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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 2  |  Page : 101-110

Optimal diagnostic strategy for coronavirus disease 2019 detection in liver transplant recipients: Critical review of available evidence


1 Department of Surgery, University of Arizona College of Medicine – Phoenix, Phoenix, Arizona, USA
2 Department of Surgery, Hippocration General Hospital of Athens, University of Athens, Athens, Greece
3 Department of GI Surgery and Liver Transplantation, Indraprastha Apollo Hospital, New Delhi, India

Date of Submission09-Mar-2021
Date of Decision29-Mar-2021
Date of Acceptance30-Mar-2021
Date of Web Publication29-Apr-2021

Correspondence Address:
Saurabh Singhal
Department of GI Surgery and Liver Transplantation, Indraprastha Apollo Hospital, Sarita Vihar, Mathura Road, New Delhi - 110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_20_21

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  Abstract 


Liver transplant recipients may face an unusually high risk for coronavirus disease 2019 (COVID-19). Observations of heightened risk, rapid progression of severe complications, greater infectivity, and potential for atypical disease presentations in transplant recipients underscore the critical importance of establishing an early diagnosis. Existing diagnostic approaches are marred by unreasonably high false-negative rates. Given the concerns for false-negative results, we performed a narrative review in effort to compile evidence for and against an optimal diagnostic algorithm for detecting COVID-19 in liver transplant recipients. In this algorithm, patients are triaged according to risk of severe acute respiratory syndrome coronavirus 2 infection. Initial testing is performed with reverse transcriptase-polymerase chain reaction, followed by chest computed tomography after 4 days. Repeat tests are performed as per the risk category, patient status, and urgency of transplant. Liver transplant centers should validate the algorithm presented herein, which is based on existing evidence and designed to maximize patient and provider safety, while assuring accuracy in diagnosis.

Keywords: Computed tomography, coronavirus disease 2019, liver transplantation, reverse transcriptase-polymerase chain reaction, severe acute respiratory syndrome coronavirus 2


How to cite this article:
Olson MT, Triantafyllou T, Singhal S. Optimal diagnostic strategy for coronavirus disease 2019 detection in liver transplant recipients: Critical review of available evidence. Apollo Med 2021;18:101-10

How to cite this URL:
Olson MT, Triantafyllou T, Singhal S. Optimal diagnostic strategy for coronavirus disease 2019 detection in liver transplant recipients: Critical review of available evidence. Apollo Med [serial online] 2021 [cited 2021 Jun 21];18:101-10. Available from: https://www.apollomedicine.org/text.asp?2021/18/2/101/315279


  Introduction Top


The disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, raising great concern, particularly in susceptible immunosuppressed populations. Transplant recipients may face an unusually significant risk of developing severe complications from SARS-CoV-2 infection, owing to their immunosuppressed status,[1] in combination with preexisting comorbidities and older age.[2] In a comprehensive report from a transplant center in New York City, USA, most solid organ transplant recipients with COVID-19 required hospitalization, and severe disease progression was common.[3] Mortality rates in these patients are particularly high among both early and long-term survivors, suggesting greater risk in allograft recipients.[4] Managing these patients can be concerning for clinicians, as transplant recipients have been found to have greater viral burden and shedding resulting in greater infectivity and potential to spread to other individuals.[5] Further challenging the issue is the possibility for atypical presentations among transplant recipients with COVID-19.[6] These observations underscore the critical importance of establishing the diagnosis in transplant recipients.

Unfortunately, COVID-19 is susceptible to underdiagnoses given the limitations in available diagnostic testing modalities. At present, a SARS-CoV-2 virus-specific reverse transcriptase-polymerase chain reaction (RT-PCR) test is routinely used and considered the gold standard for clinical detection. Notably, RT-PCR can take up to 2 days to complete, and serial testing may be required to rule out the possibility of false-negative results, which have been reported in 29%–40% of patients with COVID-19.[7],[8] Failing to establish the diagnosis of COVID-19 in a transplant recipient can have especially detrimental consequences for the patient and provider, and for this reason, we advocate for the utility of additional diagnostic testing in this population. The purpose of this narrative review is three-fold: (1) to review the optimal diagnostic algorithm for COVID-19 in patients undergoing liver transplant, (2) offer our expert recommendations for diagnosis in the preoperative and posttransplant settings while compiling notable liver transplant society guidelines, and (3) to assess the evidence for and against the use of this algorithm and other testing modalities in confirming a diagnosis.


  Methods Top


Literature search strategy

We performed a narrative review in effort to compile evidence for and against an optimal algorithm for diagnosing COVID-19 in liver transplant recipients. Although this review was not conducted according to the PRISMA framework, three authors (MTO, TT, and SS) performed an independent search of the existing literature through the LitCovid database, a curated literature source which is actively tracking up-to-date reports restricted to SARS-CoV-2, from February 1, 2020 to December 1, 2020. Early evidence from the start of the pandemic (before February 1, 2020) may no longer be up-to-date for best practice recommendations. The search was performed with the following search terms: “liver,” “transplant,” “chest CT,” “RT-PCR,” “diagnosis,” and logical combinations of these terms using Boolean operators.

Eligibility criteria

All articles relevant to transplant specific practices were extensively reviewed and collected. Additionally, the authors sought to compile available evidence published from the four leading liver transplant and disease international societies – namely, the American Association for the Study of Liver Disease (AASLD), American Society of Transplantation, European Association for the Study of the Liver, and Liver Transplantation Society of India.

Study selection and considerations

Studies were initially selected for further evaluation based on the title and abstract. Reference lists of relevant publications were assessed for additional references. Special attention was paid to studies that (1) compared the false-negative rates, sensitivity, specificity, or utility of alternate diagnostic approaches in confirming suspect COVID-19 cases, and (2) discussed risk of transmission, severity of disease, and progression or disease course among liver transplant (or solid organ transplant) recipients. Studies with these considerations will be discussed in reference to our diagnostic approach, presented below.


  Results Top



  Literature search results Top


From February 1 to December 1, 2020, there were 2597 articles published on the LitCovid database related to “diagnosis.” In the same time period, there were 224 articles published with relevance to solid organ transplant. In subjectively evaluating these records for relevance in establishing a diagnostic algorithm for transplant recipients, the authors compiled 51 reports from the following sources: international guidelines (n = 6), literature reviews and/or meta-analyses (n = 18), case reports and series (n = 9), cohort studies (n = 14), and editorials (n = 4). [Table 1] compiles best practice recommendations for liver transplant recipients in the preoperative and posttransplant settings according to the four previously mentioned liver transplant and disease societies.
Table 1: Recommendations from international agencies on the management of liver transplantation amidst the COVID-19

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Algorithm

[Figure 1] details the algorithm for diagnosis in liver transplant recipients triaged according to the risk of infection during the preoperative planning period. This protocol should ideally be used for patients with end-stage liver disease, or any other disease with the indication for liver transplant, who present to the transplant center with a confirmed, noninfected donor organ to proceed with transplant. The risk categories are stratified as follows:
Figure 1: Algorithm for confirming the diagnosis of coronavirus disease 2019 in liver transplant recipients in the preoperative period. *Radiologic findings should be graded according to the coronavirus disease 2019 Reporting and Data System, as detailed in reference 10. If patients develop red flag symptoms of coronavirus disease 2019, they should be re-triaged, and further investigations should be conducted per institution protocol. If a patient becomes positive at any point in time, they are to be managed according to the institution's coronavirus disease 2019 protocol. Any emergency transplant should be performed with appropriate PPE and all infection control precautions

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  • Category I (minimal risk): Patients with no typical or atypical symptoms suggestive of the possibility of COVID-19 infection, no recent travel history to endemic areas, and no prior exposure to individuals with confirmed infection
  • Category II (moderate risk): Patients with no typical symptoms suggestive of the possibility of COVID-19 infection, but with recent travel history or prior exposure to individuals with confirmed infection not amounting to significant exposure as outlined below
  • Category III (high to very high risk): Symptomatic patients, or patients with significant exposure history. Our definition for significant exposures has been adapted from the Centers for Disease Control and Prevention (CDC)[9] as any prolonged exposure (≥15 min) to individuals with confirmed COVID-19 infection when the patients' eyes, nose, or mouth were not covered (very high risk), or other exposures including having body contact with individual with suspected or confirmed COVID-19 infection, particularly when hand hygiene is not performed after such contact and the patient proceeds to touch their eyes, nose, or mouth (high risk). The specific factors quantifying a significant or insignificant history of exposures should be elicited by the transplant clinician and necessitates case-by-case evaluation.


At the initial presentation, we recommend performing a SARS-CoV-2 virus-specific RT-PCR. Patients with a positive result on RT-PCR should be treated with COVID-19 specific management protocols, and transplant should be delayed. Patients with a negative result on RT-PCR should undergo CT 4 days after the initial presentation. Radiologic findings should be graded according to the COVID-19 Reporting and Data System to better categorize pulmonary involvement and confirm suspect disease with improved accuracy.[10] Patients with typical radiographic findings on CT should be treated according to COVID-19 specific management. Depending on patient status, risk categorization, and urgency of transplant, repeat testing with either RT-PCR or RT-PCR with chest CT, may be indicated after an additional 4 days.

This algorithm is based on evidence that suggests false-negative rates for RT-PCR, as well as the expression and distribution of chest CT abnormalities, tend to vary depending on the time since exposure.[8],[11],[12] We advocate for chest CT scans performed 4 days after symptom onset (initial presentation) because those performed after 4 days are likely to reveal a progressive infection with diffuse ground-glass opacities, consolidations, and crazy-paving pattern.[11],[12] Comparatively, those performed within 4 days since symptom onset are less likely to show typical radiographic features. The indication to perform repeat RT-PCR testing with or without chest CT after an additional 4 days is supported by findings that after 8 days since symptom onset, the probability of a false-negative result in an infected person maximally decreases to 20% (confidence interval [CI], 12% to 30%).[8]

Recommendations

Preoperative setting

The complex decision-making involved in determining whether it is appropriate to proceed with surgical intervention has now become further complicated amid the COVID-19 pandemic.[13] We recommend transplant centers continue assessing their local COVID-19 burden, while considering urgent transplant in the waitlisted patients with severe risk of decompensation or disease progression. Our understanding of the risk of donor-derived disease transmission is evolving, as Hong et al.[8] detailed the case of a patient who underwent ABO-incompatible living donor liver transplant without knowing that the liver donor was infected with COVID-19 during the donation procedure. Ultimately, one of the most important considerations for transplant clinicians in the preoperative setting is recognizing the significant false-negative testing rate. Thus, we advise transplant centers to take extreme caution, particularly when observing symptoms of COVID-19 in a potential donor or recipient. These symptoms may be suggestive of infection, despite negative testing, and thus, we recommend additional testing in the form of chest CT to confirm the diagnosis in the preoperative setting for both donors and recipients.

Posttransplant setting

As mentioned above, the symptoms of COVID-19 may be varied and nonspecific in transplant recipients. Additionally, any pulmonary symptoms may be due to other common causes of chest infection routinely identified after transplant surgery. In the posttransplant period, we recommend maintaining a high index of suspicion for COVID-19 while taking all precautions to avoid viral transmission between patient and provider during or after the hospital stay.


  Discussion Top


Variability of testing protocols in transplant recipients

The CDC, Organ Procurement Organization, and the aforementioned societies are actively updating guidelines for transplant clinicians and programs. However, these guidelines must rely heavily on the experiences of initial, single-center investigations and expert discussions.[5] There remains significant variation in transplant center-specific practices, which are likely driven by the limited experience of managing solid organ transplant recipients with COVID-19.[14] This uncertainty and lack of uniform protocols, especially as it pertains to testing for COVID-19, may worsen the existing rates of hospital admissions and deaths in the vulnerable transplant population.

At present, the diagnosis of COVID-19 in solid organ transplant recipients is similar to those in the general population. However, clinicians are advised to maintain a higher index of suspicion for infection in immunosuppressed patients. For solid organ transplant recipients with suspected COVID-19 who are hospitalized, testing is recommended. In contrast, routine screening in asymptomatic transplant recipients is generally not recommended so as to avoid unnecessary exposure. For those with mild symptoms, the optimal practice is not yet defined. Some centers have favored testing for all such patients given the potential for rapid disease progression, while others favor making a clinical diagnosis and monitoring these patients at home. The decision is individualized based on local disease burden, available resources, and patient-provider preference. Collectively, this diversity in the diagnostic protocol by transplant center is magnified at the international level. Chew et al.[15] detailed an extensive comparison of protocol changes across transplant centers in Hong Kong, Singapore, South Korea, USA, Germany, and the UK from late March 2020. The current paradigm of diagnosis using a combination of RT-PCR and assessment of lower respiratory symptoms and exposure risk may underestimate disease prevalence.[16] Thus, this significant variation calls for uniformity according to a comprehensive, evidence-based algorithm that considers patients' symptomatic presentation, history of exposure, and risks associated with disease in transplant recipients. Importantly, this algorithm must confirm the diagnosis at all costs, especially as the patient is prepped to receive the donor organ.

Evidence for diagnostic algorithm

Combination of reverse transcriptase-polymerase chain reaction and chest computed tomography

The early recognition and isolation of COVID-19 patients is of crucial importance, especially in those with false-negative RT-PCR results. There have been unfortunately high false-negative rates reported with RT-PCR testing for SARS-CoV-2 in hospitalized patients clinically diagnosed with COVID-19,[17] likely attributed to immature development of nucleic acid detection technology, variation in detection rate from different manufacturers, low patient viral load, or improper sampling.[18] Therefore, several studies have since evaluated the sensitivity of chest CT in detecting SARS-CoV-2 infection in hopes of complementing RT-PCR with imaging. In a cohort of 51 patients, Fang et al.[19] demonstrated a 98% detection rate for initial chest CT, compared to 71% in first RT-PCR (P < 0.001). Caruso et al.[20] corroborated these findings, reporting a similar sensitivity (97%) for chest CT in detecting COVID-19, albeit with poor specificity (56%).

Given the superior specificity of RT-PCR in detecting SARS-CoV-2, studies have proposed combining this testing modality with chest CT to avoid a missed diagnosis due to false-negative nucleic acid.[21] He et al.[22] observed comparable diagnostic performance in identifying suspected COVID-19 using initial RT-PCR and chest CT. But, when applied together, the sensitivity, specificity, and accuracy of RT-PCR with chest CT were 94% (CI 86–100%), 100%, and 98%, respectively, demonstrating the ability to compensate for the potential risk of false-negative results. Most recently, the AASLD advocated for additional testing, including chest imaging and inflammatory markers, to avoid missing a diagnosis (due to false-negative results) in suspect liver transplant recipients and potential donors.[23] Thus, our algorithm recommends performing chest CT with RT-PCR to in effort to detect typical COVID-19 radiologic features that would support the diagnosis. In high-risk patients (Category III), we advocate for repeat chest CT and RT-PCR after 4 days, which leverages both the improved sensitivity of chest CT and repeat RT-PCR in this time course.

Other advantages of obtaining chest computed tomography

Beyond its ability to improve sensitivity of clinical detection, chest CT also has the potential to characterize viral co-infection and bacterial superinfection, evaluate the nature and extent of pulmonary lesions, monitor disease activity, and offer alternative diagnoses in a significant subset of patients.[24] Chest CT is particularly valuable in that it can provide prompt, convenient, and highly efficient results for patients with dynamic conditions.[25] CT findings can guide transplant clinicians when making decisions pertaining to appropriate management, or effectiveness of ongoing therapy. When facing the difficulty of sampling in patients with poor compliance or performance status, chest CT can offer a testing modality that limits sampling error or artifactual variability.

Variability of presentation, prolonged viral shedding, and false-negative results

Data on the spectrum of clinical manifestations of COVID-19 in transplant recipients remain insufficient. In the early pandemic period, initial reports supported similar clinical features of COVID-19 among transplant recipients compared to nonimmunosuppressed patients.[26] However, in the most recent reports, fever has been less commonly observed among transplant recipients, perhaps due to their inability to surmount an appropriate immune response to clear the SARS-CoV-2 infection; meanwhile, lymphopenia seems more profound.[27] As these patients are under chronic immunosuppression, the possibility of atypical presentations cannot be disregarded. Guillen et al.[6] detailed the case of a renal transplant recipient who presented with rarely observed gastrointestinal symptoms in the absence of typical respiratory complaints. Such cases presenting with infrequently observed symptoms underscore the necessity to re-evaluate existing screening protocols. Meanwhile, Man et al.[28] reported the case of a renal transplant recipient who experienced five continuous negative test results for SARS-CoV-2 RNA in the recovery period before a sixth test of nasopharyngeal swab turned positive, despite relief in symptoms. This case highlights the challenge in the fluctuant results of SARS-CoV-2 RNA testing in transplant recipients. This case, and those similar, illustrates the concern in relying on poorly sensitive RT-PCR tests. Variability in disease presentations, prolonged viral shedding in transplant recipients, and false-negative test results place all involved parties at greater risk of viral transmission with severe consequences.[29] These findings serve as evidence toward implementing a new diagnostic algorithm in this subset of patients.

Severe disease complications and rapid progression

From the experience of limited solid organ transplant recipient cohort studies, evidence suggests that these patients with COVID-19 may be subject to higher risk for severe disease compared to nontransplant patients. Pereira et al.[3] published a study of 90 transplant recipients with COVID-19, and 76% of the cohort had moderate (admitted to the general inpatient floor) to severe disease (mechanical ventilation, admission to intensive care unit, or death). Those with severe disease were older and more likely to have hypertension or cancer. Lee et al.[4] reported a single-center experience of 38 liver transplant recipients with COVID-19. Most recipients required hospitalization (71%), and most patients who were admitted to the hospital were older (65 vs. 39 years; P < 0.02) with at least one comorbid condition (66% vs. 18%; P < 0.047) compared to nonhospitalized patients. The severity of disease was assessed in 24 of 27 hospitalized patients, of which 92% had moderate to severe disease. Mortality rates were similar between the current study and the cohort reported by Pereira et al. (18% vs. 18% overall). The prevalence of severe disease among transplant recipients, in addition to considerable mortality rates, suggests a significant risk of complications among allograft recipients.

Gao et al.[1] published a seminal investigation on the impact of immunosuppression and immunodeficiency on severe disease progression and mortality in patients with COVID-19. Importantly, the meta-analysis of three studies (n = 776 patients) showed that immunosuppression was associated with a 3.29-fold increased risk of severe COVID-19 disease, albeit statistically insignificant (P < 0.075). However, this finding certainly supports a heightened awareness for an increased risk of serious disease progression associated with COVID-19 infection in immunosuppressed patients. Akalin et al.[27] shared their experience in managing the care of 36 renal transplant recipients with COVID-19 between March 16 and April 1, 2020. These patients had lower CD3, CD4, and CD8 cell counts, and a more rapid clinical progression than patients with COVID-19 in the general population. This potential for severe disease and rapid clinical deterioration underlines the importance of early detection of disease, which is facilitated in our algorithm presented above.

Risks for declining status and effective treatments

At present, the risks for the precipitous decline in a transplant recipient with COVID-19 remain unknown. Although age and preexisting comorbid conditions are risk factors for severe disease, the factors which predispose a patient with mild symptomatology to a rapid decline in status have not yet been confirmed in large-scale studies. Perhaps, the immunosuppressive regimens are related to the rapid clinical deterioration, as lower levels of T-cell subsets have been noted in transplant patients who rapidly decline.[27] Reducing doses of immunosuppressive agents in these patients requiring hospitalization is thus warranted, but additional study is required to determine the impact of specific immunosuppressive regimens on disease course. Unfortunately, the optimal management of acute COVID-19 infection has otherwise not been determined in either the immunosuppressed or nontransplant populations. Although many potential therapies (e.g., immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion) have provided some benefit in treating patients,[30] no interventions have been deemed substantially curative. Given the risks for declining status and current lack of effective treatment modalities, it remains crucial to confirm an early diagnosis in liver transplant recipients with COVID-19. For these reasons, it is also important to identify patients who may benefit from urgent transplant, including patients with high Model for End-stage Liver Disease scores, or those with high risk of decompensation or tumor progression.

Safety of transplant clinician and recipient

Ultimately, the safety of the transplant clinician and patient hinges on establishing a proper diagnosis, which cannot be confirmed in all cases when relying on existing diagnostic approaches. Public health agencies and health-care systems have, thus far, largely relied on the poor sensitivity of RT-PCR to detect disease and guide decisions on quarantining. Biostatistical experts have since modeled the long-term consequences of this approach, and the risk of false-negative results may be catastrophic.[31] These consequences weigh even heavier on vulnerable populations, and thus, it is paramount to aggressively identify the disease to protect those patients and others at greater risk.

Limitations of diagnostic algorithm

All considerations involving disadvantages of chest computed tomography

Chest CT has emerged as a valuable component in the evaluation of symptomatic, hospitalized patients with suspected SARS-CoV-2 infection. Nevertheless, the American College of Radiology advises against the use of CT alone as a screening technique or as a first-line test to diagnose COVID-19.[32] Findings on chest CT are not specific and may overlap with other infectious etiologies, while some patients may have normal or atypical radiological findings.[33] The usage of chest CT in low-prevalence regions may result in a larger number of false-positive results, which can inflate medical costs after further diagnostic testing is pursued.[34] Additionally, the reported sensitivity of chest CT may be affected by the distribution of disease severity, comorbidities, and proportion of asymptomatic patients.[34] Due to the poor methodological quality of studies, the sensitivity of chest CT may also be falsely elevated. Studies reporting high sensitivities in the early pandemic period are marred by selection bias, confounding variables, and abnormally low thresholds for positivity.[35]

Regardless, clinicians and authorities must rely on the best available evidence to guide clinical practice. The superiority of sensitivity in chest CT compared to RT-PCR is well documented, and thus, the combination of imaging with RT-PCR may be leveraged to confirm a diagnosis of suspect COVID-19 in transplant recipients.[36] The dual testing approach of chest CT and RT-PCR offers optimal sensitivity while retaining the high specificity of RT-PCR as a reference standard, and it may limit the risk of obtaining continuous false-negative results on RT-PCR alone. Even though false-positive results may occur, they are overwhelmingly likely to occur in patients with lung abnormalities who may actually benefit from temporary quarantine and further diagnostic assessment.[37] Understandably, chest CT should not to be used for diagnosis alone, and this algorithm does not advocate for its utility as a primary diagnostic tool, but rather an intervention that can confirm with confidence a diagnosis in a highly vulnerable patient subset.

Risks associated with radiation exposure

Even though a combination of chest CT and repeat RT-PCR testing may be beneficial for the diagnosis of COVID-19 in the setting of strong clinical suspicion, few have argued against its use given patients' exposure to radiation. Multiple chest CT examinations may cause radiation-related harm and worsen existing leukopenia in patients with COVID-19. Understandably, radiation exposure remains a limitation to its continued use in diagnostic algorithms, and thus, radiation doses must be kept as low as possible.

In April 2020, Agostini et al.[38] proposed the use of a low-dose chest CT protocol for diagnosing COVID-19 in suspect patients. Subjective and objective analyses to assess the diagnostic reliability of this protocol deemed it comparable to existing regular-dose chest CT protocols. This study, and others since,[39] have demonstrated the feasibility and safety of implementing an effective, low-dose chest CT protocol for use in confirming suspect SARS-CoV-2 infection. Future, head-to-head comparisons of low-dose and conventional protocols in detecting early stages of the disease are warranted. Moreover, it remains to be determined whether all transplant centers have the capability to implement low-dose CT scans.

Expenses and safety of health-care staff in performing multiple diagnostic tests

The medical expenses and workload burden to health-care staff should receive adequate consideration when weighing a decision of performing chest CT in combination with other molecular or serologic tests to confirm the diagnosis of COVID-19. At present, a cost-effectiveness analysis and assessment of practicability are not available to guide decisions regarding when to perform chest CT in suspect patients. However, it is logical to avoid the unnecessary expense of performing chest CT in patients at low risk for infection. Furthermore, physicians and nurses are under heavy workload conditions and psychological burden, especially in high-prevalence regions.[40] Pursuing chest CT in a patient suspected of disease also carries the risk of exposing these providers and other nonaffected patients in imaging suites to infection.[41] Any diagnostic algorithm should be mindful of the resources and staff required to test and re-test a high volume of patients. For these reasons, an appropriate categorization of patients by risk of infection is warranted, and in our proposal, we opt to avoid repeat chest CT in minimal risk patients requiring transplant. This algorithm is designed to consider the limitations of expense and workload burden, while also abiding by existing recommendations to avoid unnecessary exposure in asymptomatic or minimal risk liver transplant recipients.

Alternatives to improve diagnostic quality and accuracy

Several studies have since postulated alternative methods to improve the poor sensitivity and clinical accuracy of RT-PCR in confirming the diagnosis of suspect COVID-19. One such method involves improving the sampling technique. Although both upper (e.g., nasopharyngeal and oropharyngeal) and lower respiratory tract specimens (e.g., sputum, bronchoalveolar lavage, tracheal aspirate, pleural fluid, and lung biopsy) are suitable for detection of SARS-CoV-2 on RT-PCR, lower respiratory tract specimens have the highest positive rates (>90%) for viral detection compared to other samples noted in the literature.[42] However, obtaining a lower respiratory tract sample requires a more invasive approach, and these methods would present logistical challenges if employed in all transplant cases. The nasopharyngeal swab presents the easiest route for obtaining a sample, and thus, the best way to improve accuracy for this technique is to collect a sample when viral load is maximal.[18] Although poorly defined for nasopharyngeal samples, one study found viral loads to be highest in throat swabs in the first 5 days after symptom onset.[43] If obtaining routine lower respiratory tract specimens is impracticable, studies should instead seek to better define the boundaries of the optimal diagnostic testing window. Alternatively, serological tests have emerged as a rapid, noninvasive means of testing for current or past SARS-CoV-2 infection, yet they remain less sensitive than RT-PCR,[18] and thus may prove more valuable for other uses, such as identifying convalescent plasma donors.

Another alternative method that has been proposed to improve diagnostic accuracy is complementing RT-PCR with lung ultrasound. Lung ultrasound has been suggested by several authorities as an accurate tool for detecting pulmonary involvement in patients with COVID-19.[44] Lung ultrasound examinations are considered advantageous in that they can be performed by a single provider (thus, limiting exposure and contamination of additional personal protective equipment) directly at the bedside in symptomatic, hospitalized patients. This examination is safe in all patient cohorts being that it is a radiation-free testing modality, and it can be used to monitor those requiring serial testing. Mongodi et al.[45] demonstrated how the use of an ultrasound-based approach to assess for acute respiratory failure could limit the number of chest x-rays and chest CT scans required in COVID-19 patients, while obtaining reliable examinations to guide management. While we do not recommend against the use of lung ultrasound at the bedside in symptomatic transplant recipients, it remains prudent to consider chest CT in the diagnostic algorithm given its superior specificity.

Lastly, chest X-rays have been proposed as a fundamental tool in the diagnosis, follow-up, and evaluation of response to therapy in patients with COVID-19. Chest X-rays are low cost, widely available, easy to execute, and have little radiation risk. However, this modality is unreliable in the context of confirming diagnosis, as false negatives are not uncommon. Cellina et al.[46] reported four cases of false-negative chest X-rays in patients who were later diagnosed positive for COVID-19 by RT-PCR. These patients required chest CT examination after undergoing X-ray, which ultimately demonstrated signs of COVID-19 pneumonia. Chest CT remains superior to other imaging and sonographic modalities in confirming the diagnosis of COVID-19.

Fluidity of evidence

Diagnostic approaches, management options, and understanding of burden in liver transplant candidates and recipients have evolved, and continue to evolve, since the beginning of the pandemic. At the time of this writing, a systemic review of five studies with a total of 154 adult liver transplant recipients found lower mortality in these patients when compared to the general population.[47] Notably, these findings contradict other available evidence in solid organ transplant recipients, but nonetheless demonstrate the fluidity of the current scientific landscape. Hence, this protocol will undergo the test of time and may need future updates as new, reliable evidence emerges and novel techniques of detection are produced. A complete summary of the main concepts and learning points from the literature review are shown in [Table 2].
Table 2: Main concepts and learning points

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  Conclusion Top


Liver transplant recipients and potential donors should receive strict screening for COVID-19, as missed infections may have detrimental consequences. We present an evidence-based diagnostic algorithm to confirm SARS-CoV-2 infection in liver transplant recipients, as well as important recommendations for patients in the preoperative planning and posttransplant periods. The limitations for this algorithm, as well as alternative measures to confirm diagnosis, are presented to narrow the bias involved in constructing this approach. This algorithm should be validated in transplant centers, and importantly, this approach may have value in confirming disease in other solid organ transplant recipients (excluding heart and lung allografts).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Gao Y, Chen Y, Liu M, Shi S, Tian J. Impacts of immunosuppression and immunodeficiency on COVID-19: A systematic review and meta-analysis. J Infect 2020;81:e93-5.  Back to cited text no. 1
    
2.
Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant 2020;20:1849-58.  Back to cited text no. 2
    
3.
Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant 2020;20:1800-8.  Back to cited text no. 3
    
4.
Lee BT, Perumalswami PV, Im GY, Florman S, Schiano TD. COVID-19 in Liver Transplant Recipients: An Initial Experience from the U.S. Epicenter. Gastroenterology 2020;159:1176-8.e2.  Back to cited text no. 4
    
5.
Michaels MG, La Hoz RM, Danziger-Isakov L, Blumberg EA, Kumar D, Green M, et al. Coronavirus disease 2019: Implications of emerging infections for transplantation. Am J Transplant 2020;20:1768-72.  Back to cited text no. 5
    
6.
Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant 2020;20:1875-8.  Back to cited text no. 6
    
7.
Woloshin S, Patel N, Kesselheim AS. False negative tests for SARS-CoV-2 infection – Challenges and implications. N Engl J Med 2020;383:e38.  Back to cited text no. 7
    
8.
Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med 2020;173:262-7.  Back to cited text no. 8
    
9.
CDC. Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention; Published February 11, 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html. [Last accessed on 2020 July 01].  Back to cited text no. 9
    
10.
Prokop M, van Everdingen W, van Rees Vellinga T, Quarles van Ufford H, Stöger L, Beenen L, et al. CO-RADS: A Categorical CT Assessment Scheme for Patients Suspected of Having COVID-19 – Definition and Evaluation. Radiology 2020;296:E97-104.  Back to cited text no. 10
    
11.
Abbasi-Oshaghi E, Mirzaei F, Farahani F, Khodadadi I, Tayebinia H. Diagnosis and treatment of coronavirus disease 2019 (COVID-19): Laboratory, PCR, and chest CT imaging findings. Int J Surg 2020;79:143-53.  Back to cited text no. 11
    
12.
Pan F, Ye T, Sun P, Gui S, Liang B, Li L, et al. Time course of lung changes at chest CT during recovery from coronavirus disease 2019 (COVID-19). Radiology 2020;295:715-21.  Back to cited text no. 12
    
13.
Olson MT, Triantafyllou T, Singhal S. Resumption of elective surgery during the COVID-19 pandemic: what lessons can we apply? Eur Surg. 2020:1-3.  Back to cited text no. 13
    
14.
Boyarsky BJ, Po-Yu Chiang T, Werbel WA, Durand CM, Avery RK, Getsin SN, et al. Early impact of COVID-19 on transplant center practices and policies in the United States. Am J Transplant 2020;20:1809-18.  Back to cited text no. 14
    
15.
Chew CA, Iyer SG, Chieh Kow AW, Madhavan K, Wong AS, Halazun KJ, et al. An international multicentre study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise. J Hepatol 2020;73:873-81.  Back to cited text no. 15
    
16.
Xiao N, Abboud S, McCarthy DM, Parekh N. Incidentally discovered COVID-19 in low-suspicion patients – A threat to front line health care workers. Emerg Radiol 2020;27:589-95.  Back to cited text no. 16
    
17.
Li Y, Yao L, Li J, Chen L, Song Y, Cai Z, et al. Stability issues of RT-PCR testing of SARS-CoV-2 for hospitalized patients clinically diagnosed with COVID-19. J Med Virol 2020;92:903-8.  Back to cited text no. 17
    
18.
Bohn MK, Lippi G, Horvath A, Sethi S, Koch D, Ferrari M, et al. Molecular, serological, and biochemical diagnosis and monitoring of COVID-19: IFCC taskforce evaluation of the latest evidence. Clin Chem Lab Med 2020;58:1037-52.  Back to cited text no. 18
    
19.
Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology 2020;296:E115-7.  Back to cited text no. 19
    
20.
Caruso D, Zerunian M, Polici M, Pucciarelli F, Polidori T, Rucci C, et al. Chest CT Features of COVID-19 in Rome, Italy. Radiology 2020;296:E79-85.  Back to cited text no. 20
    
21.
Li S, Liu J, Xiong Z, Luo W, Tang H, Pend W, et al. Clinical and CT imaging features between the first nucleic acid b-b negative and first nucleic acid positive COVID b-b 19 patients. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2020;45:257-61.  Back to cited text no. 21
    
22.
He JL, Luo L, Luo ZD, Lyu JX, Ng MY, Shen XP, et al. Diagnostic performance between CT and initial real-time RT-PCR for clinically suspected 2019 coronavirus disease (COVID-19) patients outside Wuhan, China. Respir Med. 2020;168:105980.  Back to cited text no. 22
    
23.
Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC, et al. Clinical best practice advice for hepatology and liver transplant providers during the COVID‐19 pandemic: AASLD expert panel consensus statement. Hepatology 2020;72:287-304.  Back to cited text no. 23
    
24.
Jędrusik P, Gaciong Z, Sklinda K, Sierpiński R, Walecki J, Gujski M. Diagnostic role of chest computed tomography in coronavirus disease 2019. Pol Arch Intern Med 2020;130:520-8.  Back to cited text no. 24
    
25.
Yang B, Wang L, Xu G, Duan W, Zhang F, Cui C et al. Computed tomography findings in a case of coronavirus disease 2019. Radiol Infect Dis. 2020;7:81-3.  Back to cited text no. 25
    
26.
Zhu L, Xu X, Ma K, Yang J, Guan H, Chen S, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am J Transplant 2020;20:1859-63.  Back to cited text no. 26
    
27.
Akalin E, Azzi Y, Bartash R, Seethamraju H, Parides M, Hemmige V, et al. Covid-19 and Kidney Transplantation. N Engl J Med. 2020;382:2475-7.  Back to cited text no. 27
    
28.
Man Z, Jing Z, Huibo S, Bin L, Fanjun Z. Viral shedding prolongation in a kidney transplant patient with COVID-19 pneumonia. Am J Transplant 2020;20:2626-7.  Back to cited text no. 28
    
29.
Qin J, Wang H, Qin X, Zhang P, Zhu L, Cai J, et al. Perioperative presentation of COVID-19 disease in a liver transplant recipient. Hepatology 2020;72:1491-3.  Back to cited text no. 29
    
30.
Zhang J, Xie B, Hashimoto K. Current status of potential therapeutic candidates for the COVID-19 crisis. Brain Behav Immun 2020;87:59-73.  Back to cited text no. 30
    
31.
West CP, Montori VM, Sampathkumar P. COVID-19 Testing: The threat of false-negative results. Mayo Clin Proc 2020;95:1127-9.  Back to cited text no. 31
    
32.
ACR Recommendations for the use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection. Available from: https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection. [Last accessed on 2020 May 27].  Back to cited text no. 32
    
33.
Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): A pictorial review. Eur Radiol 2020;30:4381-9.  Back to cited text no. 33
    
34.
Kim H, Hong H, Yoon SH. Diagnostic performance of CT and reverse transcriptase-polymerase chain reaction for coronavirus disease 2019: A meta-analysis. Radiology 2020;296:E145-55.  Back to cited text no. 34
    
35.
Raptis CA, Hammer MM, Short RG, Shah A, Bhalla S, Bierhals AJ, et al. Chest CT and Coronavirus Disease (COVID-19): A Critical Review of the Literature to Date. Am J Roentgenol 2020;215:1-4.  Back to cited text no. 35
    
36.
Xu B, Xing Y, Peng J, Zheng Z, Tang W, Sun Y, et al. Chest CT for detecting COVID-19: A systematic review and meta-analysis of diagnostic accuracy. Eur Radiol 2020;30:5720-7.  Back to cited text no. 36
    
37.
Fraiman JB. Chest CT and coronavirus disease (COVID-19): A more complete review. AJR Am J Roentgenol 2020;215:W35.  Back to cited text no. 37
    
38.
Agostini A, Floridi C, Borgheresi A, Badaloni M, Esposto Pirani P, Terilli F, et al. Proposal of a low-dose, long-pitch, dual-source chest CT protocol on third-generation dual-source CT using a tin filter for spectral shaping at 100 kVp for CoronaVirus Disease 2019 (COVID-19) patients: A feasibility study. Radiol Med 2020;125:365-73.  Back to cited text no. 38
    
39.
Li J, Wang X, Huang X, Chen F, Zhang X, Liu Y, et al. Application of CareDose 4D combined with Karl 3D technology in the low dose computed tomography for the follow-up of COVID-19. BMC Med Imaging 2020;20:56.  Back to cited text no. 39
    
40.
Lai J, Ma S, Wang Y, Cai Z, Hu J, Wei N, et al. Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019. JAMA Netw Open 2020;3:e203976.  Back to cited text no. 40
    
41.
Waller JV, Kaur P, Tucker A, Lin KK, Diaz MJ, Henry TS, et al. Diagnostic tools for coronavirus disease (COVID-19): Comparing CT and RT-PCR viral nucleic acid testing. Am J Roentgenol 2020;215:1-5.  Back to cited text no. 41
    
42.
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;323:1843-4.  Back to cited text no. 42
    
43.
Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020;581:465-9.  Back to cited text no. 43
    
44.
Piscaglia F, Stefanini F, Cantisani V, Sidhu PS, Barr R, Berzigotti A, et al. Benefits, open questions and challenges of the use of ultrasound in the COVID-19 pandemic era. The views of a panel of worldwide international experts. Ultraschall Med 2020;41:228-36.  Back to cited text no. 44
    
45.
Mongodi S, Orlando A, Arisi E, Tavazzi G, Santangelo E, Caneva L, et al. Lung ultrasound in patients with acute respiratory failure reduces conventional imaging and health care provider exposure to COVID-19. Ultrasound Med Biol 2020;46:2090-3.  Back to cited text no. 45
    
46.
Cellina M, Orsi M, Toluian T, Valenti Pittino C, Oliva G. False negative chest X-Rays in patients affected by COVID-19 pneumonia and corresponding chest CT findings. Radiography (Lond) 2020;26:e189-94.  Back to cited text no. 46
    
47.
Gavriilidis P, Pai M. The impact of COVID-19 global pandemic on morbidity and mortality of liver transplant recipients children and adults: A systematic review of case series. J Clin Med Res 2020;12:404-8.  Back to cited text no. 47
    


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