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Frequent Neurologic Manifestations and Encephalopathy‐Associated Morbidity in COVID‐19 Patients

Paper summary by Dr. Aliaksandr Skrahin

Summary

SARS‐CoV‐2 manifests itself not only with respiratory tract infection and flu‐like symptoms of varying severity, but also with multi‐organ disease affecting the central and peripheral nervous systems as well. A wide range of neurologic manifestations of SARS‐CoV‐2 infection have been recognized. Their frequency and associated risk factors remain unclear. Encephalopathy has been associated with unfavorable clinical outcomes in other conditions, including sepsis. However, association of encephalopathy with COVID-19 clinical outcomes is still unknown.

In a recent study, Liotta et al., (2020) have demonstrated that neurologic symptoms occur in most hospitalized COVID‐19 patients and encephalopathy occurs in one third of them.

There were 509 consecutive hospitalized COVID-19 patients that entered the study (age 58.5 ± 16.9 years, 281 (55.2%) males), including 134 (26.3%) with severe disease requiring mechanical ventilation. Neurologic signs and symptoms were recorded in more than 80% of them. Younger adults were more likely to develop any neurological events, while encephalopathy developed more frequent in older patients. The greater likelihood of encephalopathy development was associated with severe COVID‐19 disease, a history of any neurologic disorders, chronic kidney disease, lower white blood cell count at admission, and shorter time from COVID‐19 onset to hospitalization.

The patients with neurologic manifestations had longer hospitalization period (8 [4, 14] vs. 5 [2, 8] days, P < 0.001). The hospitalization time in patients with encephalopathy was three times longer than in other patients. (17 [11, 25] vs 5 [3, 8] days, P <0.001).

Favorable discharge functional outcome was less likely to be achieved by the patients with encephalopathy and greater likelihood of death at 30 days after hospitalization was also typical for them.

Take-away message

  • Neurologic manifestations occur in most hospitalized COVID‐19 patients and might determine the overall prognosis
  • Encephalopathy is associated with increased morbidity and mortality



    Could an Inborn Error of the Immune System Aggravate the COVID-19 Severity?

    Paper summary by Dr. Jefri Jeya Paul

    Summary

    While the coronavirus disease 2019 (COVID-19) still has many mysteries, various cohort studies have been able to unlock insights. Of these, it was revealed that individuals who are male, older (60 and above), obese, and suffer from diabetes or hypertension are more vulnerable to acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. On the other hand, it is unclear whether or not other factors, such as people carrying specific gene variants are more susceptible to disease severity.

    One group of researchers decided to dive into the topic of COVID-19 and genetics, and the results were insightfully surprising. Within the study, two sets of brothers (age ranges from 21 to 32) from unrelated families infected by SARS-CoV-2 depicts that the alteration in the Toll-like receptor 7 (TLR7) gene could increase the COVID-19 severity. TLR7 is a receptor expressed on immune cells, especially on dendritic cells. It can detect viral single-stranded ribonucleic acid (ssRNA) and leads to the activation of the innate immune system (antiviral host defence mechanism). The activation in turn produces Type I Interferon (IFN), an antiviral factor which can interfere with viral proliferation.

    Upon analyzing the whole exome data from the two sets of brothers, the Dutch researchers have found that all four had rare variants in the TLR7 gene located on the X chromosome. One group of brothers had a four-nucleotide deletion in the TLR7 gene, while the other set had a missense variant and resulted in the loss of function of TLR7 gene that could have hampered the host immune response against SARS-CoV-2 infection. It was also speculated that the differential expression of X-linked TLR7 between men and women could be a reason why men are increasingly inclined to develop COVID-19 compared to women. Overall, it is concluded that TLR7 is necessary to protect against infection with SARS-CoV-2.

    Take-away message

    • Being critically ill with the infection is an interplay of the virus with the immune response of the host
    • To protect against SARS-CoV-2, functional TLR7 is required
    • Interferons could be used to combat COVID-19 infection



    The Self-Sampling Solution to Combat COVID-19

    Paper summary by Dr. Selen Zülbahar

    Summary

    While the early medical response to the COVID-19 pandemic has come with several obstacles, such as availability of tests, testing capacity, and access to appropriate protective equipment for health care workers, improvements in sampling methods, and development of rapid testing procedures have started to bring overwhelmed healthcare systems to some level of manageability.

    One such common method is nasopharyngeal swabs, which can only be collected by a healthcare worker. This sampling technique may bring the patient to sneezing, coughing, or gagging – resulting in a not-so-pleasant experience for individuals and putting health care workers at risk. This is even more so true for health care workers in several geographical regions that are facing a shortage of personal protective equipment (PPE).

    In a recent study, Jennings et al., (2020) has demonstrated that tongue, nasal, and mid-turbinate samples collected by patients themselves may be the ideal solution – serving as a valid sampling approach for the reliable detection of the SARS-CoV-2 virus. They have used a pairwise analysis to compare the sensitivity of the tongue, nasal, and mid-turbinate samples collected by patients to a nasopharyngeal sample collected by a health care worker from the same subject with an evidence of symptoms suggestive of an upper respiratory illness.

    Results of the study suggest that tongue, nasal, and mid-turbinate samples collected by the patients are useful for the rapid and accurate diagnosis of SARSCoV-2 virus. Adoption of such-self sampling approaches would not only reduce the PPE use, but also provide a more comfortable patient experience, while keeping the health and safety of health care workers at the forefront.

    Take-away message

    Self-collected samples by patients can serve as an excellent and reliable solution for combatting COVID-19 and preventing spread of infection within the health care setting.



    Rapid Expansion of COVID-19 Testing in the U.S.

    Paper summary by Dr. Toni Förster

    Summary

    The global SARS-CoV-2 pandemic hit the United States hard with >3.3 million documented infections by mid-July 2020. To combat the spread of COVID-19, the National Institutes of Health (NIH) launched a program to increase the development, production, and deployment of diagnostic coronavirus tests. The paper by Tromberg et al. summarizes this test initiative called Rapid Acceleration of Diagnostics (RADx). The planned expansion of testing capacity shall enable the testing of appr. six million U.S. residents per day by December 2020.

    The RADx initiative is divided into four components:

    1. RADx-tech - Leveraging scientific creativity to identify, develop, and deploy point-of-care technologies
    2. RADx-Advanced Technology Platforms (RAD-ATP) – Supporting more advanced technologies to achieve short-term, rapid scale-up
    3. RADx-rad (standing for ‘radical’) – Fostering non-traditional approaches to enable long-term testing solutions
    4. RADx- Underserved Populations (RADx-UP) – Establishing community-based initiatives to increase improved testing accessibility for underserved populations


    The NIH has prompted innovators throughout the country to develop new diagnostic technologies and solutions to diagnose COVID-19. Within the RADx-tech program, applications will be reviewed via a rigorous, rapid review process where they have to pass several phases (“innovation funnel”). Selected, promising approaches will be supported financially, regulatory-wise, and within the clinical setting in order to bring them quickly from development to deployment. The RADx-ATP program enables a short-term solution for scaling up advanced technologies with already existing and authorized workflows by forwarding them to a later phase of the mentioned review process. In contrast, RADx-rad is looking into repurposing existing technologies with the aim of enabling testing capacities on a longer horizon. RADx-UP focuses on the increased pandemic impact on underserved populations within the U.S. and plans necessary steps to support access and uptake of diagnostic testing in these populations.

    The success of the RADx initiative depends on truly innovative ideas, a robust expert evaluation system, and extensive collaborations between different sectors in an entrepreneurial spirit. Challenges ahead are thus high, but all partners are motivated by the high urgency and responsibility in times of a global pandemic.

    Take-away message

    The U.S. is increasing efforts for the development, deployment, and up-scaling of new diagnostic tests for COVID-19 within a structured program (RADx). While challenging, the initiative underlines the power of collaboration and innovation in times of need.



    The Power of Mobile Apps and Artificial Intelligence in Fighting the COVID-19 Pandemic

    Paper summary by Dr. Hanaa Gaber

    Summary

    The demonstration of COVID-19 disease symptoms is heterogenous, and the ability to predict required medical support ahead of time is insufficient. Therefore, using data mining, artificial intelligence, and mobile applications for symptom tracking could be used as an early detection tool to support prioritizing testing and predicting the need for hospitalization. A team of scientists in the United States, the United Kingdom, and Sweden (Benjamin Murray et al 2020) worked on developing a smartphone-based clinical tool focused on the time series of the early COVID-19 development , which could be valuable in estimating the need for high-level care in individuals more likely to seek medical help.

    The smartphone app was utilized in the COVID Symptom Study to collect daily reports from millions of users in order to report a range of symptoms, demographic information, and comorbidities. The participants provided daily updates on symptoms, information on health care visits, COVID-19 testing results, and whether they are seeking medical support, including the level of intervention and related outcomes. Case reports have highlighted that COVID-19 infected individuals may present with different sets of symptoms, which supports the hypothesis that continuous symptom reporting during the infection would support clustering patients into distinct subtypes that could then be used for resource allocation and improvement of COVID-19 patient care. A predictive system focused on the need for respiratory support was then built, featuring the inferred cluster, the aggregated sum of symptoms, and features of individual characteristics using five days of symptom reporting. Both clustering and predictive models were applied to the independent replication set of 1,047 individuals.

    The ability to predict the symptom clusters of participants with COVID-19 may enable the establishment of adequate respiratory monitoring with pulse oximetry to patients at risk. On day five, it appeared that headaches were the most consistently reported symptoms across all clusters, while loss of smell or taste was reported over a longer duration in milder clusters. Symptom reporting for five days enabled stable symptom clusters – allowing for the construction of a predictive system that utilized data collected as the following:

    • Type One - ‘Flu-like’ with no fever: headache, loss of smell, muscle pains, cough, sore throat, chest pain

    • Type Two - ‘Flu-like’ with fever: headache, loss of smell, cough, sore throat, hoarseness, fever, loss of appetite

    • Type Three - GI: headache, loss of smell, loss of appetite, diarrhea, sore throat, chest pain, no cough

    • Type Four - Severe level one, fatigue: headache, loss of smell, cough, fever, hoarseness, chest pain

    • Type Five - Severe level two, confusion: headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, muscle pain

    • Type Six - Severe level three, abdominal/respiratory: headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain, shortness of breath, diarrhea, abdominal pain



    The team sought to develop a clinically useful tool using these clusters as a feature in a machine-learning-based system for predicting the need for respiratory support for COVID-19 patients. Using this tool will enable medical resource requirements to be better predicted days before they arise and can be extremely useful in combatting the COVID-19 pandemic.

    If applications and portals are widely utilized, healthcare providers and managers could track large groups of patients and predict the number of patients requiring hospital care and respiratory support days ahead of these needs arising – allowing for improved staff allocation, sufficient capacities, and intensive care planning. As a clinical tool, this approach could be implemented at a local level – enabling patients to be monitored remotely by their primary healthcare teams with alert systems being triggered when individuals demonstrate symptomatology associated with a high-risk cluster. Higher risk individuals could be targeted for increased care to ensure that they do not struggle to access advice when becoming more unwell. For instance, patients who fall into certain symptom clusters on day five of the illness have a significant risk of hospitalization and respiratory support and may benefit from home pulse oximetry with daily phone calls from their general practitioner to ensure that hospital attendance occurs at the appropriate point in the course of their illness.

    Additionally, some patients and practitioners may be incentivized by a clinical tool which they could use to input longitudinal symptom tracking and personal characteristics – allowing them to receive personalized information.


    Take-away messages

    • COVID-19 disease symptoms are heterogenous
    • Collecting data using mobile applications for symptom tracking could be used as an early identification tool to predict the need for hospitalization
    • Using apps as predictive tools can lead to better allocation of resources and increased testing in hot spots



    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.



    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


    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 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.