key: cord-0860003-uxl8liil authors: Tobaiqy, Mansour; Qashqary, Mohammed; Al-Dahery, Shrooq; Mujallad, Alaa; Hershan, Almonther Abdullah; Kamal, Mohammad Azhar; Helmi, Nawal title: Therapeutic Management of COVID-19 Patients: A systematic review date: 2020-04-17 journal: Infect Prev Pract DOI: 10.1016/j.infpip.2020.100061 sha: 02206b0c97058d5723e4a7a65d0654229834cbf9 doc_id: 860003 cord_uid: uxl8liil Abstract Background SARS-CoV-2 is the causative agent of COVID-19; that has been declared a global pandemic by the WHO in 2020. The COVID-19 treatment guidelines vary in each country, and yet there is no approved therapeutic for COVID-19. Aims of the study this review aimed to report any evidence of therapeutics used for the management of COVID-19 patients in clinical practice since the emergence of the virus. Methods A systematic review protocol was developed based on PRISMA Statement. Articles for review were selected from electronic databases (Embase, Medline and Google Scholar). Readily accessible peer-reviewed, full articles in English published from December 1st , 2019 to March 26th , 2020 were included. The search terms included combinations of: COVID, SARS-COV-2, glucocorticoids, convalescent plasma, antiviral and antibacterial. There were no restrictions on the type of study design eligible for inclusion. Results As of March 26th, 2020, of the initial manuscripts identified (n=449); forty-one studies were included. These consisted of clinical trials (n=3), case reports (n=7), case series (n=10), retrospective (n=11) and prospective (n=10) observational studies. Thirty-six studies were conducted in China (88%). The most commonly reported medicine in this systematic review was corticosteroids (n=25), followed by Lopinavir (n=21) and Oseltamivir (n=16). Conclusions This is the first systematic review to date related to the therapeutics used in COVID-19 patients. Only 41 research articles on COVID-19 and therapeutics were found eligible to be included, most conducted in China. Corticosteroid therapy was found to be the most studied medicine in the literature. Severe acute respiratory syndrome coronavirus SARS-CoV-2 is the cause of the coronavirus disease 2019 (COVID- 19) that has been declared a global pandemic by the World Health Organization (WHO) in 2020. SARS-CoV-2 was discovered in December 2019, in Wuhan City (the capital of Hubei province), China. The origin of the virus is unknown, but initially newly diagnosed cases were linked to the Huanan Seafood Wholesale Market where people can buy wild animals, such as bats (1) . SARS-CoV-2 has phylogenetic similarity to SARS-CoV and MERS-CoV. The virus was identified as a novel enveloped RNA betacoronavirus that has been named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (2) . One of the characteristics of COVID-19 is that it is highly contagious; many countries were affected, including China and 164 other countries in less than three months. Despite China reaching 81,151 confirmed cases with 3,242 deaths, the country reported only one new domestic case as of March 18 th , 2020. As of that date, the total worldwide confirmed cases are 193,475 with 7,864 deaths (WHO). Although protective measures have been implemented in China (such as isolation from confirmed and suspected cases) to reduce the spread of the virus, the need for effective treatment is imperative to stop the outbreak and reduce the morbidity and mortality of COVID-19 (1) . Since onset of the outbreak, researchers have proposed many agents that could have efficacy against COVID-19. Different antiviral agents were included in the latest guidelines from the National Health Commission (NHC) including Interferon, Lopinavir/Ritonavir, Chloroquine Phosphate, Ribavirin, and Arbidol (3) . Angiotensin receptor blockers, such as Losartan, are another suggestion to treat COVID-19 (4) . COVID-19 treatment guidelines vary in each country. The WHO guidelines are very general, to manage only the symptoms and advise to be cautious with paediatric patients, pregnant, and patients with underlying co-morbidities. There is no approved treatment for COVID-19; the care advised is to give supportive management according to each patient's need; Such as antipyretics for fever and oxygen therapy for patients with respiratory distress. Moreover, WHO recommendations for severe cases are to give empiric antimicrobial therapy and implement mechanical ventilation depending on the patient's clinical condition. Some of the Asian guidelines were not easy to interpret because they are not yet translated to English, such as the Japanese guidelines. The treatment protocols across countries are similar. They are using Hydroxychloroquine, Chloroquine phosphate, Remedesivir, and Lopinavir/Ritonavir (5) (6) (7) . There are slight differences between some countries treatment guidelines which will be represented in the Table 1 (8) (9) (10) (11) . In light of limited and scarce evidence around therapeutics for COVID-19 in the literature, this review aims to retrospectively evaluate the therapeutic management that was given to COVID-19 patients since the emergence of the virus. A systematic review protocol was developed based on PRISMA-P and the PRISMA statement. Articles for review were selected from electronic databases (Embase, Medline and Google Scholar). Readily accessible peer-reviewed, full articles in English, published from December 1 st , 2019 to March 26 th , 2020 were included. The search terms included combinations of: COVID-19, SARS-COV-2, Glucocorticoids, Chloroquine, convalescent plasma, antiviral, antibacterial, Oseltamivir, Hydroxychloroquine, Chloroquine phosphate and monoclonal antibodies. There were no restrictions on the type of study design eligible for inclusion; however, these were likely to be quantitative and RCT studies. The focus of the review was therapeutics for use of the management of COVID-19 patients. Primary outcomes were: (1) the evidence of therapeutics used for the management of COVID-19 patients in clinical practice, irrespective of patient characteristics, setting and outcome measures to discuss the most common reported medicines in this review. (2) the clinical outcome of the therapeutic treatment (recovery, mortality) in COVID-19 patients. The secondary outcome was adverse events associated with the treatment. Duplicate articles were removed. Titles were independently screened by both reviewers with abstracts followed by full articles reviewed where any doubt remained. Inclusions and exclusions were recorded following PRISMA guidelines presented in the form of a PRISMA flow diagram and detailed reasons recorded for exclusion. Critical appraisal checklists appropriate to each study design were applied and checked by a second team member. Any bias or quality issues identified were considered prior to a quantitative meta-analysis and meta-narrative. CASP appraisal checklist tools were used for quality assessments. A data extraction tool was designed to capture focus of interest, population, geographical location, methodology, specific mention of therapeutic treatment and adverse events, key findings and further research. Ethical approval was not required for this review of existing peer reviewed literature. As of March 26 th , 2020, the initial manuscripts identified 449 articles. Inclusions and exclusions are reported following PRISMA guidelines presented in the form of a PRISMA flow diagram ( Figure 1 ) with reasons for exclusion recorded (Table 2) as follows: duplicates removed (n=213), 28 records were excluded of which 18 were excluded due to language (9 Chinese, 2 Dutch, 1 Vietnamese, 1Spanish, 1 Italian, 1 Russian, 1 Portuguese, 1 Iranian and 1 German). Ten articles were excluded for other reasons, including incomplete and irrelevant articles. Consensus on final inclusion of studies (n=41) (negotiated without the need for a third reviewer) is presented in Table 3 . Forty-one studies were included, of which clinical trials (n=3), case reports (n=7), case series (n=10), retrospective (n=11) and prospective (n=10) observational studies. Thirtysix studies were conducted in China, and one in each of; Korea, USA, France, Singapore and Macau . Total number of patients reported in these studies were 8,806. The mean of age was 50.8 years in 39 studies; the age was not specified in other studies. The most commonly reported therapeutic in this systematic review was the antiinflammatory medication, Corticosteroid (n=25) with different names and product characteristics, (Corticosteroid n=21, Methylprednisolone n=3, Dexamethasone n=1). This was followed by the antiviral HIV medication Lopinavir (n=21), as combination Lopinavir/Ritonavir (n=18), alone (n=3), followed by the Oseltamivir (n=16) and Arbidol Hydrochloride (n=8). In terms of antibacterial medicines, Moxifloxacin (n=4) and Tigecycline were the most reported. Convalescent plasma therapy was reported in one multi center retrospective observational study of six patients. The outcome measures recorded vary between patients discharge and recovery, ongoing hospitalization, and mortality. Available data concerning this issue is shown in Table 3 . This is the first up to date review related the therapeutics used in COVID-19 patients in a systematic manner. As of March 26 th , 2020 (since the emergence of COVID-19) only 41 eligible research articles on COVID-19 and therapeutics were found to be included in the current systematic review (2, 5, . Only three were clinical trials; most were either case reports, case series or prospective and retrospective observational studies. Systemic Corticosteroid of different names and formulation was the most commonly reported, medication, followed by the antivirals Lopinavir , Oseltamivir and Arbidol hydrochloride. Convalescent plasma therapy was mentioned in one multi-center retrospective observational study and was administered to six patients. Although quality assessment was applied to the included research articles, there was insufficient evidence from the articles identified in this review to conduct a metaanalysis. Nor was a subgroup analysis (adults and children, different formulations, dosages and duration) appropriate. Most reported articles in this review are low quality; the design and outcome of the studies are incomplete or inconsistent, hence difficult to interpret the therapeutics in terms of efficacy and safety. Despite these limitations, this is the first systematic review linked the therapeutics used in COVID-19 patients. Furthermore, the review provided up-to-date insight on the current therapeutics' guidelines for the management of COVID-19 patients; most of reported medicines in this review were already in place in the USA, Saudi Arabia, Europe, and Egypt (Table 1) . Corticosteroids were the most commonly reported and used medicine in this review, however, they are not recommended in any of the mentioned guidelines. The World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC), in the absence of conclusive scientific evidence, recommended that Corticosteroids should not be routinely used in patients with COVID-19 for treatment of viral pneumonia or acute respiratory distress syndrome (ARDS) unless indicated for other conditions, such as asthma or chronic obstructive pulmonary disease (COPD) exacerbation, or septic shock (5, (50) (51) . Careful use of Corticosteroids with low-to-moderate doses in short courses is advised. Hyperglycemia, hypernatremia and hypokalemia are the most common adverse effects associated with Corticosteroid use and should be routinely monitored (5, 51) . Lopinavir/Ritonavir is available as the brand name Kaletra and was the second most reported medicine in this review. In their RCT, Cao B et al reported negative outcomes of this HIV treatment for COVID-19 patients (Table 2) (30, (52) (53) (54) . No benefit was observed with Lopinavir/Ritonavir treatment beyond standard care in this study, 19 patients who received the intervention died. However, some limitations were observed in the study, including the lack of blinding. RCT NCT04252885 and SOLIDARITY trial are ongoing to determine the efficacy in Lopinavir/Ritonavir COVID-19 patients (52) . Oseltamivir was the third most reported therapeutic in this review, and sold under the brand name Tamiflu, it is used to treat influenza A and influenza B. Oseltamivir was recommended by WHO for people at high risk of infection for prevention of pandemic influenza. Guan W and colleagues in their retrospective observational study reported the use of Oseltamivir in 1,099 patients; however, the study was not able to provide any solid data on the effectiveness of Oseltamivir in the prevention or treatment of COVID-19 patients. Study limitations included incomplete documentation of patients' data and recall bias (55) (56) . Arbidol hydrochloride was the fourth most reported medicine in this review; it is a broad-spectrum inhibitor of influenza A and B virus, parainfluenza virus, and other viruses, including hepatitis C virus. It is used in Russia and China, yet not approved for use in other countries (52) . However, no conclusive evidence of its efficacy in COVID-19 was reported. In this review, it was reported together with Favipiravir, which was approved recently for treatment of novel influenza on February 15 th , 2020 in China (52) . Chloroquine phosphate and Hydroxychloroquine were reported in this review and showed favorable outcomes in the recovery of COVID-19 patients (6) (7) (57) (58) (59) (60) . The mechanism of action on viruses for these two medicines is likely the same effect. Chloroquine has been used for a long time to treat malaria and showed positive outcomes in patients. Furthermore, Hydroxychloroquine showed a significant effectiveness to kill intracellar pathogens such as Coxiella burnetii, the agent of Q fever (22) . The French open label, non-randomized clinical trial was promising and the first clinical trial of these medications in COVID-19 patients. The effect of Hydroxychloroquine was significant because it showed reduction in the viral load when it compared with the control group (22) . Moreover, the effect of Hydroxychloroquine was significantly more potent when Azithromycin was added to the patients according to their clinical need. However, clinical follow-up and occurrence of adverse effects were not discussed in the paper; further work should be done on these medicines with the aim of reducing the morbidity and mortality of COVID-19 (57) (58) (59) . Although these two medicines have shown promising activity against SARSCoV-2, there is a risk of arrhythmia associated with their administration. Therefore caution is required for use at higher cumulative dosages. It is recommended that their use in suspected/confirmed COVID-19 is to be restricted to hospitalized patients. On March 30 th , 2020 the U.S Food and Drug Administration (US FDA) has issued an emergency use authorization (EUA) for Chloroquine and Hydroxychloroquine to treat patients hospitalized with Covid-19 (60) . Convalescent plasma treatment was mentioned once in this review, in a multi-centre cohort research trial of 45 critically ill COVID-19 patients admitted to ICU in Wuhan. The findings showed that convalescent plasma was administered to six patients and no transfusion reactions occurred; however, the study could not provide adequate information about the efficacy of convalescent plasma, due to limited sample sizes and lack of randomized control group (61-62) . In fact, convalescent plasma therapy could be a promising method of treatment for COVID-19 patients. A very recent case series reported from China, showed that five critically ill patients with laboratory confirmed COVID-19 (who had ARDS) improved. After receiving plasma transfusion, their body temperature normalized within 3 days (in 4 of 5 patients), their viral loads became undetectable within 12 days and 3 of 5 patients were discharged from the hospital and were in stable condition at 37 days post transfusion (63) . On March 24 th , 2020 the US FDA has approved convalescent plasma treatment for investigational use under the traditional Investigational New Drug Applications (IND) regulatory pathway, and for eligible patients who have confirmed COVID-19 and severe or immediately life-threatening conditions such as respiratory failure, septic shock, and/or multiple organ dysfunction or failure (64) (65) . Notably there are some potential risks and ethical issues associated with their use, including increased thrombotic event risk (0.04 to 14.9%), lack of high quality research in this particular area and the selection of donors with high neutralizing antibody titers (65) . This is the first up to date systematic review of therapeutics used in COVID-19 patients. Only 41 research articles on COVID-19 and therapeutics were found eligible to be included, most conducted in China, of which only three were clinical trials. The anti-inflammatory medication Corticosteroid was found to be the most mentioned and widely used medicine in these studies, despite the safety alert issued by WHO and CDC, followed by antiviral medication Lopinavir, Oseltamivir and Arbidol hydrochloride. Although further research is warranted as the amount of the evidence increases, this study presents the current picture of treatment modalities used for COVID-19. Efficacy and safety profiles of treatments for COVID-19 will need to be characterized in future studies. Two recipients had self-limited skin eruptions. The study addressed a focused issue. Randomization done with intention to treat analysis. The population who entered the study are properly accounted for its conclusion. Blindness not done. The 2 groups who enter the study were similar together and treated equally. The primary outcome clearly specified. One patient stopped the treatment on day3 postinclusion because of nausea. Clinical follow-up and occurrence of side-effects were not discussed in the paper. . Huang For more information, visit www.prisma-statement.org. 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The Lancet Clinical evidence does not support corticosteroid treatment for 2019-CoV lung injury Corticosteroid therapy for sepsis: a clinical practice guideline Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV It is a case report, we cannot assure the positive impact on the patient's health is due to the medication that he has taken.Need randomized control trials to be done. . Huang C, Wang It is only one case study and it does not represent the whole population.The patient refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula.Need randomized control trials to be done. The researchers acknowledged that some specific information from the ICU was missing, such as mechanical ventilation settings.The study did not include the drugs' doses, frequency, and duration.