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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 7  |  Page : 16-21

COVID-19: Evaluation and diagnosis


1 Department of Pediatric Intensive Care, NMC Royal Hospital, AD, UAE
2 Department of Pediatric Intensive Care, Advanced Pediatric Critical Care Centre, Wanless Hospital, Miraj, Maharashtra, India

Date of Submission20-Apr-2020
Date of Decision24-Apr-2020
Date of Acceptance30-Apr-2020
Date of Web Publication29-May-2020

Correspondence Address:
Dr. Vinayak Patki
Pediatric Intensive Care, Advanced Pediatric Critical Care Centre, Wanless Hospital, Miraj - 416 410, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPCC.JPCC_74_20

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  Abstract 


Rapid and accurate COVID-19 diagnostic testing is essential for controling the ongoing COVID-19 pandemic. Evaluation and diagnosis of COVID-19 infection is done on the basis of the clinical suspicion and appropriate laboratory tests. The current gold standard for COVID-19 diagnosis is real-time reverse transcription–polymerase chain reaction detection of SARS-CoV-2 from nasopharyngeal swabs. The World Health Organization, Centre for Disease control and Indian Council of Medical Research has published various guidelines about the scientific use and interpretation of results. Recently rapid antibody testing has also been recommended for clusters with influenza-like illness. These laboratory tests have their own limitations about their sensitivity and specificity; clinician has to interpret the results in the light of clinical condition of patient with suspected COVID-19 infection. Health-care provider should take due precautions while collecting, packaging, and transport of these samples. One has to adhere strictly to the guidelines published by the Government authorities in the diagnosis of these patients.

Keywords: COVID-19, laboratory diagnosis, rapid antibody testing, reverse transcription-polymerase chain reaction


How to cite this article:
Benkatti G, Patki V. COVID-19: Evaluation and diagnosis. J Pediatr Crit Care 2020;7, Suppl S1:16-21

How to cite this URL:
Benkatti G, Patki V. COVID-19: Evaluation and diagnosis. J Pediatr Crit Care [serial online] 2020 [cited 2020 Jul 14];7, Suppl S1:16-21. Available from: http://www.jpcc.org.in/text.asp?2020/7/7/16/285380




  Introduction Top


Epidemiology and virology studies show that COVID-19 transmission can occur from asymptomatic, presymptomatic, as well as symptomatic persons. Symptomatic transmission: typically, respiratory viruses are most contagious when a patient is symptomatic. Samples from confirmed patients showed that shedding of the virus is the highest in the upper respiratory tract (nose and throat) early in the course of the disease[1] within the first 3 days from the onset of symptoms. Presymptomatic transmission: Data suggest that person could transmit virus during the incubation period of 5–6 days, can be up to 14 days. Asymptomatic transmission: COVID-19-positive patients who never develop symptoms have been reported as a source of transmission. Reports of high titers of virus in the oropharynx early in the course of disease support the view of increased infectivity during the period of minimal symptoms.[2],[3] SARS-CoV-2 was isolated from the fecal swabs of a severe pneumonia patient indicating possible transmission from multiple routes. It is still unclear about the transmission through breast milk and vertical transmission in pregnant women.


  Clinical Suspicion Top


The possibility of COVID-19 should be considered primarily in patients with new-onset fever and/or respiratory tract symptoms (e.g., cough and dyspnea). It should also be considered in patients with severe lower respiratory tract illness without any clear cause. Although these syndromes can occur with other viral respiratory illnesses, the likelihood of COVID-19 is increased if the patient:

  • Resides in or has travelled within the prior 14 days to a location where there is community transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., large numbers of cases that cannot be linked to specific transmission chains) or
  • Has had close contact with a confirmed or suspected case of COVID-19 in the prior 14 days, including through work in health-care settings. Close contact includes being within approximately six feet (about two meters) of a patient for a prolonged period of time while not wearing personal-protective equipment (PPE) or having direct contact with infectious secretions while not wearing PPE.[4]


Diagnosis

The diagnosis cannot be definitively made without microbiologic testing, but limited capacity may preclude testing all patients with suspected COVID-19.


  Who Case Definition for the Surveillance of Covid-19 Top
[5]

Case definition and criteria for testing

Case definition and criteria for testing are evolving everyday being regularly revised depending on their local epidemiological situation, and therefore, it varies geographically. According to the WHO[4] on case definitions for the surveillance of COVID-19 are defined as:

Suspect case

A. A patient with acute respiratory illness (fever and at least one sign/symptom of respiratory disease, e.g., cough and shortness of breath) and a history of travel to or residence in a location-reporting community transmission of COVID-19 disease during the 14 days before symptom onset

or

B. A patient with any acute respiratory illness and having been in contact with a confirmed or probable COVID-19 case in the last 14 days before symptom onset;

or

C. A patient with severe acute respiratory illness (fever and at least one sign/symptom of respiratory disease, e.g., cough, shortness of breath; and requiring hospitalization) and in the absence of an alternative diagnosis that fully explains the clinical presentation.

Probable case

D. A suspect case for whom testing for the COVID-19 virus is inconclusive

or

E. A suspect case for whom testing could not be performed for any reason.

Confirmed case

A person with laboratory confirmation of COVID-19 infection irrespective of clinical signs and symptoms.


  Indian Council of Medical Research Has Published Revised Strategy for Covid-19 Testing in India as Top
[6]

  1. All symptomatic individuals who have undertaken the International travel in the last 14 days
  2. All symptomatic contacts of laboratory-confirmed cases
  3. All symptomatic health-care workers
  4. All patients with severe acute respiratory illness (fever and cough and/or shortness of breath)
  5. Asymptomatic direct and high-risk contacts of a confirmed case should be tested once between day 5 and day 14 of coming in his/her contact.


In hotspots/cluster (as per MoHFW) and in large migration gatherings/evacuees centers.

  1. All symptomatic influenza-like illness (ILI) (fever, cough, sore throat, and runny nose)


    1. Within 7 days of illness – Real-time reverse transcription-polymerase chain reaction (rRT-PCR)
    2. After 7 days of illness – Antibody test (If negative, confirmed by rRT-PCR).



  Contact Top


A contact is a person that is involved in any of the following:

  1. Providing direct care without proper PPE for COVID-19 patients
  2. Staying in the same close environment of a COVID-19 patient (including workplace, classroom, household, and gatherings)
  3. Traveling together in close proximity (1 m) with a symptomatic person who later tested positive for COVID-19.


High risk contact

  1. Touched body fluids of the patient (respiratory tract secretions, blood, vomit, saliva, urine, and feces)
  2. Had direct physical contact with the body of the patient including physical examination without PPE
  3. Touched or cleaned the linens, clothes, or dishes of the patient
  4. Lives in the same household as the patient
  5. Anyone in close proximity (within 3 feet) of the confirmed case without precautions
  6. Passenger in close proximity (within 3 feet) of a conveyance with a symptomatic person who later tested positive for COVID-19 for more than 6 h.


Low-risk contact

  1. Shared the same space (same class for school/worked in same room/similar and not having a high-risk exposure to confirmed or suspect case of COVID-19)
  2. Travelled in same environment (bus/train/flight/any mode of transit) but not having a high-risk exposure.


Along with above, clinicians should use their judgment to determine if a patient has signs and symptoms compatible with COVID-19 and whether the patient should be tested. Since many children may be asymptomatic or manifest only fever, CDC guidelines on “priorities for testing” recommend with high priority (PRIORITY 1) to test all hospitalized patients.[7]


  Laboratory Tests for the Diagnosis of Covid-19 (Molecular Diagnosis) Top


Published data suggest that the presentation could be nonspecific in 50%–80% of COVID-19 patients. Hence, rapid and reliable diagnostic test is the need of the hour for accurate diagnosis, management, prevention of spread, and hence, containment of epidemic.


  Reverse Transcription-Polymerase Chain Reaction Top


Molecular diagnosis (RT-PCR) being used worldwide remains the standard of reference to detect COVID-19. Upper respiratory specimen (nasopharyngeal swab) is the preferred primary sample for testing. When NP (nasopharyngeal swab) is not available, CDC recommends the following acceptable alternatives:[8]

  • An oropharyngeal (OP) specimen collected by a health-care professional or
  • A nasal mid-turbinate (NMT) swab collected by a health-care professional or by onsite self-collection (using a flocked-tapered swab) or
  • An anterior nares (nasal swab; NS) specimen collected by a health-care professional or by onsite self-collection (using a flocked or spun polyester swab)
  • Nasopharyngeal wash/aspirate or nasal aspirate (NA) specimen collected by a health-care professional.


When lower respiratory tract samples are available, i.e., if the patient is on mechanical ventilation, CDC recommends bronchoalveolar lavage (BAL), tracheal aspirate, pleural fluid, and lung biopsy. For patients who develop a productive cough, sputum should be collected. The induction of sputum is not recommended. Specimens should be collected as soon as possible once a PUI is identified, regardless of the time of symptom onset.


  Indian Council of Medical Research Has Recommended Guidelines for Respiratory Sample Collection from Suspected Covid-19 Cases Top
[9]

General guidelines for sample collection

  • Health-care providers should contact their local/state health department immediately to notify them of patients who meet the updated/recent case definition for COVID 19 as given by the health authorities, Government of India available on the website www.mohfw.gov.in complete the standard requisition form for each specimen submitted. Ensure restricted entry of visitors or attendants during the sample collection
  • Appropriate clinical sample should be collected by laboratory personnel/health-care worker trained in specimen collection following all biosafety and biosecurity precautions and using PPEs with latex-free purple nitrile gloves while collecting the sample from the patient
  • Ensure proper disposal of all waste generated (yellow bin)
  • Clinical samples need to be sent to the Government of India designated laboratory ensuring standard triple packaging for transportation
  • Combined throat (i.e., oropharyngeal swab) and nasal swab should be sent for patients who are not on mechanical ventilator (alternatively nasopharyngeal swab may be sent). For mechanically ventilated patients, lower respiratory tract aspirate (BAL) is the preferred sample.


Sample collection technique



a.Upper respiratory tract

  • Oropharyngeal swab (e.g., throat swab): Tilt patient's head back 70°. Rub swab over both tonsillar pillars and posterior oropharynx and avoid touching the tongue, teeth, and gums. Use only synthetic fiber swabs with plastic shafts. Do not use calcium alginate swabs or swabs with wooden shafts. Place swabs immediately into sterile tubes containing 2–3 ml of viral transport media
  • Nasopharyngeal swab: Tilt patient's head back 70°. Insert flexible swab through the nares parallel to the palate (not upward) until the resistance is encountered or the distance is equivalent to that from the ear to the nostril of the patient. Gently, rub and roll the swab. Leave the swab in place for several seconds to absorb secretions. Slowly remove swab while rotating it
  • The nasopharyngeal and oropharyngeal swabs should be placed in the same tube to increase the viral load
  • Combined nasal and throat swab: Tilt patient's head back 70°. While gently rotating the swab, insert swab less than one inch into nostril until resistance is met at turbinates. Rotate the swab several times against nasal wall and repeat in other nostril using the same swab. Place tip of the swab into sterile viral transport media tube and cut off the applicator stick. For throat swab, take a second dry polyester swab, insert into mouth, and swab both tonsillar pillars and the posterior pharynx. Avoid touching tongue, teeth, and gums. Place the tip of swab into the same tube and cut off the applicator tip. Separate swabs for throat and nose should be taken, but same viral transport medium tube be used to increase the viral load.


b.Lower respiratory tract: collect 2–3 mL of BAL, tracheal aspirate or sputum into a sterile, leak-proof, screw-cap sputum collection cup, or sterile dry container which has to be mixed with the viral transport medium and transported on the ice.

Packaging

Sample should be collected in a proper container that should be sealed and made leak-proof using parafilm and absorbent material. It must be appropriately labeled and secured in a zip-lock pouch with absorbent material such as tissue paper. The zip-lock container should further be placed in the sturdy plastic container, and its neck should be sealed. Disinfect the zip-lock pouch and secondary container by wiping with surface disinfectant and pack it further in “bio hazard-labeled thermocol box/hard card board box” with hard-frozen gel packs. Properly seal the box and secure ziplock pouch with test requisition form on the outer surface of the container. Label the box as shown in [Figure 1] below and transport to the designated laboratory.
Figure 1: Procedure for specimen packing and transport[9]

Click here to view


Test requisition form should be sent attached with specimen box as explained above or a scanned copy through e-mail (if such arrangement is done with the laboratory) to minimize the risk of transmission through fomites.

Storage

Store specimens at 2°C–8°C for up to 72 h after collection. If a delay in testing or shipping is expected, store specimens at −80°C.


  Role of Saliva for Diagnosing Covid19 Top


Wyllie et al. evaluated SARS-CoV-2 detection in paired nasopharyngeal swabs and saliva samples collected from COVID-19 inpatients and asymptomatic health-care workers at moderate-to-high risk of COVID-19 exposure. The study results indicate that using saliva for SARS-CoV-2 detection is more sensitive and consistent than using nasopharyngeal swabs and concluded that saliva is a viable and more sensitive alternative to nasopharyngeal swabs and could enable at-home self-administered sample collection for accurate large-scale SARS-CoV-2 testing.[10]


  Interpretation of Reverse Transcription-Polymerase Chain Reaction Results Top


A positive RT-PCR for SARS-CoV-2 generally confirms the diagnosis of COVID-19. Negative result does not exclude COVID-19. Negative results must be interpreted in combination with clinical findings, case history, and epidemiological information. Negative result should alone not be used as a criteria for the management. If initial testing is negative but the suspicion for COVID-19 remains and determining the presence of infection is important for the management or infection control, we suggest repeating the test. In such cases, the WHO also recommends testing lower respiratory tract specimens, if possible.[11] Infection control precautions for COVID-19 should continue while repeat evaluation is being performed

With limitations of sample collection, transportation, issues with kit performance, sensitivity of RT-PCR for NP swab was reported to be about 30%–60% at initial presentation.[12] In an another study that analyzed the sensitivity of RT-PCR at various tissue sites by examining 1070 specimens that were collected from 205 patients with confirmed COVID-19 from three hospitals in China and found that, of the specimens collected, BAL fluid specimens demonstrated the highest-positive rates (93%), followed by sputum (72%), nasal swabs (63%), fibrobronchoscope brush biopsy (46%), pharyngeal swabs (32%), feces (29%), and blood (1%). The authors pointed out that testing of specimens from multiple sites may improve the sensitivity and reduce false-negative test results.[13]

The accuracy and predictive values of SARS-CoV-2 testing have not been systematically evaluated, and the sensitivity of testing likely depends on the precise test as well as the type of specimen obtained. Negative RT-PCR tests on oropharyngeal swabs despite CT findings suggestive of viral pneumonia have been reported in some patients who ultimately tested positive for SARS-CoV-2.[14]


  Coinfections: Other Respiratory Pathogens Top


The importance of testing for other pathogens was highlighted in a report of 210 symptomatic patients with suspected COVID-19; 30 tested positive for another respiratory viral pathogen, and 11 tested positive for SARS-CoV-2.[15] Detection of other respiratory pathogens is not uncommon in COVID-19-infected patients, and their detection does not exclude COVID-19.[16],[17]


  Rapid Tests Top


In response to the growing COVID-19 pandemic and shortages of laboratory-based molecular testing capacity and reagents, multiple rapid, point-of-care, diagnostic tests (based on both antigen and antibody detection) are being developed. These are rapid, easy-to-use, improve surveillance efforts, and detect recovery. At present, based on current evidence, the WHO recommends the use of these new point-of-care immunodiagnostic tests only in epidemiological research and disease surveillance. They are not recommended to be used for clinical decision-making, until evidence-supporting use for specific indications is available.[18]

The Indian Council of Medical Research has approved rapid antibody testing in clusters for surge suspected cases of ILI with suggested protocol to use these tests with RT-PCR, as shown in [Figure 2].[19]
Figure 2: Indian Council of Medical Research protocol for rapid antibody testing[19]

Click here to view


In one study that included 58 patients with clinical, radiographic, and epidemiologic features suspicious for COVID-19 but with negative SARS-CoV-2 PCR testing, an IgM enzyme-linked immunosorbent assay was positive in 93 percent (and was negative when tested separately on plasma specimens that predated the COVID-19 outbreak.[20]

For safety reasons, specimens from a patient with suspected or documented COVID-19 should not be submitted for viral culture.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organisation. Situation Report – 73. Coronavirus Disease 2019 (COVID-19). SUBJECT IN FOCUS: The Routes of Transmission from COVID-19 Patients; 02 April, 2020. Available from: https://www.who.int/docs/default-sou rce/coronaviruse/situation-reports/20200402-si trep-73-covid-19.pdf?sfvrsn=5ae25bc7. [Last accessed on 2020 Apr 20].  Back to cited text no. 1
    
2.
Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020;382:929-36.  Back to cited text no. 2
    
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Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-9.  Back to cited text no. 3
    
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World Health Organization. Infection Prevention and Control During Health Care when Novel Coronavirus (nCoV) Infection is Suspected; 25 January, 2020. Available from: https://www.who.int/publications-detail/infect ion-prevention -and-control-during-hea lth-care-when-novel-corona virus-(ncov)-infection-is-suspected-20200125 (). [Last accessed on 2020 Feb 04].  Back to cited text no. 4
    
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World Health Organization. Global Surveillance for COVID-19 Caused by Human Infection with COVID-19 Virus Interim Guidance. World Health Organisation; 20 March, 2020. Available from: https://www.who.int/emergencies/dise ases/novel-coronavirus-2019/technical-guidan ce/surveillance-and-case-definitions (). [Last accessed on 2020 Apr 24].  Back to cited text no. 5
    
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Indian Council of Medical Research (ICMR). Revised Strategy for COVID19 Testing in India (Version 4, dated 09/04/2020). Available from: https://icmr.nic.in/content/covid-19 (). [Last accessed on 2020 Apr 24].  Back to cited text no. 6
    
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Centers for Disease Control and Prevention (CDC). Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). Available from: https://www.cdc.gov/coronavi rus/2019-nCoV/hcp/clinical-crit eria.html (). [Last accessed on 2020 Apr 24].  Back to cited text no. 7
    
8.
Centers for Disease Control and Prevention (CDC). Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons under Investigation (PUIs) for Coronavirus Disease 2019 (COVID-19). Updated April 14; 2020. Available from: https://www.cdc.gov/corona virus/2019-nCoV/lab/guideli nes-clinical-specimens.html. [Last accessed on 2020 Apr 24].  Back to cited text no. 8
    
9.
Available from: https://www.mohfw.gov.in/p df/5 Sample%20collection_packa ging%20%202019-nCoV.pdf. [Last accessed on 2020 Apr 24].  Back to cited text no. 9
    
10.
Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, et al. Saliva is more sensitive for SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs. medRxiv 2020;medRxiv 2020.04.16.20067835. [Doi: 10.1101/2020.04.16.20067835].  Back to cited text no. 10
    
11.
World Health Organization. Coronavirus disease (COVID-19) Technical Guidance: Surveillance and Case Definitions. Available from: https://www.who.int/emerg encies/diseases/novel-coronavirus-2019/tech nical-guidance/surveillance-and-case-definitions (). [Last accessed on 2020 Feb 28].  Back to cited text no. 11
    
12.
Yang Y, Yang M, Shen C, Wang F, JYuan J, Li J, et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. 2020; medRxiv 2020.02.11.20021493. [Doi: 10.1101/2020.02.11.20021493].  Back to cited text no. 12
    
13.
Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA 2020;e203786. doi:10.1001/jama.2020.3786. [Published online ahead of print, 2020 Mar 11].  Back to cited text no. 13
    
14.
Xie X, Zhong Z, Zhao W, Zheng C, Wang F, Liu J. Chest CT for typical 2019-nCoV pneumonia: Relationship to negative RT-PCR testing. Radiology 2020;200343. doi:10.1148/radiol.2020200343. [Published online ahead of print, 2020 Feb 12].  Back to cited text no. 14
    
15.
Bajema KL, Oster AM, McGovern OL, Lindstrom S, Stenger MR, Anderson TC, et al. Persons evaluated for 2019 novel coronavirus-United States, January 2020. MMWR Morb Mortal Wkly Rep 2020;69:166-70.  Back to cited text no. 15
    
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Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol 2020;10.1002/jmv.25781. doi:10.1002/jmv.25781. [Published online ahead of print, 2020 Mar 20].  Back to cited text no. 16
    
17.
Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of Co-infection between SARS-CoV-2 and other respiratory pathogens. JAMA 2020;e206266. doi:10.1001/jama.2020.6266. [Published online ahead of print, 2020 Apr 15].  Back to cited text no. 17
    
18.
World Health Organization. Advice on the Use of Point-of-Care Immunodiagnostic Tests for COVID-19. Scientific Brief. World Health Organization; 8 April, 2020. Available from: https://www.who.int/news-room/commen taries/detail/advice-on-the-use-of-po int-of-care-immunodiagnostic-te sts-for-covid-19 (). [Last accessed on 2020 Apr 24].  Back to cited text no. 18
    
19.
Available from: https://www.mohfw.gov.in/pdf/Advisory and StrategyforUseofRapidAntibo dyBasedBloodTest.pdf. [Last accessed on 2020 Apr 24].  Back to cited text no. 19
    
20.
Guo L, Ren L, Yang S, Xiao M, Chang, Yang F, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis. 2020;ciaa310. doi:10.1093/cid/ciaa310. [Published online ahead of print, 2020 Mar 21].  Back to cited text no. 20
    


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  In this article
Abstract
Introduction
Clinical Suspicion
Contact
Laboratory Tests...
Reverse Transcri...
Role of Saliva f...
Interpretation o...
Coinfections: Ot...
Rapid Tests
Who Case Definit...
Indian Council o...
Indian Council o...
References
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