COVID-19 is the largest outbreak to strike humanity. The wide scale of fatalities and morbidities lead to a concurrent pandemic of uncertainty in scientific evidence. Conflicting evidences are released on daily basis about the neonatal outcomes of COVID-19-positive mothers. The aim of this study was to use the relevant case reports and series to determine the percentage of newborns who test positive for COVID-19 who are born to COVID-19-positive mothers. Secondary outcomes included examining laboratory abnormalities among COVID-19-positive neonates, and any depicted placental abnormalities in COVID-19-positive mothers. For this purpose, systematic review was performed on all studies reporting primary data on fetus-mother pairs with COVID-19. Data bases were searched for studies that met our inclusion and exclusion criteria.Final screening revealed 67 studies, from which the primary data of 1787 COVID-19 mothers were identified and had their pregnancy outcome analyzed. Only 2.8% of infants born to COVID-19-positive mothers tested positive, and this finding is identical to percentages reported in former Coronaviridae outbreaks, whereas 20% manifested with intrauterine hypoxia alongside placental abnormalities suggestive of heavy placental vaso-occlusive involvement.These findings suggest that while vertical transmission is unlikely, there appears to be an underlying risk of placental insufficiency due to the prothrombotic tendency observed in COVID-19 infection. Guidelines for proper prophylactic anticoagulation in COVID-positive mothers need to be established. COVID-19 (coronavirus disease 2019), which has been declared a pandemic in March 2020, has caused an unprecedented uncertainty within the scientific community. Contradictory scientific evidences are released almost every day, on every aspect of the pandemic from its pathogenesis, to the methods of transmission, and to the possible compassionate use of medications to combat it. Transplacental transmission of COVID-19 is one of the topics that have raised conflicting evidences across the globe. The dilemma about transplacental transmission of Coronaviridae is not exclusive to the current outbreak. To our knowledge, nine studies  reportedThis systematic review has been conducted in agreement with the guidelines of the PRISMA Statement  .A computer run has been performed in EMBASE, MEDLINE, and the Cochrane Central Register (From 1 November 2019 to 1 of August 2020). The following terms were included in the search: “COVID-19” OR “SARS-CoV-2” (Severe Acute Respiratory syndrome Coronaviridae 2) AND “Pregnancy” AND “Perinatal”.Population: Pregnant womenIntervention: COVID-19Comparison: No comparison has been a purpose of the studyOutcome: Neonatal infection by COVID-19, placental abnormalities, laboratory abnormalities in the newborn.Observational epidemiological studies and case reports addressing the clinical conditions of mother–fetus pairs. Primary data of patients over 18 years old were considered eligible. Manuscripts that contained only data from pregnant women, or only fetuses, or that did not address the period of delivery, such as puerperium, were disregarded. All data from eligible studies were extracted by 2 independent investigators according to a standard protocol.n) and percentages. Cases where evidence of placental thrombotic process have been detected and in which maternal co-morbidities were mentioned (whether ruled out or confirmed/n = 17) have been analyzed using receiver operating characteristic (ROC) analysis, and Fig. P value of 0.6.Each of the maternal manifestations, neonatal manifestations, placental microscopic and macroscopic changes, and laboratory changes in COVID-19-positive newborns was quantified and expressed as number (The literature search identified initially 114 studies, of which 50 studies were excluded. Twenty three were excluded as they did not tackle the primary outcome parameter of the study; while 27 studies were excluded due to repetition. Total number of studies included was 64 studies, comprising 1787 Mother-infant pair –76. (PRIThe studies carried out in 15 countries are listed in Table These data are further analyzed in Table Table Table Figure Bias assessment was performed using the Cochrane revised tool for bias assessment and illustrated  in Fig. Vertical transmission of COVID-19 follows the same pattern of uncertainty as almost everything concerning COVID-19. New evidences being unraveled every day make meta-analysis the only possible solution to reach consensus about points of dilemma.This report is by far the largest systematic review to be implemented in this context, not only regarding the number of mother-infant pairs, but also the targeted outcome parameters. The largest report preceding us is Lopes de Sousa et al.’s report . Lopes dOur study confirmed the previous impression from the former outbreaks by CoV that transplacental transmission is very unlikely occurring in 2.8% of all positive mothers. Despite being unlikely, it has been reported to happen and this should warrant further studies on the mechanisms underlying the variability of vertical transmission from pregnancy to another.The commonest laboratory finding in affected neonates was lymphopenia. This finding goes in agreement with the same pattern of haematologic abnormalities encountered in adult patients. The programmed cell death receptor 1 secreted from macrophages in the lung environment as well as from resident T cells leads finally to T cell exhaustion with subsequent lymphopenia in affected patients.P value of 0.6. Moreover, 7 cases were born premature in Shanes et al. series [The most intriguing finding uncovered in our review is the strong evidence pointing towards placental damage with subsequent intrauterine hypoxia of the fetus. This finding was supported at several stages in our study. As mentioned earlier, 20% of all infants in whom manifestations have been reported have showed evidence of intrauterine hypoxia. Placental damage could not be attributed to maternal co-morbidities as proven by the ROC analysis performed which showed that maternal co-morbidities failed to predict the occurrence of placental vascular compromise with an insignificant . series , all of A report by Wang and colleagues  suggesteThis old evidence of longstanding viremia might explain the observed placental damage, as placenta is a heavily vascularized organ; however, more studies should correlate the degree of placental damage with the duration and degree of viremia.st trimester, while defective proliferation and formation of villi was observed in a similar percentage of cases.Placental changes were more prevalent than COVID-19-positive neonates, 62 vs. 45 respectively, out of which 64% showed evidence of ischemia. Placental changes encountered seemed to mirror the timeline at which infection was detected in COVID-19-positive mothers. Three percent of mothers were infected in the 1Defective formation of villi can be accounted due to the role played by an intracellular enzyme termed Furin in the genesis of placental villi –83. AbdeThe findings of our study also go in agreement with that of Cardenas and colleagues; Cardenas et al proved that viruses that do not exhibit vertical transmission might cause placental damage. They also proved that viral infection of the placenta can elicit a fetal inflammatory response that, in turn, can cause organ damage and potentially downstream developmental anomalies. Furthermore, we demonstrate that viral infection of the placenta may sensitize the pregnant mother to bacterial products and promote preterm labor .One of the final reports included in our review concluded that vertical transmission is unlikely in COVID-19. The case/control study performed by Edlow and colleagues showed that placental malperfusion even without gross visible pathology in the placenta is not uncommon event, with resultant risk of fetal distress .In view of the above findings, proper hydration and prophylactic anticoagulation might be needed for COVID-19 pregnant women, especially those whose tests suggest strong prothrombotic tendency such as elevated D-Dimer, or those whose abdominal ultrasound and fetal cardiotocography offer a strong evidence of placental insufficiency. The guidelines of several obstetrics and gynecological international societies were clustered by D’Souza et al. and were in agreement with our suggestions .Fetal hypoxia can also impact neonatal outcome. Meconium staining with subsequent risk of meconium aspiration is particularly prevalent in pregnancies complicated with fetal hypoxia. Anticipation of meconium staining in pregnancies complicated by COVID-19 would be highly indicated to neonatologists in the delivery room . MoreoveThe sampling time was not reported in 31% of cases which is a non-negligible number putting a huge risk of reporting bias. Forty two percent of positive newborns were tested in the first 12 h after delivery while the remainder 58% of cases were tested after 12 h, raising suspicion of possible postnatal infection.The lack of homogenous outcome parameter illustrated in Fig. The aggregated data in this systematic review are by far the largest to date regarding neonatal outcomes of COVID-19. Results suggest that vertical transmission of COVID-19 is unlikely as it occurred in 2.8% of neonates but underlines an important and underestimated risk, which is the possible placental insufficiency due to the prothrombotic tendency created by COVID-19. These findings should warrant more case/control studies to compare placental abnormalities with the duration and degree of viremia. Also thorough antenatal care should be offered to COVID-19-positive mothers to evaluate their prothrombotic tendency and to monitor their need for anticoagulation. Finally, yet importantly, complications such as meconium aspiration and PPHN should be compared in COVID-19-positive vs. COVID-19-negative mothers and should be anticipated by neonatologists in the delivery room and during follow-up after delivery.


Road Traffic Injuries (RTIs) impose a worldwide burden on public health and economy. RTIs result in a wide range of immediate and long-term consequences. However, little is known about post-discharge consequences of RTIs at national levels. In addition, reliable and producing valid data mostly through prospective studies is fundamentally required to address the issue. The aim of this paper was to describe the research protocol for development and psychometric evaluation of post-discharge consequences of road traffic injuries as part of the Persian Traffic Cohort (PTC) and complementary to the Iranian Integrated Road Traffic Injury Registry (IRTIR).Literature review and expert’s opinion were used to develop data collection tools. Registry timeframe was designed based on experts’ opinion. Reliability of tools will be assessed using intra- and inter-rater reliability. The pilot phase of the Phone interviews on Post-discharge Consequences of Road Traffic Injuries (PCRTI) will be conducted in Tabriz in 2019.The PCRTI is designed to be applied at three different time points: one, six and twelve months after the crash. The PCRTI tools’ main domains are: demographic, psychological, medical, social and financial which will be assessed through PC-PTSD, PHQ2, WHODAS, SES-Iran, EQ-5D-3L and Economic assessment standardized tools. The descriptive outcomes will be reported to the Ministry of Health and Medical Education of Iran.The protocol satisfies the requirements of developing valid data collection tools for PCRTI. Moreover, the impact of RTIs on economic are estimated to be between 1% to 3% of the counties’ gross national product.6 Studies showed that the quality of life (QoL) of road traffic victims significantly decrease following the crash and majority of them never reach the general population standards of QoL.7 RTIs are major portion of injuries and the third leading cause of death in Iran. Years of healthy life lost due to RTIs estimated to be 1.2 million years.8 A study in Iran estimated the cost of road traffic injuries and death to be 6.46% of gross national income.9 Nevertheless, the real cost of road traffic crashes in Iran seems to be much higher than the stated figure. It should also include cost to the roadway infrastructure as well as to the vehicle itself. Costs related to lost-income in death, hospitalization or physical disability are estimated 1.4 billion US dollar. 10 However, researches on road traffic crashes (RTCs) predominantly focused on immediate and severe outcomes, a large number of road traffic victims suffer from permanent disabilities, functional impairments and psychological problems.14Road Traffic Injuries (RTIs) are a global public health problem and major leading cause of death and disability around the world.15 Trauma registries in high-income countries verified to be beneficial at identifying risk factors and subsequent injury outcomes and determining defects and gaps in care services.17 However, data sources in Low- and Middle-Income Countries (LMICs), including Iran, are often of poor quality, contain an insufficient number of relevant elements or have difficulty to be assessed which had resulted in weak estimation of morbidity and consequences of road traffic crashes.8Sustainable and significant reduction in RTIs requires reliable and accurate data to inform policy makers, set priority, manage strategies, facilitate cooperation, optimize post-crash services and tack appropriate actions.18 are scant in Iran. Little is known about post-discharge consequences of road traffic crashes. As the integrated road traffic injury registry is implemented in East Azerbaijan of Iran and the Persian Traffic Cohort is at the same time being implemented in East Azerbaijan capital, there was a profound need for developing valid tools in order to collect data on crash outcomes for post-discharge follow-up of crash victims. As a part of the Persian Traffic Cohort (PTC) and complementary to the Iranian Integrated Road Traffic Injury Registry (IRTIR), the aim of this paper was to describe the research protocol for development and psychometric evaluation of the phone interview measurement tools for post-discharge consequences of road traffic injuries.Although different organizations or research studies in Iran are gathering road traffic data in Iran, these data mostly limited to crash scene data, pre-hospital and hospital data. Valid and reliable post-crash data, which are fundamentally required for an effective post-crash response,Persian Traffic CohortThe Persian Traffic Cohort is the national prospective cohort on road safety and traffic injuries established in Iran to quantify the health effects related with road safety. This cohort is also a parallel contribution to the national population-based study of PERSIAN Cohort. PTC is comprised of two main sections namely Pre-crash Cohort and Post-crash Cohort. Iranian Integrated Road Traffic Injury Registry (IRTIR)Iranian Integrated Road Traffic Injury Registry is a comprehensive national road traffic injury registry. Different organizations collaborate in this registry including: Police, Forensic medicine organization, Ministry of Health and Medical Education (MoHME) and Iranian Red Crescent Organization. Each one of these organizations collects road traffic data at a particular station. Then the data will be integrated through an electronic system. IRTIR study was financially supported by Ministry of Health & Medical Education through the contract number 700-1482 95-10-4 between MOH and Tabriz University of Medical Sciences.Study protocolStudy settings and participants19 The post-discharge registry eligibility criteria will be as follows: being inpatient for at least 24 hours, all types of road traffic crash injuries, all types of road users and having a registered telephone number. The PCRTI will be conducted through phone interviews. Trained coders will explain the study purpose to road traffic victims and will receive informed verbal consent. For children under the age of 18, informed consent will be sought out from their parents or his/her legal guardian. Data will be collected via three separate structured data collection tool packages through telephone interviews. If the victim is unable to answer because of health problems or other disabilities, the most informant family member will be interviewed.The pilot phase of PCRTI project will be conducted in Tabriz in two referral trauma hospitals . Study Participants will be selected from road traffic victims who admitted into trauma hospitals. Baseline road traffic injury data will be extracted from IRTIR databank. Baseline data are being collected through face to face interview at nursing station of integrated road traffic injury registry (IRTIR). The data includes description of the crash, victim’s demographics, crash’s environment data, vehicle-related data and the injured person’s behavior data. Details of development and psychometrics of baseline nursing station data collection tool of IRTIR is provided elsewhere.Developing PCRTI data collection variables and toolsA comprehensive literature review was done to identify the most important consequences due to road traffic crashes. Main domains and minimum data variables for PCRTI were defined based on literature review and experts’ opinion and the preliminary data collection tool packages were developed. Post-discharge follow-up time-frameThe timeframe was discussed in a panel of 12 experts who were from different academic backgrounds including epidemiology, medical informatics, medical, psychology, psychiatry, healthcare management, health economics, and forensic medicine. The research group reached a consensus on follow-up timeframe at 1, 6 and 12 months after the crash date.• One month after the traffic crash • Six months after the traffic crash • Twelve months after the traffic crash 14 Besides, the first month after the crash and injuries is the period when major health outcomes occurs. 2- According to previous research, most of road traffic victims might be adapted to post-crash condition or their health status have recovered six months after the traffic crash.22 3- The influence of RTI on health related quality of life and socioeconomic conditions may not be apparent in short- and medium-term periods. Therefore long-term assessments are also required. Previous studies showed no further improvement in health status after 12 months.24The expert panel chose this timeframe because of the following reasons: 1- It is recommended that deaths within 30 days post-crash to be considered as road traffic fatality.Reliability AssessmentReliability of data collection tool packages will assess using intra- and inter-rater reliability method. Data management and reporting Data will be entered into IRTIR and PTC electronic linkage database and will be integrated with baseline data. In order to report public health and economic outcomes of RTIs, descriptive and analytical statistics will be reported to the ministry of health and medical education every six month. Data collection tool packagesSince there were valid and reliable scales in registry’s desired domains, there was no need to develop new tools. Therefore, researchers only designed data collection tool packages suitable for follow-up time points. Three different time points were distinguished to be meaningful for PCRTIs based on experts’ perspectives. The registry time points were as follows:The main domains, time points and contents of each PCRTI data collection tool-package are shown in MeasuresPost-Traumatic Stress Disorder25 The PC-PTSD has high diagnostic efficiency. The screening has showed good test-retest reliability (r=80), high sensitivity (0.91%) and specificity (0.80).26Post-traumatic stress disorder (PTSD) will be assessed using Primary Care Post-Traumatic Stress Disorder (PC-PTSD) which is a 4-item yes/no screening questionnaire designed for use in primary care and other medical settings. The instrument includes an introductory sentence to point respondents to traumatic events.Depression27The 2-item Patient Health Questionnaire (PHQ2) has been recommended for depression screening in first step approach. PHQ-2 includes the first two items of PHQ-9. The PHQ-2 asks respondents to estimate frequency of major depression and anhedonia symptoms over the past two weeks, scoring each mood from 0  to 3 (nearly every day).Disability and functioning28 Administration time for 12-item WHO-DAS is less than five minutes.29 The full version is considered to be used for yearly face to face interviewed assessments needed in PTC. World Health Organization Disability Assessment Schedule (WHODAS) 12-item version was selected to be used in order to assess the overall functioning and disability. The scale covers six life domains including: cognitive, mobility, self-care, interacting with other people, life activities and participation in community activities.Health Related Quality of Life30 The tool covers most of the important domains of disability and has other practical advantages such as brevity, being applicable in all kinds of road traumas as well as being applicable in various age groups and recommended by previous injury-related outcomes study.31Health Related Quality of Life (HRQoL) of road traffic victims were assessed using Euro Quality of Life five-dimension three-level (EQ-5D-3L).Socio-Economic Status33Socio-economic status is assessed using ultra short version of socio-economic status tool for health studies in Iran (SES-Iran). The SES ultra-short version was comprised of six items as follows: occupation, years of education, household income per month, financial value of private car and housing.Economic Impact35 which contained hospitalization, physician visits, diagnostic care , medications and rehabilitation as direct medical costs, and travel, accommodation, vehicle damage and any other non- medical expenses resulted by RTIs as direct non-medical costs. The micro-costing approach was used to calculate the direct costs. 36 Indirect costs present the lifetime earnings foregone as the result of a RTI; therefore, the amount of lost working days was asked from the patients and then the indirect cost was calculated using the Human Capital Approach.37 Assessing the economic Impact of RTIs was applied to 1-monrh and 6-month follow up data collection tools. In our study, three cost components including direct medical costs, direct non-medical costs, and indirect costs are estimated to indicate the economic burden of RTIs on victims. Direct costs is assessed through a validated Iranian questionnaireEmployment statusTo reach a better understanding of how RTIs can economically affect the victims’ lives, any changes in their employment status after the crash will be asked through a scale of losing the job, changing the job to another, the same job with lower function, and the same job without any changes. Also the patients were asked to state their purchasing power after the crash as if the costs resulted by RTIs could change it than before or not.These tools are selected because they are short, simple, and easy to administer, applicable through phone interview, and general interview techniques are sufficient to administer these tools, therefore they are appropriate for the registry purposes.


Across Africa, there is some evidence of COVID-19 private sector activities to tackle COVID-19 which include the development of rapid diagnostic kits, deployment of e-health platforms for bespoke health workforce training, disease surveillance, reporting, auto-screening and advisories. Inequities in living and access to care by disadvantaged populations in the rural areas have been ameliorated by multi-pronged responses such as that mounted by the Joseph Ukpo Hospitals and Research Institute (JUHRI) in Nigeria. The provision, production and donation of personal protective equipment (PPE), the production of hand sanitizers and the engagement of the local community in the process represents an effective strategy to contain COVID-19, protect health workers and provide pathways for economic support for people whose sources of income have been upended during the pandemic. The JUHRI experience underpinned by Catholic medical ethics provides concrete evidence of the value of private sector participation in dealing with public health emergencies. COVID-19: humankind is facing its greatest existential threat: against the background of the fragile health systems and inadequate health financing in Africa, the need for private sector participation in controlling a public health emergency has never been so dire as with the SARS-CoV-2 (COVID-19) pandemic. COVID-19 has brought the capacity of governments, even of the resource-rich nations, to deal with a global health crisis that has killed well over half a million people [th February 2021 [n people . Africa´n people . In 2020n people . COVID-1ary 2021 . The emeary 2021 . With thary 2021  but the Does the private sector have a role in controlling COVID-19: there is emerging evidence that Africa is lagging far behind the rest of the world in domestic resource mobilization from private sector engagement [th February 2021, a total of 1,302,410 COVID-19 diagnostic tests had been carried out on Nigeria´s teeming population of over 200 million people [th March 2020, the Coalition Against COVID-19 (CACOVID) was formed to mobilize private sector resources to support measures against COVID-19 in Nigeria. There has been a pledge of US $30 million to support the activities of the NCDC from the Nigerian National Petroleum Corporation alongside some oil companies [gagement . Whilst gagement . Nigerian people . These an people . The priompanies . Many otompanies . With ovompanies , Nigeriaompanies .The Joseph Ukpo Hospitals and Research Institute (JUHRI): in a bid to promote structured engagement of the private sector with healthcare in Nigeria, the Joseph Ukpo Hospitals and Research Institute (JUHRI) was established in 2018. Consistent with Catholic medical ethics, JUHRI has been working with the government, organizations and individuals who share her vision: that healthcare is a human right and it is our collective responsibility to ensure universal access to it. With the overarching objective of bringing the benefits of modern medical science to those most in need of healthcare, JUHRI has successfully provided 100% free healthcare to a total of 6,570 patients at JUHRI in Afua, Nigeria as of 31st May, 2020. JUHRI´s mobile outreach services that have provided both diagnostic and therapeutic services to thousands of underserved persons have been reported previously [eviously -18.JUHRI´s multipronged response to COVID-19: Nigeria´s first case of COVID-19 was an Italian citizen who was diagnosed on February 27, 2020 [st 2020. 4) Provision of hand sanitizers and extra hand-washing stations on the verandah of JUHRI for immediate use by staff and patients on arrival at the facility. 5) Ensuring appropriate social and physical distancing measures of at least 1.5m amongst patients while waiting for medical attention. 6) Providing daily health education to patients on the dangers of COVID-19 and how to reduce transmission. 7) Donating PPE to nearby hospitals to enhance their COVID-19 preparedness. On a larger scale, JUHRI has acquired SARS-CoV-2 antibody testing kits and supported the government´s COVID-19 control measures by providing free COVID-19 antibody testing in a bid to determine the extent of COVID-19 spread in the Akwa Ibom and Cross River States of Nigeria. Research assistants were trained to facilitate this multi-centre research project. Ethical approvals were obtained from the Health Ethics Committees of University of Calabar and University of Uyo Teaching Hospitals. The antibody testing has been completed and preliminary report shared.Applicability to similar contexts/lessons learned: in the early days of the COVID-19 response, Nigeria like most LMICs lacked a multisectoral containment strategy. This was subsequently instituted by the Presidential Task Force on COVID-19 in collaboration with the NCDC. Most health systems in LMICs are fragile and have poor institutional capacity to initiate and effectively implement the complex multisectoral physical, economic, and behavioural interventions required to contain the COVID-19 outbreak. Often, the national response is driven by a focus on the core elements of an outbreak response including diagnostics, bed capacity, commodity, health workforce and data management [nagement . In Nigenagement . Useful nagement ,23. Againagement . These pnagement . ArguablStructured engagement of the private sector could potentially mobilize the necessary capital and harness innovations to mitigate the COVID-19 pandemic in Nigeria and similar settings. The magnitude of the task of providing workable solutions for COVID-19 such as vaccination requires bold collective action from the private sector, multinational organizations and governments. The JUHRI experience provides concrete evidence of the value of private sector participation in dealing with public health emergencies.General recommendations on how the private sector can contribute to curbing the COVID-19 pandemic: i) Partner with governments and communities to provide a multisectoral response to the COVID-19 pandemic. ii) Explore ways of producing and distributing sanitizers, face masks and vital medical supplies needed to tackle COVID-19. iii) Contribute essential products including food, manpower, equipment, transportation and logistics to support the pandemic control. iv) Provide economic initiatives to cushion the financial shocks arising from COVID-19. v) Establish services to protect people’s mental health and provide moral support for all through this pandemic.


The COVID-19 pandemic has disrupted immunization services critical to the prevention of vaccine-preventable diseases in many low- and middle- income countries around the world. These services will need to be modified in order to minimize COVID-19 transmission and ensure the safety of health workers and the community. Additional budget will be required to implement these modifications that ensure safe delivery.Using a simple modeling analysis, we estimated the additional resource requirements associated with modifications to supplementary immunization activities (campaigns) and routine immunization services via fixed sites and outreach in 2020 US dollars. We considered the following four categories of costs: (1) personal protective equipment (PPE) & infection prevention and control (IPC) measures for immunization sessions; (2) physical distancing and screening during immunization sessions; (3) delivery strategy changes, such as changes in session sizes and frequency; and (4) other operational cost increases, including additional social mobilization, training, and hazard pay to compensate health workers.We found that implementing a range of measures to protect health workers and communities from COVID-19 transmission could result in a per-facility start-up cost of $466–799 for routine fixed-site delivery and $12–220 for routine outreach delivery, and $12–108 per immunization campaign site. A recurrent monthly cost of $137–1,024 for fixed-site delivery and $152–848 for outreach delivery per facility could be incurred, and a $0.32–0.85 increase in the cost per dose during campaigns.By illustrating potential cost implications of providing immunization services through a range of strategies in a safe manner, these estimates can provide a benchmark for program managers and policy makers on the additional budget required. These findings can help country practitioners and global development partners planning the continuation of immunization services in the context of COVID-19. These modifications may change the cost of conducting immunization services, and may require additional budgetary support and planning to implement. World Health Organization (WHO) guidance advises countries to explore innovative methods for vaccine delivery to optimize service delivery while allowing for physical distance and minimizing the risks of COVID-19 transmission To help decision-makers in LMICs and global stakeholders understand the cost of such programmatic adaptations, we assessed the additional resource requirements associated with a number of modifications to various vaccine delivery strategies using a simple modeling analysis.2We analyzed the cost of four programmatic adaptations to illustrate the impact of global guidance and country practices on the cost of conducting immunization through routine fixed-site delivery, routine outreach, and campaigns. Two levels of intensity (low and high) were used to vary the measures for each cost category. WHO guidance provides a minimum standard for what is required to ensure the safe delivery of immunization services. The low-intensity scenarios and the cost assumptions were based on guidance and protocols from WHO on delivering immunization Costs are reported as one-time investments and monthly costs that are assumed to recur as long as COVID-19 risk is present. Each cost category is presented as the incremental financial outlays required  for the relevant adjustments. Costs are presented as per-dose estimates, and for routine fixed-site and outreach delivery, costs are also aggregated at the facility level for two facility types: low-volume and high-volume facilities.2.1Country delivery cost data were extracted from studies published in the Immunization Delivery Cost Catalogue (IDCC) For routine fixed-site delivery, the number of health care workers, immunization sessions, and patients per session were simulated based on two typical facility profiles: a low-volume facility that organizes 1–2 immunization session per week, involving 2–4 health workers and immunizing 15 children per session; and a high-volume facility that organizes 5 sessions per week, involving a team of 2–4 health workers and administering doses to approximately 45 children each session (Appendix Table A). These facility profiles were based on the median sessions per week, health workers per session, and delivery volume from costing studies in Indonesia, Sierra Leone, Tanzania, and Vietnam For campaign and outreach, all data were extracted from the studies, including the number of doses delivered, the number of vaccination team members, and salaries and per diem costs. From the campaign studies included for each analysis category, the median result is presented. Based on the distribution of volume delivered through outreach, Tanzania outcomes were considered as low-volume and Indonesia as high-volume facility examples.Unit costs for personal protective equipment (PPE) and infection, prevention, and control (IPC) supplies and equipment were taken from WHO and UNICEF price lists, or from published literature 2.2The first cost category estimated the cost of providing health workers with PPE and offering hand hygiene facilities at vaccination sites. In the low-intensity scenario, medical masks were included for health workers, as recommended by the WHO in areas with known or suspected sporadic transmission of COVID-19 The high-intensity scenario also included vaccinators wearing reusable goggles and changing gloves between beneficiaries, and non-vaccinator staff using one pair of gloves per half day session. The use of gloves during immunization sessions was reported in the DRC For all delivery strategies and scenario intensities, 12 ml of hand sanitizer per beneficiary was included. Two handwashing stations were added at outreach and campaign vaccination sites, to accommodate both the entry and exit points of each fixed outreach site, as seen during the measles outbreak response in Kinshasa in April 2020 2.3The second cost category included the cost of additional staff and supplies to conduct screening and ensure physical distancing during immunization sessions. One (low intensity) or two (high intensity) additional staff were added to campaign and outreach teams, as was the case during the measles campaign in Kinshasa in April 2020. To support routine immunization at fixed sites, we aligned additional staff assumptions based on the number of sessions per week in low-volume and high-volume facilities. We assumed 0.2 additional FTE for the low-intensity scenario and 0.4 additional FTE for the high-intensity scenario were allocated to each low-volume facility and we assumed 1 additional FTE for the low-intensity scenario and 1.4 additional FTE for the high-intensity scenario were allocated to each high-volume facility To better manage the flow of beneficiaries into and around health facilities, the routine fixed-site scenario included the provision of a roll of floor tape per week per facility for physical distance markings in both intensities and a screening tent per facility in the high-intensity scenario. The high-intensity scenario also included an infrared thermometer per vaccination team or facility for efficient screening of potential COVID-19 cases during immunization sessions, as listed in the priority medical devices list for the COVID-19 response as released by WHO 2.4The third cost category estimated the cost of changes in daily targets, session sizes and frequency, focusing on routine outreach and campaign delivery. For campaign delivery, campaigns may reach fewer children per day, requiring more days to complete the campaign, which in turn would increase the per diem requirements for health workers, as well as any PPE and hand hygiene supplies. Reductions in daily coverage to 80% and 50% of the previous target were tested in the low- and high-intensity scenarios, respectively.For routine outreach delivery, on the one hand, to reduce the number of touchpoints between health workers and the community, countries may choose to either: reduce the number of routine outreach sessions conducted; or, organize outreach sessions more frequently to ensure that session sizes stay small. The low-intensity scenario modelled the impact of halving the number of outreach sessions, while the high-intensity scenario modelled doubling the number of sessions. The number of children vaccinated in outreach overall was assumed to remain equal. These changes in session frequency had an impact on the per diem and transport costs.On the other hand, to compensate for drops in attendance at routine facility- and school-based immunization sessions due to lockdown measures and community fear of COVID-19 transmission, countries may choose to increase outreach activities during or post lockdowns. In other words, the outreach efforts might be strategically scaled up to compensate for reductions in routine facility- and school-based delivery coverage. In addition to the previous approach regarding session frequency, we assumed intensified outreach to compensate for a 25% reduction in fixed-site coverage as a low-intensity scenario, and a 50% reduction in fixed-site coverage as a high-intensity scenario. These coverage drops are based on findings from a study on the impact of the pandemic on routine immunization in Karachi, Pakistan 2.5The fourth category assessed increases in other operational cost components that could reasonably be impacted by the COVID-19 pandemic. For example, WHO recommends that in order to sustain community demand for vaccination services, a tailored communication strategy should be implemented to provide accurate health information, address community concerns, enhance community linkages, and encourage continued use of immunization services For the routine program, potential cost increases of 50% (low intensity) or 100% (high intensity) of the mean training costs of a new vaccine introduction was assumed to cover the cost of ensuring physical distancing and other protective measures. Increases of 50% (low intensity) and 100% (high intensity) of mean new vaccine introduction costs for social mobilization were assumed to cover increased communication with the public regarding routine immunization services amidst the COVID-19 pandemic. The base level for training and social mobilization costs was based on 12 studies of new and underutilized vaccine introductions (Appendix Table B) WHO recommends that renumeration should be commensurate with factors including additional hazards 2.6To illustrate the total programmatic cost of the adjustments needed to safely conduct immunization activities during the COVID-19 pandemic, we estimated total incremental costs of running the immunization program in Tanzania for one year (Appendix Table E). Using Tanzania-specific programmatic and costing data, the additional cost of implementing the previously described adjustments to maintain the routine vaccination schedule was assessed, as well as the additional cost of conducting a hypothetical nationwide measles follow-up or outbreak response campaign that would target all children aged 9 to 59 months old. The campaign cost assessment was based on a review of the IDCC and other forthcoming studies that report the unit cost of delivering measles, measles-rubella, meningitis A, and yellow fever vaccines through campaigns 33.1For the low-intensity scenario, monthly PPE and IPC costs (masks and hand sanitizer) were estimated at $47–247 at fixed sites and $15–125 for outreach in low- and high-volume facilities, respectively, as shown in For the high-intensity scenario, in addition to the adjustments in the low-intensity scenario, gloves for all vaccination team members resulted in a total estimated monthly recurrent cost of $58–297 per facility for fixed-site delivery and $19–219 per facility for outreach. The one-time cost for reusable protective goggles and advanced handwashing stations at outreach sites amounted to $2–4 for fixed-site delivery and $84–157 for outreach. For campaigns, these measures resulted in an estimated 39% increase in the cost per dose.For routine outreach delivery, masks accounted for the largest proportion of the recurrent cost in the low-intensity scenario (55–56%), while hand sanitizer was the biggest driver for campaigns and routine fixed-site delivery . The greatest recurrent cost in the high-intensity scenario was gloves for routine outreach and campaigns, and hand sanitizer for routine fixed-site delivery. The upfront cost consisted entirely of the handwashing stations in the low-intensity scenario and the handwashing stations (95%) and reusable goggles in the high-intensity scenario (5%).3.2For routine fixed-site delivery, For outreach, mean monthly recurrent costs for additional distancing and screening measures amounted to $19–24 (low intensity) and $40–105 (high intensity), as well as $25–47 of upfront costs per facility. In the low-volume delivery setting where almost all workers conducting outreach receive per diems, these accounted for 84–87% of the costs between the two intensities, with the remainder being masks and gloves.For campaigns, a 10% and 20% increase in the recurrent cost per dose were seen when applying the low- and high-intensity scenarios respectively. In both intensities, per diems for the additional crowd controllers were the major cost driver, accounting for upwards of 92% of costs in the low-intensity scenario and 89% in the high-intensity scenario. PPE for the crowd controllers covered the remainder.3.3Doubling the frequency of outreach sessions resulted in an increased monthly recurrent cost of $79 according to the cost profile of Tanzania, where facilities delivered 1–41% through outreach, and $91 according to the cost profile of Indonesia, where facilities delivered 39–74% through outreach. The monthly recurrent cost consisted mostly of per diem payments in low-volume facilities (84%) and transport costs in high-volume facilities (97%), only 5/24 of which paid per diems for outreach activities. Halving the number of outreach sessions did not generate additional costs, and in our model would technically result in cost savings if health workers would receive less per diems for outreach as a result.A 25% increase in the number of outreach beneficiaries to compensate for a fall in fixed-site coverage led to a $2–238 monthly increase in transport and per diem costs (low intensity). Reducing daily campaign coverage to 80% of previous levels and extending the campaign to cover the same number of beneficiaries results in a 9% increase in the cost per dose ($0.06). This rises to a 35% increase in cost per dose ($0.25) with a fall in daily coverage to 50%. The additional costs are from per diems for health workers.3.4For routine fixed-site delivery, we estimated the mean monthly recurrent costs of hazard pay per facility to be $84 in the high-intensity scenario, as can be seen in If campaign expenses on social mobilization activities, training, transport, communication and microplanning were to increase by 50% (low intensity), the cost of the campaign would increase by 20% or approximately 40% if they were to double.3.5If all low-intensity measures were to be implemented simultaneously, this would result in a $466 start-up cost (at both low- and high-volume facilities) and $137–680 monthly recurrent cost per facility for fixed-site delivery on average, as shown in 3.6We applied the assumptions and parameters discussed above to data from a recent study conducted in Tanzania on the cost of vaccine delivery as an illustration. Implementing all the proposed adjustments to safely conduct immunization activities during the COVID-19 pandemic across all facilities offering routine immunization services in Tanzania would result in an incremental annual cost of $19.0 million to $123 million, depending on the scenario intensity. This represents an overall cost increase of 89–147% from a baseline annual EPI total cost of $138 million In the low-intensity scenario, fixed upfront costs represent an increase of $707,000 (0.5% of baseline program costs). These costs are split evenly between IPC and distancing and screening costs and include costs to provide basic handwashing stations to teams conducting routine outreach immunization services, as well as tape to facilitate physical distancing during facility-based immunization sessions. For the low-intensity scenario, recurrent annual costs are estimated to be $18.3 million (a 13% increase from baseline). This includes costs of providing PPE for all workers, soap and hand sanitizer, as well as a moderate increase in training and social mobilization costs. In the low-intensity scenario, the biggest costs drivers of recurrent costs are PPE costs and distancing and screening costs, each contributing about 30% of the total increase in recurrent costs.In the high-intensity scenario, fixed upfront costs amount to an increase of $3.8 million (or 3% of baseline costs). Additional one-off costs for this scenario intensity include providing a tent and an infrared thermometer for screening at each health facility, as well as protective goggles for vaccinators, and an advanced handwashing station for outreach teams. Recurrent costs for the high-intensity scenario represent an increase of $119 million (86% of baseline program costs). Among these costs, a doubling in the frequency of outreach sessions represents the biggest cost driver , followed by the additional costs to enforce distancing and screening measures (22% of recurrent costs) and PPE costs (17% of recurrent costs).Implementing all the adjustments in a nation-wide measles campaign with a target population of 9,738,602 children 4This study found that implementing a range of measures to protect health workers and communities from COVID-19 transmission could result in a per-facility start-up cost of $466–799 for routine fixed-site delivery and $12–220 for routine outreach delivery, and $12–108 per immunization campaign site. A recurrent monthly cost of $137–1,024 for fixed-site delivery and $152–848 for outreach delivery per facility could be incurred, and a $0.32–0.85 increase in the cost per dose during campaigns. We also presented a case study in Tanzania in order to provide a real-world example of the cost implications investigated in our analysis; however, alternative country settings may have different cost implications compared to this case study. For example, the estimated cost increase of 89–147% is based on the annual program cost of $138 million in Tanzania, but we might expect cost increases to vary according to the annual program cost.Several modeling studies have shown the detrimental impact that essential health service disruptions could have on the burden of vaccine-preventable diseases Some of the scenarios presented included more PPE than is required as per WHO’s minimum guidance. WHO guidance indicates that vaccinators could consider extended use of masks in areas with widespread transmission, that masks are not needed for screening, and that vaccinators do not need to wear gloves if the skin is intact The Ebola epidemic and its devastating impact on the immunization program and broader health system are well-documented, providing valuable programmatic lessons The results of this analysis are meant to offer general guidance but should be interpreted with caution, as several limitations apply. First, the analysis relied on the data as reported by the authors, and several assumptions had to be made in the classification of certain costs, in the estimations of salaries, etc. We also relied on evidence from four country costing studies to develop our low- and high-volume profiles for facilities Finally, we are comparing cost implications for routine fixed facility, routine outreach, and mass vaccination campaign delivery strategies. However, each delivery strategy relies on a different set of studies, and the underlying group of countries and studies between strategies are not perfectly comparable. In addition, there are many additional delivery modalities, delivery strategies, antigens, and country settings that would have different cost implications that have not been included in this analysis. Furthermore, there is methodological heterogeneity within the studies for each strategy.In order to improve cost estimates for strategic planning in the COVID-19 pandemic, improved documenting of the country-level costs of conducting immunization services during the COVID-19 pandemic may be required. These analyses are meant to illustrate potential cost implications from providing immunization services through a range of strategies in a safe manner, based on global guidance and country protocols. These estimates can provide a benchmark for program managers and policy makers on the additional budget required. The findings can help country practitioners and global development partners in the design and implementation of strategies to ensure the continuation of immunization services in the context of COVID-19.5CB, LBo, FM, AP, SCR carried out the analysis. CB, LBo, FM, AP drafted the initial manuscript. All authors conceptualized and designed the study, critically reviewed the analysis, revised the manuscript, and approved the final manuscript as submitted.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [LBr was employed by the Bill & Melinda Gates Foundation while contributing to the study. The other authors declare no competing interests.].


Osteopoikilosis (OPK) is a rare benign sclerosing bone dysplasia and is often incidentally found on plain radiography. OPK generally does not require treatment. Nevertheless, osteonecrosis or degenerative joint disease can occur in the setting of OPK, and little is known with regard to the longevity of arthroplasty prostheses implanted into OPK-bearing bones.A 55-year-old male presented with progressive right hip pain in 2012. He was diagnosed with coexisting osteopoikilosis and developmental dysplasia of the right hip with advanced osteoarthritis after a series of imaging studies including radiographs, magnetic resonance imaging (MRI), and bone scan. A cementless total hip arthroplasty was performed to treat his right hip pain. Radiographs at eight-year follow-up showed the prosthetic components were well-fixed. Harris hip score of the patient’s right hip was 93. The patient can walk without assistance and work as a construction worker.Cementless arthroplasty can be considered in patients with hip arthropathies and co-existing osteopoikilosis. Continued follow-up is required to establish the long-term results. Osteopoikilosis (OPK) is a rare and benign sclerosing bone dysplasia . It has Although OPK generally does not require treatment , it has In 2012, a 55-year-old male with diabetes and a hemoglobin A1c level ranging from 6.5 to 6.8% in the past year presented to our orthopedic clinic with progressive right hip pain for 1 month. Detailed history-taking revealed that he had been bothered by vague pain in the right hip since 4 months ago, and had undergone weekly chiropractic manipulation in the past 3 months. The pain worsened significantly 1 month ago, and now was limiting his level of activity and distance of walking. His right hip had a positive Patrick test and decreased range of motion. Plain radiography of the pelvis . The patient’s right femoral neck was excessively anteverted, as is often the case with DDH. Since we did not have any modular hip system (such as the Zimmer Kinectiv or the Depuy S-ROM hip system) in our country at the time of surgery, we aimed to place the femoral stem in a slightly less anteverted position relative to the patient’s native neck anatomy so that it could better match the version of the acetabular cup. Although a properly-sized broach was advanced into the femoral canal, a cortical crack developed on the residual neck during insertion of the femoral prosthesis. Despite this complication, a secure press-fit was still achieved with the femoral stem after a double-stranded wire was applied to stabilize the femur and prevent propagation of the crack. Post-operatively the patient was restricted to toe-touch-weight-bearing ambulation on the right leg for 6 weeks, and placed on a rehabilitation program that included ankle pumping, heel sliding, quadriceps setting, straight leg raising, hip abduction and extension, and glute bridging exercises. After 6 weeks, he began to bear weight to tolerance and ambulate without assistive device. He could walk independently without assistance 3 months after surgery, and returned to work as a construction worker at 4 months post-operatively. Follow-up in the clinic took place every 3 months in the first year, every 6 months in the second year, and annually afterwards. Radiographs at eight-year follow-up showed the prosthetic components were well-fixed  loss-of-function mutations in the LEMD3 gene, causing a generalized fibroproliferative or stenosing disease; 2) hereditary failure to form normal trabeculae along lines of stress; (3) dysplasia of endochondral ossification, affecting resorption or remodeling of secondary spongiosa; and (4) altered osteogenesis  heredita.OPK and DDH are both a form of skeletal dysplasia, a wide-ranging term used to describe pathologic conditions characterized by disordered development, remodeling and reabsorption of bone and cartilage. Patients with skeletal dysplasia may be predisposed to development of severe degenerative joint disease and need joint replacement at a relatively young age . In our Making a correct diagnosis of OPK is important. The characteristic radiographic feature of OPK is multiple round or oval bone lesions scattered through axial and appendicular skeleton, a picture that resembles osteoblastic metastases, mastocytosis, or tuberous sclerosis –5. SinceIn conclusion, OPK is a benign sclerosing bone dysplasia that may or may not coexist with other joint abnormalities. Bone scintigraphy plays a critical role in differentiating OPK from osteoblastic metastasis. Our experience suggested that cementless total hip arthroplasty in patients with OPK could achieve satisfactory mid-term functional and radiographic outcomes. Continued follow-up is needed to determine the long-term results.


The mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress, similar to those of other coronaviruses, remain poorly understood. The virus buds in intracellular compartments and is therefore thought to be released by the biosynthetic secretory pathway. However, several studies have recently challenged this hypothesis. It has been suggested that coronaviruses, including SARS-CoV-2, use lysosomes for egress. In addition, a focused ion-beam scanning electron microscope (FIB/SEM) study suggested the existence of exit tunnels linking cellular compartments rich in viral particles to the extracellular space resembling those observed for the human immunodeficiency (HIV) in macrophages. Here, we analysed serial sections of Vero cells infected with SARS-CoV-2 by transmission electron microscopy (TEM). We found that SARS-CoV-2 was more likely to exit the cell in small secretory vesicles. Virus trafficking within the cells involves small vesicles, with each generally containing a single virus particle. These vesicles then fuse with the plasma membrane to release the virus into the extracellular space. This work sheds new light on the late stages of the SARS-CoV-2 infectious cycle of potential value for guiding the development of new antiviral strategies. The world is currently in the grip of a pandemic of coronavirus disease 19 (COVID-19), a new transmissible infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An analysis of the genome of this virus showed it to be phylogenetically close to SARS-CoV-1, which emerged in 2003, and suggested that it probably originated from a bat coronavirus transmitted to humans [SARS-CoV-2 enters cells by fusing directly with the plasma membrane or by exploiting endocytosis mechanisms and then fusing with an endosomal membrane . After fAs with other coronaviruses, the mechanism of viral egress is one of the least understood steps in the SARS-CoV-2 infectious cycle. Most enveloped RNA viruses are released by budding at the plasma membrane or by budding in internal host cell compartments; they then exit into the extracellular space via the biosynthetic secretory pathway. The budding of SARS-CoV-2 in the ERGIC compartment, or in the Golgi apparatus, suggests that this virus also exits the host cell via the secretory pathway. However, one recent study proposed a model in which coronaviruses, including SARS-CoV-2, use lysosomes for egress rather than the biosynthetic secretory pathway . This stUsing conventional TEM, we recently described the ultrastructural characteristics of the complete infectious cycle of SARS-CoV-2 within the host cell . In thisTo generate virus stock, Vero-81 cells  were infected with the SARS-CoV-2 (strain BetaCoV/France/IDF0571/2020) as previously described . BrieflyCells were fixed by incubation for 24 h in 4% paraformaldehyde and 1% glutaraldehyde  in 0.1 M phosphate buffer (pH 7.2). They were then washed in phosphate-buffered saline (PBS) and post-fixed by incubation for 1 h with 2% osmium tetroxide  in 0.15 M phosphate buffer. They were dehydrated in a graded series of ethanol solutions and propylene oxide, impregnated with a mixture of (1:1) propylene oxide/Epon resin (Sigma), and then embedded in pure Epon resin, which was allowed to polymerise for 48 h at 60 °C. The Epon blocks were precisely resized for the cutting of a ribbon of serial ultrathin sections (80 nm thick) of individual cells with a Leica Ultracut UCT ultramicrotome . These serial sections were then placed on TEM nickel one-slot grids  coated with Formvar film. The resulting TEM grids were stained for 20 min with 2% uranyl acetate  and 5% Reynolds lead citrate for observation with a Jeol 1011  electron microscope. Electron micrographs of the sections were recorded with a digital camera driven by Digital Micrograph software  for the same region of cells in each of the series of sections.We investigated eight cells in which numerous viral particles were observed intracellularly and at the surface by serial section imaging. For five cells, we investigated two or three different areas, resulting in total section imaging for 16 different subcellular domains. For clarity, The absence of tunnel was confirmed by examining several other cells presenting the same feature. Similar observations were made for cell B, presented in Viral particle egress is one of the least well understood steps in the infectious cycle of SARS-CoV-2 in its host cell. To date, few data have been published on this topic for this and other coronaviruses. Viral morphogenesis is known to involve budding in intracellular compartments, so viral particles are generally thought to be released via the biosynthetic secretory pathway. However, one recent study suggested that coronaviruses, including, potentially, SARS-CoV-2, make use of lysosomal trafficking for egress rather than the common secretory pathway . It has A recent cryoFIB/SEM imaging study of Vero cells infected with SARS-CoV-2 has suggested the presence of “exit tunnels” connecting large intracellular virus-containing vesicles to the plasma membrane . The autOur analysis of SARS-CoV-2-infected Vero cells based on serial TEM sections provided no evidence for the presence of such exit tunnels, as shown in the serial sections of the 4 cell subdomains presented in our figures but also in the 12 other cell subdomains analysed in 3D from 6 other different cells. On the contrary, our analysis suggested that the viral particles were individually trafficked in small secretory vesicles. Some of these secretion vesicles were presumably opened to the extracellular space, leading to a possible release of the virus (Further investigations, including functional studies, will also be necessary to determine the origin of these small secretory vesicles transporting the virions and the pathway used for their progression towards the plasma membrane. Early coronavirus studies performed with the mouse hepatitis virus model suggested that after budding into the ERGIC, the virus follows the classical secretory route to the cell surface ,22. HoweThe cryoFIB/SEM study cited above also reported the occurrence of plasma membrane discontinuities next to virus particles outside the cell, suggesting possible viral release through membrane lesions . We obseNevertheless, our study suggests that small secretory vesicles carrying a single viral particle represent the main means of egress for SARS-CoV-2, at least at the early stage of infection. We cannot rule out the possibility that egress events involving large vesicles have been missed due to the limited number of cells analysed. However, these cells were fully analysed in 3D using this serial section approach, and none of them showed an egress event involving an opening of large intracellular vesicles to the outside, directly or via an exit channel. It will be certainly important to continue this type of investigation with other, more relevant, cellular models, such as human primary airway epithelial cells, although these cells will most certainly be more difficult to handle for a serial TEM sections approach. This work sheds new light on late stages in the SARS-CoV-2 infectious cycle, which could be useful for the development of new antiviral strategies in a context in which few therapeutic approaches are currently available.


The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute lung injuries, pulmonary edema, and eventually death. Mesenchymal stem cells (MSCs) might prove to be a treatment option as they have immunomodulation and regenerative properties. Clinical trials utilizing MSCs in treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have provided a basis in treating post-COVID-19 patients. In this review, we discussed the effects of MSCs as an immunomodulator to reduce the severity and death in patients with COVID-19, including the usage of MSCs as an alternative regenerative therapy in post-COVID-19 patients. This review also includes the current clinical trials in utilizing MSCs and their potential future utilization for long-COVID treatments. Coronavirus disease 2019 (COVID-19) is a newly discovered, rampantly spreading disease. According to the World Health Organization (WHO) . A mysteIn this situation, prevention steps should be taken by every individual to protect oneself and others. The Centers for Diseases Control and Prevention (CDC)  suggesteAs viruses are prone to mutation, as of 31 August 2021, 12 variants of SARS-CoV-2 were identified and classified into two categories: variant of interest (VOI) and variant of concern (VOC). The mortality of each variant appears to be independent of the virus strains. A VOC is high in transmissibility and fatality, causing a decrease in vaccine effectiveness. These variants will increase their virulence and change their clinical diseases presentation, causing false results with a clinical test. As these variants can decrease the effectiveness of vaccines developed, the public health and social measures, therapeutics, and diagnosis are also made less effective in preventing infection by these variants of the virus. VOI contains the capability to escape diagnosis and the immune system due to the changes in their genetic composition, affecting the disease’s capability and transmissibility . These mThe mechanism of action for COVID-19 currently remains unknown . In contBased on Simmons et al.  the viruWithin the cytoplasm, structural viral proteins such as proteins M, S, and E are also translated and synthesized. The proteins will be inserted into the endoplasmic reticulum (ER), and then transferred to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) . N proteCOVID-19 severity depends on several factors. The symptoms are clinically divided into five categories, some are asymptomatic or paucisymptomatic individuals, some with mild symptoms, moderate symptoms, severe symptoms, and critical symptoms  AccordinMutations of the coronavirus strains affect the severity of diseases. According to Reardon , the virInfection dose also changes the severity of the virus. It was long known that the dose of exposure to infectious diseases is important in determining the disease’s severity. As the dose of exposure to the infectious agent is low, an individual might exhibit no or mild symptoms. However, highly infectious individuals will exhibit severe symptoms and increase the severity of diseases. With a highly infectious dose, patients will develop severe and critical symptoms, and associated complications as an antiviral-based strategy does not work for them . HospitaIndividuals with at least one major underlying medical condition also affect the severity of coronavirus diseases . These cAge is also a risk factor that directly correlates to the severity of COVID-19. Individuals aged above their 50s are more likely to suffer from severe symptoms, be hospitalized, and adversely die . AccordiTo date, there is no effective cure for COVID-19. Recovery solely depends on the immunity of the individuals. Vaccines are developed as a prevention strategy to cope with the pandemic . VaccineAccording to WHO , all vacCOVID-19 infection can give rise to cytokine storms in the lungs of moderate and severe patients. A cytokine storm, also known as hypercytokinemia, is an uncontrollable inflammatory response by the immune system . This agCytokine storm should not be neglected in COVID-19 infection. Therefore, an immunomodulation approach by the stem cell is highly advocated as a main therapeutic strategy to downregulate the effect of a cytokine storm ,47. ImmuIn COVID-19, the targeted organ is the respiratory organ, the lungs. Usage of stem cells such as mesenchymal stem cells (MSCs) for immunomodulation therapy is beneficial to regulate the proliferation, activation, and effector functions of all immune cells . Stem ceMSCs contain specific mechanisms of action that are possible for prophylaxis or treatment following infection to regenerate damaged organs. First, MSCs secretes keratinocyte growth factors (KGF). This factor helps in clearing the alveolar fluid induced by excessive inflammation in the injured alveolar. It will upregulate key epithelial sodium channel gene expression and Na-K-ATPase activity or increase the trafficking of epithelial sodium channel proteins to the apical membrane. MSCs also secrete angiopoietin-1 (Ang1) that reduces lung and endothelial permeability through enhanced endothelial survival and vascular stabilization, preservation of cell adhesion molecules and cell junctions, and the prevention of actin “stress fibre” formation. These mechanisms and regulations allow MSCs to exhibit their regenerative properties in repairing damaged organs.With the unraveling of COVID-19, cytokine storm, and the immunomodulatory function of MSCs, MSCs are currently being recognized as potential cell-based therapeutic targets for COVID-19. Hence, in this review, the possible mechanisms of MSCs’ immunomodulatory, regenerative mechanisms, and current clinical trials and their challenges will be deduced for potential COVID-19 treatments.Mesenchymal stem cells (MSCs) are well known for their promising cell-based therapies in infectious diseases due to their immunomodulatory potentials in managing inflammatory diseases ,50. AccoAs mentioned previously, the best defense against COVID-19 is the immune system, as it sets up the natural ability of the body to defend against pathogens. COVID-19 will not affect us as long as our body has good immunity . HoweverIn dealing with COVID-19, both innate and adaptive immunity are involved. According to WHO , the immGenerally, the infection stops at the first line of defense if the individual immunity is strong enough, or if the viral load is low. This IFN type I response is vital for viral suppression. However, this response is not effective in dealing with SARS-CoV-2 as the response is suppressed, and the virus will induce their programmed cell death, apoptosis. Without it, the virus continues replicating and causes delayed IFN type I response, heralding the influx of macrophages and neutrophils as a source of inflammation and Th1 immune response .When the virus encounters a weaker immune system, clearance does not occur, resulting in the stimulation of adaptive immunity. Adaptive immunity via T cells and B cells would then provide the protection required. T cells are regulated by the antigen-presenting cells (APCs) by engendering the cytokine environment. It recognizes cells infected with the virus and rapidly differentiates and proliferates. CD8+ cytotoxic T cells clear virus-infected cells leading to reduced viral load. CD4+ helper T cells produce proinflammatory cytokines and mediators to further strengthen the response, including stimulating B-cells. B-cell produces antibodies against the virus leading to high amounts of neutralizing antibodies and Th2 cytokines .The immunomodulation ability of the MSCs can be exerted in various ways: soluble factors (paracrine interaction), cell–cell contact, and extracellular vesicles (EVs) ,57. The Based on a study by Mallis et al. , MSCs caThe presence of IFN-γ activates MSCs and results in the production of TNF-α, MCP1, and IL-1β. These secreted soluble factors can advance the phenotype of M1 macrophages. On the other hand, MSCs also express prostaglandins E2 (PGE2), which will induce an M2 macrophage phenotype switch. A study has shown that the activation of signal transducer transcription-3 (STAT3) occurs via cell–cell interactions between MCSs and the macrophages . STAT3 tMSCs can interfere with the maturation of DCs via the production of soluble factors. Factors such as TNF-α, IL-1β, and IL-6 produced by M1 macrophages and IFN-γ will activate the MSCs and drive the maturation of DCs. Alternatively, PGE2 secreted by the activated MSCs is vital in the inhibition of DCs maturation. This soluble factor is crucial in preventing further damage to the lung cells and tissues. According to a study by Liu et al. and Sadeghi et al. ,61, inhiThere are several ways of MSCs immunomodulation via regulation of T cells. For example, secretion of molecules that affect the T cells responses and the cell–cell contact positively and negatively to inhibit the T cells proliferation. The production of PGE2, indoleamine-2,3-dioxygenase (IDO), TGF-β, and hepatocyte growth factor (HGF) will effectively inhibit the proliferation of T cells . AccordiFor cell–cell interactions, MSCs regulate their immunomodulatory properties by T cell apoptosis. According to Mallis et al. , Fas/FasMSCs immunomodulate B cells via secretion of soluble factors and cell-cell interaction. Both of these pathways are similar to the T cell’s regulation response. IDO, PGE2, the production of TGF-β1, and HGF can lead to cell cycle arrest of B cells. Fas/Fas ligand, TRAIL/DR death signaling, and PD-L1/PD-1 pathways promote the apoptosis of B cells. The secretion of GM-CSF by MSCs also inhibits the secretion of CXCR4, CXR5, IL-6, and IL-7 by activated B cells, effectively preventing the migratory ability and homing of B cells towards CXCL12 and CXCL13 chemoattractant agents and resulting in the initiation of inflammation . MSCs arNK cells are responsible for eliminating virus-infected cells from the host. MSCs activated by IFN-γ will upregulate the expression of HLA class I to interact with killer cell immunoglobulin-like receptors (KIRs). In this way, cytolysis mediated by NK cells is inhibited. Furthermore, toll-like receptors (TLRs) presented at MSCs are important as the activation of TLR3 increases the immunosuppression against NK cells. HLA-G will also interact with KIR2DL4 to modulate the function of NK cells . Last buThe unique ability of tissue regeneration and multipotent differentiation of MSCs contributes significantly to reversing the tissue damage caused by bacterial and viral infection. This ability has developed a great interest in utilizing MSCs as therapeutic agents for a wide range of chronic diseases. Apart from controlling infection and inflammation, MSCs are capable of repairing and regenerating epithelial and endothelial tissues in the alveoli of the lungs. Secretion of paracrine mediators promotes the regeneration of tissue. For post-COVID-19 patients with severe scarring of the lungs, this might be beneficial in restoring the damaged lung tissues.Without losing sight of long-COVID patients, MSCs’ regenerative ability also foreshadows them to regenerate the lung tissues. Long-COVID patients are a subset of individuals, suffering from acute SARS-CoV-2 virus infections and developing long-term symptoms that do not unravel over months. This is also known as post-acute sequelae of COVID-19 (PASC) or post-acute COVID-19 syndrome .Several theories have surfaced explaining the syndrome, but it has yet to be concretely proven. Professor Akiko Iwasaki proposed three mechanisms for long-COVID. One of the proposed mechanisms eventuating with long-COVID is the lingering virus or its reservoirs that remain within the individual’s body, leading to the ability to induce chronic inflammation . VirusesLong-term infection leads to lingering symptoms such as insomnia, fatigue, and difficulties in breathing. To improve the condition, the regenerative properties of the MSCs as a new and rapidly developing stem cell technology are necessary for providing an up-and-coming tissue regeneration strategy for lung cell therapy of COVID-19.MSCs must first be introduced into the body to perform lung cell regeneration therapy. There are two principal methods in delivering them: local delivery  and systemic delivery (by vascular route). The delivery method is determined by the mechanism of action of the MSCs being utilized . In lungAccording to Yagi et al. , homing After tethering and rolling of MSCs, the chemokine-triggered activation of integrin adhesiveness occurs. This step is facilitated by G protein-coupled chemokine receptors in response to inflammatory signals. Stem cell-derived factor (SDF)-1 on the endothelial cells will act as the ligands of the chemokine receptor CXCR4 expressed by the MSCs. Other molecules such as CXCR7 and CCR2 also facilitate MSCs homing on the endothelial cells. SDF-1 will recruit the signaling molecules to the cytoplasmic domain of VLA-4, resulting in a confirmation shift with a higher affinity for the arrest step later .Integrins are important in the activation-dependent arrest of the third step of homing. Integrin 1 and 4 subunits combining will create a very late antigen 4 (VLA-4) that can interact with vascular cell adhesion molecule 1 (VCAM-1) to allow arrest followed by solid adherence ,72. ThesThe penultimate phase in MSCs homing is transmigration, also known as diapedesis, and interstitial migration. MSCs must pass through the basement membrane located beneath the endothelial cells and require the cleavage of connective tissue components by different matrix metalloproteinases (MMPs). Gelatinases MMP-2 and MMP-9 are important in this stage as they are proficient in preferentially breakdown collagen and gelatin. Tissue inhibitor metalloproteinase 3 (TIMP-3), TIMP-2, and membrane type 1 MMP were also found to regulate this process (MT1-MMP). More molecular interactions are thought to be involved in MSCs extravasation, although the mechanism is yet to be comprehensible ,75.MSCs will then move to the injury site guided by chemotactic signals. The growth factors platelet-derived growth factor-AB (PDGF-AB), insulin-like growth factor 1 (IGF-1), and the chemokines MDC and SDF-1 all assist the movement of MSCs . InflammStem cell population preservation and niche restoration are necessary . The estThe regeneration of lung tissues by MSCs occurs via two mechanisms: secretion at local and systemic levels and restoring the cellular component into a niche .MSCs increase the secretion of various growth factors in the extracellular matrix (ECM) in response to diverse damage-related signals. When the endothelium wall of the lungs is damaged, MSCs will separate and release type I collagen. The response to signals in controlling wound healing with fibronectin will be mediated by the secreted type I collagen. Transforming growth factor beta 1 (TGF-1) is also a type I collagen response that is important for tissue healing after damage. By attaching to molecules such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor family (FGF), TGF-β1, and neurotrophin, fibronectin will also aid in the transfer of signals to stem cells for retaining their biological activity .Furthermore, MSCs also release individual ECM components that can behave as agonists or antagonists of tyrosine kinase receptors (TKR). These components act by mimicking the effects of growth factors. The secreted growth factors will be stored within the ECM and only active when tissue damage occurs. For example, epidermal growth factor receptor (EGFR) and TKR promote interstitial lung diseases. The overexpression of EGFR will stimulate pulmonary fibrosis development, which is unfavorable for COVID-19 patients . MSCs seMSCs also release extracellular vesicles (EVs), primarily exosomes with varying internal compositions based on external cues for lung tissue regeneration ,78. ThisMSCs mediate tissue regeneration via transferring specific organelles such as mitochondria by vesicular or tunnel nanotube transport, in addition to paracrine factors and EVs . MitochoMSCs could act as a precursor for specific specialty components by replenishing the pool of niche cells . This teMSCs are considered useful cell therapy in regeneration and saving damaged organs without patients going through organ transplants. When inflammation occurs and leads to tissue damage, it will lead the MSCs to migrate to the inflamed sites and initiate its immunomodulatory effects. The occurrence of immunomodulation will supplementarily activate the regenerative mechanism of the MSCs. Therefore, MSCs can restore any level of damage spectacularly.MSCs are recognized for their regeneration and immunomodulation capacity, which causes them to be attractive in cell therapy. However, controversy often surrounds the potential of MSCs as proinflammatory or anti-inflammatory cells. MSCs are plastic cells that will modify their phenotypes according to the engrafted microenvironment. The presence of stimuli in the microenvironment will promote the differentiation of MSCs into two different phenotypes . For MSCAs an immunomodulator, MSC2 can immunomodulate by lowering down the activation of T cells within the host. It also lowers the inflammation in an acute lung injury associated with COVID-19 . IncreasAs MSCs can be isolated from different sources, they contain different differentiation potential . They doThe switching of MSCs phenotypes certainly contributed to the immunomodulatory and lung cell regeneration of MSCs in both COVID-19 and long-COVID patients. However, the switching of phenotypes also brings its pros and cons. In a proinflammatory condition, switching MSCs into the MSC1 phenotype will enhance the inflammation of the patient’s lungs, opposite to the scientist’s aim of applying MSCs as an alternative therapeutic choice to the COVID-19 and long-COVID patients and detrimental to the patient. However, this proinflammatory situation favors the MSCs by allowing them to boost the release of growth factors such as IL-6, IL-8, and GM-CSF. These molecules will stimulate more neutrophils to the inflamed regions and promote inflammation activities. Chemokines, when stimulated, will also promote inflammation by attracting other lymphocytes to the site of inflammation. In this immune-boosting milieu, MSCs are exposed to insufficient amounts of IDO, which will promote T cell proliferation. A significant amount of proliferating T cells can induce many lymphocytes to damage healthy lung cells, exacerbating the patient’s condition. Although increasing the inflammatory state does not help enhance the patient’s lung cells, it does allow MSCs to transition from immune-enhancing to immune-suppressing properties. When MSCs are exposed to adequate proinflammatory cytokines, they adopt immune-suppressive phenotypes (MSC2), reducing inflammation and facilitating lung tissue repair. Facilitating lung tissue repair due to various secretion during the proinflammatory conditions by MSCs will benefit the patients for lung tissue regeneration.https://clinicaltrials.gov/, accessed on 1 September 2021). Several registered clinical trials and studies had begun within a short period. A growing number of clinical trials and experimental studies were initiated worldwide for COVID-19 under registration at ClinicalTrails.gov . This may be for several reasons: (1) umbilical cord contains a high concentration of MSCs, (2) UC-MSCs can be obtained during and after the birth, (3) non-invasive techniques are used, (4) Wharton-jelly is considered a by-product, (5) UC-MSCs has faster doubling times than other stem cells, especially embryonic stem cells, (6) UC-MSCs are safer as they are not tumorigenic and (7) they can be used as an allogenic treatment since the cells are immune evasive and express low levels of major histocompatibility complex (MHC) class 1 molecule and no MHC class II . MoreoveFrom the tables above, it was observed that the number of Asian trials is much higher than the European trials. These may be due to the outbreak of diseases from Asia and led to clinical trials as scientists are searching for effective treatment and cures for the diseases. The higher number of trials in Asia is also affected by the number of populations infected by the diseases. For example, China has a higher population, which can contribute to many ongoing clinical trials. The diseases outbreak was also first identified in Wuhan, China, which spread quickly within a short period, providing many patients for clinical trials. For Europe, as the disease outbreak was much later than the Asian country, this may cause the number of clinical trials to be lesser than the Asian country. The surge of COVID-19 cases due to different SARS-CoV-2 variants in Asia countries such as India, Indonesia, and Iran also contributes to the large number of patients included in the clinical trials. These infected patients allow the scientists to further identify the effectiveness of MSCs as a therapeutic application towards different types of SARS-CoV-2 variants. Not only that, factors such as the quality of research and the data, the costs of conducting clinical trials and data acquisition, the ease of study approval, well-trained investigators, adequate subject availability, low regulation and control of ongoing activities also influence the number of completed and ongoing clinical trials in the Asian in comparison to the Europe country. Issues such as the side effects of the application of MSCs as an alternative treatment for COVID-19 that contains many unknowns, the ethical issues of using stem cells as a therapeutical application also hindering the application of MSCs for COVID-19 and long-COVID patients. These issues will also affect the imbalance in clinical trials between Asian and European countries.Furthermore, these are still the initial trials that include only small sample sizes. A small sample size allows quick addressing of research questions. With the current situation, it is difficult to work with large samples of COVID-19 patients. A sample size that is too large will expose more participants than necessary to risks. A lot of controls are also required to work with large samples of participants. Despite that, MSCs still contain the potential to be used as COVID-19 therapy at this outbreak time. Based on the information above, it was shown from the data that the exosomes exert a trend of improvement in lung lesion treatment. The patients who received exosomes exerted no adverse events and symptoms during and after inhalation. Furthermore, the peripheral capillary oxygen saturation (SpO2) also increased. Increased SpO2 shows the increase in the amount of oxygen in the blood, which allows a sufficient amount of oxygenated blood to be transported and supplied to all parts of the body. This will maintain the function of the lungs of COVID-19 patients, and effectively lower the number of patients that require ventilators and intensive care. In the trial, MSCs also showed significantly lower C-reactive protein and LDH levels. This indicates that MSCs are effective in avoiding inflammation and preventing increasing odds of severe COVID-19 outcomes.Stem cell therapy is a rapidly emerging technology as its unique abilities are the hope of scientists in treating various chronic medical conditions, even in COVID-19. Therefore, some guidelines are required as a regulatory control to ensure that the related procedures and experiments are conducted ethically. In Malaysia, there are no legal acts implemented for stem cell therapies as the Ministry of Health Malaysia believed that the present regulatory regime is sufficient for the stem cell technology and no effort was taken to introduce any legal framework. Therefore, Malaysia relies on guidelines alone to regulate stem cell technology .“National Standards for Stem Cell Transplantation: Collection, Processing, Storage and Infusion of Hematopoietic Stem Cells and Therapeutic Cells” is one of the guidelines made by the Ministry of Health Malaysia in 2009 . These gMalaysian stem cell guidelines have recently undergone revisions. This revised guideline will be consistent with the Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research (ISSCR) , 86 ISSCCompared to Europe, stem cell sources such as human embryonic stem cells (hESC) are permitted in the research. Despite the differences in research legislation, they have united their ethical concerns about embryonic stem cell research . The resMSCs are safe and efficient as a therapeutic approach for COVID-19. There are various studies and clinical trials that were conducted to show that it was efficient in improving the lung conditions for post and long-COVID-19 patients. Leng et al. . conductUsing stem cell-based therapies is certainly a promising alternative for this newly emerging disease, which currently has no cure. In this review, we discussed how MSCs can play a crucial role in reducing the severity of COVID-19 and possibly treat patients who suffer from long-COVID. The immunomodulation properties of MSCs provide a promising feature in inhibiting a cytokine storm and lung inflammation. As for regenerative properties, MSCs can differentiate into various cell lineages. The regenerative properties of MSCs can benefit patients in the restoration of damaged lungs scarred by the infection. This has garnered interest from researchers on cell-based therapy especially when a cure is yet to be made available.Nonetheless, despite the positive outcomes of different MSCs research and trials, several safety concerns and downsides to this therapeutic application should be considered. MSC-treated tissues with encapsulated structures were reported to have calcification and ossifications. This structure indicates that transplanted MSCs can develop into undesired cells, which may be malignant when exposed to the local tissue milieu. Furthermore, when compared to healthy MSCs donors, MSCs generated from patients with inflammatory diseases had considerably reduced proliferation and differential potential, impacting the therapeutic qualities in COVID-19 patients. The hazards of allogenic MSC-induced immune responses must also be considered. The various MSCs expressions may evoke a solid allogeneic immunological response, exacerbating the existing tissue damage. The number of MSCs that will be able to be used in the treatment is also a concern when it comes to therapeutic application for long-COVID patients. Alternatives should be implemented to ensure that the appropriate cell number is applied for therapy that can benefit the patients. Concerns such as the ability of MSCs to successfully engraft should not be overlooked too.As the pandemic only started late in 2019, we expect more results from research and clinical trials which would elucidate the benefits of MSCs in COVID-19 patients. By determining the criteria of the eligible patients, these trials may allow the discovery of the new treatment for COVID-19 within a short time. Furthermore, this treatment may be a low-cost alternative compared to the treatment via a combination of different types of drugs that are not cost-effective to the patients. As MSCs can be obtained from many sources, the high availability will reduce the cost of the treatment. Even though the findings towards this type of therapy have been reduced, MSCs trials should be continued. The trials may contribute to a better understanding of MSCs and allow the discovery of new stem cell-based treatment to prepare for future diseases.Stem cells have been studied extensively for a long time for their therapeutic ability in various diseases. It is vital to identify and comprehend therapy strategies at this critical moment so that they can be implemented successfully and cost-effectively for every sector. MSCs have a clear two-way immunoregulation ability and they can control the balance of a patient’s immune system by secreting anti-inflammatory substances. MSCs, on the other hand, can be homing into damaged tissues and secreting different growth factors to ameliorate the microenvironment, repair damaged cells, and drive cardiovascular development, which has indirect antiviral effects. As a result, the mechanism of MSCs must be thoroughly understood to avoid uncontrollable events.MSCs can be used as a standalone immunomodulatory drug for COVID-19 patients. MSCs are well suited considering their mechanism of action is via their immunomodulating properties, significantly dampening the host’s immune response and slowing down cytokine storms within the host and lung cell destruction. MSCs as multipotent cells also contain regenerative properties, which will help to stimulate the regeneration of lung tissues. This application might be beneficial for post-COVID-19 patients with conditions such as severe lung tissue scarring and long-time symptoms. The application of MSCs as an immunomodulatory drug is similar to the concept of applying Merck antiviral drug for COVID-19, known as Molnupiravir as a treatment for adult COVID-19 patients. Molnupiravir is an investigational oral antiviral medicine released by Merck & Co., Inc., which significantly reduced the COVID-19 hospitalization and death rate by 50% ,98. ThisMoreover, with a combination of both 2D and 3D technologies, modification of MSCs can be carried out to enhance their proliferation and survival to treat various chronic diseases. MSCs that have been cultured for a long time will eventually senescence, which will result in the loss of their proliferative activity . To dealEven though stem cell therapy is a promising therapeutic approach, it is still a long way off being broadly used clinically. As a therapeutic approach, our knowledge of MSCs’ abilities and outcomes in therapy is still relatively limited. Although there is an increase in stem cell therapy research for COVID-19, there is still limited data due to the small number of patients receiving this cell-based therapy. Therefore, further studies with larger enrollments are necessary to validate its efficacy for COVID-19.