The SARS-CoV-2 Outbreak: Diagnosis, Infection Prevention, and Public Perception

Abstract

At the end of 2019 and early 2020, an outbreak of pneumonia of unknown etiology emerged in the city of Wuhan in China. The cases were found to be caused by a novel beta coronavirus, which was subsequently named SARS-CoV-2 by the World Health Organization (WHO). The virus has since spread further in China and to other regions of the world, having infected more than 88 K people, and causing close to 3000 deaths as of March 1, 2020. More than 50 million people remain in quarantine at this time. Scientists and clinicians globally are working swiftly to combat COVID-19, the respiratory disease caused by the virus. Notably, diagnostic assays have been developed rapidly in many countries, and have played significant roles in diagnosis, monitoring, surveillance, and infection control. Starting February 29, 2020, the development and performance of molecular testing for SARS-CoV-2 in high complexity Clinical Laboratory Improvement Amendments (CLIA) laboratories prior to emergency use authorization was allowed by the US FDA. Although the epidemic is evolving rapidly, many valuable lessons have been learned and many questions remain to be answered. Here we invited multiple experts across the globe from clinical laboratories, public health laboratories, infection control, and diagnostic industry to share their views on the diagnosis, infection control, and public perception of SARS-CoV-2. Considering viral dynamics, growing studies indicate that viral load peaks in the first week of disease onset. Viral RNA can be detected in patients in the 2nd week of disease onset, but the viral load is low. There are asymptomatic cases and recovering cases with documented RT-PCR positivity. Assays have been validated for all performance characteristics (including sensitivity and specificity); however, some validations have been done using synthetic sequences that have been spiked into respiratory samples. This seed and recovery style testing is common for validations when true positive control material is rare (e.g., North America) or not commercially available. The analytical sensitivity and analytical specificity have been calculated for each assay, but due to the relatively low number of positive human cases that have been tested in North America, there are few data in North America for diagnostic sensitivity and specificity. Generally, respiratory viral loads peak 2 days after symptom onset, and therefore collection of specimens as close to symptom onset as possible is recommended. For example, for human metapneumovirus, nearly 60% of cases are detected by NAT within the first 2 days, while only 19% are detected greater than 4 days after symptom onset. Delays in specimen collection can result in false negative results for respiratory viruses in general, and mean viral peak time varies by virus, the severity of symptoms, and the immune status of the individual. This suggests more work will be needed to determine the exact mean viral peak time for the SARS-CoV-2 virus. Similar to other respiratory viruses, the ability of the assay to detect coronavirus will largely be dependent on the collection of the sample. If a nasopharyngeal (NP) swab is not inserted properly to the nasopharyngeal space, and only to the nares, it is likely that this will result in a false negative result, even if the patient is infected with SARS-CoV-2. we would recommend emphasizing to healthcare workers the importance of proper specimen collection, because if the specimen has not been collected from an area the virus is likely to be, the virus will not be detected regardless of how good the assay is. The optimal specimen type for SARS-CoV-2 detection is yet to be determined. One non-peer reviewed study indicated that sputa may be the best noninvasive specimen type when compared to nasal and throat swabs, although additional studies are needed to confirm the best specimen type in the context of clinical symptomatology (lower versus upper respiratory tract symptoms) and timing of collection. Yang Pan: In some regions of China where the virus is epidemic in the community and the needs of clinical diagnosis exceed the capacity of NAT, a definition of “clinically diagnosed cases” based on clinical assessment and radiological presentations has been applied. This definition is particularly useful in outpatient clinics, where timely diagnosis reduces patient gathering, shortens the length of stay, and promotes effective infection control management. For those clinically diagnosed cases, empiric antiviral treatment and supportive management can be implemented immediately. Necessary epidemic investigation will also be triggered at the same time. An essential point is that healthcare personnel must be educated on result interpretation of NAT. Despite high sensitivity, a negative NAT is insufficient to exclude SARS-CoV-2 infection in patients with high clinical suspicion. The time of sample collection, the quality of the sample (preferably lower respiratory tract samples), the performance of testing methods, the quality controls, and the training of testing professionals all contribute to the accuracy of the testing. Especially, for those patients with typical clinical presentations or clear epidemic indications, clinical treatment and case management is necessary, even if a negative NAT is observed at one or two time points. In this instance, other approaches for testing should be considered, including specific IgM and IgG assays. Leo Poon: The initial clinical presentation is nonspecific. This becomes problematic in a flu season. Thus, a virological laboratory test is still recommended. However, we are still not sure about the best type of clinical samples for the test for highly suspected cases; multiple samples should be taken. Carmen Charlton and Nathan Zelyas: In endemic areas, the case definitions for probable and confirmed cases will likely be different than areas with very low prevalence. In an endemic region, if a patient presented with SARS-CoV-2-like symptoms, and neither treatment nor management of the patient would be changed by performing a laboratory test (i.e., a positive or negative result would not impact patient management), then NAT testing would not be required. However, if a positive or negative NAT result would impact infection prevention and control procedures (i.e., isolation of the patient to a particular ward) or patient management (i.e., different therapy), then testing would be warranted. This decision will likely be handled separately by each institution based on their current level of SARS-CoV-2 circulation, and available clinical intervention. The possibility of a false-negative result exists with any laboratory test. In the case where a patient presents with SARS-CoV-2-like symptoms and is NAT-negative, but other sources of infection are not found, a physician would have to use their best clinical judgement in treatment of the patient. According the interim guidance from the WHO, a single negative test result does not exclude infection with SARS-CoV-2 (https://www.who.int/publications-detail/laboratory-testing-for-2019-novel-coronavirus-in-suspected-human-cases-20200117). Additionally, “repeat testing using a lower respiratory sample is strongly recommended in severe or progressive disease” (https://www.who.int/publications-detail/laboratory-testing-for-2019-novel-coronavirus-in-suspected-human-cases-20200117). However, repeat testing all negatives would essentially double all testing requests, and that capacity may not be available in view of otherwise increasing test requests. Some jurisdictions are requesting two samples for testing be sent on every patient (a combination of an NP and throat or lower respiratory sample) to overcome the possibility of a false negative. One case in Ontario, for example, was identified on a throat sample, but not by the NP sample, while all other cases have been identified by an NP in Canada. Daniel Rhoads: NAT should be an integral part of the routine diagnostic work up of SARS-CoV-2, especially in nonendemic areas. However, if the pretest probability is very high due to high disease prevalence and if many cases of the disease have already been confirmed by NAT in an endemic area, then there is little utility to requiring laboratory or radiological confirmation of the disease. This proposed approach is similar to the CDC recommendations for influenza testing in the US (https://www.cdc.gov/flu/professionals/diagnosis/consider-influenza-testing.htm). If NAT or computed tomography are not employed to confirm the diagnosis, then internationally harmonized diagnostic criteria based on the clinical syndrome (signs, symptoms, exposure) should be employed and used. Yang Pan: The virological, epidemiologic, and clinical settings determine the preferred flow of SARS-CoV-2 testing. In the first stage of the outbreak in China, all tests were completed by the China CDC and public health laboratories. Over time, sustained cross-regional transmission was observed. In this situation, a rapid diagnostic test becomes an essential component of patient management during the outbreak. Limited testing in centralized laboratories becomes no longer ideal, as this requires specimen transport, extends turnaround time, and increases biosafety concerns. Given the high rate of circulation in China at this time, all qualified laboratories, including CDC laboratories, public health laboratories, hospital clinical laboratories, and independent laboratories should provide in vitro diagnostic services for this outbreak. At this moment, what we know is the faster we confirm an infection, the fewer people may be infected. Carmen Charlton and Nathan Zelyas: At the current stage of the outbreak, it makes sense for public health laboratories in North America to perform SARS-CoV-2 testing. Testing is restricted to individuals with specific travel locations or exposure histories, commercial tests are only starting to become available, and testing numbers overall are relatively low, making this assay perfectly suited to public health laboratories to perform. However, given the speed with which the virus is spreading, and the inability of countries to adequately contain the virus, testing volumes will likely increase substantially. Additionally, the current test gate-keeping (i.e., testing only those with compatible symptoms and travel/exposure history) that public health is providing will quickly outstrip capacity, and this gate-keeping system will no longer be sustainable. We have already seen this occur in both Ontario and British Columbia (who have higher testing volumes) where the Medical Officer of Health triaging has been stopped. If the viral infection is sustained in the North American population, this will impact where testing is needed. At that time, a re-assessment of resources may be required to test all suspect cases. Some jurisdictions are currently examining how to incorporate SARS-CoV-2 testing into routine respiratory viral testing workflows. As the virus becomes more common-place in North America, SARS-CoV-2 testing may need to be disseminated to acute care laboratories to accommodate testing volumes. This has already started to occur in certain areas of Canada. Daniel Rhoads: The location of NAT for SARS-CoV-2 detection should be congruent with the prevalence of the virus in balance with the clinical and public health needs. If the prevalence of disease becomes high in the US, and the virus become endemic, then it would be appropriate to distribute the testing to all labs that currently are competent to perform NAT respiratory virus testing. If the cases in the US continue to be limited to mostly those acquired from foreign exposure, then it would be reasonable to continue to limit testing to public health laboratories where the laboratories can work closely with public health epidemiologists to help to identify and track cases. If a widely available medication is identified as an important measure in the management of patients with SARS-CoV-2 infection, then the turnaround time for NAT becomes of heightened importance in order to more rapidly achieve optimal medical management, and if this were to occur, then it could help to justify more distributed laboratory testing even if disease prevalence is relatively low. Yang Pan: Numerous infections of healthcare providers were reported during the outbreak of SARS. For SARS-CoV-2, healthcare providers are also at high risk of infection, and health-care-associated nosocomial infection is another key concern. Once the health-care-associated nosocomial infection is located, enhanced infection control measures should be implemented in the hospitals, which require extensive resources. Up until now, the transmission route of SARS-CoV-2 has not been fully elucidated. Besides spreading via respiratory droplets and via contact, which have been confirmed, the potential spreading via aerosol and fecal route cannot be ignored. Based on these pieces of evidence and the pathogenicity of SARS-CoV-2, biosafety level 3 laboratory is needed to perform viral isolation and related testing, while clinical samples can be handled in biosafety level 2 laboratory by specialists with appropriate personal protective equipment. Specimen processing after inactivation procedures is also practiced in some laboratories. Although its impact on analytical sensitivity is unknown, the possibility of false-negative results caused by inactivation procedures requires attention. Carmen Charlton and Nathan Zelyas: In a laboratory setting, universal precautions (gown, gloves, working inside a biosafety cabinet) are sufficient to protect health care workers manipulating primary samples. If aerosol generating procedures are performed outside of a biosafety cabinet, then enhanced level 2 precautions should be used (such as wearing an N95 mask in addition to those listed above). Healthcare workers looking after the patient should adhere to contact and droplet precautions when caring for a suspect/confirmed case. Nasopharyngeal swabs can be safely collected using contact and droplet precautions, which includes wearing a surgical mask and eye protection; an N95 respirator is not required. If any procedures are being performed where aerosols are being generated (intubation, suctioning the respiratory tract), then airborne precautions should also be implemented, including an N95 respirator and eye protection. The use of nebulizers could be sources of infection when patients are tightly packed (<1 m apart; https://www.ncbi.nlm.nih.gov/pubmed/20923611). In the SARS outbreak there were a number of factors that led to nosocomially acquired infections in hospital wards, including use of supplemental oxygen, close distance between beds, the availability of hand washing stations, and whether resuscitation was ever performed on the ward (https://www.ncbi.nlm.nih.gov/pubmed/17366443). Given the speculation that SARS-CoV-2 may be transmitted fecal-orally, the availability, and the use of, hand washing stations may be significant in preventing spread within hospital wards. Daniel Rhoads: The CDC is maintaining up to date laboratory biosafety recommendations based on the current understanding of the virus and the disease. Currently, routine biosafety level 2 laboratory practices are adequate for specimens from patients that may have SARS-CoV-2 infection with the exception that potentially infectious specimens from these patients should be manipulated only in a biological safety cabinet (https://www.cdc.gov/coronavirus/2019-ncov/lab/lab-biosafety-guidelines.html). The CDC explicitly recommends against viral culture from specimens that may contain SARS-CoV-2. Leo Poon: SARS-CoV-2 seems to have high infectivity, with an R0 of about 2.5. Unlike SARS and MERS, it can spread between humans in early disease onset. In addition, there are asymptomatic cases in this outbreak, a presentation that was not seen in the SARS outbreak. This makes it very challenging to stop the transmission chain. Even worse, most of the world population are immunologically naïve, except for those who have recovered from SARS-CoV-2 infection. Carmen Charlton and Nathan Zelyas: The transmission for MERS is quite different than what we are currently experiencing with the SARS-CoV-2 outbreak. MERS does not have sustained transmission between humans and is thought to have been re-introduced from multiple zoonotic sources to the human population. This is one reason relatively few cases have been identified (∼2500) and the outbreak has not had The R0 of MERS is to be in nosocomial of the studies have the R0 to be between 2 and on the other have sustained transmission between and led to cases. The R0 of SARS is between 2 and and transmitted airborne was most seen between close in the same contact, and infectious droplet of SARS was seen in and only in high exposure settings an procedures for healthcare This is the current outbreak with SARS-CoV-2. to close and has been with an R0 of However, as more is on the virus, this number may the outbreak has spread more widely and more people than two coronavirus SARS and current are that of cases are and the case rate is to be However, we still not know the of asymptomatic or very patients are to the case rate of all infected people, not of those who are to a healthcare for may be Daniel Rhoads: emerged respiratory viruses and SARS and MERS were more than SARS-CoV-2, but the were in because the transmission of SARS and MERS was likely to occur or because was to be more the viruses is most similar to SARS-CoV-2 in and Although many people have of SARS-CoV-2 the rate is lower than SARS and MERS The of both and SARS-CoV-2 are lower than the SARS and MERS Yang Pan: SARS public in for an infectious disease outbreak, particularly in China. some measures were implemented to control the outbreak, including cross-regional public and Considering possible transmission and asymptomatic the may not be to control the outbreak of SARS-CoV-2 in a At some positive as the number of cases and the spread of the virus, have been observed. The and of measures remain to be determined. Carmen Charlton and Nathan Zelyas: In we in many other the has a level of of the virus. have been for SARS-CoV-2 testing based on but not risk of This has led some jurisdictions to require and assessment for all cases, while in other areas, although have that some will be the of testing is to and all are The management of cases from the public health in has been largely In for example, any suspect cases are the Medical of and if the patient is not to a hospital stay, are to until SARS-CoV-2 has been are using the same to patients who are to and to as not to hospital beds, and to spread of the virus to In rare public perception of the virus in China has led to and Some of one with a have been for SARS-CoV-2 infection, and many test have in for individuals not for testing. of public health and clinical experts in the to and transmission of the virus may help more Daniel Rhoads: The on SARS-CoV-2 has the number of to emergency with that have been to the virus or have disease. are still and patients during flu with have the flu and not the in individuals in the US have had flu this the of SARS-CoV-2 to date is Yang Pan: SARS-CoV-2 some characteristics compared with the respiratory with and it a low rate with high with other human coronavirus or SARS-CoV-2 caused high and in patients and patients with The first that we learned from SARS-CoV-2 is that are and the initial assessment and based on should be in a timely of early of infection caused by novel is essential for both healthcare providers and public health management and for healthcare providers should be implemented as as the to rapid diagnostic testing needs to be for and infectious In this outbreak of COVID-19, molecular testing and were developed in a very of time. The of SARS-CoV-2 was using which the outbreak control. The will likely the development of even more more timely and tests for We need to the of to we need to be by more and and to be for the outbreak. Carmen Charlton and Nathan Zelyas: One of the we are with at the public health laboratory is maintaining for testing. We are experiencing of many specimen collection and N95 Even of for routine respiratory testing has been and we have needed to work with multiple different to testing the of the emergency of were however, the were of surgical are available for but N95 were not in the for should be to to their laboratories in the of these emergency to will be useful in the of an The public health needs to be both and that is appropriate for a number of cases may not be with community to testing is a key of the that assessment of case and community and of control Daniel Rhoads: of has been to public clinical and the There is to and this and to potentially for For example, in hospital we have for different of care as primary care emergency infection control laboratory and in clinical and public health care a different but essential and will each be important in We have the to work to a to share guidance and each patient care remain at the of these different care For example, the CDC swabs for testing, but we this specimen type as part of routine clinical have had to how to approach this primary care providers not have negative if a that a patient in the potentially has this novel infection, there is no to the infection control recommendations due to are not to one and there is to provide and more quickly and with a single Leo Poon: We learned a from SARS and MERS up a in and coronavirus has been listed as one of the we have already we can from the to for the outbreak. emerged only of work has been done in the few some of which has led to very Based on the lessons that we are each about this virus, sure there are that we will on for the of the confirmed have to the of this and have the 4 significant to the and of or and interpretation of or the for of the and to be for all of the that questions related to the accuracy or of any part of the are and all completed the potential of Clinical Medical

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