key: cord-1033750-vs5mt4w7
authors: McGrath, J.; Kenny, C.; Smyth, H.; McGinty, T.; Sheehan, G.; Gaine, S.; McCullagh, B.; MacMahon, P.; Egan, J.; Cotter, A.
title: A multidisciplinary evaluation of suspected, unconfirmed cases of COVID-19 including chest CT, as compared to World Health Organization recommendations
date: 2021-02-23
journal: Clin Radiol
DOI: 10.1016/j.crad.2021.02.006
sha: cc60e21963363946f5ff8ca393d22bd6e10f8344
doc_id: 1033750
cord_uid: vs5mt4w7

Aim To report an audit of the evaluation of suspected, unconfirmed cases of COVID-19 including chest computed tomography (CT), as compared to World Health Organization recommendations. Methods A clinical audit was undertaken examining the evaluation of patients with suspected COVID-19 with negative SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) results, with comparison to WHO recommendations. A retrospective chart review was undertaken for 90 patients examining investigations, in particular CT, used to clarify the diagnosis. Results Ninety patients underwent additional investigation. Seventy-five per cent adherence to WHO recommendations was observed. Fifty-two men (57.78%) and 38 (42.22%) women were investigated, with a median age of 69 years (range 20–96 years). Seventy-nine chest CT examinations demonstrated positive, indeterminate, and negative rates for COVID-19 of 3.79%, 24.1%, and 72.15% respectively. Three patients had discordant swab results with initially negative and subsequently positive results for SARS-CoV-2, resulting in false-negative rates of 5.1% for those retested. Combining discordant RT-PCR swab results, positive radiology, and patients treated as COVID-19-positive due to indeterminate radiology and highly consistent symptoms, resulted in a false-negative rate for initial SARS-CoV-2 RT-PCR swabs of 16.67%. Conclusion Seventy-five per cent compliance with relevant WHO guidance and a false-negative rate for initial swabs of 16.67% was demonstrated. Further evidence is needed to fully determine the utility of chest CT in the diagnosis of COVID-19 in the context of initial false-negative RT-PCR results.

Up to 27 October 2020, the COVID-19 pandemic has resulted in 43,598,033 cases worldwide, with 1,160,995 deaths, including 54,484 cases in Ireland causing 1,621 deaths (1, 2) .

At present, detection of SARS-CoV-2 RNA via real-time reverse transcription polymerase chain reaction (RT-PCR) is the reference standard for diagnosing suspected cases of COVID-19 (3) . Although this investigation is specific, test sensitivity varies according to a number of factors resulting in a false-negative rate of approximately 30% (4) .

Comprehensive guidelines on the use of chest computed tomography (CT) in the diagnosis of COVID-19 are lacking. Initial reports from China suggested a central J o u r n a l P r e -p r o o f role of CT in COVID-19 diagnosis (5, 6) , with some citing higher sensitivity rates with use of CT thorax when compared to RT-PCR for SARS-CoV-2 (5); subsequent examination of these data has noted significant methodological limitations (7). In clinical practice, chest CT has become a valuable adjunct to diagnosis (8) ; however, its value in RT-PCR-negative COVID- 19 cases has yet to be fully established.

In June 2020, the World Health Organisation (WHO) published "Use of chest imaging in COVID-19: a rapid advice guide". This guide makes recommendations for the use of chest imaging in acute care of adult patients with suspected, probable, or confirmed COVID-19, including chest radiography, computed tomography (CT) and lung ultrasound (Table 1 ) (9) .

The present authors undertook a clinical audit of the evaluation of suspected COVID-19 cases with negative SARS-CoV-2 RT-PCR results on oro/nasopharyngeal swabs, in comparison to recommendations set out by the WHO in the June 2020 rapid advice guide.

In this Level 4 tertiary referral centre, as per national Health Service Executive (HSE) guidelines, at entry to hospital all patients are segregated into two parallel streams described as COVID-19 and non-COVID-19 pathways (10) (Fig. 1) . On presentation to hospital or during an inpatient stay, a decision to test for SARS-CoV-2 is made clinically, informed and supported by the national guidelines (10) .

In this institution, a patient with confirmed COVID-19 remains on the "COVID-19 pathway" in cohort wards throughout their inpatient stay until discharge or until they J o u r n a l P r e -p r o o f have undergone a 14-day period of isolation with resolution of respiratory symptoms.

Following admission, to exclude COVID-19 as the primary diagnosis and leave the pathway, a patient must have at least one negative SARS-CoV-2 RT-PCR swab and a suitable alternative diagnosis. If clinical suspicion persists, despite the initial negative RT-PCR results, individual cases are discussed at a daily multidisciplinary team (MDT) meeting, attended by members of the infectious diseases, respiratory and admitting medical teams. Decisions regarding further investigation, including repeat SARS-CoV-2 RT-PCR testing and modality of chest imaging, are made on a case-by-case basis following specialist input. Patients with subsequently positive SARS-CoV-2 RT-PCR results, chest imaging reported as consistent with COVID-19, and highly consistent clinical presentations in addition to indeterminate imaging, in the absence of suitable alternative diagnosis, are treated as COVID-19 positive. The final decision to remove or keep a patient on the COVID-19 pathway following further investigation is made by the responsible treating physician.

Between 28 March and 4 May 2020, 90 patients with initial negative SARS-CoV-2 RT-PCR swab results were further investigated as per the MDT to further clarify the possible diagnosis of COVID-19. All included patients had, at minimum, moderate symptoms requiring admission to hospital or deterioration during an inpatient stay, necessitating MDT discussion.

CT images were categorised as (1) typical for COVID-19, (2) indeterminate for COVID-19, or (3) atypical or negative for COVID-19 by a consultant radiologist or by a registrar in radiology whose findings were confirmed by a consultant. This categorisation is derived from the Radiological Society of North America (RSNA) CT J o u r n a l P r e -p r o o f criteria related to COVID-19 (11) , where "negative for COVID-19" cited is a combination of RSNA categories "atypical appearances" and "negative for pneumonia". Decision to use unenhanced chest CT versus CT pulmonary angiography (CTPA) was based on clinical presentation, supporting clinical tools (e.g., Well's score), and was made on an individual basis via MDT discussion.

A retrospective chart review was undertaken for patients with negative SARS-CoV-2 RT-PCR swab results, but for whom clinical suspicion for a diagnosis of COVID-19 remained, examining the investigations used to further clarify or exclude the diagnosis.

Due to lack of published standards during the study dates, the above WHO guideline was not applied prospectively, with comparison being made in retrospect. The aim of this audit was to assess the extent to which investigation of this patient population following MDT discussion, in particular with use of chest CT, is in keeping with the published guidance from the WHO and to formulate recommendations for future assessment. Approval to undertake this study was granted by the institution's Clinical Audit Committee. patients included in the audit had at least one chest radiography examination with 86.67% of patients going on to have some form of CT imaging. Although this is not in keeping with guidance of R2.1, the patients studied warranted admission regardless of ultimate diagnosis and chest X-Ray is a standard part of admission work-up for many infectious/acute respiratory presentations. Indeed the WHO advice guide notes that imaging is particularly useful in those with: "moderate-severe symptoms, require admission to hospital regardless of eventual diagnosis, or in those who are at risk of complications secondary to COVID-19, such as pulmonary embolism" (9). All patients included in this audit met at least one of those criteria, and therefore, the use of at least one imaging technique in the reported work-up is consistent with the given guidelines.

Due to the limited evidence on the utility of specific imaging methods in the diagnosis of suspected/confirmed cases of COVID-19, the WHO advice guide acknowledges that radiological findings must be used as one element in the evaluation of a patient that also includes clinical and laboratory data (12) . This audit demonstrates full adherence to this advice, as all patients included were discussed in a MDT meeting, with consideration given to clinical presentation, laboratory findings, and initial imaging, e.g., chest radiography. diagnosis with some reports citing sensitivities as high as 97% and 98% (5, 6) . It has since been noted that significant methodological issues are present in these studies (7) necessitating some caution in interpretation. In clinical practice, however, CT has become a valuable adjunct to diagnosis, as well as detection of associated complications, of COVID-19, such as acute respiratory distress syndrome (ARDS), PE, superimposed pneumonia, or heart failure (8) . Chest CT is associated with high sensitivity but low specificity in most studies, resulting in weak positive likelihood ratios but stronger negative likelihood ratios (12) . A study by Ai et al., found the positive likelihood ratio was 1.28 and the negative likelihood ratio was 0.16 (6) . At present, detection of SARS-CoV-2 RNA via RT-PCR is the reference standard for diagnosing suspected cases of COVID-19 (4) and samples may be obtained from either the upper or lower respiratory tract. The test sensitivity varies according multiple factors including duration of illness (17) , the site of specimen collection (18), the quality of specimen collection, and the viral load (5) . As a result, false-negative rates have been reported to occur in ~30% of patients with COVID-19 (range <5% to 40%) (4, 19) , and therefore, one initial negative swab should not be solely relied upon to confirm or exclude a diagnosis of COVID-19 if clinical suspicion is high. One large study of 20,912 patients demonstrated that among those initially testing J o u r n a l P r e -p r o o f negative by SARS-CoV-2 RT-PCR of nasopharyngeal swabs, repeat testing within 7 days yielded a positive result in 3.5% of cases (19) .

In the present audit sample, three patients had discordant swab results with initial negative and subsequently positive results for SARS-CoV-2, 4, 6, and 8 days following initial sampling. This results in a false-negative rate of 5.1% for those retested, which is comparable to the rate of 3.5% reported by Long et al. (15) . Two There are a number of limitations in this audit that need to be considered. Although 75% compliance with recommendations was determined, the guidance included in this and other similar guidelines to date are necessarily general until further data regarding utility of specific imaging methods emerge, in particular in the context of RT-PCR-negative COVID-19 cases. The WHO guidance (9) is subcategorised by symptom severity as mild/moderate/severe and patients in this analysis were not specifically given such designations; however, based on symptom criteria cited in the guide (9) and having clinical presentations severe enough to warrant admission, COVID testing and MDT discussion, all patients meet the criteria for "moderate" symptoms at a minimum. Lack of formal designation also limits the interpretation from this analysis of chest CT utility in diagnosis of COVID-19 by symptom severity in the context of negative RT-PCR results.

J o u r n a l P r e -p r o o f Furthermore, a limitation in determining the true sensitivity and specificity of chest CT in this audit group is the lack of a reference standard, as it is presumed that the initial negative RT-PCR result could possibly represent be a false negative itself.

Fang et al. (5) utilised serial sampling as a way of defining which patients became truly positive and this could be used as a prospective method in future studies/audit to aid in this; however, this is not fully reliable, as discussed above due to reported sensitivity rates/timing of testing, etc.

Re-audit of this patient cohort and pathway will be undertaken as further guidelines from the WHO or comparable bodies are issued, to ensure best practice based on the available evidence. Recommendations for future evaluation of this pathway include classification of cases by symptom severity (mild/moderate/severe) to investigate the relative additional value CT imaging provides stratified by disease severity. Additionally, evaluation of benefit derived from chest CT imaging following indeterminate chest radiography will aid in refining patient criteria for this imaging technique. Finally, determining specific criteria for repeat SARS-CoV-2 RT-PCR testing, taking into consideration incidence of disease and community transmission, will further clarify the value of repeat RT-PCR-testing versus further radiological imaging such as chest CT in COVID-19 diagnosis.

In conclusion, a clinical audit was undertaken of the further evaluation of suspected COVID-19 cases with negative SARS-CoV-2 RT-PCR results on oronasopharyngeal swabs, in comparison to recommendations set out by the WHO in the June 2020 guidance (9) . At least 75% compliance with recommendations was J o u r n a l P r e -p r o o f determined. Chest CT resulted in a positive, indeterminate, and negative rate of 3.79%, 24.1%, and 72.15%, respectively, for COVID-19.

Further evidence is needed to fully determine the utility of chest CT in the diagnosis of COVID-19, in particular in the context of false-negative RT-PCR swab results for SARS-CoV-2. As diagnostic algorithms are refined, patient care, institutional patient flow and infection control measures will improve. For symptomatic patients with suspected COVID-19, WHO suggests using chest imaging for the diagnostic work-up of COVID-19 when: (1) RT-PCR testing is not available;

(2) RT-PCR testing is available, but results are delayed; and (3) initial RT-PCR testing is negative, but with high clinical of suspicion of COVID-19 R 4 -For patients with suspected or confirmed COVID-19, not currently hospitalized and with moderate to severe symptoms, WHO suggests using chest imaging in addition to clinical and laboratory assessment to decide on regular ward admission versus intensive care unit (ICU) admission R 5 -For patients with suspected or confirmed COVID-19, currently hospitalized and with moderate to severe symptoms, WHO suggests using chest imaging in addition to clinical and laboratory assessment to inform the therapeutic

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J o u r n a l P r e -p r o o f

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N/A J o u r n a l P r e -p r o o f