Doxycycline Based Combination for Improving Clinical Outcomes across Spectrum of Covid-19 infections
The world continues to be amidst an unprecedented health crisis caused by the global spread of a novel coronavirus, SARS-CoV-2 which leads to respiratory, and multi-organ viral infection, termed as COVID-19. The pandemic has so far resulted in 35 million infections and more than one million mortalities 1 . It is noteworthy that almost all patients present initially with a mild- moderate disease; however, about 15% of them progress within 5-14 days post-infection to a more advanced stage of the disease, rendering them critical patients 2 . The highest risk patients seem to be elderly, obese, those suffering from type 2 diabetes, cardiovascular disease, and immunosuppressed.
In a scientific endeavour for clinically utilizing an effective therapy for COVID-19 patients - this recently published clinical trial is aimed to assess if doxycycline based combinational therapy can improve outcomes in treating COVID-19 infections, specifically including patients across the different clinical spectrum of disease. 3
About the Study
The purpose of this study was to assess Doxycycline based therapy versus standard care therapy at the beginning of each stage of the disease. The recruited patients were monitored until recovery or death. 140 COVID-19 patients across a different spectrum of disease were included in this study.
The mean age of the recruited patients was 48.7 years (16 to 86 years). Patients in both groups were matched based on age and sex.
Half of the patients enrolled in the study received Doxycycline based combination therapy in addition to standard care while the other half were treated with only standard care.
The recruited patients were either in outpatient or inpatient settings, according to the severity of the disease. Mild-moderate patients were managed in outpatient care while severe and critical patients were treated in hospital settings
The enrolled COVID-19 patients were diagnosed by clinical, radiological, and laboratory PCR testing. Alike, their recovery too was based on the disappearance of symptoms, clearance of radiological chest X-ray or CT-scans, and getting negative PCR results.
Doxycycline-based combination group included 48 mild-moderate, 11 severe, and 11 critical patients while the control group comprised of 48 mild-moderate and 22 severe patients. Given ethical sanctity, no critical patient recruited in this study was allocated to the control group; they were confined only to Doxycycline based combination treatment arm.
Intervention
Doxycycline Based Combination group:
Doxycycline 100mg PO every 12h per day was given for 5-10 days, based on the clinical improvement of patients. Ivermectin 200ug/kg PO per day was administered for two days, and in some patients, who needed more time to recover, a third dose 200ug/kg PO per day was given 7 days after the first dose. Besides, standard care was given to patients based on the clinical and vital care assessment in each case.
Control group:
The patients in this group received only standard care which included all or some of the following, according to the clinical condition of each patient. The standard treatment protocol comprised of Acetaminophen 500mg on need, Vitamin C 1000mg twice/ day, Zinc 75-125 mg/day, Vitamin D3 5000 IU/day, Azithromycin 250mg/day for 5 days. Oxygen therapy/ C-Pap, Dexamethasone 6 mg/day, or methylprednisolone 40mg twice per day, were included, if needed. Mechanical ventilation too was provided, if required.
Outcome:
Three parameters used in the present study were to assess the disease progression or recovery in COVID-19 patients between the two study groups - Time to recovery, percentage of patients who progress to a more advanced stage of the disease after at least 3 days of giving therapy, and mortality rate among mild-moderate, severe, or critical patients.
Results
Time to Recovery
The time to recovery was shown to be significantly reduced in the Doxycycline based combination group compared to the control group; mean recovery time in Doxycycline based combination group was 10.61± 5.3 days versus mean recovery time in the control group, 17.9±6.8 days (p<0.05).
Hence, using Doxycycline based combination treatment reduced the mean time to recovery up to 7 days.
Further analysing the mean time to recovery in mild-moderate, severe, or critical patients in each group, it was found that the mean time to recovery in Doxycycline based combination group was 6.34±2.4, 20.27±7.8, 19.77±9.2 days, respectively versus 13.66±6.4, 24.25±9.5 days, in the control group, respectively (P<0.01). Thus, it could be interpreted that Doxycycline based combination group reduced recovery time about 7.32 days in mild-moderate and approximate 4 days in severe patients
Progression of the disease
In beginning, not even a single mild-moderate patient in both groups progressed to a more advanced stage of the disease. For severe COVID-19 patients, 9% of patients in the Doxycycline-based combination group versus 31.81% in the control group progressed to a more advanced stage of the disease, namely being classified as critical cases (p>0.05).
Thus, Doxycycline based combination therapy regimen was shown to slow the progression of the disease in severe patients if given within the first two days of the severe stage of the disease. For critical patients, ethically, critical patients were not included in the control group as critical patients need to receive all possible medications for saving their lives; hence, it was not possible to compare the rate of progression of the disease in critical patients between the two studied groups
Mortality rate
The mortality rate was shown to be 0/48 (0%) in mild-moderate patients in both groups. Nevertheless, the mortality rate was diminished to 0/11 (0%) in Doxycycline based combination group compared to 6/22 (27.27%) (P=0.052) in control group.
For critical patients, Doxycycline based combination therapy did not prevent death in those patients as the mortality rate was shown to be 2/11 (18.2%), No critical patients were included in the controlgroup to compare with.
Clinical Learnings from the Study
COVID-19 is a multiphasic disease starting with virus replicative phase lasting for 7-10 days, subsequently, in some patients,which is followed with hyper inflammatory phase and cytokine storm where most of the fatalities are likely to occur 4 .
If the viral and hyper inflammatory phases of the disease were not addressed early and properly, the patient might progress to ARDS. which is more often life-threatening 5 . Hence, antiviral, anti-inflammatory, and immunomodulatory medications are necessary to stop the vicious progression of COVID-19 from mild-moderate to severe and to prevent the clinical deterioration in COVID-19 infected patients
Doxycycline based combination treatment was used in this study have demonstrated dual - antiviral and immunomodulatory activities 6 . Also, noteworthy is that Doxycycline is a broad-spectrum antibiotic which tackles secondary bacterial infections in COVID-19 patients 7
Doxycycline is generally well tolerated, unlike Azithromycin, which, with or without Hydroxychloroquine, are known to interact adversely for prolonged QT interval and may have cardiac safety implications in a vulnerable patient population 8
Doxycycline based treatment arm lowered the rate of progression of severe patients from 31.81% to as low as 9%. More interestingly, it was able to abolish death in severe patients, 0% mortality rate,as compared to the control arm, 27.27%.
Summary
This recently published study indicates that Doxycycline based therapy regimen protocols prove to be effective in speeding up recovery in both mild-moderate COVID-19 outpatients and severe COVID-19 inpatients. Such treatment options may have a tremendous impact on lowering the burden of the disease, minimizing the chance of developing disrupted immune manifestations, and reduce hospital stay, thereby making it available to the larger infected population, which may be in need. Such therapies may be considered early in COVID-19 infection management, as they seem to benefit across a wider clinical spectrum of COVID-19 infection.
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Doxycycline, click HERE
References
Adapted from
1 World meter. Coronavirus update, October 6th. https://www.worldometers.info/coronavirus/?
2 Kuldeep Dhama, Sharun Khan, Ruchi Tiwari, Shubhankar Sircar, Sudipta Bhat, Yashpal Singh Malik, Karam Pal Singh, Wanpen Chaicumpa, D. Katterine Bonilla-Aldana, Alfonso J. Rodriguez-Morales. Coronavirus Disease 2019–COVID-19. Clinical Microbiology Reviews Jun 2020, 33 (4) e00028-20; DOI: 10.1128/CMR.00028-20.
3 Hashim A. Hashim et al, Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Baghdad, Iraq, https://doi.org/10.1101/2020.10.26.20219345
4 Rod J.E., Oviedo-Trespalacios Oscar, Cortes-Ramirez Javier. A brief-review of the risk factors for covid-19 severity. Rev. Saúde Pública [Internet]. 2020 [cited 2020 Oct 08] ; 54: 60. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0034-89102020000100701&lng=en. Epub June 01, 2020. http://dx.doi.org/10.11606/s1518-8787.2020054002481.
5 Rasheed AM, Fatak DF, Hashim HA, Maulood MF, Kabah KK, Almusawi YA, Abdulamir AS. The therapeutic potential of convalescent plasma therapy on treating critically ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq. Infez Med. 2020 Sep 1;28(3):357-366. PMID: 32920571.
6 Heidary, F., Gharebaghi, R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot 73, 593–602 (2020). https://doi.org/10.1038/s41429-020-0336-z
7 Alexandre E.MalekBruno P.GranwehrDimitrios P.Kontoyiannis. Doxycycline as a potential partner of COVID-19 therapies. IDCases-Volume 21, 2020, e00864
8 Thomas F. O'Connell, Christopher J. Bradley, Amr E. Abbas, Brian D. Williamson, Akash Rusia, Adam M. Tawney, Rick Gaines, Jason Schott, Alex Dmitrienko, David E. Haines. Hydroxychloroquine/Azithromycin Therapy and QT Prolongation in Hospitalized Patients with COVID-19. Am Coll Cardiol EP. 2020 Aug 05. Epublished DOI:10.1016/j.jacep.2020.07.016
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