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Laboratory testing of Covid-19

Dr. Waliul I Khan
Laboratory testing of Covid-19

Coronavirus (Covid-19) is a viral respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggering a significant threat to global health and the economy. The outbreak of Covid-19 has sparked alarm worldwide.

Because of the very fast increase in number of cases and uncontrolled and vast spread worldwide, the World Health Organization (WHO) has declared SARS-CoV-2 infection a pandemic. As of 28 April 2020, the WHO reported 2, 954, 222 confirmed cases, and 202,597 deaths worldwide. Covid-19 swept across 213 countries which include developed countries like USA, UK and Canada, and developing countries like Bangladesh. Although most cases were mild to moderate, some patients developed severe symptoms characterized by respiratory dysfunction and/or multiple organ failure leading to deaths. 

Laboratory testing has been moved to the forefront of the global response to the COVID-19 pandemic. As the number of individuals infected with COVID-19 continues to rise globally and healthcare systems become increasingly strained, it is clear that the clinical diagnostic laboratory will play an essential role in this crisis, contributing to patient diagnosis, monitoring/treatment, as well as assessing immune status, contact tracing and surveillance.  However, in this unprecedented situation there are new questions and challenges regarding laboratory testing of this new virus which includes who to test, when to test, what to test and, what tests are useful at different stages of infection, and what to do with test results. 

Implementation of testing for Covid-19 varied widely across the globe depending on testing capacity, healthcare resources, and the spread of the virus in the community. A few countries have shown the power of awareness, meticulous case finding, and effective isolation systems. Intensive diagnostics placement perhaps contributed to the success in controlling virus transmission in a few countries like South Korea, Taiwan and Hong Kong. These countries rapidly organized resource-intensive strategies that prioritized substantial laboratory testing and isolation to disrupt viral transmission.

There are two major types of tests for Covid-19: one is to determine if someone is actively infected with Covid-19, and another to determine if someone had Covid-19 infection and now has developed antibodies against the SARS-CoV-2 virus. For the first type which is meant to be diagnostic, real-time reverse transcription polymerase chain reaction (RT-PCR)-based molecular assays performed in the laboratory on respiratory specimens are the most widely used.  RT-PCR is a nucleic acid amplification test that detects unique sequences of the virus that causes Covid-19 (SARS-CoV-2).  A nasopharyngeal specimen is the preferred choice for swab-based SARS-CoV-2 testing, but when collection of a nasopharyngeal swab is not possible oropharyngeal, nasal mid-turbinate, anterior nares samples, nasopharyngeal wash/aspirate can also be used. For hospitalised patients and with pneumonia, a sample of lower respiratory tract secretions (such as sputum and bronchoalveolar lavage fluid) is useful. Detection rates in each sample type vary from patient to patient and may change over the course of individual patients’ illnesses. As for example, some patients with pneumonia may have negative results with nasal or oropharyngeal samples but positive results with lower airway samples. Synthetic fiber swabs with plastic shafts are preferred for swab-based tests. Swabs that contain calcium alginate or wood should be avoided, because they may contain substances that inhibit RT-PCR testing. Ideally, swabs should be transferred into universal transport medium immediately after sample collection to preserve viral nucleic acid for RT-PCR testing. After specimen collection, samples undergo RNA extraction followed by qualitative RT-PCR for target detection. After a patient has had a positive test result, several authorities have recommended obtaining at least 2 negative upper respiratory tract samples, collected at intervals of 24 hours or longer, to document SARS-CoV-2 clearance. There are reports where RT-PCR-based test given false negative (around 20%) results. The reason of false negative results could be due to the inadequate/improper sample collection, handling, transport and improper extraction of nucleic acid from samples. In addition, inadequately validated assays, instrument malfunctioning, along with other specific technical issues may also interfere in test accuracy.

The other major type of tests is serological tests which detect IgM, IgA, IgG, or total antibodies in blood.  Recently there is growing interest in serological tests for Covid-19. IgM antibodies usually are the first to be detectable in response to the infection but become undetectable after a few weeks.  IgG is formed around the time of resolution of symptoms and the level continues to increase for a period.  Another antibody type, IgA, is secreted by mucous membranes in the respiratory tract, but is also found in blood. These serological tests are relatively less complex than molecular tests and are used to identify the presence of antibodies against SARS-CoV-2 after someone is infected.

Development of an antibody response to infection can be host dependent and take time; in the case of SARS-CoV-2, studies suggest that the majority of patients seroconvert between 7 and 11 days post-exposure to the virus, although some patients may develop antibodies sooner. As a result of this natural delay, antibody testing may not be useful around the time of symptoms onset. Therefore, negative results would not exclude the infection, particularly among those with recent exposure to the virus. Cross-reactivity of antibody to non-SARS-CoV-2 coronavirus proteins is also a potential drawback of serological testing; whereby positive results may be the result of past or present infection with other human coronaviruses.

These serological tests will help to detect susceptible individuals (antibody negative) and those previously infected. A serological test can show who carries antibodies, even if the virus is no longer present. Researchers are also studying plasma therapy for treating Covid-19 patients.  The treatment involves taking blood plasma which contains antibodies from people who have recovered from Covid-19 infection and giving it to patients who are sick enough to be hospitalized with the same disease. Serological tests can be useful in identifying potential plasma/antibody donors for plasma therapy. As it is still not clear what level of antibody is protective against this and for how long it persists, if these tests prove protective immunity, then front-line staffers who are deemed immune could return to work. These tests can be instrumental in contact tracing, surveillance, and vaccine evaluation studies. Serological tests (typically based on lateral flow immunochromatography or enzyme-linked immunosorbent assays; ELISA) method have recently become available. However, to achieve reliable and quality results these tests need proper validation, identification of proper test kit and maintenance of test quality in the laboratory.

The other common laboratory features reported in patients with Covid-19 include decreased albumin, elevated C-reactive protein (CRP), increased erythrocyte sedimentation rate (ESR),  elevated lactate dehydrogenase (LDH) levels, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), increased creatinine, and decreased lymphocytes. In addition to these common laboratory tests, evidence suggests that patients with severe Covid-19 could be at risk for cytokine storm syndrome. Cytokines are signalling mediators released by cellswhich regulate a wide range of biological functions including immune response and inflammation.  Cytokine tests, particularly interleukin (IL)-6, may be useful to assess severity of the infection and inflammation.

The Covid-19 pandemic has dramatically highlighted the essential role of diagnostics in the control of communicable diseases. Urgent clinical and public health needs now drive an unprecedented global effort to increase SARS-CoV-2 testing capacity. Doing as many tests as possible are pivotal in combating this critical situation. “Test, test, test.”  That was the advice of the Director General of the World Health Organisation (WHO). In this critical situation, it is important to understand the role of laboratory testing at this stage of a new and emerging infection.  In the absence of proven effective therapy or a vaccine, laboratory diagnostic testing becomes a notably important tool for patient diagnosis and management and for potentially helping to save lives by limiting the spread of SARS-CoV-2.

Dr. Waliul I. Khan, MBBS, PhD, FRCPath
Professor, Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada 
Immunologist, Laboratory Medicine, Hamilton Health Sciences, Hamilton, Ontario, Canada



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Editor : M. Shamsur Rahman
Published by the Editor on behalf of Independent Publications Limited at Media Printers, 446/H, Tejgaon I/A, Dhaka-1215.
Editorial, News & Commercial Offices : Beximco Media Complex, 149-150 Tejgaon I/A, Dhaka-1208, Bangladesh. GPO Box No. 934, Dhaka-1000.

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