Hussain Ahmed Raza ( The Aga Khan University, Karachi. )
Mohummad Hassan Raza Raja ( 4th Year MBBS Student, The Aga Khan University, Karachi, Pakistan. )
Paul Arthur Bain ( Countway Library, Harvard Medical School, Boston, USA. )
Harmeet Bedi ( Department of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, USA. )
Rehana Salam ( Department of Paediatrics and Child Health. )
Bushra Jamil ( Department of Medicine, Aga Khan University, Karachi, Pakistan. )
Majid Shafiq ( Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA. )
January 2023, Volume 73, Issue 0
Hussain Ahmed Raza ( The Aga Khan University, Karachi. )
Objective: To investigate the diagnostic performance of bronchoscopy in patients with coronavirus disease 2019 infection.
Method: The systematic review was conducted in April 2021 and comprised search of published articles and preprint servers for original articles assessing diagnostic performance of bronchoscopy in patients with suspected coronavirus disease 2019 infection. The primary outcome of interest was diagnostic sensitivity of bronchoalveolar lavage in the patients. The quality of each study was assessed using the Quality Assessment, Data Abstraction and Synthesis-2 tool.
Results: Of the 29 full-text articles assessed for eligibility, 4(13.8%) were included collectively comprising 209 patients who had undergone bronchoalveolar lavage. Mean sensitivity of bronchoalveolar lavage was 83.5% ± 10.63 (range: 68.2-940%). Overall, the 4 studies had an unclear or low risk of bias.
Conclusion: Limited data suggested that bronchoscopy with bronchoalveolar lavage did not have reliably higher diagnostic sensitivity than that reported for either nasopharyngeal or oropharyngeal swabs.
Keywords: Bronchoscopy and interventional techniques, COVID-19, Diagnostic techniques.
Submission completion date: 04-02-2022 Acceptance date: 16-07-2022
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and has since caused a global pandemic with well over 156 million confirmed cases of coronavirus disease 2019 (COVID-19) and over 3 million attributable deaths.1 As the name implies, the virus belongs to the coronavirus family along with other viruses, such as Middle East Respiratory Syndrome (MERS-CoV) and severe acute respiratory syndrome CoV-1 (SARS-CoV-1). Both SARS-CoV-1 and SARS-CoV-2 bind to the angiotensin-converting enzyme 2 (ACE-2) receptor, which is preferentially expressed in the lower respiratory tract (LRT) as opposed to the upper respiratory tract (URT), with a notable exception being the oral cavity where ACE-2 is abundantly expressed.2 A study showed that LRT samples, like sputum, endotracheal tube aspirate and bronchoalveolar lavage [BAL], had greater diagnostic sensitivity for SARS-CoV-1 compared to URT samples.3
Laboratory diagnosis of SAR-CoV-2 is usually obtained through reverse transcription polymerase chain reaction (RT-PCR) testing of URT samples, typically either with a nasopharyngeal swab (NPS) or an oropharyngeal swab (OPS). However, published data show widely varying detection rates of SARS-CoV-2 among such samples.4,5 This raises concerns about the ability of these diagnostic procedures to reliably confirm or exclude a SARS-CoV-2 infection. False negatives (FNs) may be attributed to poor sample collection technique and an early course of infection with a low viral load. Additionally, it may also be attributed to the pathogenesis of the disease itself due to the spatial location of the ACE-2 receptors.
A number of publications report instances where suspected COVID-19 patients who tested negative after OPS and NPS were found to be positive for SARS-CoV-2 on PCR involving samples obtained via bronchoscopy.2,5,6 However, the diagnostic sensitivity of bronchoscopy in COVID-19 is unclear. Given its higher risk of procedural complications and greater occupational hazard due to aerosolization, societal guidelines recommend against it unless necessary.7 On the other hand, knowledge of the sensitivity of bronchoscopy and its ability to capture false negative results from less invasive testing could help clinicians obtain accurate diagnosis where it could make an impact on management decisions (e.g., to enable antiviral drug administration as per institutional policy, to enable enrollment in a clinical trial as per study protocol, or to avoid discontinuation of pathogen-specific isolation precautions following FN diagnostic tests). The current systematic review of studies was planned to investigate the diagnostic performance of bronchoscopy in patients with COVID-19 infection.
Materials and Methods
The systematic review was conducted in April 2021 and comprised search of published articles and preprint servers for original articles assessing diagnostic performance of bronchoscopy in patients with suspected VOVID-19 infection. The study was done in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) checklist.8
Literature search was conducted on MEDLINE (Ovid), Embase (Elsevier), Web of Science Core Collection (Clarivate) and the Cochrane COVID-19 Study Register.9 Controlled vocabulary terms were used when available and appropriate, and no language limits were applied. Bibliographies of the shortlisted articles were also reviewed (Appendix). Given the rapidly expanding literature on COVID-19, preprints available through medRxiv.org, bioRxiv.org, and preprints.org were also examined through Google Scholar.10
The search was done following the population, intervention, comparison, outcome, study type (PICOS) framework.11
The included studies were either observational or experimental those with adult patients aged 18 years and above infected with SARS-CoV-2 using bronchoscopy with BAL, with or without additional sampling, such as bronchial brushing (BB) or bronchial washing (BW), and where the primary outcome was diagnostic sensitivity for SARS-CoV-2 infection.
Those excluded were case reports or series with <5 subjects, conference abstracts, articles published in language other than English, studies with overlapping datasets, and review papers.
Study selection was a two-staged process with titles and/or abstracts of studies screened first, following retrieval using the search strategy. The full texts of shortlisted studies were assessed for eligibility by two reviewers. Any disagreement was resolved through discussion with a third reviewer.
To systematically assess study quality, the Quality Assessment, Data Abstraction and Synthesis-2 (QUADAS-2) tool12 was used. Studies were independently scored by two researchers across four domains, namely index test, reference standard, patient selection and flow and timing. The risk of bias for each publication was labelled as low, high or unclear for each domain. Inter-rater agreement was determined using Cohen's kappa statistics.
The primary outcome of interest was the diagnostic sensitivity of BAL in patients with confirmed COVID-19 infection. Sensitivity was defined as the proportion of SARS-CoV-2-infected patients, as confirmed by any PCR-based laboratory test, who were BAL PCR-positive. The diagnostic performance of other bronchoscopic sampling methods, such as BB and BW, were also examined and so were endotracheal aspirates, if possible. Data on safety of bronchoscopy in these patients was also reviewed.
In a separate post-hoc analysis, the researchers reviewed published studies on adult patients with suspected SARS-CoV-2 infection and negative initial testing by OPS and/or NPS who subsequently underwent bronchoscopy with BAL. Such analysis sought to assess the real-world clinical utility of BAL among suspected COVID-19 patients with one or more negative tests performed through less invasive means.
Of the 2447 search results, 2393(97.7%) were located through electronic database searching and 54(2.2%) from preprint and bibliography searching. After removing duplicate records, 1501(61.3%) records were screened for relevance. Finally, of the 29(1.9%) full-text documents assessed for eligibility, 4(13.8%) studies were included (Figure).
Altogether, 209 BAL samples and 13 BB samples were obtained (Table-1). PCR kits used in the studies were noted in detail (Table-2). The mean sensitivity values of PCR-based testing using bronchoscopic samples showed mean values of 83.5%±10.6 (range: 68.2-94.0%) (Table-3).
None of the studies reported any adverse patient event, like respiratory failure, hemodynamic compromise, or deaths resulting from bronchoscopy. No data were reported on occupational exposures to SARS-CoV-2 stemming from bronchoscopy.
The risk of bias varied widely but was felt to be either unclear or low in most cases, while the Cohen kappa statistic for interrater agreement was 0.87 (Tables-4, 5).
During the post-hoc analysis, 2 case series and 11 case reports described patients who were successfully diagnosed with COVID-19 using BAL PCR following negative URT sampling, while 2 sizeable prospective observational studies showed that BAL PCR returned negative in all of the initially negative URT samples among 205 adults with suspected COVID-19 infection (Table-6).
The systematic review of limited observational data found that bronchoscopy with BAL had a reasonably high but variable sensitivity for the diagnosis of active SARS-CoV-2 infection, with reported values ranging from 68.2% to 94%. The yield of bronchoscopy was likely to be low in patients who may have undergone more than one URT sampling.
The reported diagnostic sensitivity of bronchoscopy with BAL compared favourably with that for NPS, which is variably reported to be anywhere from 54% to 98.3% but mostly around 70%.13-15 On the other hand, OPS have been reported to have a sensitivity significantly lower than NPS with sensitivity reported as low as 21.1%.14 Throughout the pandemic, NPS and OPS have by and large remained the diagnostic modality of choice in diagnosing COVID-19. A combination of relatively easy sampling and accessibility as well as favourable economics has made these tests widespread in use. Yet variable sensitivities and diagnostics yields, likely due to variations in sampling techniques and viral loads, have also meant that several COVID-19 cases remain undetected, leading to a delay in appropriate isolation and institution of specific therapies.
How does bronchoscopic sampling compare to less invasive means of obtaining LRT samples, such as obtaining expectorated or induced sputum, or obtaining tracheal aspirates in patients with an existing endotracheal or tracheostomy tube? According to one systematic review, RT-PCR testing of sputum samples had a reported sensitivity of 97.2% (90.3-99.7%).16 Another systematic review found that the sample positivity was higher in sputum specimens compared to NPS and OPS.13 There is paucity of data on the ability of tracheal aspirates to diagnose SARS-CoV-2 infection. Ling et al. reported that in 2 patients, viral loads from tracheal aspirates were consistently higher than NPS samples.17 Previous studies with regard to SARS-CoV-1 and MERS-CoV have reported that tracheal aspirates had a greater diagnostic yield for SARS-CoV-1 than URT samples.3
So, where should bronchoscopy be placed in the diagnostic algorithm for suspected SARS-CoV-2 infection? Should we move to the potentially most sensitive test upfront or reserve it for cases where an NPS, for example, comes back negative? There are various layers to this question. First, the laws of probability dictate that repeating any test, such as NPS, would add to pooled sensitivity and, therefore, decrease the number of FN cases. Thus, if repeating a less invasive test is safer or cost-effective, it may be preferable to choosing a more invasive option for repeat testing. Secondly, there is little reported data on the safety or cost of bronchoscopy in these patients. Finally, it is not clear to if bronchoscopy has a distinctly higher sensitivity for SAR-CoV-2 infection than the less invasive alternatives.18 Ora et al. found that bronchoscopy did not identify a single case of previously missed COVID-19 infection in a series of 28 consecutive patients with clinically suspected infection in correlation with three negative NPS and/or OPS smears on consecutive days.19 Similarly, Geri et al. reported that among 79 consecutive patients undergoing BAL due to negative or indeterminate URT samples and continued clinical suspicion of COVID-19 infection, only 2 were positive for CVOID-19 PCR.20 A more recent study of asymptomatic adults undergoing scheduled bronchoscopy for various reasons found a 100% concordance between negative pre-procedure NPS testing and BAL testing.21 As such, in the presence of consistently negative URT samples as well as normal computed tomography (CT) scans, the utility of diagnostic bronchoscopy may be limited. One potential exception may be any situation in which it would be desirable to sample higher viral loads (as perhaps may be suitable in certain research studies). Hamid et al. found that "deeper" samples (i.e., BAL samples coupled with endotracheal aspirates) had a significantly higher viral load than less invasive samples, such as NPS.22 This may vary with disease timeline and disease severity, however, with some data suggesting that BAL viral load may decrease with disease progression and may in fact be lower than NPS viral load among more severely sick, critically ill patients.23,24
Furthermore, institutional clinical protocols for cases of suspected or confirmed SARS-CoV-2 infection should be borne in mind when weighing the pros and cons of opting for a diagnostic bronchoscopy. If "suspected" and "confirmed" SARS-CoV-2 infected patients are managed in an identical manner in terms of isolation protocols, provision of critical care where needed, administration of anti-inflammatory and anticoagulant pharmacotherapy, etc., the value added by a diagnostic bronchoscopy in the setting of one or more negative less invasive tests may be diminished. This becomes all the more relevant considering the presumable additional occupational hazards associated with performance of a bronchoscopy. It is also worth investigating, though outside the immediate scope of the current review, whether the viral load associated with a negative FN NPS or OPS can be expected to be low enough to make transmission significantly less likely even in the presence of active COVID-19 illness. However, a confirmed diagnosis of COVID-19 via a bronchoscopy may well lead to a distinct change in management in certain cases.25 Experts have published guidelines to suggest that diagnostic bronchoscopy should only be considered as a last resort for COVID-19 testing.7
The current systematic review has several limitations. The studies included generally had modest sample sizes. Due to regional differences, a non-uniformity of PCR-based assays and differences in test characteristics within the laboratories were also noted. Furthermore, a uniform gold standard test was not used in all the studies reviewed. Robust prospective data is required to directly compare BAL with other LRT samples, including sputum testing and, where applicable, tracheal aspirate testing. This would enable accurate assessment of concordance rates and quantify the value added by bronchoscopy in the setting of negative LRT samples from other sources.
Though limited, data suggested that bronchoscopy with BAL did not reliably have higher diagnostic sensitivity than that reported for either NPS or OPS. Larger studies are needed for a head-to-head comparison of each test's diagnostic performance. The real-world clinical utility of BAL in suspected COVID-19 patients with one or more negative diagnostic tests merits further investigation. While it may be an option for suspected COVID-19 cases with previous negative tests, physicians should tread with caution while assessing the risks and benefits on a case-by-case basis keeping in mind the actual clinical utility of achieving a confirmatory diagnosis using a procedure that carries higher costs and potentially higher risks to the patient as well as to the medical personnel.
Conflict of Interest: None.
Source of Funding: None.
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