This study aimed to explore the relationship between clinical, laboratory and radiological characteristics of a cohort of patients undergoing LRT sampling due to suspect SARS-CoV-2 infection, after at least two negative NPSs.
We found 7 positive cases out of 59, 11.9% of the analyzed population. We did not find any relevant relationship between clinical symptoms at admission and positivity of LRT samples, nor between any of the laboratory values considered (lymphocyte count, D-dimer assay, LDH and PCR) and SARS-CoV-2 diagnosis in LRT samples.
Revision of the CT scans by two blinded radiologists showed a sensitivity as high as 71.4% with a diagnostic accuracy of 81.3% using the Radiological Society of North America score. A very high negative predictive value was also detected (95.7%).
Other studies explored the role of bronchoscopy in COVID-19, with heterogeneous populations, patients selection criteria and conclusions. Ora et al studied BAL performance in SARS-CoV-2 search in patients with suspect COVID-19 based on symptoms and CT scan, at least two negative swabs and negative serologic test for SARS-CoV-2. They report no detection of SARS-CoV-2, and conclude that in such cases BAL should not be considered for testing [17]. Geri et al also used BAL to search for SARS-CoV-2 on 79 consecutive patients admitted to respiratory units of three Italian hub hospitals, finding high concordance for negative result (97.5%) between NPS and BAL. The Authors suggest that BAL has a limited role in the diagnosis of COVID19 when both thoracic imaging and upper respiratory swabs are negative [18]. However, only 50 out of 79 patients had at least two negative swabs, which would seem more prudent to spare health workers from exposure in unnecessary aerosol generating procedures, as per international recommendations. Furthermore, only 63 patients had a CT scan, and only 38 of them showed signs compatible with viral infection. Most importantly, the 2 patients with positive BAL had highly compatible CT scan for COVID19. Mondoni et al assessed the yield of both BAL and BW in 78 patients from six different Italian Hospitals, who underwent bronchoscopy for SARS-CoV-2 search for suspicion of COVID-19 despite two negative NPSs. The Authors report a very high prevalence of COVID-19 (55.1%) and report no significant differences between BAL and BW [19]. More recently, another Italian multicenter study by Patrucco et al isolated SARS-CoV-2 on BAL in 43/131 (32.8%) patients [20]. Included patients differed in key characteristics, such as number of pre-test negative NPSs, suspicion of infection and indications to perform a bronchoscopy. High agreement is reported in this work between NPSs and BAL especially in negative samples, but on the other hand only 10 out of 43 positive patients had a positive NPS. Most of the included patients presented chest CT alterations. A subsequent review of the CT scan in 46 patients from this cohort using international societies recommended scores showed good correlation between suggestive features and BAL positivity for SARS-CoV-2 for both the CO-RADS and the Radiological Society of North America score [21].
We included in our analysis suspected patients with at least 2 consecutive negative NPSs. We included BNTA as a sampling technique for its less invasive nature and ease of performance even for less trained personnel. At the time of analysis, serology for SARS-CoV-2 was not available in our hospital setting to rule out infection with SARS CoV2. Hence, the conclusion of the work from Ora et al do not apply to our cohort. In fact, not performing LRT sample analysis would have led to 7 missed cases, with possible great risk of in-Hospital spreading of the infection.
The potential of the CT of the thorax in the diagnosis of COVID-19 has been first suggested by Ai et al who, after reviewing more than 1000 CT scans from Chinese patients, calculated a sensitivity of 97% for SARS-CoV-2 associated pneumonia. Since then, knowledge on radiological appearance of SARS-CoV-2 related lung alterations has increased, leading to the development of suggested standardized report systems [10,22].
However, the diagnostic performance of CT scan not merely depends on the prevalence of the disease in the studied population, but is also affected by non-specific findings of COVID-19 that overlap with those of other conditions, resulting in a substantial rate of false-positive examinations [23]. A Cochrane meta-analysis by Salameh et al including 78 studies evaluating CT scan on 8105 participants found a 93.1% sensitivity for studies including confirmed cases and a 86.2% sensitivity in studies including suspected cases. However, specificity resulted much lower (18.1%) [24]. Another meta-analysis by Kovacs et al reported sensitivity between 67 and 100% for chest CT. Interestingly, the Authors notice that the sensitivity of NPS test clearly influences the calculated CT scan specificity, which may therefore be underestimated. Korevaar et al retrospectively evaluated the added value of chest CT scan analyzed with the CO-RADS score to RT-PCR testing [22]. The Authors found a CT score consistent with COVID19 in 92.9% of the patients with initial positive RT-PCR test. They also reported that 13 cases out of 38 with positive CT but negative NPS test ultimately had confirmed SARS-CoV-2 infection after repetition of RT-PCR testing. As in previous reports, specificity was lower, being only 25% [25].
Our data further support the importance of chest CT in COVID19 diagnosis, especially when a standardized scoring system is applied. We had our CT scans reviewed by two radiologists, finding good sensitivity, specificity and NPV resulting in promising diagnostic accuracy. Not to overestimate CT performance, we included in the reported calculation 2 patients who already had been admitted and treated with a COVID-19 diagnosis, and had been discharged from hospital with negative RT-PCR on NPS. It has already been described that BAL retains RT-PCR positivity for longer than NPS [26], though it is not clear whether this positivity really reflects infectivity. The CT features for these 2 cases may not represent the acute phase of the disease, therefore misleading the reading radiologist [27]. By excluding these two patients from the analysis, CT sensitivity would have resulted 100%, and diagnostic accuracy would have been 86%. Certainly, the low incidence of infection in our population, also as a consequence of considering only patients with 2 negative NPSs, lead to a higher calculated specificity and NPV, which may not be applicable to other scenarios.
Our results are consistent with published works on the topic, confirming the overall good concordance between negative CT findings, negative NPSs and negative LRT RT-PCR testing. An important finding of this study is that even 2 negative NPSs cannot safely rule out SARS-CoV-2 infection, especially when typical features are detected on CT scan, as reported by other groups [18,19,21]. Data also seem to suggest that since most symptoms are overlapping in different diseases, they should not be considered disease specific per se, and confirm that probably most of the interest for lab values stands in their predictive value for clinical outcomes [2,4,8].
In this scenario, having the CT scan revised and scored according to an objective and repeatable score is key in interpreting imaging features, as imaging revision by respiratory clinician would have led to a greater number of false positives, given the presence of ground glass opacities in most of the cases included.
Our work suggests bronchial washing to be as effective as BAL. In selected cases, even BNTA can be a valuable choice, with lower risks for complications, considering the high prevalence of pre-examination respiratory failure in this population.
In fact we only report five complications during BW sampling, none severe and all consisting in drop in oxygen saturation during sample collection.
Ora et al and Patrucco et al found alternative specific infective agents in a significant proportion of their patients [17,20]. In our cohort BW identified respiratory infection by either bacteria or fungi in more than 40% of the included population, with overlapping bacterial and fungal infection in 13.6%. This confirms the high value of LRT sampling in managing lung infections, potentially leading to clinical changes in terms of antibiotic choice.
Our study certainly has all the limitations connected with its retrospective design. Other limitations include its mono centric nature and the relatively small number of cases analyzed. Data on specificity and NPV should be weighted with regards to the low prevalence of infection we found in this population.
However, our study clearly reflects real life clinical scenario in a hub University Center during the pandemic phase of the infection, where promptly confirming SARS-CoV-2 infection is mandatory to avoid in-hospital spreading of the disease. The lower incidence of SARS-CoV-2 detection in the lower respiratory tract as compared to that of Mondoni et al and Patrucco et al, probably reflects differences in epidemiologic prevalence of the infection between different areas. To the best of our knowledge, we are the first to assess a repeatable combined clinical, laboratory and radiological score in the diagnostic workup of COVID-19, despite only showing good correlations with CT scan.
Our data suggest that COVID-19 is a multi-modal diagnosis which should not rely on only one test, but rather on a panel of tests, which to the best of our knowledge should include CT scan and LRT samples, when CT scan is consistent and less invasive tests cannot be conclusive. A multi-disciplinary discussion should be advised in more complex cases, including at least radiologists and pulmonologists. Our data also show that bronchoscopy, when protective equipment is used as indicated in several reports, can be performed preserving health workers' safety. It must be noticed that SARS-CoV-2 diagnosis is not only necessary for preventing spreading of the infection, but also for treatment access (e.g. participation in clinical trials), and for safety reasons before undertaking immunosuppressive or chemotherapy treatment. Another application of bronchoscopy in suspected cases can include differential diagnosis with other infectious diseases.