Doxycycline and Lopinavir - Novel way of Managing COVID-19
The outbreak of COVID-19 identified by the World Health Organization as a global pandemic, unfolding an urgent need to identify safe and effective drugs or potential adjuvant therapy in this regard and repurposing existing agents whilst the discovery of the vaccine is still underway (1).
We review one of the largest single centred retrospective observational study involving patients suffering from COVID-19 in a tertiary care hospital setting and describe the characteristics of COVID-19 patients and outcomes of a treatment algorithm through the use of doxycycline and lopinavir added to standard care (2)
Defining COVID-19 Case Severity in the Study
A patient was defined as a case with an epidemiologic risk factor who had a body temperature of ≥ 38 °C and/or respiratory system symptoms which could not be completely explained by any other condition or disease. Polymerase chain reaction (PCR) was found to be positive in nasopharyngeal samples of 475 adult patients.
A mild case was confined to having no signs of respiratory dysfunctions, while a moderate case was defined as the one which had any sign of respiratory dysfunction and a severe clinical case had an acute respiratory failure (ARF) and required ICU support either via invasive or non-invasive means. Non-invasive ventilation support was provided with high-flow masks. Respiratory dysfunction was assessed by the following criteria: shortness of breath, the respiration rate of > 23 breaths per minute, and O2 saturation < 94%
Patient Population
About 475 COVID-19 positive hospitalised patients, with a mean age of about 61 years, and included 35% hypertensives and about 20% of them had diabetes, with about a quarter of them running high temperature (> 380 C)
Treatment Modalities
Hydroxychloroquine 200 mg, lopinavir 400 mg, and doxycycline 100 mg were all orally administered twice daily as recommended.
A standard regimen was administered along with lopinavir plus doxycycline plus ceftriaxone, to these hospitalized patients.
The patients were treated with a 3-step management protocol:
1. Mild cases were isolated at home and prescribed with hydroxychloroquine plus doxycycline for 3 days
2. Moderate to severe cases were admitted to the hospital and treated with a regimen of lopinavir plus doxycycline plus ceftriaxone for 5 days.
3. Salvage therapy was adopted for patients who did not respond to or in those who clinically worsened under lopinavir treatment. This group was treated with oral administration of favipiravir 600 mg twice daily after two loading doses.
Key Outcomes
Among the 161 cases, 31 required intensive unit care, and 20 died during their stay in the ICU. It needs to be, however, noted that 12 of these patients were severely infected at the time of admission. Of these nine patients were immediately admitted to the ICU, five of whom died. Three other patients were transferred to the ICU on the second day after admission to the hospital also died.
Of the 161 hospitalized patients, 149 received lopinavir for at least 2 days before being admitted to the ICU. Only 12.7% needed ICU support with lopinavir treatment, two patients suddenly died. One hundred and twenty - eight patients recovered from the disease.
Only 24% (38/158) of patients had a fever (≥ 38 °C). Deceased patients were older, had a higher prevalence of hypertension, and had a higher neutrophil count than the rest, while their lymphocyte counts, platelet counts, and levels of oxygen saturation levels were lower.
No difference was observed between the two genders. Deceased patients had shorter elapsed time between the onset of symptoms and hospitalization. The overall case-fatality rate was 4.2%. 1
Clinical Message
This study presents a 3-step treatment protocol to manage COVID-19 patients.
Hydroxychloroquine was administered to mild cases isolated at home, lopinavir plus doxycycline to hospitalized moderate to severe cases, and favipiravir in the salvage treatment. This approach seemed to work with fair effectiveness.
Hydroxychloroquine to mild cases for only 3 days because of its potential side effects on cardiac functions (3). The cardiac effects of hydroxychloroquine are reported to depend on the accumulation of the drug and may likely present on the third day of usage. These effects are more prominent among critically ill patients.
Lopinavir was administered in moderate to severe cases for 5 days. Doxycycline was supplemented to both lopinavir and hydroxychloroquine due to its immunomodulatory activity. Recent findings revealed the association dysregulated immunity on the clinical outcomes in COVID-19 patients (4 ).
Doxycycline induces the suppressor of cytokine signalling (SOCS) proteins, a regulatory system on cytokine release (5). Scientific evidence suggests that SOCS proteins, mainly SOCS-3 protein, prevent interleukin- and interferon-associated toxicity (6). Interestingly in the early stage of the disease, when there are enough healthy cells in the bronchi and alveoli, doxycycline might have some effect on preventing impending cytokine storm. In the past, doxycycline had been successfully used in dengue haemorrhagic fever due to its immunomodulatory activity (7).
Final Words
Based on this published piece of evidence from a tertiary care setting, bringing out a fair conclusion at this time that doxycycline-based combination treatment regimen is a valuable option to current treatment regimens for managing COVID-19 infections.
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 Roshanravan N, Seif F, Ostadrahimi A, Pouraghaei M, Ghaffari S. Targeting Cytokine Storm to Manage Patients with COVID-19: A Mini-Review. Arch Med Res. 2020 Jun 19:S0188-4409(20)30590-7. doi: 10.1016/j.arcmed.2020.06.012. Epub ahead of print. PMID: 32682575; PMCID: PMC7303639.
2 Cag Y, Icten S, Isik-Goren B, Baysal NB, Bektas B, Selvi E, Ergen P, Aydin O, Ucisik AC, Yilmaz-Karadag F, Caskurlu H, Akarsu-Ayazoglu T, Kocoglu H, Uzman S, Nural-Pamukcu M, Arslan F, Bas G, Kalcioglu MT, Vahaboglu H. A novel approach to managing COVID-19 patients; results of lopinavir plus doxycycline cohort. Eur J Clin Microbiol Infect Dis. 2020 Aug 27:1–5. doi: 10.1007/s10096-020-04016-1. Epub ahead of print. PMID: 32856202; PMCID: PMC7452614.
3 Fernandes FM, Silva EP, Martins RR, Oliveira AG (2018) QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications. PLoS One [Internet] 13:e0199028. https://doi.org/10.1371/journal.pone.0199028
4 Nicholls JM, Poon LLM, Lee KC, Ng WF, Lai ST, Leung CY et al (2003) Lung pathology of fatal severe acute respiratory syndrome. Lancet 361:1773–1778. https://doi.org/10.1016/S0140-6736(03) 13413-7
5 Song MM, Shuai K (1998) The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem 273: 35056–35062. https://doi.org/10.1074/jbc.273.52.35056
6 Karlsen AE, Rønn SG, Lindberg K, Johannesen J, Galsgaard ED, Pociot F et al (2001) Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-γ-mediated toxicity. Proc Natl Acad Sci U S A 98:12191–12196. https://doi.org/10.1073/pnas.211445998
7 Fredeking T, Zavala-Castro J, Gonzalez-Martinez P, Moguel- RodrÃguezW, Sanchez E, FosterMet al (2015) Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF levels. Recent Pat Antiinfect Drug Discov 10:51–58. https://doi.org/10.2174/1574891x10666150410153839
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