clinical Hospital "Ángel C. Padilla"; ArgentinaFil: Barreiro, Francisco. Medical Center Emergence; ArgentinaFil: George, Alexia. Medical Center Emergence; ArgentinaFil: Mancilla, Cesar. Clinical Hospital "Ángel C. Padilla"; ArgentinaFil: D´ Amato, Sylvia. Clinical Hospital "Ángel C. Padilla"; ArgentinaFil: Barrenechea, Guillermo. Health Research Institute; ArgentinaFil: Goroso, Daniel Gustavo. Health Research Institute; Argentina. Mogi das Cruzes University; BrasilFil: Peral, Maria de Los Angeles. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentin

Barreiro, Francisco

Barrenechea, Guillermo

Chalha, Rossana E.

D´ Amato, Sylvia

George, Alexia

Goroso, Daniel Gustavo

Mancilla, Cesar

Medina Ruiz, Luis Antonio

Morales, Marcelo F.

Ortega, Eugenia Silvana

Peral, Maria de Los Angeles

American Journal of Therapeutics

English

CONICET Digital

9. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect ofangiotensin-converting- enzyme inhibition on diabeticnephropathy. The Collaborative Study Group. N Engl JMed. 1993;329:1456.10. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotec-tive effect of the angiotensin-receptor antagonist irbesar-tan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001;345:851.Intensive Treatment With Ivermectin and Iota-Carrageenan asPre-exposure Prophylaxis for COVID-19 in Health CareWorkers From Tucuman, ArgentinaTo the Editor:After COVID-19 emerged, a multitude of both noveland repurposed therapeutic agents were used empiri-cally and studied in controlled clinical trials.1–3 Iver-mectin is a broad spectrum antiparasitic agent that hasshown to have antiviral activity against a wide rangeof viruses.4,5 On March 31, the World Health Organi-zation (WHO) stated that evidence about ivermectinuse for COVID-19 treatment is not conclusive. How-ever, it encouraged its utilization in controlled clinicaltrials. At June 2021, there were 65 studies registered athttps://www.ClinicalTrials.gov and 45 studies listedat https://ClinicalTrials.gov/ct2/who_table about thesafety and effectiveness of ivermectin in subjects withCOVID-19, of which 16 studies have been completed(for COVID-19 treatment). Most of these studies onivermectin repositioning came from developing coun-tries like ours, Argentina, with limited access to vac-cines. These emergent economies have the need to findsupportive therapies that are synergistic or alternativesto contain the spread of the disease and deter thehealth systems’ collapse.Kory’s meta-analysis (2021) reported that ivermectinhas antiviral and anti-inflammatory mechanisms withstatistically significant positive outcome.6 However,most of these studies were not published in peer-reviewed journals; nevertheless, several expert groupsincluding the WHO have undertaken a global effort tocontact all active clinical trials to rapidly gather thedata needed to perform a systematic review andmeta-analyses. In Kory’s publication,6 ivermectinshowed ability to prevent transmission and improve-ment in the treatment in both observational9,10 andrandomized trials.7,8,11,12,13 Our work was includedin this systematic review. This letter to the editor aimsto provide more details of our findings, presentingexperimental evidence for the prophylactic use ofivermectin associated with iota-carrageenan in healthworkers.12We conducted a randomized controlled 1-1 clinical trial(registry number NCT04701710 www.ClinicalTrial.gov)in 234 adults. The subjects were divided into the experi-mental group (EG), n 5 117, median age5 40 years [in-terquartile range (IQR), 32–46], and 65 F (55.56%) and thecontrol group (CG) n5 117, 37 years (IQR, 33–44), and 69F (58.97%). All subjects completed the study; 134 werefemale (57.3%) and 100 were men (42.7%), and 77.4%were health care workers (Table 1). The experimentalgroup received ivermectin orally 2 tablets of 6 mg every7 days and iota-carrageenan 6 sprays per day for 4 weeks.All participants were evaluated by physical examinationand COVID-19 diagnosedwith negative reverse transcrip-tion polymerase chain reaction at the protocol baseline.We calculated odds ratio (OR) and created a logisticregression using comorbidity, sex, age, and job designa-tion as covariables. A P value , 0.05 was consideredsignificant.The number of subjects who were diagnosed withCOVID-19 in the EG was lower than subjects in theCG (P value 5 0.0001), Figure 1A. Overall, 19 patientshad mild symptoms, 4 were in the EG whereas 15 werein the CG (P value5 0.001), Figure 1B. The probability ofbecoming ill with COVID-19 was significantly lower inthe EG [OR 0.13, 95% confidence interval (CI) 0.03–0.40;P value 5 0.0001]. We also found that increasing agedecreases the risk of contagion (OR 5 0.93, 95% CI0.88–0.98, P value 5 0.02). The probability of contractingCOVID-19 was dependent on the subject’s pre-existingcomorbidity (OR 3.45, 95% CI 1.55–7.67, P value 50.002). The other variables (sex and job designation)did not have influence on COVID-19 infection.Health personnel are one of the most exposed groups toCOVID-19 because of their steady contact with infectedpatients. In this study, treatment with IVER/IOTACRCLetters to the Editor e601www.americantherapeutics.com American Journal of Therapeutics (2021) 28(5)Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.for pre-exposure prophylaxis to COVID-19 has showna protective effect over the control group. People infectedwith COVID-19 at the end of the follow-up was signifi-cantly higher in the CG compared with the EG (Figure 1B).Our findings are supported by several recent preven-tion trials such as Alam et al10 (also cited by Kory’s meta-analysis), who conducted an observational prophylacticstudy in 118 health care workers and found significantless contagious infection in subjects who received iver-mectin.6,10 Our findings, similarly to Carvallo et al andAbd-Elsalam et al, confirm the hypothesis that IVER/IOTACRC decreases the possibility of infection withsevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and possibly acts synergistically.9,14,15 We hypoth-esize that a double viral barrier is formed, enhancing itsaction in the following ways: (1) The first barrier for viralprotection would be at the entry of the virus into the nasalcavity where the carrageenan would behave as a muco-lytic agent in the barrier of sulfated polysaccharides withnegative charge9; (2) ivermectin decreases the viral loadbased on its systemic cellular action.5,16 Ivermectin hasshown viral clearance in other clinical trials whichTable 1. Demographic profile.Variables Experimental Group (n5 117) Control Group (n5 117)Demographic profileMedian age (in yr) 40 37IQR IQR25: 32; IQR75: 46 IQR25: 33; IQR75: 44Sex, no. (%)Female 65 (55.56%) 69 (58.97%)Male 52 (44.44%) 48 (41.03%)Comorbidities, no. (%)Hypertension 13 (11.11%) 8 (7.55%)Diabetes 10 (8.55%) 7 (6.60%)Obesity 10 (8.55%) 18 (16.98%).60 yrs 5 (4.27%) 5 (4.27%)Chronic kidney disease 3 (1.36%) 2 (1.89%)DesignationHealth care personnel 99 (84.62%) 82 (70.09%)Not an health care personnel 18 (15.38%) 35 (29.91%)FIGURE 1. COVID-19 case in the EG versus the CG. (A) Number of COVID-19 cases and healthy cases in the experi-mental and control group (n 5 234). (B) Clinical state of the COVID-19 cases in the experimental and control group (n 5234). The most frequent symptoms were fever experienced by 21 patients (17%) in the CG versus 1 (0.9%) in the EG (21),P , 0$0001. Nineteen patients (16%) in the CG experienced taste and/or smell disturbances and 0 (0%) in the EG, P ,0$0001. Furthermore, 19 patients (16%) experienced headache in the CG versus 1 (0$9%) in the EG, P , 0.0001. A higherfrequency of polyarthralgia, diarrhea, abdominal pain, and low oxygen saturation was also reported in the controlgroup. Acute lower respiratory infection symptoms and signs were reported in 1 patients in the control group.e602 Letters to the EditorAmerican Journal of Therapeutics (2021) 28(5) www.americantherapeutics.comCopyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.evaluate its use to treat COVID-19. Kolewieski et al foundthat a 5-day intensive treatment of ivermectin resulted inearlier clearance of the virus compared with the controlgroup.8Ivermectin can prevent the entry into the cell nucleusof the viral RNA by blocking importin alpha/beta,thereby preventing replication because SARS-CoV-2does not have the nuclear mechanisms and enzymaticactions for the transcription of new viral replicates.4Our study is supported by findings which demon-strated the effect of ivermectin as a drug for inhibitingviral replication in vitro and places the drug as a newtherapeutic candidate against SARS-CoV-2.16,17 Ina meta-analysis published in June 2021, Bryant et alafter analyzing different clinical trials showed that iver-mectin may have beneficial effects in both prophylaxisand treatment of Covid-19.18Our study shows agreement with other researchgroups regarding positive findings in the use of iver-mectin for the treatment of COVID-19 that deservesfurther studies about repurposing ivermectin.Rossana E. Chahla, MD, PhD1Luis Medina Ruiz, MD2Eugenia S. Ortega, MSc3Marcelo F. Morales, RN4Francisco Barreiro, MD5Alexia George, MD5Cesar Mancilla, RN4Sylvia D’ Amato, RN4Guillermo Barrenechea, MSc3Daniel G. Goroso, PhD3,6Maria Peral de Bruno, PhD3,71Ministry of Health, Tucumán, Argentina2Province Health System, SI.PRO.SA, TucumánArgentina3Health Research Institute, Ministry of HealthTucumán, Argentina4Clinical Hospital “Ángel C. Padilla,” TucumánArgentina5Medical Center Emergence, Tucumán, Argentina6Research and Technology Center, Mogi das CruzesUniversity, Brazil7School of Medicine-Superior Institute of BiologicalResearch (INSIBIO—CCT CONICET), TucumánArgentinaThe authors have no conflicts of interest to declare.REFERENCES1. Chong CR, Sullivan DJ. New uses for old drugs. Nature.2007;448:645–646.2. Liu Z, Fang H, Reagan K, et al. In silico drug repositioning:what we need to know.Drug Discov Today. 2013;18:110–115.3. Ashburn TT, Thor KB. Drug repositioning: identifying anddeveloping new uses for existing drugs. Nat Rev Drug Dis-cov. 2004;3:673–683.4. Caly L, Wagstaff KM, Jans DA. Nuclear trafficking ofproteins from RNA viruses: potential target for antivi-rals? Antivir Res. 2012;95:202–206.5. Caly L, Druce JD, Catton MG, et al. Since January 2020Elsevier has created a COVID-19 resource centre withfree information in English and Mandarin on thenovel coronavirus COVID-19. The COVID-19 resourcecentre is hosted on Elsevier Connect , the company’ spublic news and information. Antivir Res. 2020;178:104787.6. Kory P, Meduri GU, Varon J, et al. Review of the emerg-ing evidence demonstrating the efficacy of ivermectin inthe prophylaxis and treatment of COVID-19. Am J Ther.2021;28:e299–e318.7. Chaccour C, Casellas A, Matteo AB, et al. The effect ofearly treatment with ivermectin on viral load, symp-toms and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedi-cine. 2021;3:100720.8. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviraleffect of high-dose ivermectin in adults with COVID-19:A proof-of-concept randomized trial. EClinicalMedicine.2021;37:100959.9. Hector C, Roberto H, Psaltis A, et al. Study of the efficacyand safety of topical ivermectin + iota-carrageenan in theprophylaxis against COVID-19 in health personnel.J Biomed Res Clin Investig. 2020;2:1007.10. Alam MT, Murshed R, Gomes PF, et al. Ivermectin aspre-exposure prophylaxis for COVID-19 among health-care providers in a selected tertiary hospital in dhaka—an observational study. Eur J Med Heal Sci. 2020;2:1–5.11. Shouman WM, Hegazy AA, Nafae RM, et al. Use ofivermectin as a potential chemoprophylaxis forCOVID-19 in Egypt: a randomized clinical trial. J ClinDiagn Res. 2021;15:27–32.12. Chahla E. Prophylaxis covid-19 in health workersthrough intensive treatment with ivermectin and iota-carrageenan (Ivercar-Tuc). ClinicalTrials.gov. 2020;20:NCT047017.13. Chaccour C, Ruiz-Castillo P, Richardson MA, et al. Thesars-cov-2 ivermectin navarra-isglobal trial (saint) toevaluate the potential of ivermectin to reduce covid-19transmission in low risk, non-severe covid-19 patients inthe first 48 hours after symptoms onset: a structuredsummary of a study protocol. Trials. 2020;21:1–4.14. Hirsch R, Hector C. Covid 19 and ivermectin preventionand treatment update. J Infect Dis Trav Med. 2020;4:1–4.15. Abd-Elsalam S, Noor RA, Badawi R, et al. Clinical studyevaluating the efficacy of ivermectin in COVID-19 treat-ment: A randomized controlled study [published onlineahead of print, 2021 Jun 2]. J Med Virol. 2021. doi: 10.1002/jmv.27122.Letters to the Editor e603www.americantherapeutics.com American Journal of Therapeutics (2021) 28(5)Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.16. Sharun K, Dhama K, Patel SK, et al. Ivermectin, a newcandidate therapeutic against SARS-CoV-2/COVID-19.Ann Clin Microbiol Antimicrob. 2020;19:23–25.17. Şimşek Yavuz S, Ünal S. Antiviral treatment of covid-19.Turkish J Med Sci. 2020;50:611–619.18. Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin forPrevention and Treatment of COVID-19 Infection: A Sys-tematic Review, Meta-analysis, and Trial SequentialAnalysis to Inform Clinical Guidelines. Am J Ther. 2021;28:e434–e460.Immune-Mediated Thrombocytopenia Associated WithAd26.COV2.S (Janssen; Johnson & Johnson) VaccineTo the Editor:Immune thrombocytopenia (ITP) is an acquired coa-gulopathy caused by antibody-mediated platelet de-struction. Patients may be asymptomatic or maypresent with mucocutaneous to life-threatening bleed-ing.1 Vaccines such as influenza, MMR, hepatitis B,and diphtheria-tetanus-pertussis have been reportedto cause ITP.2 Approximately 40 cases of ITP werereported to the Vaccine Adverse Event Reporting Sys-tem after receiving the Pfizer and Moderna COVID-19vaccines by the end of January 2021.3 It is unknownwhether these cases include those with pre-existingthrombocytopenia. Here, we present a case report ofan elderly woman presenting with life-threateningthrombocytopenia after receiving the Ad26.COV2.S(Janssen; Johnson & Johnson, New Brunswick, NJ) vac-cine. To the best of our knowledge, this is the firstpublication of isolated severe thrombocytopenia in apatient with no pre-existing risk factors after receivingthe Ad26.COV2.S vaccine.A 63-year-old woman with a medical history of cer-vical cancer status after total hysterectomy, presentedto the hospital with complaints of bleeding from hergums for the past 3 days. Seventeen days before pre-sentation, the patient had received the Ad26.COV2.S(Janssen; Johnson & Johnson) vaccine. She did notexperience any major side effects after her vaccinationexcept for muscle soreness at the administration site.She did not have fever, chills, shortness of breath, orrecent infections. A week later, she went for a routinedental checkup which was unremarkable. She startedexperiencing bleeding in her gums 3 days before pre-sentation. She later had sudden onset nose bleeds whichprompted her to go to the emergency department.On presentation to the emergency department, thepatient was hemodynamically stable and afebrile. Herbleeding had resolved. Complete blood count showedhemoglobin 12.2 g/dL, hematocrit 36.3%, white bloodcell count 10.9 3 103 cells/uL, and significant severethrombocytopenia 2 3 109/L. Her international nor-malized ratio was 1.02, with a prothrombin time of13.5 seconds and a partial thromboplastin time of27.0 seconds. Hemolytic workup was completed withlactate dehydrogenase 150 U/L, haptoglobin 192mg/dL, and D-dimer 0.76.On admission, she received 2 units of platelets. Shewas also given a one-time dose of prednisone 60 mgorally. Her repeat platelet count posttransfusion im-proved to 14 3 109/L. Hematology was consultedand recommended starting the patient on immuneglobulin (human) infusion intravenously and dexa-methasone 20 mg daily.Throughout admission, the patient’s platelet countsteadily increased. She did not have further bleedingepisodes and did not require additional platelet trans-fusions. Testing for HIV and hepatitis B and C wasnegative. Heparin-induced platelet IgG antibody wasnegative. Imaging including ultrasound Doppler of theabdomen/pelvis, ultrasound Doppler of upper andlower extremities, magnetic resonance venogram ofthe head, and computed tomography angiography ofthe thorax showed no evidence of thrombosis. Thepatient remained hemodynamically stable throughoutadmission with no signs of active bleeding. She wasultimately deemed stable for discharge 5 days afteradmission, with a platelet count of 252 3 109/L.Immune thrombocytopenia purpura (ITP) is a diag-nosis of exclusion characterized by a decrease in plate-let count and prolonged bleeding time secondary toimpaired platelet production or destruction of circulat-ing platelets. Patients are commonly asymptomatic;however, based on the severity of thrombocytopenia,clinical features include easy bruising, petechiae,bleeding gums, hematuria, or melena. ITP is often trig-gered idiopathically; however, other triggers includeprevious viral or bacterial infections, lymphoma ore604 Letters to the EditorAmerican Journal of Therapeutics (2021) 28(5) www.americantherapeutics.comCopyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Intensive treatment with ivermectin and Iota carrageenan as pre-exposure prophylaxis for COVID-19 in health care workers from Tucuman, Argentina

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Intensive treatment with ivermectin and Iota carrageenan as pre-exposure prophylaxis for COVID-19 in health care workers from Tucuman, Argentina

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