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COVID-19 Testing: Institutions' Challenges and Approaches

PAPER SUMMARIES BY DR. FILIPA CURADO, CLINICAL STUDY RESEARCHER

Importance of Diagnostic Tool Validation

The group of Dr. Grubaugh (Yale School of Public Health, New Haven, USA) compared a) RNA transcript standards, b) full-length SARS-CoV-2 RNA, c) pre-COVID-19 nasopharyngeal swabs, and d) clinical samples from COVID-19 patients using WHO recommended diagnostic tools. The authors reported that all tested qRT-PCR primer-probe sets shared similar results in terms of specificity and analytical efficiency, in which the primer-probe sets from Charité Berlin (E-Sarbeco), Hong Kong University (HKU-ORF1, HKU-N), China Center Disease Control (CCDC-N), and United States CDC (2019-nCoV_N1, 2019-nCoV_N3) could detect SARS-CoV-2 at 1 (25%) and 10 (25-50%) virus copies per µL of RNA, with the exception of RdRp-SARSr primer-probe from Charité Berlin that had lower sensitivity, likely due to the mismatch in the reverse primer. They also highlighted the importance of analytical sensitivity validation of the assays concerning PCR kits and thermocyclers used locally for testing.

In conclusion, the authors showed that the compared primer-probe sets from the WHO recommended list were reliable for accurate detection of SARS-CoV-2, and that it is necessary to take into account the standardization of the conditions, such as the concentrations of primers and probes, PCR kits, and thermocycler conditions when comparing results from different tests, as these conditions may differ from the recommended for each assay. As a final note, authors stated that each country may use different diagnostic tests according to the most widely used assays and recommendation guidelines (Vogels et al, 2020).

CENTOGENE’s diagnostic method for SARS-CoV-2 has been extensively validated with 96.8% sensitivity and 100% specificity.


Relevance of Clinical Diagnostic Data Interpretation

A recent paper describes that the interpretation of diagnostic data, including sensitivity (proportion of patients with the disease who have a true positive test) and specificity (proportion of patients without disease who have a negative test and are true negative) are necessary parameters to consider. 

The authors state that the interpretation of test results needs to take into account that a positive RT-PCR test has more relevance than a negative one due to their high specificity but moderate sensitivity; therefore patients need to be confident that the result is correct and must be isolated and monitored. When patients have strong suggestive symptoms but a negative test result, a positive case should not be ruled out, thus patients are recommended to self-isolate (Watson et al, 2020).


CENTOGENE diagnostic results have been confirmed by external testing – confirming that both negative and positive cases were accurately diagnosed, bypassing a potential concern about false negatives in our diagnostics.



Neurological Implications of SARS-CoV-2 Infection

PAPER SUMMARIES BY DR. JEFRI PAUL, CLINICAL STUDY RESEARCHER

Summary

To date, it has been demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a severe form of pneumonia which further escalates to acute respiratory distress (ARDS) followed by death in a small group of patients. However, studies have shown that the infection also affects other systems like the central nervous system (CNS) and peripheral nervous system (PNS) with diverse neurological symptoms and signs. Here we summarize the neurological implications of SARS-CoV-2 infection.

Currently, it has been shown in some studies that headaches and impaired consciousness occur during the early symptomatic phase of infection. Loss of smell and taste (hyposmia and hypogeusia) are common symptoms which were experienced globally in SARS-CoV-2 positive patients confirmed by Polymerase Chain Reaction (PCR), testing performed to confirm Coronavirus disease (COVID-19). Such testing has been performed by CENTOGENE since March on a rapid way to fight this outbreak.

For instance, a study involving 417 mild to moderate Coronavirus disease (COVID-19) patients from 12 European hospitals demonstrated loss of olfactory function in 85.6% and gustatory dysfunction in 88% of individuals. Dysfunction of the olfactory and gustatory system leads to loss of smell and taste. (Lechien, J.R., Chiesa-Estomba, C.M., De Siati, D.R. et al, 2020). These symptoms indicate that coronavirus has the potential to affect olfactory nerve (cranial nerve I), the olfactory brain and the brain stem causing the irreversible failure of the respiratory system. In rare cases, it may also increase the risk of ischemic stroke in elderly patients. These neurological symptoms and signs emphasize the involvement of the nervous system in COVID-19 via SARS-CoV-2 neurotropism.

Take-away messages

  • SARS-CoV-2 could invade and infect nerve cells
  • Impairs olfactory and gustatory system
  • Loss of smell and taste

Next steps

The complete neurological impact of COVID-19 has yet to be understood and is urgently needed. 



SARS-CoV-2 Testing Blueprint

Rapid Large-Scale COVID-19 Testing Amid the Pandemic

Summary

The Coronavirus disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in economic and social lockdowns in most countries all over the globe. An early identification of infected individuals is regarded as one of the most important pre-requisites for fighting the pandemic and for returning to a ‘New Normal.’ Large-scale testing is therefore crucial, but is challenging due to several obstacles, including a shortage of sample collection tools and molecular biological reagents, as well as the need for safe electronical communication of medical reports. In a recent paper, CENTOGENE researchers reported on the successful establishment of a holistic SARS-CoV-2 testing platform, which covers proband registration, sample collection and shipment, sample testing, and report issuing.

The RT-PCR-based virus detection, being central to the platform, was extensively validated: sensitivity and specificity were defined as 96.8% and 100%, respectively; intra-run and inter-run precision were <3%. A novel type of sample swab and an in house-developed RNA extraction system were shown to perform as well as commercially available products. The resulting flexibility guarantees independence from the current bottlenecks in SARS-CoV-2 testing.

Leveraging existing technology and diagnostic expertise, CENTOGENE began offering testing at local, national, and global levels. The study presents results from approx. 18,000 SARS-CoV-2 tests in almost 10,000 individuals from a low frequency SARS-CoV-2 pandemic area in a homogenous geographical region in north-eastern Germany for a period of 10 weeks (March 21st to May 31st, 2020). Among the probands, five SARS-CoV-2 positive cases were identified. Comparative analysis of corresponding virus genomes revealed a diverse origin from three of the five currently recognized SARS-CoV-2 phylogenetic clades.

The study, which was published in the journal Diagnostics, exemplifies how preventive SARS-CoV-2 testing can be set up in a rapid and flexible manner. The application of this test has enabled a safe maintenance/resumption of critical local infrastructure, e.g., nursing homes where more than 5,000 elderlies and care takers got tested. The outlined strategy may serve as a blueprint for the implementation of large-scale preventative SARS-CoV-2 testing elsewhere.

Take-away messages

  • Despite current obstacles resulting from this global COVID-19 pandemic, it is possible to leverage resources and expertise to deploy rapid and reliable testing for the detection of SARS-CoV-2
  • Large-scale, preventative testing is a key factor in preventing further outbreaks and returning to a new normal

Next steps

Further implementation of widespread testing throughout communities around the world.


  • Rapid Large-Scale COVID-19 Testing During Shortages

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COVID-19 Outbreak Linked to Air Travel

How SARS-CoV-2 May Be Traveling Alongside Passengers

Paper summaries by Dr. Xenia Bogdanovic, Clinical Studies Researcher

Summary

The initial transmission and spread of COVID-19, and ultimately the resulting pandemic, has been linked to subjects traveling from Wuhan, China – the documented origin of the outbreak. Investigations of flight dates within the early stages of the Coronavirus and a linear regression modeling approach of exported travelers from Wuhan lead to an estimated 1.3% infection rate among travelers before the implementation of a travel ban – by far one of the highest estimates ever published. The travel ban from Wuhan has seemed to be a rather effective method of reducing the global spread of COVID-19, which based on the calculations, would have been much worse had the travel ban occurred any later.

The critical question for passengers is how likely it is to get infected during a flight while wearing a mask, but not being continuously able to respect social distancing. A recent case report of a patient who was infected while traveling on the same plane with a person that was diagnosed with COVID-19 ten days after the flight conflicts with another report about a positive subject with symptoms traveling on a plane without infecting other passengers, despite having close contact. In another case, 11 COVID-19 patients were diagnosed after a flight with no passengers on board who could be directly linked as the source of infection.

In addition to the novel virus spreading as a result of close contact with an infected individual coming from an impacted region, transmission during international flights and at airports may in fact be another route for the pandemic to spread; however, this needs a more detailed and thorough analysis. As of today, only very limited reports with a direct infection during the flight have been published.

Take-away messages

  • Traveling has been a main factor for the spread of COVID-19 – resulting in a pandemic
  • SARS-CoV-2 transmission routes during traveling are not yet clearly understood
  • As of today, it seems unlikely to get infected by COVID-19 during a flight
  • Disease control and prevention of transmission needs to be further elaborated


Transmission of COVID-19 by Aerosols

A growing concern among scientists that tiny droplets can carry SARS-CoV-2

Paper summaries by Dr. Maria Olmedillas, Clinical Studies Researcher

Summary

The role of aerosols in the transmission of SARS-CoV-2 has been a matter of debate. However, recent case studies have suggested that this route of transmission plays a major role in the spreading of COVID-19, particularly in indoor settings with poor ventilation. An interesting case example occurred during a 2.5-hour choir practice in Washington, U.S., where at least 33 out of 61 choristers contracted SARS-CoV-2 – despite the precautionary measures taken, such as the presence of hand sanitizers and avoidance of hand shaking (Hammer et. al 2020). The authors discussed the potential role that super emitters had by releasing more aerosol particles during speech than their peers, possibly contributing to airborne transmission.

In another case, members from three non-associated families were infected from SARS-CoV-2 in a restaurant in Guangzhou, China (Lu et al 2020). By using a tracer gas to measure droplet dispersion in the room and analyzing the video records, the authors came to the conclusion that airflow from the air conditioner contributed to the propagation of virus-laden droplets from an asymptomatic patient, which resulted in 10 people being infected (all >1 m distance from the index patient). None of the waiters nor the 68 patrons at the remaining 15 tables were infected (Lu et al 2020).

Recently, a review summarizing literature concerning the mechanisms of transmission of virus-laden droplets and aerosols in different confined settings (e.g., airplanes, passenger cars, and healthcare centers) has been published by Jayaweera and colleagues (Jayaweera et al 2020). The case studies that have come out in the past months have highlighted the importance of airborne transmission in the spreading of COVID-19.


Although certainly more work is needed to understand the viability of SARS-CoV-2 in aerosol droplets, as well as the viral load needed to infect, the World Health Organization (WHO) already acknowledges that airborne transmission is plausible. Recommendations for physical distancing, wearing masks, and avoiding confined spaces with poor ventilation can be considered as precautionary measures to control airborne transmission.

Take-away message

Case study examples have pointed out the major role aerosols may be playing in the transmission of COVID-19.