Since a cluster of unknown pneumonia patients wasfound in December 2019 in Wuhan, China, a new coronavirus (CoV), which was temporarily named 2019 novel coronavirus (2019-nCoV) by the World Health Organization (WHO)on 7 January, suddenly came into our sight [1]. The virus was subsequently renamed Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) and disease it causes named Corona Virus Disease-2019 (COVID-19). As of February 10, 2020, there have been over 43,000 patients confirmed positive by nucleic acid testing in China and 23 other countries and it has caused 1017deaths due toacute respiratory failure or other related complications. In addition, over 21,000 suspected infected people were isolated and are waiting to be tested. On January31, WHOannounced the outbreak of COVID-19 in China as a Public Health Emergency of International Concern. In 2002-2003 more than 8000 patients suffered from Severe Acute Respiratory Syndrome (SARS)due to a corona virus with 774 virus-related deaths reported to WHO. Since September 2012, there were 2494 laboratory-confirmed cases of infection with Middle East Respiratory SyndromeCorona Virus (MERS-CoV)with 858 virus-related deaths reported to WHO[2,3]. All three of these emerging infectious diseases leading to a global spread are caused by beta-coronaviruses.In China, prior outbreaks of emerging infections have had an unfavorable impact on the blood supply.[4]. However, consideration must also be given to the safety of the transfusion recipient even if the emerging infectionis a respiratory disease. Previous studies indicated that viralRNA could be detected from plasma or serum of patients infected with SARS-CoV [5-8], MERS-CoV [9]orSARS-CoV-2[1]during differentperiodsaftertheonset of symptoms. However, the detection of viral RNA by the polymerase chain reaction (PCR) is not equivalent to the detection of intact infectious virus. Although WHO noted in 2003 that no cases of SARS-CoVhavebeen reporteddue to transfusion of blood products,there was still a theoretical risk of transmission of SARS-CoVthrough transfusion
Diversity of coronaviruses
As the largest known RNA viruses, CoVs are further divided into four genera: alpha-CoVs,beta-CoVs, gamma-CoVs and delta-CoVs [11], among which alpha-and beta-CoVs are able toinfect mammals while the other two genera caninfect birds and could also infect mammals [12]. So far, seven coronaviruses have been found toinfect humansand cause respiratory diseases. Four of seven are common human CoVs (HCoVs) usually leading to common self-limitedupper respiratory disease: HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1.These viruses canoccasionally cause more serious disease in young, elderly, or immunocompromised individuals.The first two HCoVs, HCoV-229E and HCoV-OC43 have been known sincethe1960s. Withtheemergenceof SARS in 2002, a novel beta-coronavirus came to attention;and subsequentlyHCoV-NL63 and HCoV-HKU1 were identified in 2004 and 2005, respectively [13]. MERS-CoV which was isolated in 2012, is similar to SARS-CoV--both can infect the lower respiratory tract and usually cause a severe respiratory syndrome in humans[14]with a case fatality rate of 35.5% and 10%, respectively [15]. SARS-CoV-2was recentlyisolated from human airway epithelial cells, characterizedby next-generation sequencing in January 2020,and identified to be a new member of beta-CoVs [16]. SARS-CoV-2 can also infectthelower respiratory tract but the clinical symptoms are milder than SARS and MERS according to currentlimited evidence and report
SARS-CoV
Atypical pneumonia putatively caused by SARS-CoV was first identified following an outbreak in Guangdong Province, China inNovember 2002. The infection quickl
spread to Beijing, Hong Kong, Vietnam, Singapore, and Canada in March 2003. This disease proved to be highly infectious with respiratory droplets as the main route oftransmission. Infectedfeces also played an important role in some cluster outbreak cases [17,18]. Fortunately, it has been proved that SARS patients are not infectiousduringthe period of incubation (within 16 daysof infection, usually 3-5 days). Many studies found that SARS-CoV RNA could be detected in the plasma of SARS patients,even thoughit is a respiratory disease. The first report published on April 10, 2003 [5]indicated that extremely low concentrationsof viral RNA existed in plasma of a SARS patient during the acute phaseof illness, at 9 days aftertheonset of symptoms. The viral content of plasma was low. Researchers could only detectSARS-CoV RNA usinga nestedPCRassay established in house and the viral load was 190 copies/mLperformed after ultracentrifugation of 2mLof plasma. They could not detect viral RNA in the plasma collected from two contacts, although the sputum of one was positive by three of four different PCR assays and the viral loadin sputum was as high as 6.3×104copies/ml. Based on this studyand other information, WHO [10]andtheUS Food and Drug Administration (FDA) [19]drafted recommendations on blood safety and pointed out a theoretical risk of transmission of the SARS virusthrough transfusion of blood products. They also recommended some precautionary principles regarding the deferral of blood donation byindividualsfrom areas with recent local transmission. In addition, blood donors should report to collection agencies ifthey were diagnosed as suspected or confirmed SARS patients within one month following theirdonation;and in such instances, efforts would be made to tracerecipientsor recall any blood products not transfused. Later, two studies focused on new PCR methods for detectionof SARS-CoV RNA. One study wasbased on serial analysis of plasma viral RNA concentrations in adult SARS patients by quantitative RT-PCR with a limit of detection of74 copies/ml. The study found that, on the first day of fever onset, 50%(6/12)ofconfirmed patients had detectableviral RNA in plasma;and that byday 14,the proportion fell to 25% (3/12).Overall, 78% of patientshad detectableviral RNA in the first week oftheirillness [7]. Similar to the
Journal Pre-prooffirst study, the average viralconcentration was low at140 copies/mlin patients who had relatively mild symptoms and did not require intensive care unit (ICU) admission in hospital.Inpediatric patients, 87.5% (7/8) of childrenhad viremia and the median concentration of plasma was 357 copies/mLbased on the same PCR method used with adult SARS patients above [8]. Finally, Grant et al. [6]reported that within three days after fever onset, 79% (19/24) of patientshad detectableSARS-CoV RNA inplasma. The viral load level rose fast and the maximal viral load was at around day 4 or day 5 after the onset of fever, after which the viral load quickly decreased. Their findings showed viral shedding in plasma was common when people were clinically illwith SARS virus and that plasma may be a better sample compared with nasal and throat swabs. The detection sensitivity of plasma was equivalent to that of nasopharyngeal aspirates withinthefirst three days aftertheonset of fever. In addition,researchers found that lymphocytes have a muchhigher concentration of SARS-CoV RNA than plasma whether tested intheacute phase orconvalescent phase [20], although plasma viral RNA from only five patients in acute phase and five in convalescent phase wasdetected. It was subsequently shown that SARS-CoV could not only infect lymphocytesbut also replicate in them ina self-limitedmanner [21-23]. Thesefindings providedevidence that lymphocytes might be one of targets for SARS-CoV and indicated the potential for a transmission risk byblood productswith high concentrations of donor lymphocytes (peripheral blood stem cells, bone marrow, granulocyte concentrates, etc).Although thesefindings provided someevidence that SARS-CoV indeed existed in plasma or lymphocytes of SARS patients, no nation including those with local transmission of SARS,and noorganizations including WHO[10]and the American Association of Blood Banks (AABB), recommended screeningdonors for SARS-CoV RNA or related antibodies based on the following facts: (1) SARS patients are not infectious in the period of incubation time and the incubation time is relatively short; (2) Almost all SARS-CoV infected people have severe symptoms, and few fasymptomatic carriers were found; (3) Data showed that the viral load from plasma of SARSpatients was low [17,24,25];(4) No transfusion transmission cases have been reported so far [10];and studiesthat screened blood donations for SARS-CoV RNA in 2003 failed to identifyany positives[26]. However,an alternative view was expressedin 2004. Researchers in Hong Kong [27]found thattests of theplasma from 3 of 400 healthy blood donors and 1 of 131 non-pneumonic pediatricinpatients collected during the outbreak of SARStested positive for IgG antibody toSARS-CoV. The resultswere confirmed by two western blot assays. The presence of antibody does not imply infectious material. Nevertheless, becauseHong Kong was among the worst-hit regionsin the world during the 2002-2003 outbreak of SARS, they concluded that in Hong Kong subclinical or non-pneumonic SARS-CoV infections existedindicating apotential transmission risk of SARS virus via blood products. Soon afterward, four different groups raised questions and objectionsto the Hong Kongstudy focusing on the specificity of the assays and the representativeness of the population [28-31]. To provide additional information the theoreticalthe risk of SARS-CoV transmission through blood transfusion was estimated in Shenzhen, Guangdong Provincein China. Theestimateused data from Shenzhen, Hong Kong,and Taiwan in 2003 and calculated the mean risk was 14.11 (95%CI: 11.00-17.22) per million and the maximum risk was 23.57 (95%CI: 6.83-47.69) per million on April 2, 2003
nactivation of coronavirus in blood
productsCoronavirusesareenveloped, positive-sense,single-stranded RNA viruses. Usually, coronaviruses are vulnerable to acid-pH, basic-pH and heat [43]but seem to be more stable at4°C [44]. The infectious titer of virus did not show any significant reduction after 25 cycles of thawing and freezing [44]. After the outbreak of SARS and MERS, a few studies investigatedpathogen inactivation/reductiontechnologies (PRTs) based on in-house or commercial methodswith the aimto decrease or completely eradicate the potential risk of transmission of coronaviruses via blood products or blood derivatives Generally, no singlePRTtechnology is suitable for all blood products, since some blood components aredamaged by the PRT treatment[55,56]. In-housestudies ofmethods to inactivatecoronaviruses in plasma and platelet concentrates focused mainly on heat and solvent/detergent (S/D) treatment. Usually, 60°C for 15-30minutesis enough for reduction of SARS-CoV from plasmawithout cells [49], and inactivation could be achieved by the 60 °Cfor 10 hoursfor plasma products [52]. In the other study, 56°Cfor 25minutesheating could reduce more than 4log10TCID50/mlof MERS virus [53]. Since heating could denature protein in blood products, it could only be used in manufactured plasma-derived products. In addition, SARS-CoV was found to be sensitive to solvent and detergent, such as TNBP/Triton X-100, TNBP/Tween 80, sodium cholate [49]. After 30min treatment using S/D produced by Octaplas (Octapharma), the virus was reduced more than 5.75±0.3 log10TCID50/ml[50]. Illumination with different wavelengthsalso influenced activities of SARSand MERS virus in blood. Ultraviolet (UV)-A [46,47,51]and UV-B light [54]in the presence of amotosalen or riboflavin could inactivate the pathogens’ nucleic acids, while a third PRT method uses UV-C light only [45,48]. These commercial systems could reduce the activities of SARS and MERS virus in plasma or platelet concentrates to different degrees. Methylene blue plus visible light also hasthe ability toinactivatecoronaviruses in plasma [45,48]. Cost remains a major administrative obstacle to PRT use [55]. Therefore whether or not these PRTs should be implemented in response to SARS-CoV-2dependson the severity and prevalence ofCOVID-19in different regions and on theactualrisk of transfusion transmission ofSARS-CoV-2.
References
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