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Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen
Abstract
Serological, molecular and phylogenetic analyses of a recently imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) in Greece are reported. Although MERS-CoV remained detectable in the respiratory tract secretions of the patient until the fourth week of illness, viraemia was last detected 2 days after initiation of triple combination therapy with pegylated interferon, ribavirin and lopinavir/ritonavir, administered from Day 13 of illness. Phylogenetic analysis of the virus showed close similarity with other human MERS-CoVs from the recent Jeddah outbreak in Saudi Arabia. Immunoglobulin G (IgG) titres peaked 3 weeks after the onset of illness, whilst IgM levels remained constantly elevated during the follow-up period (second to fifth week of illness). Serological testing confirmed by virus neutralisation assay detected an additional case that was a close contact of the patient.
... Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses in the Coronaviridae family of the Nidovirales order. CoVs usually cause mild to severe Viruses 2021, 13 respiratory tract infections [1]. The two types of human coronaviruses that had been described prior to 2003, coronavirus 229E and OC43, caused mild, cold-like symptoms [2,3]. ...
... Due to the severity of MERS infection and the urgent need for effective treatment, several approaches for therapeutic development have been attempted [10]. In clinical studies, a combination of ribavirin and interferon-alpha (IFN-α) therapy improved patient survival rates when administered early after the onset of infection, but had no significant effect in the late stage of infection [11][12][13]. These results suggest that broad-spectrum antivirals can be effective in MERS patients at some stages of infection, but for complete antiviral activity, a treatment specific for MERS-CoV may be required. ...
... Viruses 2021, 13, 651 ...
Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.
... Corman et al. 26 detected antibodies in both ELISA and neutralization tests in 24 of 27 MERS-CoV patients within the first week. Many studies describe an immune response, characterized by a robust increment of antibody titers for HCoV-229E, MERS-CoV, SARS-CoV, and SARS-CoV-2 after the second or third week following the onset of illness 8,20,23,[26][27][28][29][30][31][32][33][34][35][36][37] . ...
... Multiple studies reported that while IgM and IgG titers increased during the first week following symptom onset, IgM levels gradually waned (while remaining detectable) for SARS-CoV and MERS-CoV in comparison to IgG levels about a month post follow-up 20,23,27 ...
... Dots and lines below each histogram indicate the median values and interquartile range (IQR) across all severity ratings (black), mild symptoms (blue), severe symptoms (red), and no reported severity (gray). Data were digitized from 17 studies19,20,24,25,[27][28][29][30]32,33,38,40,46,[147][148][149][150] . MERS-CoV antibody kinetics. ...
Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.
... We show that the extrinsic term is crucial for explaining the broad stability window of discocyte RBC shapes [18]. In studies of biological cells, such terms were considered already previously and referred to as deviatoric terms [19][20][21][22][23][36][37][38]. ...
... Suprafacial parotidectomy (32,33) Ear External ear Auricle amputation (34) Middle ear Acute eardrum perforation (35) Chronic eardrum perforation (36)(37)(38)(39)(40)(41)(42)(43)(44)(45) Reconstruction of the posterior external ear canal wall (46) Mastoid reconstruction after CWD mastoidectomy (47,48) Remarks: PVRP -platelet-and extracellular vesicle-rich plasma; PVRG -platelet-and extracellular vesicle-rich gel; CWD -canal wall down; * -systematic review or meta-analysis. ...
Abstract
Hearing loss is a substantial health issue that affects approximately 18.5% of the world
population. Currently there is no medical treatment that would cure cochlear malfunction.
Once the hearing deteriorates only hearing rehabilitation with hearing aids and implantable
hearing devices can be offered to the patients. To overcome this global health problem
novel methods of treatment are being studied. Extracellular vesicles could have regenerative
and therapeutical effect on the inner ear. Gene therapy is another new developing
treatment. The delivery of therapeutic agents to the inner ear presents an obstacle and a lot
of studies are investigating the best way to overcome it. Studies show that extracellular
vesicles may serve as nanocarriers for the delivery of different agents that will act against
preventing and treating hearing loss.
... Robust antibody responses to MERS-CoV develop by week 3 [38][39][40][41]. IgG titres decline during weeks 4-5 and though the IgM titres start decreasing earlier, they are seropositive for > 1 month, albeit at a lower titre than IgG [39]. ...
... Robust antibody responses to MERS-CoV develop by week 3 [38][39][40][41]. IgG titres decline during weeks 4-5 and though the IgM titres start decreasing earlier, they are seropositive for > 1 month, albeit at a lower titre than IgG [39]. Observations have been made that while a more severe disease is associated with higher antibody titre peaks [38,[42][43][44], a delayed nAb response has been observed [40,42]. ...
Objectives
The coronavirus disease 2019 (COVID-19), caused by the novel betacoronavirus severe acute respiratory syndrome 2 (SARS-CoV-2), was declared a pandemic in March 2020. Due to the continuing surge in incidence and mortality globally, determining whether protective, long-term immunity develops after initial infection or vaccination has become critical.
Methods/Results
In this narrative review, we evaluate the latest understanding of antibody-mediated immunity to SARS-CoV-2 and to other coronaviruses (SARS-CoV, Middle East respiratory syndrome coronavirus and the four endemic human coronaviruses) in order to predict the consequences of antibody waning on long-term immunity against SARS-CoV-2. We summarise their antibody dynamics, including the potential effects of cross-reactivity and antibody waning on vaccination and other public health strategies. At present, based on our comparison with other coronaviruses we estimate that natural antibody-mediated protection for SARS-CoV-2 is likely to last for 1–2 years and therefore, if vaccine-induced antibodies follow a similar course, booster doses may be required. However, other factors such as memory B- and T-cells and new viral strains will also affect the duration of both natural and vaccine-mediated immunity.
Conclusion
Overall, antibody titres required for protection are yet to be established and inaccuracies of serological methods may be affecting this. We expect that with standardisation of serological testing and studies with longer follow-up, the implications of antibody waning will become clearer.
... We show that the extrinsic term is crucial for explaining the broad stability window of discocyte RBC shapes [18]. In studies of biological cells, such terms were considered already previously and referred to as deviatoric terms [19][20][21][22][23][36][37][38]. ...
... Suprafacial parotidectomy (32,33) Ear External ear Auricle amputation (34) Middle ear Acute eardrum perforation (35) Chronic eardrum perforation (36)(37)(38)(39)(40)(41)(42)(43)(44)(45) Reconstruction of the posterior external ear canal wall (46) Mastoid reconstruction after CWD mastoidectomy (47,48) Remarks: PVRP -platelet-and extracellular vesicle-rich plasma; PVRG -platelet-and extracellular vesicle-rich gel; CWD -canal wall down; * -systematic review or meta-analysis. ...
Platelet- and extracellular vesicle-rich plasma (PVRP) is a blood-derived product with concentrations of platelets and extracellular vesicles (EVs) above the blood levels. Moreover, EVs are believed to possess the PVRP's leading regenerative roles since they are essential mediators of inter-and intracellular communication. PVRP has been named inconsistently, e.g. as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), platelet concentrate, platelet-rich growth factors, platelet-rich fibrin matrix and platelet-rich gel due to different methods of preparation, activation and analyses. Taken nomenclature aside, autologous PVRP has been applied in various medical specialities, including in otorhinolaryngology, head & neck surgery (ORL-HNS). Despite that, there is a lack of comparable randomised controlled clinical studies. This article presents autologous PVRP and platelet- and extracellular vesicle-rich gel (PVRG) preparation protocols and autologous PVRG's role in skull-base surgery, performed by ORL-HNS. Since the autologous PVRG can provide a watertight seal and induce osteogenesis, the mini-review presents PVRG's role in skull-base reconstruction via anterior and lateral approaches.
... 22 Besides, successful cases of MERS treatment with a triple combination therapy of lopinavir/ritonavir, ribavirin, and interferon-alpha 2a have been reported. [23][24][25] However, the efficacy of lopinavir/ritonavir is unconvincing because of the concomitant use with ribavirin and/or interferon. Recently, the use of lopinavir/ritonavir treatment in a randomized, controlled, open-label trial involving 199 patients with COVID-19 showed no significant benefit in either overall mortality or reduction of viral loads beyond standard care. ...
... Some case studies have reported that the combination of interferon-a and ribavirin with lopinavir/ritonavir resulted in improved outcomes. [23][24][25] Thus, the use of interferon in combination with other effective antivirals should be evaluated in clinical trials. ...
The recently emerged coronavirus disease 2019 (COVID-19) has rapidly evolved into a pandemic with over 10 million infections and over 500 thousand deaths. There are currently no effective therapies or vaccines available to protect against this coronavirus infection. In this review, we discuss potential therapeutic options for COVID-19 based on the available information from previous research on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Substantial efforts are underway to discover new therapeutic agents for COVID-19, including the repurposing of existing agents and the development of novel agents that specifically target SARS-coronavirus 2 (SARS-CoV-2) or host factors. Through the screening of compound libraries, various classes of drugs, such as ribavirin, remdesivir, lopinavir/ritonavir, and hydroxychloroquine have been identified as potential therapeutic candidates against COVID-19. Novel antiviral drugs for SARS-coronavirus 2 are being developed to target viral enzymes or functional proteins, as well as host factors or cell signaling pathways.
... Three case reports and one retrospective study described the use of Lopinavir/Ritonavir in MERS patients [18][19][20] . Lopinavir/Ritonavir was used in combination with ribavirin and interferon in two case reports; one patient died and two survived [18][19][20] . ...
... Three case reports and one retrospective study described the use of Lopinavir/Ritonavir in MERS patients [18][19][20] . Lopinavir/Ritonavir was used in combination with ribavirin and interferon in two case reports; one patient died and two survived [18][19][20] . One retrospective matched-cohort study evaluated the use of Lopinavir/Ritonavir as post-exposure prophylaxis in 43 healthcare workers at a high risk of MERS exposure 21 . ...
Objective:
Lopinavir/ritonavir has been used for the treatment of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) coronavirus infections. It has been suggested that, based on this experience, this drug should also be studied in SARS-CoV2 infection.
Materials and methods:
We performed a systematic review of the literature regarding the use of lopinavir/ritonavir for the treatment of these three infections. We systematically searched the PubMed database from inception to April 30th, 2020, to identify in-vitro and animal studies and any reports of human use of lopinavir/ritonavir for the treatment of SARS, MERS and COVID-19. We also searched the Clinicatrial.gov to identify ongoing trials.
Results:
Five in-vitro studies evaluated the effect of lopinavir/ritonavir in SARS. Three additional in-vitro studies reported the EC50 of the antiviral activity of lopinavir/ritonavir in MERS. We identified no in vitro studies evaluating the effect of lopinavir/ritonavir on the novel coronavirus. Two retrospective matched-cohort studies reported the use of lopinavir/ritonavir in combination with ribavirin for SARS patients. Three case reports and one retrospective study described the use of lopinavir/ritonavir in MERS. Twenty-two papers describe the use of lopinavir/ritonavir in adult patients with COVID-19.
Conclusions:
The existing literature does not suffice for assessing whether Lopinavir/ritonavir has any benefit in SARS, MERS or COVID-19.
... Lopinavir, was discovered to be active against SARS-CoV, the virus causing SARS in 2003 in an in vitro screening, and later, was shown together with Ritonavir to reduce ARDS and mortality rate in humans with SARS 19 . Case reports also suggested that the triple combination of Lopinavir-Ritonavir with IFNa or b improved virus clearance and survival (24)(25)(26). Our discovery also supports a recently a clinical trial program, called SOLIDARITY, launched by the WHO, aiming to quickly repurpose known or clinical drugs for CIVID-19 pandemic, has one arm of triple combination, Lopinavir-Ritonavir with IFNb (27). ...
... The SARS-CoV-2 mimics the influenza virus in clinical presentation, transmission mechanism, and seasonal coincidence. A recent study reports four co-transfection cases with the SARS-CoV-2 and influenza virus, highlighting the urgent need for precision diagnosis and treatment for the co-infection (26,27). In the last pandemic of the SARS in 2003, patients with fever, cough or sore throat had a 5% of influenza virus positive rate (29). ...
Various medical treatments for COVID-19 are attempted. After patients are discharged, SARS-CoV-2 recurring cases are reported and the recurrence could profoundly impact patient healthcare and social economics. To date, no data on the effects of medical treatments on recurrence has been published. We analyzed the treatment data of combinations of ten different drugs for the recurring cases in a single medical center, Shenzhen, China. A total of 417 patients were considered and 414 of them were included in this study (3 deaths) with mild-to-critical COVID-19. Patients were treated by 10 different drug combinations and followed up for recurrence for 28 days quarantine after being discharged from the medical center between February and May, 2020. We applied the Synthetic Minority Oversampling Technique (SMOTE) to overcome the rare recurring events in certain age groups and performed Virtual Twins (VT) analysis facilitated by random forest regression for medical treatment-recurrence classification. Among those drug combinations, Methylprednisolone/Interferon/Lopinavir/Ritonavir/Arbidol led to the lowest recurring rate (0.133) as compared to the average recurring rate (0.203). For the younger group (age 20-27) or the older group (age 60-70), the optimal drug combinations are different, but the above combination is still the second best. For obese patients, the combination of Ribavirin/Interferon/Lopinavir/Ritonavir/Arbidol led to the lowest recurring rate for age group of 20-50, whereas the combination of Interferon/Lopinavir/Ritonavir/Arbidol led to lowest recurring rate for age group of 50-70. The insights into combinatorial therapy we provided here shed lights on the use of a combination of (biological and chemical) anti-virus therapy and/or anti-cytokine storm as a potentially effective therapeutic treatment for COVID-19.
... The INF antiviral activity has already been investigated in various studies, and some studies in animal models have presented promising results (18). For instance, INF-β-1 has demonstrated the strong inhibition of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus in laboratory studies (12); nevertheless, other studies reported some contradictory results (19)(20)(21)(22). ...
Background: About a year after the start of the coronavirus disease 2019 (COVID-19) pandemic, the results of the studies conducted to investigate the effectiveness of interferon (INF) compounds in this disease were contradictory. Objectives: This study was carried out to examine the safety and efficacy of a treatment protocol containing INF-β-1b, hydroxychloroquine, and Kaletra (lopinavir/ritonavir) in patients with severe COVID-19. Methods: In this open-label, randomized controlled trial, severe cases of COVID-19 were included. Patients were eligible if they had epidemiological and radiological evidence compatible with COVID-19 or a positive polymerase chain reaction result and their disease was severe. They were randomly allocated into a control group that received the standard regimen (hydroxychloroquine and Kaletra) and an intervention group that received INF-β-1b treatment and the standard treatment regimen. Then, the two groups were compared in terms of in-hospital mortality, intubation, length of hospital stay, oxygen saturation, and lactate dehydrogenase before and after the intervention. Results: A total of 91 cases of severe COVID-19 were enrolled for analysis [intervention (n = 47) and control (n = 44)]. The length of hospital stay in the intervention group was significantly longer than in the control group (13.21 ± 6.88 vs. 10.52 ± 5.77 days; P = 0.047). The mortality rate did not significantly differ between the intervention and control groups (19.15% and 13.64%, respectively; P = 0.509). The intubation rate did not significantly differ between the intervention and control groups (12.76% and 11.36%, respectively; P = 0.838). Conclusions: The use of INF-β-1b-containing treatment regimens does not reduce mortality and intubation rates among patients with severe COVID-19. Furthermore, it might even increase the severity of the disease and the length of hospital stay for some patients; therefore, it is not recommended to use INF-β-1b in severe cases of COVID-19.
... As there are no specific anti-coronavirus drugs; inspired by the studies that recommended lopinavir-ritonavir combination as a promising therapy for both MERS-CoV and SARS-CoV infections (Chu et al.,2004;Spanakis et al., 2014;Kim et al.,2016;Min et al.,2016). Chinese medical specialist decided to try this combination for management of patients with SARS-CoV-2 infection. ...
On 31 December 2019, the cases of pneumonia caused by unknown etiology had emerged. These cases were reported in Wuhan city, Hubei Province of China. Chinese authorities identified the causative agent and announced to be a novel coronavirus. The tentative name of disease is COVID-19, abbreviating of coronavirus disease-19. The incubation period of the disease ranges from 2 to 14 days, however, 80% of the patients have mild or asymptomatic illness while 15 % and 5% of the patients had exhibited sever and critical cases respectively. The etiology of COVID-19 was known as SARS-CoV-2 and belongs to betacoranviruse as reported by the International Committee on Taxonomy of Viruses (ICTV) especially Coronaviridae Study Group (CSG). In addition, this virus is currently believed to be within bat-coronaviruses besides it possesses a close relationship with SARS-CoV more than MERS-CoV. Although, the majority of the diagnosed patients had symptoms, there were asymptomatic persons who can spread the SARS-CoV-2. Upon the emergence of worldwide distribution of this virus, the WHO had declared it as a global outbreak and pandemic. Unfortunately, at present time, there are neither vaccine and nor an approved COVID-19 specific drug against SARS-CoV-2. One of the remarkable pathogenesis mechanistic step of this virus is taking possession of the affinity to angiotensin-converting enzyme 2 (ACE2). This mini-review summarizes the origin and molecular identification of the virus as well as the host immune responses.
... Clinical studies of MERS: After two days of treatment with LPV/r, interferon, and ribavirin on patients, it exposed resolution of viremia, but eventually, the patient died from septic shock 62 MERS-COV induces immune responses which cause severe lung damage and eventually lead to death. Corticosteroids are common treatments for patients with such a disease, but the crucial question is if this strategy is safe and effective enough or not. ...
Severe acute respiration syndrome coronavirus 2 (SARS-CoV-2) is characterized by severe cytokine storm syndrome following inflammation. SARS-CoV-2 is the 7th coronavirus that causes infection in human bodies; SARS-CoV, MERS-CoV, and SARS-CoV-2 can purpose severe diseases. SARS-CoV-2 at once interacts with angiotensin-converting enzyme 2 (ACE-2) receptors inside the body and causes respiratory problems. Interestingly, complementary medicines and herbal drugs affect the expression of IgE and IgG antibodies and improve the immune system; for that reason, complementary medicine could be beneficial for infectious diseases like SARS-COV-2. In this review, we assessed some related articles to evaluate the effect of complementary medicine on SARS-COV2 and MERS-COV.
... LPV/r is approved by the FDA for treatment of HIV-1 infection in adult and pediatric patients [88]. LPV/r has also exhibited efficacy to treat influenza, severe acute respiratory syndrome (SARS), and Middle Eastern respiratory syndrome (MERS) infection [89][90][91]. Nine RCTs included LPV/r for COVID-19 therapy: two large trials (RECOVERY [26] and TOGETHER [27]), and seven relatively smaller trials (n = 86-664) [24,31,37,40,44,47]. The trial conducted by Solaymani-Dodaran et al. compared LPV/r to favipiravir and found no significant differences, as discussed in the Favipiravir section above [44]. ...
Background
Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment.
Methods
A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics.
Results
Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials.
Conclusions
Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy.
... In addition, the combination of INF-α2b and ribavirin showed augmentation of action and reduction of IFN-α2b and ribavirin does [145]. Clinical data of IFN-α2b and ribavirin are based on retrospective studies and there two agents did not improve the survival of MERS patients [146][147][148][149][150][151]. However, one study showed that the case-fatality rate was 90% and 44% in RT-PCR positive vs. 44% in those with negative MERS-CoV test [107]. ...
The past two decades have witnessed the emergence of three zoonotic coronaviruses which have jumped species to cause lethal disease in humans: severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. MERS-CoV emerged in Saudi Arabia in 2012 and the origins of MERS-CoV are not fully understood. Genomic analysis indicates it originated in bats and transmitted to camels. Human-to-human transmission occurs in varying frequency, being highest in healthcare environment and to a lesser degree in the community and among family members. Several nosocomial outbreaks of human-to-human transmission have occurred, the largest in Riyadh and Jeddah in 2014 and South Korea in 2015. MERS-CoV remains a high-threat pathogen identified by World Health Organization as a priority pathogen because it causes severe disease that has a high mortality rate, epidemic potential, and no medical countermeasures. MERS-CoV has been identified in dromedaries in several countries in the Middle East, Africa, and South Asia. MERS-CoV-2 causes a wide range of clinical presentations, although the respiratory system is predominantly affected. There are no specific antiviral treatments, although recent trials indicate that combination antivirals may be useful in severely ill patients. Diagnosing MERS-CoV early and implementation infection control measures are critical to preventing hospital-associated outbreaks. Preventing MERS relies on avoiding unpasteurized or uncooked animal products, practicing safe hygiene habits in health care settings and around dromedaries, community education and awareness training for health workers, as well as implementing effective control measures. Effective vaccines for MERS-COV are urgently needed but still under development.
... Evidence from laboratory, animal and human investigations, as well as clinical trials on ~ 233 ~ traditional medicine medicines including remdesivir [9] , lopinavir/ritonavir [10] , lopinavir/ritonavir with in-terferon-1a [11] , chloroquine [12,13] . According to a recent comprehensive study, combining traditional Chinese medicine with "western medicine" enhanced cure rates and symptom amelioration in COVID19 [14][15][16] . Homeopathy, on the other hand, could be viewed as a complementary treatment to traditional medicine. ...
... Serological tests could be useful in the determination of asymptomatic cases because they are easy to use and inexpensive and can also be applied to investigate mass screening and epidemiologic researches (29). ELISA, antibody array, immunofluorescence, microneutralization plaque reduction neutralization, and MERS spike pseudoparticulate neutralization tests are used for detecting antibodies against MERS (30)(31)(32). ...
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes Middle East Respiratory Syndrome (MERS). Since the vast majority of cases (more than 85%) are reported from Saudi Arabia, there is a pandemic potential for pilgrimage due to Hajj or Umrah. It is reported from Turkey that more than 400 thousand people went to Saudi Arabia for umrah and 61 thousand people for Hajj in 2014. In this study it is aimed to investigate the patients who had just returned from Makkah for Umrah and who also applied to the Infectious Disease Clinics at the Hitit University Erol Olcok Training and Research Hospital for having respiratory tract symptoms. Their serologic situations have been determined by ELISA whether there is any risk in terms of performing the Hajj and Umrah, and contracting MERS-CoV. Between January 1st to the 31st of October 2015, 40 people were included in this study, which were admitted to our hospital with upper respiratory tract complaints and had previously been in Saudi Arabia for Umrah within the last 15 days. As a control group, 40 healthy people without any complaints and travel histories to risky areas were selected. Their serum samples were taken and searched by MERS-CoV IgG ELISA (Euroimmun AG, Lübeck, Germany). The results ≤0.8 were considered as negative, ≥1.1 were as positive, 0.8-1.1 were suspected. All suspected and positive results have been revaluated and confirmed. Only two (5%) individuals from the patients’ group were found as positive for the MERS-CoV IgG antibodies, but individuals from the remaining patients’ group and also all control group members were determined as negative. Travels to Saudi Arabia could be a risk for exposure to MERS-CoV. Although there is no evidence, contamination could be realized by anthropologically due to crowds.
... However, the lack of randomization and a contemporary control group and the concomitant use of glucocorticoids and ribavirin in that study made the effect of lopinavir-ritonavir difficult to assess. Similarly, lopinavir has activity, both in vitro [19] and in an animal mode [20], against Middle East respiratory syndrome coronavirus (MERS-CoV), and case reports have suggested that the combination of lopinavir-ritonavir with ribavirin and interferon alfa resulted in virologic clearance and survival [21][22][23].Chao et. Al [24] conducted a randomized controlled open label trial in hospitalized adult Covid-19 patients to evaluate the efficacy and safety of oral lopinavir-ritonavir for SARS-CoV-2 infection from January 18, 2020, through February 3, 2020 at Jin Yin-Tan Hospital, Wuhan, Hubei Province, China. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spread across the globe resulting in a pandemic affecting 215 countries. At the time of this review, COVID-19 has been diagnosed in more than 15,000,000 patients and associated with over 1,00,000 deaths globally (Canters for Disease Control and Prevention, World Health Organization). In this review, we herein summarize the current evidence as on June 15, 2020 to provide guidance on potential drugs for COVID-19 treatment or prophylaxis, their scientific rationale and their clinical efficacy and safety. New data continue to emerges daily regarding clinical characteristics, treatment options, and outcomes for COVID-19. Optimized supportive care remains the mainstay of therapy, and the clinical efficacy for the potential therapeutic agents is still under investigation.
... Early in the pandemic HCQ and Azithromycin received wide attention in its use in COVID19 patients 17 . Similarly, Kaletra and Ribavirin in were also used [18][19][20] . Hence, it was common to prescribe these drugs in hospital settings at that time. ...
Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is known to suppress the antioxidant system and is likely to aggravate severity of COVID-19, which results in a pro-oxidant response. This possible association has not been explored adequately in human studies. In this research, we report that the occurrence of non-invasive ventilation, intubation or death—all of which are indicative of severe COVID-19, are not significantly different in hospitalized COVID-19 patients with and without G6PDd (4.6 vs. 6.4%, p = 0.33). The likelihood of developing any of these severe outcomes were slightly lower in patients with G6PDd after accounting for age, nationality, presence of comorbidities and drug interventions (Odds ratio 0.40, 95% confidence intervals 0.142, 1.148). Further investigation that extends to both, hospitalized and non-hospitalized COVID-19 patients, is warranted to study this potential association.
... The activity of lopinavir has been observed in an animal model [2] and in vitro [8] for Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Previous studies have also shown virologic clearance and survival of patients after administrating a combination of lopinavirritonavir with ribavirin and interferon Alfa [9][10][11]. Clinical trials have shown promising results for MERS [12,13]; however, there is a lack of studies about the efficacy of this approach in humans [11]. ...
Aims: Globally the focus is towards finding an effective treatment for COVID-19 patients in order to suppress the spread of this pandemic disease. An antiviral combination of lopinavir-ritonavir is considered to be effective in treating COVID-19 patients. Therefore, the present study aims to assess the clinical improvements of lopinavir-ritonavir in COVID-19 patients. Study Design: a systematic review study was conducted and articles published since December 2019 were included. The statistical analysis of quantitative data was performed using Review Manager (RevMan) to generate forest plots. Results: The study showed that there was no significant difference in COVID-19 patients treated with lopinavir-ritonavir or in combination with anti-viral therapy or other conventional methods. Conclusion: the use of lopinavir-ritonavir resulted in greater adverse consequences among COVID-19 patients. It further recommends conducting meta-analysis studies with a greater number of studies to highlight the clinical improvement associated with the use of Lopinavir-ritonavir.
... Por fim, um estudo acompanhou o caso de uma paciente com MERS que recebeu Lopinavir/Ritonavir, Interferon peguilado e Ribavirin a partir do 13º dia de doença. Dois dias após o início do tratamento, não foi mais constatada viremia, entretanto, a presença de RNA viral nas secreções respiratórias persistiu até a quarta semana da doença e, posteriormente, a paciente foi a óbito (Spanakis et al., 2014). Outro estudo não constatou atividade in vitro do Lopinavir contra o MERS-CoV (Chan J et al., 2013). ...
A pandemia causada pelo novo coronavírus (SAR-CoV-2) representa um desafio para a saúde pública do mundo inteiro, em função da alta transmissibilidade do vírus, consequente sobrecarga dos sistemas de saúde e grande número de óbitos. Assim, estudos e pesquisas estão sendo realizados no intuito de identificar alternativas terapêuticas seguras e eficazes para a COVID-19, doença causada pelo SAR-CoV-2, visto que ainda não há um consenso nem evidência científica de que algum medicamento possa suprimir a excreção viral sem trazer massivos efeitos colaterais ao paciente. Nessa perspectiva, alguns fármacos estão sendo utilizados na prática clínica e, dentre eles, encontra-se a combinação do Lopinavir com o Ritonavir, antiretrovirais comumente utilizados no tratamento do HIV. O objetivo dessa revisão narrativa é analisar o uso da combinação Lopinavir/Ritonavir como alternativa terapêutica para a COVID-19. Os resultados indicam que a associação Lopinavir/Ritonavir tem sido utilizada como tratamento coadjuvante nos casos de COVID-19, normalmente combinada com outros medicamentos. Estudos sugerem que essa combinação não interfere no tempo de UTI e que a porcentagem de óbitos não é significativa. Quando aplicada no início dos sintomas, essas medicações causam redução na excreção viral e menor número de intubação. No entanto, há contradição referente a isso, já que alguns estudos sugerem aumento na excreção viral em pacientes que receberam esses medicamentos. Reforça-se a necessidade de intensificar os estudos relacionados ao tratamento para COVID-19 no sentido de gerar dados conclusivos para que as medicações possam ser utilizadas com eficácia e segurança.
... Lopinavir was also found to have anti-MERS-coronavirus (CoV) activity both in vitro (67) and in a non-human primate animal model (68). Although several clinical case reports indicated that lopinavir/ritonavir (LPV/r)-based combination therapy with ribavirin and interferon alpha led to virological clearance and clinical resolution of infection (69)(70)(71), more convincing clinical trial data about the efficacy of this combined therapeutic strategy are needed (71). Therefore, a randomized controlled clinical trial of LPV/r and recombinant interferon-β1b vs. placebo for MERS is currently under way (ClinicalTrials.gov: ...
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and rapidly developed into a worldwide pandemic. The sudden outburst and rapid dissemination of SARS-CoV-2, with overwhelming public health and economic burdens, highlight an urgent need to develop effective strategies for the diagnosis and treatment of infected patients. In this review, we focus on the current advances in the diagnostics and treatment for SARS-CoV-2 infection. Notably, we also summarize some antineoplastic drugs repurposed for COVID-19 treatment and address the diagnostic and therapeutic challenges for oncologists to manage cancer patients in this COVID-19 era. In addition, we emphasize the importance of organoid technology as a valuable experimental virology platform to better understand the pathogenesis of COVID-19 and assist rapid screening of drugs against COVID-19.
... 53 Although a similar combination involving ribavirin, lopinavir/ritonavir, and an interferon-a did not prove effective against MERS-CoV, 54,55 reduction in blood viral titers was observed. 56 No differences in antiviral activity were observed with various routes of drug administration. 57 Ribavirin has demonstrated the inhibition of viral replication in SARS-CoV-2 in vitro models established by the Bojkova group. ...
Novel 2019 coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) and coronavirus disease 2019 (COVID-19), the respiratory syndrome it causes, have shaken the world to its core by infecting and claiming the lives of many people since originating in December 2019 in Wuhan, China. World Health Organization and several states have declared a pandemic situation and state of emergency, respectively. As there is no treatment for COVID-19, several research institutes and pharmaceutical companies are racing to find a cure. Advances in computational approaches have allowed the screening of massive antiviral compound libraries to identify those that may potentially work against SARS-CoV-2. Antiviral agents developed in the past to combat other viruses are being repurposed. At the same time, new vaccine candidates are being developed and tested in preclinical/clinical settings. This review provides a detailed overview of select repurposed drugs, their mechanism of action, associated toxicities, and major clinical trials involving these agents.
... Lopinavir has also been reported for its efficacy against MERS-CoV, during the in vitro and in vivo studies [27,28]. Another combination of lopinavir-ritonavir and ribavirin with interferon-α demonstrated an increased rate of survival and virologic clearance [26,[29][30][31]. ...
COVID-19 outbreak hit the world worse at the start of 2020, as of December 11, 2020, more than 1.5 million people have died and more than 68.8 million people have been infected globally. SARS-CoV-2 induces mild to severe progressive respiratory pneumonia, leading to failure of different body organs and ultimately death. Hitherto, there are no specific and potential therapeutic agents available against the virus. The spike protein is a type I surface glycoprotein facilitating entry of the virus into the host cell via hACE2 receptors. The two subunits of the spike protein have a polybasic link as cleavage site (PRAR) in SARS-CoV-2, with additional attachment of O-linked glycans. SARS-CoV and SARS-CoV-2 have 76.5% similarity in amino acid sequences. The pathogenesis and viral entry of SARS-CoV-2 are different from SARS-CoV, therefore, it is a dire need of the time to develop a target-based treatment. Alternative strategies and multidisciplinary research approaches are crucial for developing new antiviral and improved therapies against COVID-19. Nanotechnology has opened new horizons for evaluating the biological properties and efficacy of different materials having biological origin, such as Nigella sativa. It contains various active components such as thymoquinone, thymol, thymohydroquinone, and dithymoquinone with different biological potentials. Metallic nanomaterials have been reported to exhibit antiviral activities against various strains. Understanding molecular interactions and modifying the surface properties of nanomaterials with optimum activity may result in the development of novel antiviral therapies.
... In a case report study conducted in Greece, 2014, a 69year-old patient who received oral LPV in combination with interferon and ribavirin had a resolution of viremia after two days of treatment. However, the patient eventually died after two months and 19 days of the initial diagnosis as a result of septic shock [24]. In 2015, a case report of the use of lopinavir/ritonavir-based combination antiviral therapy was conducted for a patient with MERS infection showed positive disease outcomes, including defervescence, viral clearance from serum and sputum, and survival [25]. ...
Background
Coronaviruses including COVID-19, MERS and SARS have affected millions of people around the world since its emerge. Still, there is not a certain drug treatment strategy for Coronaviruses.
Objective
This review aims at a compilation of a comprehensive study on literature reporting the treatment strategies and regimens used for COVID-19, MERS and SARS with an emphasis on the clinical trials and experimentations.
Results
According to the literature, the most effective drugs reported so far for treatment strategies include: lopinavir/ritonavir, favipiravir, ribavirin, oseltamivir, remdesivir, hydroxychloroquine, herbal extracts, monoclonal antibodies and anticytokine agents. Some combinations of drugs have been very effective to reduce the death rate, hospitalization stay and to prevent the progress of the disease to the later critical and severe stages.
Conclusions
However, a combination of drugs and regimens have been useful and saved millions of patient’s lives but the clinical data reviewed in this essay indicate that the current drugs do not make an impervious barrier against coronavirus infections and cannot protect or treat patients completely. Therefore, there is a much demand towards discovery and introduction of new antiviral drugs.
... A research suggests that the application of lopinavir-ritonavir (400 mg and 100 mg, respectively) with ribavirin decreased the adverse clinical consequences (acute respiratory distress syndrome [ARDS] or death) as well as viral activity among SARS affected patients (164). Activity against MERS-CoV was shown in animal models and invitro by lopnivir and it has been suggested in some case studies that the combine medication of lopinavir+ritonavir with interferon alfa and ribavirin which resulted in virological clearance and survival [167][168][169][170][171]. In total, 199 patients suffering from severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infections in a hospital underwent a clinical trial applying lopinavir plus ritonavir group and standard-care group. ...
A highly pathogenic viral infection with several symptoms have been reported such as fever, cough, breathing
difficulty, fatigue, headache, failure of taste or smell sensation, sore throat, congestion and diarrhoea in December,
2019 in Wuhan, China. In 30th January, 2020 World Health Organization (WHO) declared the outbreak of
coronavirus disease to be a Public Health Emergency of global Concern. This virus is highly contagious and can be
transmitted after close contact with an infected patient, and has quickly spread globally. In this pandemic, several
types of drugs, non-drugs treatment, and their combination are being used to manage the coronavirus disease
(COVID-19) affected patients which caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Although none of them are officially recommended by any national and international committee such as U.S. Food
and Drug Administration (USFDA) because the efficacy and the safety aspects of these treatments are still
unidentified and extensively investigated. Different types of potential pharmacotherapy and treatments such as
antimalarial, antiviral, antibiotics and many more are presently undertaking clinical-trials to prove their
effectiveness in COVID-19 and some of them also showing promising results. This narrative review article
summarizes some potential drugs used for the symptoms of coronavirus disease such as antivirals, antibiotics,
antimalarial, anti-inflammatory and possible treatments such as neutralizing antibodies from convalescent plasma,
umbilical cord mesenchymal stem cells (UC-MSCs) against SARS-CoV-2.
... The positive impact of LPV/r on clinical outcome and reduction of the viral load in nasopharyngeal swabs were documented in the patients participating in the open-label study performed at the outbreak of SARS in 2003. Three case reports and one retrospective study described the use of LPV/r in patients with MERS, suggesting improved clinical outcome [6,7]. Hence, due to the structural similarity of all betacoronaviruses, the relevance of LPV/r in the treatment of COVID-19 was considered. ...
... Lopinavir/ritonavir (400 mg and 100 mg, separately) to ribavirin decreases the risk of adverse clinical conditions (Acute Respiratory Distress Syndrome [ARDS] or death) as well as viral load among patients with SARS. Lopinavir has action, both in vitro 8 and in an animal model 9 , against Middle East respiratory syndrome coronavirus (MERS-CoV), and case reports have recommended that the blend of lopinavir-ritonavir with ribavirin and interferon alfa came about in virologic clearance and survival 11 . Lopinavir/Ritonavir used in combination with other medications to treat adults and children over 14 days of age infected with HIV-1. ...
Background: Early in December 2019, a novel coronavirus, named SARS-CoV-2, caused an outbreak of respiratory disease named COVID-19. The COVID-19 disease has led to severe pneumonia, multiorgan failure, and death. Methods: A detailed literature survey was performed using various databases. Results: Lopinavir/Ritonavir is an orally administrable drug, and after its administration, the viral load is being tested. On the other end, remdesivir even at a very low micromolar concentration blocked the viral infection. Ribavirin combination with Lopinavir/ Ritonavir was intravenously infused for not more than 10 days. The presence or absence of viral load was determined to be the endpoint. Gastrointestinal adverse events were more common in the lopinavir-ritonavir administered patients. Lopinavir-ritonavir treatment was stopped early in patients because of adverse events. Hypertransaminasemia and acute kidney injury were also the most frequent severe adverse events observed. Remdesivir benefited patients with SARS-CoV-2 pneumonia hospitalized outside ICU where the clinical outcome was better and adverse events are less frequently observed. Ribavirin combination with Lopinavir/ Ritonavir was intravenously infused for not more than 10 days and was found to be less effective. Conclusion: The antiviral drugs involved in the treatment of COVID 19 are Lopinavir/Ritonavir, Remdesivir, and Ribavirin. Among which Remdesivir was found to be more effective against COVID 19 with 30% speedy recovery. However, prevention is always better than cure, the prevention methods involve Hand sanitization, gloves, masks, protective suits, social distancing, and self-isolation.
... The positive impact of LPV/r on clinical outcome and reduction of the viral load in nasopharyngeal swabs were documented in the patients participating in the open-label study performed at the outbreak of SARS in 2003. Three case reports and one retrospective study described the use of LPV/r in patients with MERS, suggesting improved clinical outcome [6,7]. Hence, due to the structural similarity of all betacoronaviruses, the relevance of LPV/r in the treatment of COVID-19 was considered. ...
Background
Remdesivir (RDV) is the only antiviral drug registered currently for treatment of COVID-19 after a few clinical trials with controversial results. The purpose of this study was to evaluate the effectiveness and safety of RDV in patients with COVID-19 in real world settings.
Methods
Patients were selected from 1496 individuals included in the SARSTer national database; 122 of them received therapy with RDV and 211 were treated with lopinavir/ritonavir (LPV/r)-based therapy. The primary end-point of effectiveness was clinical improvement in the ordinal 8-point scale, which was defined as a 2-point decrease from baseline to 7, 14, 21 and 28 days of hospitalization. The secondary end-points of effectiveness included: death rate, rate of no clinical improvement within 28 days of hospitalization in the ordinal scale, rate of the need for constant oxygen therapy, duration of oxygen therapy, rate of the need for mechanical ventilation, total hospitalization time, and rate of positive RT PCR for SARS-CoV-2 after 30 days.
Findings
Significantly higher rates of clinical improvement, by 15% and 10% respectively, were observed after RDV treatment compared to LPV/r at days 21 and 28. The difference between regimens increased with worsening of oxygen saturation (SpO 2 ) and depending on the baseline score from the ordinal scale. Statistically significant differences supporting RDV were also noted regarding the rate of no clinical improvement within 28 days of hospitalization and hospitalization duration in patients with baseline SpO 2 ≤90%. In the logistic regression model only the administration of remdesivir was independently associated with at least a 2-point improvement in the ordinal scale between baseline and day 21.
Interpretation
In conclusion, data collected in this retrospective, observational, real world study supported use of remdesivir for treatment of SARS-CoV-2 infection particularly in patients with oxygen saturation ≤95%.
... During the acute phase of illness (1-7 days), detectable specific antibody responses against coronaviral infections were rarely observed [75][76][77]. Marked augmentations in antibody titers were observed after the second or third week of infection due to HCoV-229E, MERS-CoV, and SARS-CoV infections [78][79][80][81]. In case of SARS-CoV, a very long immunological response was observed. ...
The aggressive outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) as COVID-19 (coronavirus disease-2019) pandemic demands rapid and simplified testing tools for its effective management. Increased mass testing and surveillance are crucial for controlling the disease spread, obtaining better pandemic statistics, and developing realistic epidemiological models. Despite the advantages of nucleic acid- and antigen-based tests such as accuracy, specificity, and non-invasive approaches of sample collection, they can only detect active infections. Antibodies (immunoglobulins) are produced by the host immune system within a few days after infection and persist in the blood for at least several weeks after infection resolution. Antibody-based tests have provided a substitute and effective method of ultra-rapid detection for multiple contagious disease outbreaks in the past, including viral diseases such as SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). Thus, although not highly suitable for early diagnosis, antibody-based methods can be utilized to detect past infections hidden in the population, including asymptomatic ones. In an active community spread scenario of a disease that can provide a bigger window for mass detections and a practical approach for continuous surveillance. These factors encouraged researchers to investigate means of improving antibody-based rapid tests and employ them as reliable, reproducible, sensitive, specific, and economic tools for COVID-19 mass testing and surveillance. The development and integration of such immunoglobulin-based tests can transform the pandemic diagnosis by moving the same out of the clinics and laboratories into community testing sites and homes. This review discusses the principle, technology, and strategies being used in antibody-based testing at present. It also underlines the immense prospect of immunoglobulin-based testing and the efficacy of repeated planned deployment in pandemic management and post-pandemic sustainable screenings globally.
... The addition of RBV to lopinavir/ritonavir reduced the risk of ARDS or death, as well SARS-CoV-1 viral load among patients with SARS (21). The combination of lopinavir/ritonavir, RBV and IFN α has been associated with survival in case reports of patients with MERS (22)(23)(24). In this systematic review, one RCT did not nd lopinavir/ritonavir to be associated with shorter time to clinical improvement, or have mortality bene t in patients with SARS-CoV-2 (25). ...
Background: The best treatment for COVID-19 is not known, with numerous agents under investigation. We determined the outcomes of patients with COVID-19 treated with different pharmacological agents.
Methods: In this systematic review, we searched Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials for studies published between 1stJanuary and 12thAugust, 2020. We included randomized controlled trials (RCTs) of patients with COVID-19 treated with any pharmacological agent and compared with a different pharmacological agent, placebo or standard of care.
Results: From 6346 citations, 19 studies were included, with an overall low risk of bias. Two RCTs evaluated the use of remdesivir in laboratory-confirmed moderate-to-severe COVID-19. One study found that 10 days of remdesivir was associated with shortened recovery time. Neither found reduction in mortality. One RCT found no association of lopinavir/ritonavir with time to clinical improvement, or mortality benefit. Two RCTs of hydrochloroquine in patients with mild, early disease demonstrated no reduction in disease severity, hospitalization rate, death or viral load. Two RCTs observed no association of hydrochloroquine in hospitalized patients with mild-to-moderate disease with virological clearance, improvement in symptoms, need for respiratory support or death. One RCT showed that the use of steroids was associated with improved survival in patients with moderate-to-severe disease, especially those requiring respiratory support.
Conclusions: There is evidence for the benefit of steroids in patients with moderate-to-severe disease. Remdesivir might shorten recovery time in patients hospitalized with moderate-to-severe disease. There is currently no evidence to support the use of lopinavir/ritonavir or hydrochloroquine.
Study’s Registration: PROSPERO CRD42020184433.
... supplementary Appendix G for table of papers used).[25,32,33,34,35,36,37,38,24,39,40, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95] ...
Background: Since the emergence of COVID-19, tens of millions of people have been infected, and the global death toll approached 1 million by September 2020. Understanding the transmission dynamics of emerging pathogens, such as SARS-CoV-2 and other novel human coronaviruses is imperative in designing effective control measures. Viral load contributes to the transmission potential of the virus, but findings around the temporal viral load dynamics, particularly the peak of transmission potential, remain inconsistent across studies due to limited sample sizes.
Methods: We searched PubMed through June 8th 2020 and collated unique individual-patient data (IPD) from papers reporting temporal viral load and shedding data from coronaviruses. We analyzed viral load trajectories using a series of generalized additive models, and the duration of viral shedding by fitting log-normal models accounting for interval censoring.
Results: We identified 115 relevant papers and obtained data from 66 (57.4%) - representing a total of 1198 patients across 14 countries. SARS-CoV-2 viral load peaks prior to symptom onset and remains elevated for up to three weeks, while MERS-CoV and SARS-CoV viral loads peak after symptom onset. SARS-CoV-2, MERS-CoV, and SARS-CoV had median viral shedding durations of 4.8, 4.2, and 1.2 days after symptom onset. Disease severity, age, and specimen type all have an effect on viral load, but sex does not.
Discussion: Using a pooled analysis of the largest collection of IPD on viral load to date, we are the first to report that SARS-CoV-2 viral load peaks prior to -- not at -- symptom onset. Detailed estimation of the trajectories of viral load and virus shedding can inform the transmission, mathematical modeling, and clinical implications of SARS-CoV-2, MERS, and SARS infection.
... Sometimes, IFNα is used as a combined regimen with ribavirin, although the beneficial effect of these therapies is not fully understood [145,146]. The protease inhibitors lopinavir and ritonavir may lead to improved outcomes for SARS patients when used in combination with ribavirin [147]. ...
Disease fatality associated with Ebola, SARS-CoV and dengue infections in humans is attributed to a cytokine storm that is triggered by excessive pro-inflammatory responses. Interleukin (IL)-6 acts as a mediator between pro- and anti-inflammatory reactivity by initiating trans- and classical-signaling, respectively. Hence, IL-6 is assumed to provide a target for a broad range of antiviral agents. Available immunosuppressive antivirals are directed to control an often exaggerated pro-inflammatory response that gives rise to complex clinical conditions such as lymphocytopenia. It is known that IL-6, via its soluble receptor (sIL-6R), initiates a pro-inflammatory response while an anti-inflammatory response is triggered by the membrane-bound IL-6 receptor (IL-6R). Future antivirals should thus aim to target the mechanism that regulates switching between IL-6 trans- and classical-signaling. In this review, we propose that the tumour necrosis factor-α converting enzyme ADAM-17 could be the master molecule involved in regulating IL-6 class switching and through this in controlling pro- and anti-inflammatory responses to viral antigenic stimuli. Therefore, ADAM-17 should be considered as a potential target molecule for novel antiviral drug discovery that would regulate host reactivity to infection and thereby limit or prevent fatal outcomes.
... 356 Antivirus antibodies could be detected in the plasma of convalescent patients' infected SARS-CoV and MERS-CoV. 357,358 Convalescent plasma therapy has been applicated in treating patients infected by numerous viruses involving Ebola virus, Junin virus, Machupo virus, and Lassa fever. [359][360][361][362] As for SARS-CoV, higher day-22 discharge rate and lower mortality rate have been observed among SARS patients who received convalescent plasma transfusion before day 14 of the illness. ...
Coronaviruses (CoVs), a subfamily of coronavirinae, are a panel of single‐stranded RNA virus. Human coronavirus (HCoV) strains (HCoV‐229E, HCoV‐OC43, HCoV‐HKU1, HCoV‐NL63) usually cause mild upper respiratory diseases and are believed to be harmless. However, other HCoVs, associated with severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID‐19, have been identified as important pathogens due to their potent infectivity and lethality worldwide. Moreover, currently, no effective antiviral drugs treatments are available so far. In this review, we summarize the biological characters of HCoVs, their association with human diseases, and current therapeutic options for the three severe HCoVs. We also highlight the discussion about novel treatment strategies for HCoVs infections. Current mechanisms of anti‐CoV therapeutic strategies. The idea to disturb the normal life cycle of the virus provides significant insights into the clinical treatment strategies. All of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 encode structure proteins (like S protein), nonstructure proteins (eg, PLpro, 3CLpro, RdRp, and helicase), and accessory proteins that are essential for the viral life cycle and that are considered as important targets for the development of antiviral agents. Additionally, enhancement of INF response and several other cell signaling pathways are also regarded as potential anti‐CoV strategies.
... During the acute phase of illness (1-7 days), detectable specific antibody responses against coronaviral infections were rarely observed [75][76][77]. Marked augmentations in antibody titers were observed after the second or third week of infection due to HCoV-229E, MERS-CoV, and SARS-CoV infections [78][79][80][81]. In case of SARS-CoV, a very long immunological response was observed. ...
... With respect to drug repurposing, the combination of lopinavir and ritonavir (Kaletra®), which represents a co-formulation of protease inhibitors approved by the US FDA for the treatment of human immunodeficiency (HIV) type-1 infection (Chandwani and Shuter, 2008). The aspartate protease inhibitors, were shown to have modest antiviral effects against SARS-CoV-1 and MERS-CoV (Chu et al., 2004, Spanakis et al., 2014. Although there is interest, in the potential of lopinavir and ritonavirwhich have been investigated for their binding to the SARS-CoV-2 M profor the treatment of COVID-19 findings from clinical trials to date are not encouraging (Muralidharan et al., 2020;Cao et al., 2020;Hung et al., 2020). ...
The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (Mpro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised
by the dimerization of two monomers each which contains the catalytic dyad defined by Cys145 and His41 residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the Mpro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually
indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the Mpro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the Mpro active site and any potential allosteric sites.
... Similarly, ribavirin was used during the MERS-CoV outbreak and showed no improvement of clinical outcome, even if combined with IFN α2a, IFN α2b, or IFN β1a. A combination of ribavirin, lopinavir/ritonavir and IFN α2a proved effective in one patient with severe MERS, who had resolved viremia two days after the onset of treatment Introduction : Treatments and vaccines (Spanakis et al., 2014). The use of corticosteroids showed no improvement of the clinical outcome regardless of the combination with antivirals or IFNs. ...
Coronaviruses are an important family of emerging pathogens, as shown by therecent emergence of pathogenic SARS-CoV (Severe acute respiratory syndromecoronavirus) and MERS-CoV (Middle-East respiratory syndrome coronavirus) in the lasttwo decades. There are still some knowledge gaps concerning the biology ofcoronaviruses and we do not have any specific treatment or vaccine.Among the four structural proteins of the virus, the M protein is considered to bethe motor of viral assembly. Expressed alone in cells, M proteins can go beyond theassembly site of the virus (Endoplasmic reticulum-Golgi intermediate compartment,ERGIC) in the secretory pathway. We confirmed MERS-M localization in the Trans-Golginetwork (TGN) and identified two signals involved in its intracellular trafficking in its Cterminaldomain: a DxE ER export signal, and a KxGxYR TGN retention signal. The DxEsignal was already identified on another viral protein, whereas the KxGxYR signal is anew motif. To confirm the role of KxGxYR signal in TGN retention, we constructedchimeras between MERS-M and the protein M of the Infectious bronchitis virus (IBV),located in the ERGIC. Our results suggest that for both MERS-M and IBV-M the Cterminaldomain is determinant for the specific localization of the proteins.We also initiated a project on the characterization of the antiviral activity ofdigoxigenin against HCoV-229E. Our results demonstrated that it inhibits HCoV-229E ata post-entry step, with an IC50 of 250nM, and that it is not toxic at this concentration.Digoxigenin also inhibits hepatitis C virus (HCV) and likely has an effect on an early stepof replication of RNA (+) viruses.
... Diarrhea, vomiting, and rash are the most common adverse reactions of LPV/r [98]. The most frequently reported adverse reactions in patients who received LPV were diarrhea, nausea, and asthenia [99]. The changes in laboratory findings included high levels of total bilirubin, triglyceride, and hepatic enzyme activities have also been reported [100,101]. ...
The viral infection due to the new coronavirus or coronavirus disease 2019 (COVID-19), which was reported for the first time in December 2019, was named by the World Health Organization (WHO) as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2), because of the very similar genome and also its related symptoms to SARS-CoV1. The ongoing COVID-19 pandemic with significant mortality, morbidity, and socioeconomic impact is considered by the WHO as a global public health emergency. Since there is no specific treatment available for SARS-CoV2 infection, and or COVID-19, several clinical and sub-clinical studies are currently undertaken to find a gold-standard therapeutic regimen with high efficacy and low side effect. Based on the published scientific evidence published to date, we summarized herein the effects of different potential therapies and up-to-date clinical trials. The review is intended to help readers aware of potentially effective COVID-19 treatment and provide useful references for future studies.
... A case was reported in which a patient with MERS-CoV pneumonia improved and showed viral clearance after 6 days of triple antiviral therapy with lopinavir/ritonavir, ribavirin, and pegylated interferon (IFN)-alpha 2a (30). In another case, a patient with MERS-CoV pneumonia who later developed renal failure was started on triple antiviral therapy (lopinavir/ritonavir, ribavirin, and pegylated interferon) and showed resolution of viremia 2 days after treatment initiation, though virus shedding continued, highlighting the importance of starting ribavirin treatment early (31). ...
Background: The recent COVID-19 pandemic sweeping the globe has caused great concern worldwide. Due to the limited evidence available on the dynamics of the virus and effective treatment options available, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a huge impact in terms of morbidity and mortality. The economic impact is still to be assessed.
Aims: The purpose of this article is to review the evidence for the multiple treatment options available, to consider the future of this global pandemic, and to identify some potential options that could revolutionize the treatment of COVID-19. Moreover, this article underscores the sheer importance of repurposing some of the available antiviral and antimicrobial agents that have long been in use so as to have an effective and expeditious response to this widespread pandemic and the need to conduct a multicenter global randomized controlled trial to find an effective single antiviral agent or a cocktail of available antimicrobial agents.
Method: We thoroughly searched and reviewed various case reports, retrospective analyses, and in vitro studies published in PubMed, EMBASE, and Google Scholar regarding the treatment options used for SARS-CoV, MERS-CoV, and SARS-CoV-2 since its outbreak in an attempt to highlight treatments with the most promising results.
Conclusion: We are currently facing one of the worst pandemics in history. Although SARS-CoV-2 is associated with a lower mortality rate than are SARS-CoV and MERS-CoV, its higher infectivity is making it a far more serious threat. Unfortunately, no vaccine against SARS-CoV-2 or effective drug regimen for COVID-19 currently exists. Drug repurposing of available antiviral agents may provide a respite; moreover, a cocktail of antiviral agents may be helpful in treating this disease. Here, we have highlighted a few available antimicrobial agents that could be very effective in treating COVID-19; indeed, a number of trials are underway to detect and confirm the efficacy of these agents.
Middle East respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012 in the Kingdom of Saudi Arabia. Since then, it has been reported from 27 countries, and all cases were epidemiologically linked to the Arabian Peninsula. The transmission of MERS-CoV is thought be either through intra-familial transmission or large healthcare-associated infections, in addition to sporadic isolated cases. The clinical presentation includes asymptomatic, mild cases, and severe fatal disease. The best diagnostic test relies on molecular identification of MERS-CoV by PCR. The mainstay of therapy for patients with MERS relies on supportive care. The MIRACLE study, a randomized controlled trial, utilized lopinavir-ritonavir and interferon-β1b vs. placebo with the start of treatment within 7 days after symptom onset. The study showed a reduction in the 90-day mortality with a relative risk of 0.19 (95% CI, 0.05–0.75). In addition, using a human polyclonal IgG antibody (SAB-301) was safe and well tolerated in phase I clinical trials.
In response to the challenges posed by the coronavirus (COVID-19) pandemic, Ukraine has undergone the necessary legislative changes, harmonized with international approaches, which in turn have led to significant changes in health care practices. The Law of Ukraine “On Amendments to Some Legislative Acts of Ukraine on Provision of Treatment of Coronavirus Disease (COVID-19)” № 539-IX, the Order of the Ministry of Health “On Approval of the Procedure for Prescribing and Using Medicines for the Treatment of Coronavirus Disease (COVID-19)” of 30.06.2020 № 1482, registered in the Ministry of Justice of Ukraine on July 08, 2020 for № 641/34924, establish the conditions of use of registered medicines according to the indications not specified in the instructions for medical use (off label), and unregistered medicines, recommended by the relevant official bodies outside Ukraine for the treatment of COVID-19. In pursuance of legislative acts, the Standard of Emergency Care “Coronavirus Disease (COVID-19)”, the Standards of Medical Care “Coronavirus Disease (COVID-19)”, the Standard of Pharmaceutical Care “Coronavirus Disease (COVID-19)”, the Protocol “Provision of medical care for the treatment of coronavirus disease (COVID-19)” were developed, approved and updated in accordance with the established procedure. At the same time, in order to assist the doctor and the patient in making a rational decision in different clinical situations, a clinical guideline “CLINICAL MANAGEMENT OF PATIENTS WITH COVID-19. “LIVE” CLINICAL INSTRUCTION” was developed – a document containing systematic provisions on medical and medico-social assistance, developed using the methodology of evidence-based medicine on the basis of reliability and proof confirmation. The basis of this clinical guideline is the WHO guideline “Clinical management of COVID-19: interim guidance” (27.05.2020), supplemented by the provisions of other WHO documents, as well as clinical guidelines of Great Britain, Belgium, USA and Australia. This guideline, as a living guideline, is a WHO innovation driven by the urgent need for global collaboration to provide reliable data and guidance emerging in the world as the result of numerous randomized clinical trials on COVID-19. The clinical guideline reflects the sequence of evidence on COVID-19 treatment in the world during a pandemic, on the basis of which the treatment strategy depending on the stage of the disease was formed and the decisions to include and exclude drugs in the protocol for COVID-19 treatment were justified, and will be further updated.
Background
There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials.
Objective
Develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19.
Methods
In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations.
Results
Based on the most recent search conducted on May 31, 2022, the IDSA guideline panel has made 30 recommendations for the treatment and management of the following groups/populations: pre- and post-exposure prophylaxis, ambulatory with mild-to-moderate disease, hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines.
Conclusions
At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were done which provided much needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved which we hope future trials can answer.
Nanomachines hold promise for the next generation of emerging technology; however, nanomachines are not a new concept, viruses, nature's nanomachines, have already existed for thousands of years. In 2019, the whole world has had to come together to confront a life-threatening nanomachine named "SARS-CoV-2", which causes COVID-19 illness. SARS-CoV-2, a smart nanomachine, attaches itself onto the ACE2 and CD147 receptors present on the cell surfaces of the lungs, kidneys, heart, brain, intestines, and testes, etc. and triggers pathogenesis. Cell entry triggers a cascade of inflammatory responses resulting in tissue damage, with the worst affected cases leading to death. SARS-CoV-2 influences several receptors and signalling pathways; therefore, finding a biomaterial that caps these signalling pathways and ligand sites is of interest. This research aimed to compare the similarities and differences between COVID-19 and its elderly sisters', MERS and SARS. Furthermore, we glanced at emerging therapeutics that carry potential in eliminating SARS-CoV-2, and the tissue damage it causes. Simple prophylactic and therapeutic strategies for the treatment of COVID-19 infection have been put forward.
Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is known to suppress the antioxidant system and is likely to aggravate severity of COVID-19, which results in a pro-oxidant response. This possible association has not been explored adequately in human studies. In this research, we report that the occurrence of non-invasive ventilation, intubation or death – all of which are indicative of severe COVID-19, are not significantly different in hospitalized COVID-19 patients with and without G6PDd (4.6 vs. 6.4%, p=0.33). The likelihood of developing any of these severe outcomes were slightly lower in patients with G6PDd after accounting for age, nationality, presence of comorbidities and drug interventions (Odds Ratio: 0.40, 95% confidence intervals: 0.142, 1.148). Further investigation that extends to both, hospitalized and non-hospitalized COVID-19 patients, is warranted to study this potential association.
Background
Lopinavir-ritonavir is a repurposed drug for coronavirus disease-2019 (COVID-19). In this study, a pooled effect of lopinavir-ritonavir on mortality, virological cure, radiological improvement and safety profile in COVID-19 patients has been evaluated.
Methods
The databases were searched for comparative randomized controlled studies evaluating the efficacy and/or safety of lopinavir-ritonavir in COVID-19 patients. The mortality outcome was pooled as a risk difference (RD) with 95% CI. The virological cure, radiological improvement and adverse events were pooled as risk ratio (RR) with 95% CI. All outcomes were pooled using the Mantle-Hanzle method random effect model. The heterogeneity was assessed using the I² test.
Results
Out of 82 full text assessed, seven studies were included in the analysis. The included studies had five different control interventions: supportive care (n = 4), umifenovir (arbidol) (n = 2), navaferon (recombinant anti-tumour and anti-virus protein) (n = 1), lopinavir-ritonavir + novaferon (n = 1) and lopinavir-ritonavir + interferon beta 1b + ribavirin (n = 1). Lopinavir-ritonavir group did not show significant difference in mortality [RD: 0.00 (95% CI: -0.01, 0.02), I² = 0], virological cure [RR: 1.06 (95% CI: 0.85, 1.31), I² = 0%], radiological improvement [RR: 0.81 (95% CI: 0.62, 1.05)] and adverse events [RR: 2.59 (95% CI: 0.17, 38.90), I²= 75%] than supportive care. Similarly, no difference was observed for any efficacy outcomes between lopinavir-ritonavir and other control interventions. We observed significantly high risk of adverse events with lopinavir-ritonavir as compared to umifenovir [RR: 2.96 (95% CI: 1.42-6.18); I² = 0%].
Conclusion
There is no benefit of the addition of lopinavir-ritonavir to the standard care in COVID-19 patients.
Introduction
Currently there is no approved therapeutic entity for coronavirus disease 2019 (COVID-19) and clinicians are primarily relying on drug repurposing. However, findings across studies are widely disparate, making it difficult to draw firm conclusions. Since clinicians need accurate evidence to treat COVID-19, this manuscript systematically analyzed the published and ongoing studies evaluating the pharmacological interventions for COVID-19.
Areas Covered
A systematic search of observational studies and Clinical Trials on the treatment and prevention of COVID-19 was performed by using various databases from inception to December 02, 2020.
Expert Opinion
A total of 460 studies met the inclusion criteria. Of these, 37 were research studies, 386 were ongoing trials and 37 were completed trials. Anti-virals, steroids, anti-malarial, plasma exchange and monoclonal antibodies were the most common treatment modalities used alone or in combination in these studies. However, tocilizumab, plasma exchange and steroids have shown significant improvements in patient’s clinical and radiological status. Tocilizumab reported minimum hospital stay of 2 days along with maximum recovery and patient`s stability rate. Existing literature demonstrate promising results of tocilizumab, plasma exchange and steroids among COVID-19 patients. Nevertheless, these studies are accompanied by several methodological disparities which should be considered while interpreting the results.
In late 2019 a novel coronavirus (SARS-CoV-2) emerged, and has since caused a global pandemic. Understanding the pathogenesis of COVID-19 disease is necessary to inform development of therapeutics, and management of infected patients. Using scRNAseq of blood drawn from SARS-CoV-2 patients, we asked whether SARS-CoV-2 may exploit immune cells as a 'Trojan Horse' to disseminate and access multiple organ systems. Our data suggests that circulating cells are not actively infected with SARS-CoV-2, and do not appear to be a source of viral dissemination.
The Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has gained research attention worldwide, given the current pandemic. Nevertheless, a previous zoonotic and highly pathogenic coronavirus, the Middle East Respiratory Syndrome coronavirus (MERS-CoV), is still causing concern, especially in Saudi Arabia and neighbour countries. The MERS-CoV has been reported from respiratory samples in more than 27 countries, and around 2500 cases have been reported with an approximate fatality rate of 35%. After its emergence in 2012 intermittent, sporadic cases, nosocomial infections and many community clusters of MERS continued to occur in many countries. Human-to-human transmission resulted in the large outbreaks in Saudi Arabia. The inherent genetic variability among various clads of the MERS-CoV might have probably paved the events of cross-species transmission along with changes in the inter-species and intra-species tropism. The current review is drafted using an extensive review of literature on various databases, selecting of publications irrespective of favouring or opposing, assessing the merit of study, the abstraction of data and analysing data. The genome of MERS-CoV contains around thirty thousand nucleotides having seven predicted open reading frames. Spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins are the four main structural proteins. The surface located spike protein (S) of betacoronaviruses has been established to be one of the significant factors in their zoonotic transmission through virus-receptor recognition mediation and subsequent initiation of viral infection. Three regions in Saudi Arabia (KSA), Eastern Province, Riyadh and Makkah were affected severely. The epidemic progression had been the highest in 2014 in Makkah and Riyadh and Eastern Province in 2013. With a lurking epidemic scare, there is a crucial need for effective therapeutic and immunological remedies constructed on sound molecular investigations.
Therapeutic options for coronavirus remain limited. To address this unmet medical need, we screened 5,406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6. Time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI >100), atovaquone, an anti-malarial (TI >34), and ciclosonide, an inhalable corticosteroid (TI >6). Furthermore, utilizing the severe acute respiratory syndrome CoV-2 (SARS-CoV-2), combinations of remedesivir with selected dugs were evaluated, which identified ciclosonide and nelfinavir to be additive and synergistic drugs in vitro, respectively. Together, we screened FDA-approved drugs using patient-derived MERS-CoV, triaged hits to discriminate between early and late viral life cycle inhibitors, confirmed selected drugs using SARS-CoV-2, and demonstrated the added value of selected medications in combination with remedesivir. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.
Convalescent plasma therapy has been implemented in a few cases of severe coronavirus disease 2019. No report about convalescent plasma therapy in treating patients with prolonged positivity of SARS-CoV-2 RNA has been published. In this study, we conducted a retrospective observational study in 27 patients with prolonged positivity of SARS-CoV-2 RNA, the clinical benefit of convalescent plasma therapy were analyzed. qRT-PCR test of SARS-CoV-2 RNA turned negative (≤ 7 days) in a part of patients (early negative group, n = 15) after therapy, others (late negative group, n = 12) turned negative in more than 7 days. Pulmonary imaging improvement was confirmed in 7 patients in early negative group and 8 in late negative group after CP therapy. Viral load decreased in early negative group compared with late negative group at day 3, 5, 7 after implementing convalescent plasma therapy. Patients in early negative group had a shorter median length of hospital stay. In conclusion, convalescent plasma therapy might help eliminate virus and shorten length of hospital stay in patients with prolonged positivity of SARS-CoV-2 RNA.
There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections. On behalf of the PK/PD of Anti-Infectives Study Group (EPASG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID); all authors are affiliated with this group.
We obtained the full genome of Middle East respiratory syndrome coronavirus (MERS-CoV) from a camel in Qatar. This virus is highly similar to the human England/Qatar 1 virus isolated in 2012. The MERS-CoV from the camel efficiently replicated in human cells, providing further evidence for the zoonotic potential of MERS-CoV from camels.
We found serologic evidence for the circulation of Middle East respiratory syndrome coronavirus among dromedary camels in Nigeria, Tunisia, and Ethiopia. Circulation of the virus among dromedaries across broad areas of Africa may indicate that this disease is currently underdiagnosed in humans outside the Arabian Peninsula.
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly recognized transmissible viral infection with high virulence and case fatality rates for which there is no currently defined primary treatment or prophylaxis. Saudi Arabia has the largest reported number of cases so far. Like SARS, MERS-CoV is a coronavirus. Combination therapy with Interferon α-2b and Ribavarin has been used successfully as primary treatment and prophylaxis in SARS. Because of similarities between the two coronaviruses, treatment with Ribavarin and Interferon α-2b has been suggested as a potential therapy for MERS-CoV. Studies in animal models of MERS-CoV have shown the combination of Ribavirin and Interferon α-2b to be effective both as primary treatment and prophylaxis. In this report, we describe for the first time use of this combination as a primary treatment for a patient with MERS-CoV infection and as prophylaxis for his spouse and discuss its possible role.
IMPORTANCE
In most cases of Middle East respiratory syndrome (MERS), the route for human infection with the causative agent, MERS coronavirus (MERS-CoV), is unknown. Antibodies to and viral nucleic acids of MERS-CoV have been found in dromedaries, suggesting the possibility that they may serve as a reservoir or vector for human infection. However, neither whole viral genomic sequence nor infectious virus has been isolated from dromedaries or other animals in Saudi Arabia. Here, we report recovery of MERS-CoV from nasal swabs of dromedaries, demonstrate that MERS-CoV whole-genome consensus sequences from dromedaries and humans are indistinguishable, and show that dromedaries can be simultaneously infected with more than one MERS-CoV. Together with data indicating widespread dromedary infection in the Kingdom of Saudi Arabia, these findings support the plausibility of a role for dromedaries in human infection.
On 18 April 2014, a case of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection was laboratory confirmed in Athens, Greece in a patient returning from Jeddah, Saudi Arabia. Main symptoms upon initial presentation were protracted fever and diarrhoea, during hospitalisation he developed bilateral pneumonia and his condition worsened. During 14 days prior to onset of illness, he had extensive contact with the healthcare environment in Jeddah. Contact tracing revealed 73 contacts, no secondary cases had occurred by 22 April.
Since the initial description of Middle East Respiratory Syndrome-coronavirus (MERS-CoV), the disease has been associated with a high case-fatality rate. There is a lack of proven effective medications for therapy of MERS-CoV. The current knowledge of therapeutic options for MERS-CoV is based on the experience from SARS-CoV and from in vitro studies. In this article we review the different therapeutics available for MERS-CoV from SARS experience, in vitro and animal studies of this emerging disease.
The Middle East respiratory syndrome coronavirus (MERS-CoV) has been reported to have a high case-fatality rate. Currently, there is no specific therapy or vaccine with proven effectiveness for MERS-CoV infections.
A combination of ribavirin and interferon therapy was used for the treatment of five MERS-CoV-positive patients. We reviewed the therapeutic schedule and the outcome of these patients.
All patients were critically ill with acute respiratory distress syndrome treated with adjunctive corticosteroids and were on mechanical ventilation at the time of initiation of therapy. The median time from admission to therapy with ribavirin and interferon was 19 (range 10-22) days. None of the patients responded to the supportive or therapeutic interventions and all died of their illness.
While ribavirin and interferon may be effective in some patients, our practical experience suggests that critically ill patients with multiple comorbidities who are diagnosed late in the course of their illness may not benefit from combination antiviral therapy as preclinical data suggest. There is clearly an urgent need for a novel effective antiviral therapy for this emerging global threat.
The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes symptoms similar to SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus), yet involving an additional component of acute renal failure (ARF) according to several published case reports. Impairment of the kidney is not typically seen in Coronavirus infections. The role of kidney infection in MERS is not understood.
A systematic review of communicated and peer-reviewed case reports revealed differences in descriptions of kidney involvement in MERS versus SARS patients. In particular, ARF in MERS patients occurred considerably earlier after a median time to onset of 11 days (SD +/-2,0 days) as opposed to 20 days for SARS, according to the literature. In-situ histological staining of the respective cellular receptors for MERS- and SARS-Coronavirus showed highly similar staining patterns with a focus of a receptor-specific signal in kidney epithelial cells. Comparative infection experiments with SARS- and MERS-CoV in primary human kidney cells versus primary human bronchial epithelial cells showed cytopathogenic infection only in kidney cells, and only if infected with MERS-CoV. Kidney epithelial cells produced almost 1000-fold more infectious MERS-CoV progeny than bronchial epithelial cells, while only a small difference was seen between cell types when infected with SARS-CoV.
Epidemiological studies should analyze kidney impairment and its characteristics in MERS-CoV. Virus replication in the kidney with potential shedding in urine might constitute a way of transmission, and could explain untraceable transmission chains leading to new cases. Individual patients might benefit from early induction of renoprotective treatment.
In Saudi Arabia, including regions of Riyadh and Al Ahsa, pseudoparticle neutralisation (ppNT) and microneutralisation (MNT) tests detected no antibodies to Middle East Respiratory Syndrome coronavirus (MERS-CoV) in sheep (n= 100), goats (n= 45), cattle (n= 50) and chickens (n= 240). Dromedary camels however, had a high prevalence of MERS-CoV antibodies. Bovine coronavirus (BCoV) infected sera from cattle had no cross-reactivity in MERS-CoV ppNT or MNT, while many dromedary camels’ sera reacted to both BCoV and MERS-CoV. Some nevertheless displayed specific serologic reaction profiles to MERS-CoV.
Between June and September 2013, sera from 11 dromedary camels, 150 goats, 126 sheep and 91 cows were collected in Jordan, where the first human Middle-East respiratory syndrome (MERS) cluster appeared in 2012. All sera were tested for MERS-coronavirus (MERS-CoV) specific antibodies by protein microarray with confirmation by virus neutralisation. Neutralising antibodies were found in all camel sera while sera from goats and cattle tested negative. Although six sheep sera reacted with MERS-CoV antigen, neutralising antibodies were not detected.
The Middle East respiratory syndrome coronavirus (MERS-CoV) presents a novel emerging threat to public health worldwide. Several treatments for infected individuals have been suggested including interferon (IFN), ribavirin, and passive immunotherapy with convalescent plasma. Administration of IFN-α2b and ribavirin has improved outcomes of MERS-CoV infection in rhesus macaques when administered within eight hours post challenge. However, detailed and systematic evidence on the activity of other clinically available drugs is limited. Here we compared the susceptibility of MERS-CoV to different interferon products (IFN-α2b, IFN-γ, IFN-universal, and IFN-α2a, IFN-β) as well as to two antivirals, ribavirin and mycophenolic acid (MPA) against MERS-CoV (Hu/Jordan-N3/2012) in vitro. Out of all IFNs tested, IFN-β had the strongest inhibition of MERS-CoV in vitro, with an IC50 of 1.37 U ml-1, 41 times lower than the previously reported IC50 (56.08 U ml-1) of IFN-α2b. IFN-β inhibition was confirmed in the virus yield reduction assay with an IC90 of 38.8 U ml-1. Ribavirin did not inhibit viral replication in vitro at a dose that would be applicable to current treatment protocols in humans. In contrast, MPA showed strong inhibition with an IC50 = 2.87 µM. This drug has not been previously tested against MERS-CoV and may provide an alternative to ribavirin for treatment of MERS-CoV. In conclusion, IFN-β, MPA, or a combination of the two may be beneficial in the treatment of MERS-CoV or as a post exposure intervention in high risk patients with known exposures to MERS-CoV.
The high mortality associated with the novel Middle East respiratory syndrome coronavirus (MERS-CoV) has raised questions on the possible role of cytokine storm in its pathogenesis. Although recent studies showed that MERS-CoV infection is associated with attenuated interferon response, no induction of inflammatory cytokines was demonstrated during early phase of infection. To study both early and late cytokine responses associated with MERS-CoV infection, we measured the mRNA levels of eight cytokine genes (TNF-α, IL-1β, IL-6, IL-8, IFN-β, MCP-1, TGF-β and IP-10) in cell lysates of polarized airway epithelial, Calu-3, cells infected with MERS-CoV or SARS-CoV up to 30 h post infection. Among the eight cytokine genes, IL-1β, IL-6 and IL-8 induced by MERS-CoV were markedly higher than those induced by SARS-CoV at 30 h, while TNF-α, IFN-β and IP-10 induced by SARS-CoV were markedly higher than those induced by MERS-CoV at 24 and 30 h in infected Calu-3 cells. The activation of IL-8 and attenuated IFN-β response by MERS-CoV were also confirmed by protein measurements in the culture supernatant when compared to SARS-CoV and Sendai virus. To further confirm the attenuated antiviral response, cytokine response was compared to HCoV-229E in embryonal lung fibroblast, HFL, cells, which also revealed higher IFN-β and IP-10 levels induced by HCoV-229E than MERS-CoV at 24 and 30 h. While our data supported recent findings that MERS-CoV elicits attenuated innate immunity, this represents the first report to demonstrate delayed proinflammatory cytokine induction by MERS-CoV. Our results provide insights into the pathogenesis and treatment of MERS-CoV infections.
The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease that recapitulates mild to moderate human MERS-CoV cases. The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.
BACKGROUND
In September 2012, the World Health Organization reported the first cases of pneumonia
caused by the novel Middle East respiratory syndrome coronavirus (MERSCoV).
We describe a cluster of health care–acquired MERS-CoV infections.
METHODS
Medical records were reviewed for clinical and demographic information and determination
of potential contacts and exposures. Case patients and contacts were interviewed.
The incubation period and serial interval (the time between the successive
onset of symptoms in a chain of transmission) were estimated. Viral RNA was
sequenced.
RESULTS
Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were
reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients
(87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal
symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs.
As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered,
and 2 (9%) remained hospitalized. The median incubation period was 5.2 days
(95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95%
CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person
transmission in hemodialysis units, intensive care units, or in-patient units in three
different health care facilities. Sequencing data from four isolates revealed a single
monophyletic clade. Among 217 household contacts and more than 200 health care
worker contacts whom we identified, MERS-CoV infection developed in 5 family
members (3 with laboratory-confirmed cases) and in 2 health care workers (both
with laboratory-confirmed cases).
CONCLUSIONS
Person-to-person transmission of MERS-CoV can occur in health care settings and
may be associated with considerable morbidity. Surveillance and infection-control
measures are critical to a global public health response.
BACKGROUND
In September 2012, the World Health Organization reported the first cases of pneumonia
caused by the novel Middle East respiratory syndrome coronavirus (MERSCoV).
We describe a cluster of health care–acquired MERS-CoV infections.
METHODS
Medical records were reviewed for clinical and demographic information and determination
of potential contacts and exposures. Case patients and contacts were interviewed.
The incubation period and serial interval (the time between the successive
onset of symptoms in a chain of transmission) were estimated. Viral RNA was
sequenced.
RESULTS
Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were
reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients
(87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal
symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs.
As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered,
and 2 (9%) remained hospitalized. The median incubation period was 5.2 days
(95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95%
CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person
transmission in hemodialysis units, intensive care units, or in-patient units in three
different health care facilities. Sequencing data from four isolates revealed a single
monophyletic clade. Among 217 household contacts and more than 200 health care
worker contacts whom we identified, MERS-CoV infection developed in 5 family
members (3 with laboratory-confirmed cases) and in 2 health care workers (both
with laboratory-confirmed cases).
CONCLUSIONS
Person-to-person transmission of MERS-CoV can occur in health care settings and
may be associated with considerable morbidity. Surveillance and infection-control
measures are critical to a global public health response.
The identification of a novel β coronavirus, nCoV, as the causative agent of severe respiratory illness in humans originating in Saudi Arabia, Qatar and Jordan has raised concerns about the possibility of a coronavirus pandemic similar to that of SARS-CoV. As a definitive treatment regimen has never been thoroughly evaluated for coronavirus infections, there is an urgent need to rapidly identify potential therapeutics to address future cases of nCoV. To determine an intervention strategy, the effect of interferon-α2b and ribavirin on nCoV isolate hCoV-EMC/2012 replication in Vero and LLC-MK2 cells was evaluated. hCoV-EMC/2012 was sensitive to both interferon-α2b and ribavirin alone in Vero and LLC-MK2 cells, but only at relatively high concentrations; however, when combined, lower concentrations of interferon-α2b and ribavirin achieved comparable endpoints. Thus, a combination of interferon-α2b and ribavirin, which are already commonly used in the clinic, may be useful for patient management in the event of future nCoV infections.
The recent emergence of a novel human coronavirus (HCoV-EMC) in the Middle East raised considerable concerns, as it is associated with severe acute pneumonia, renal failure, and fatal outcome and thus resembles the clinical presentation of severe acute respiratory syndrome (SARS) observed in 2002 and 2003. Like SARS-CoV, HCoV-EMC is of zoonotic origin and closely related to bat coronaviruses. The human airway epithelium (HAE) represents the entry point and primary target tissue for respiratory viruses and is highly relevant for assessing the zoonotic potential of emerging respiratory viruses, such as HCoV-EMC. Here, we show that pseudostratified HAE cultures derived from different donors are highly permissive to HCoV-EMC infection, and by using reverse transcription (RT)-PCR and RNAseq data, we experimentally determined the identity of seven HCoV-EMC subgenomic mRNAs. Although the HAE cells were readily responsive to type I and type III interferon (IFN), we observed neither a pronounced inflammatory cytokine nor any detectable IFN responses following HCoV-EMC, SARS-CoV, or HCoV-229E infection, suggesting that innate immune evasion mechanisms and putative IFN antagonists of HCoV-EMC are operational in the new host. Importantly, however, we demonstrate that both type I and type III IFN can efficiently reduce HCoV-EMC replication in HAE cultures, providing a possible treatment option in cases of suspected HCoV-EMC infection.
We present a rigorously validated and highly sensitive confirmatory real-time RT-PCR assay (1A assay) that can be used in combination with the previously reported upE assay. Two additional RT-PCR assays for sequencing are described, targeting the RdRp gene (RdRpSeq assay) and N gene (NSeq assay), where an insertion/deletion polymorphism might exist among different hCoV-EMC strains. Finally, a simplified and biologically safe protocol for detection of antibody response by immunofluorescence microscopy was developed using convalescent patient serum.
We present a rigorously validated and highly sensitive confirmatory real-time RT-PCR assay (1A assay) that can be used in combination with the previously reported upE assay. Two additional RT-PCR assays for sequencing are described, targeting the RdRp gene (RdRpSeq assay) and N gene (NSeq assay), where an insertion/deletion polymorphism might exist among different hCoV-EMC strains. Finally, a simplified and biologically safe protocol for detection of antibody response by immunofluorescence microscopy was developed using convalescent patient serum.
We present two real-time reverse-transcription polymerase chain reaction assays for a novel human coronavirus (CoV), targeting regions upstream of the E gene (upE) or within open reading frame (ORF)1b, respectively. Sensitivity for upE is 3.4 copies per reaction (95% confidence interval (CI): 2.5–6.9 copies) or 291 copies/mL of sample. No cross-reactivity was observed with coronaviruses OC43, NL63, 229E, SARS-CoV, nor with 92 clinical specimens containing common human respiratory viruses. We recommend using upE for screening and ORF1b for confirmation
This study investigated the long-term excretion of severe acute respiratory syndrome-associated coronavirus in sputum and stool specimens from 56 infected patients. The median (range) duration of virus excretion in sputa and stools was 21 (14-52) and 27 (16-126) days, respectively. Coexisting illness or conditions were associated with longer viral excretion in stools.
The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents.
The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls.
In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 micro g/ml and 50 micro g/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls-both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)-but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level.
The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.
Background Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe lower respiratory tract infection in people. Previous studies suggested dromedary camels were a reservoir for this virus. We tested for the presence of MERS-CoV in dromedary camels from a farm in Qatar linked to two human cases of the infection in October, 2013.
Background: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. Methods: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. Results: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 µg/ml and 50 µg/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls—both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)—but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level. Conclusions: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.
Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited.
To describe the critical illness associated with MERS-CoV.
Case series.
3 intensive care units (ICUs) at 2 tertiary care hospitals in Saudi Arabia.
12 patients with confirmed or probable MERS-CoV infection.
Presenting symptoms, comorbid condition, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure.
Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a healthcare-associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16-36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive.
The sample size was small.
MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extrapulmonary organ dysfunction and is associated with high mortality. Community-acquired and healthcare-associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The healthcare-associated cluster suggests that human-to-human transmission does occur with unprotected exposure.
None.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe lower respiratory tract infection in people. Previous studies suggested dromedary camels were a reservoir for this virus. We tested for the presence of MERS-CoV in dromedary camels from a farm in Qatar linked to two human cases of the infection in October, 2013.
We took nose swabs, rectal swabs, and blood samples from all camels on the Qatari farm. We tested swabs with RT-PCR, with amplification targeting the E gene (upE), nucleocapsid (N) gene, and open reading frame (ORF) 1a. PCR positive samples were tested by different MERS-CoV specific PCRs and obtained sequences were used for phylogentic analysis together with sequences from the linked human cases and other human cases. We tested serum samples from the camels for IgG immunofluorescence assay, protein microarray, and virus neutralisation assay.
We obtained samples from 14 camels on Oct 17, 2013. We detected MERS-CoV in nose swabs from three camels by three independent RT-PCRs and sequencing. The nucleotide sequence of an ORF1a fragment (940 nucleotides) and a 4·2 kb concatenated fragment were very similar to the MERS-CoV from two human cases on the same farm and a MERS-CoV isolate from Hafr-Al-Batin. Eight additional camel nose swabs were positive on one or more RT-PCRs, but could not be confirmed by sequencing. All camels had MERS-CoV spike-binding antibodies that correlated well with the presence of neutralising antibodies to MERS-CoV.
Our study provides virological confirmation of MERS-CoV in camels and suggests a recent outbreak affecting both human beings and camels. We cannot conclude whether the people on the farm were infected by the camels or vice versa, or if a third source was responsible.
European Union projects EMPERIE (contract number 223498), ANTIGONE (contract number 278976), and the VIRGO consortium.
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been detected in a number of countries in the Middle East and Europe with an apparently high mortality rate. It is phylogenetically related to the SARS coronavirus and has also been associated with severe respiratory illness as well as nosocomial transmission in healthcare settings. Current international recommendations do not support any specific therapies; however, there are a number of agents, which were used during the SARS epidemic of 2003. It is possible that these might be active against the related MERS coronavirus. We have reviewed the literature on the safety and efficacy of therapies used in patients with SARS with a view to their potential use in patients with MERS-CoV infections.
A new betacoronavirus-Middle East respiratory syndrome coronavirus (MERS-CoV)-has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock.
We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus.
50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies.
MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection.
European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.
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