key: cord-0698644-y4ijq5ua
authors: Kovoor, Joshua G.; Scott, N. Ann; Tivey, David R.; Babidge, Wendy J.; Scott, David A.; Beavis, Vanessa S.; Kok, Jen; MacCormick, Andrew D.; Padbury, Robert T. A.; Hugh, Thomas J.; Hewett, Peter J.; Collinson, Trevor G.; Maddern, Guy J.; Frydenberg, Mark
title: Proposed delay for safe surgery after COVID‐19
date: 2021-03-03
journal: ANZ J Surg
DOI: 10.1111/ans.16682
sha: 608cbdcf6b7ef92baaed49a56859ee3b475cba8e
doc_id: 698644
cord_uid: y4ijq5ua

BACKGROUND: Long‐term effects after COVID‐19 may affect surgical safety. This study aimed to evaluate the literature and produce evidence‐based guidance regarding the period of delay necessary for adequate recovery of patients following COVID‐19 infection before undergoing surgery. METHODS: A rapid review was combined with advice from a working group of 10 clinical experts across Australia and New Zealand. MEDLINE, medRxiv and grey literature were searched to 4 October 2020. The level of evidence was stratified according to the National Health and Medical Research Council evidence hierarchy. RESULTS: A total of 1020 records were identified, from which 20 studies (12 peer‐reviewed) were included. None were randomized trials. The studies comprised one case–control study (level III‐2 evidence), one prospective cohort study (level III‐2) and 18 case‐series studies (level IV). Follow‐up periods containing observable clinical characteristics ranged from 3 to 16 weeks. New or excessive fatigue and breathlessness were the most frequently reported symptoms. SARS‐CoV‐2 may impact the immune system for multiple months after laboratory confirmation of infection. For patients with past COVID‐19 undergoing elective curative surgery for cancer, risks of pulmonary complications and mortality may be lowest at 4 weeks or later after a positive swab. CONCLUSION: After laboratory confirmation of SARS‐CoV‐2 infection, minor surgery should be delayed for at least 4 weeks and major surgery for 8–12 weeks, if patient outcome is not compromised. Comprehensive preoperative and ongoing assessment must be carried out to ensure optimal clinical decision‐making.

Perioperative management has had to adapt to coronavirus disease 2019 . Triage during the pandemic has required consideration of local COVID-19 prevalence and hospital resources alongside surgical presentation. 1 Prior COVID-19 carries considerable surgical risk during the preoperative assessment. 2 High mortality and pulmonary complications associated with perioperative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 3 have modified both preoperative risk-benefit assessment and postoperative care. Appropriate screening and testing for SARS-CoV-2 have become crucial. 4 Ongoing risks of nosocomial spread to both surgical staff and patients have disrupted surgical systems on a global scale. 5 Clinical characteristics associated with laboratory-confirmed COVID-19 have mostly been documented in an acute setting. 6 However, long-term persistence of symptoms has also been reported, 7, 8 leading to prolongation of the potential timeline of the associated spectrum of disease. [9] [10] [11] Cases of clinical recurrence after complete recovery have been described. 12 While the pathophysiology of acute SARS-CoV-2 infection is known to include significant inflammation and dysfunctional immune responses, 13 longer-lasting effects are poorly understood. 14 The potential for long-term effects after SARS-CoV-2 infection has ramifications for perioperative management. Undertaking surgery without allowing adequate time for recovery from COVID-19, risks compromising patient safety. The necessary recovery period before safely undertaking surgery must be understood to optimize surgical decision-making. This study aimed to evaluate the literature and produce evidence-based guidance regarding the period of delay necessary for adequate recovery of patients with COVID-19 before undertaking surgery.

In a similar fashion to previous publications, 1, 4, 15, 16 a rapid review of the literature was combined with advice from a working group of clinical experts across Australia and New Zealand. 17, 18 The working group comprised seven senior surgeons (one urologist and six general surgeons), two senior anaesthetists and a senior medical virologist.

Research questions and inclusion criteria were established a priori (Table 1) 20 and searches for studies of any design in any setting were applied using rapid review methodology. 21 Searches were conducted in MEDLINE and medRxiv databases to identify articles in English published from 31 December 2019 (identification of SARS-CoV-2) 22 to 4 October 2020 (Appendix I). No publication restrictions were applied. Grey literature was also searched according to the Grey Matters checklist, 23 including content from international health networks, guideline repositories, surgical and anaesthesia societies, the USA Food and Drug Administration website, and the COVID-19 Evidence Accelerator. 24 Additional articles were identified by screening the reference lists of any full-text articles retrieved.

One reviewer (NAS) screened titles and abstracts and reviewed full texts of relevant articles to extract data into a standard extraction form. Data extracted included study design, setting, population characteristics, clinical observations relating to COVID-19, and duration of effects after acute SARS-CoV-2 infection. Data were synthesized in tabular and narrative formats. Where possible, data were coded according to surgical urgency and complexity. Level of evidence provided by the included studies was stratified according to the National Health and Medical Research Council evidence hierarchy. 25 

A total of 1020 records were identified, from which 94 full-text articles were retrieved. After applying the specified research criteria, 20 studies were included in the rapid review. Of the 20 studies, 12 contained peer-reviewed data and eight were non-refereed publications or conference abstracts. All but one of the studies investigated the long-term clinical characteristics associated with COVID-19. One study directly explored the effect of past SARS-CoV-2 infection on the postoperative outcomes of recovered patients. Regarding study design and level of evidence, 25 the studies comprised one case-control study (level III-2 evidence), one prospective cohort study (level III-2 evidence) and 18 case-series studies (level IV evidence). No randomized trials were identified that addressed the research questions. Characteristics of the included studies are outlined in Table 2 .

Studies reporting clinical characteristics persisting after acute SARS-CoV-2 infection comprised one case-control study 32 and 18 case-series studies. 7, [26] [27] [28] [29] [30] [31] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] Median study sample size was 100 (range 20-701, interquartile range 41.5-124). All studies included adult patients, while two case-series studies also included adolescents. 27, 31 The case-control study evaluated a mixed population of patients who had required inpatient or outpatient management of COVID-19. 32 Of the 18 case-series studies, 10 reported solely on patients who had required hospitalization for COVID- 19. 7,27-30,34,36,37,41,43 The remainder reported on either mixed populations of patients who had required inpatient or outpatient management for past acute COVID-19, 26, 35, 39, 42 solely outpatients, 33, 38, 40 or did not report if hospital admission had been required. 31 Case-series studies only of patients who had required hospitalization (Table 3) , reported a wider range of clinical characteristics compared to those reported in studies of mixed patient populations (Table 4) .

Within the case-series studies, new or excessive fatigue and breathlessness were the most commonly reported symptoms, followed by dysfunction in smell (anosmia or hyposmia) or taste (ageusia or hypogeusia), cough and chest pain (Tables 3 and 4 ). Regarding non-specific clinical characteristics, rates of new or excessive fatigue ranged from 16-65% within individual study populations, 7, 28, 29, 36, 39, 40, 42, 43 chest pain occurred in 1-42% of participants, 7, 28, 30, 35, 39 two studies reported myalgia in 5% of participants, 7,39 one study reported arthralgia in 27% of participants 7 and one study reported low-grade fever in 12% of participants. 40 Regarding respiratory symptoms, breathlessness was reported in 15-50% of participants, 7,28,29,34-36,39,41 cough in 1-15% of participants 28, 36, 39, 41 and one study reported general respiratory symptoms in 92% of participants. 40 Abnormal pulmonary investigation or imaging findings were reported in five studies. 27, 34, 36, 41, 43 Issues with smell and taste were reported at rates of 11-45% 7,28,31,39 and 7-11%, 7, 26, 28, 36, 39 respectively, within individual study populations, with one study describing issues with smell and/or taste in 39% of participants. 33 Other symptoms of potential neurological origin included headache, reported in 4-50% of participants 7, 36, 39, 40 ; memory issues, reported in 5-34% of participants 28, 39 ; and attention disorder, in 1-27% of participants. 28, 39 One study reported sleep disorder in 31% of paticipants 28 and another reported new-onset bowel or bladder incontinence in 13%. 29 Regarding gastrointestinal symptoms, general gastrointestinal issues were reported in 31-35% of participants, 36, 40 diarrhoea was reported in 1-2% 39 and one study reported abdominal pain in 1% of participants. 7, 39 Regarding cardiac issues, palpitations of unspecified severity were reported in 23% of participants in one study 40 and three studies reported abnormalities on investigation or imaging. 30, 35, 41 Two studies reported at least one ongoing symptom in 57% 42 and 87% 7 of their respective study populations.

The follow-up periods in which clinical characteristics were observed ranged from approximately 3-16 weeks in the case-series studies. Starting timepoints varied, with eight studies beginning with the onset of symptoms, 7, 26, 27, 30, 31, 33, 37, 40 five beginning with hospital discharge, 29,36,41-43 two beginning with diagnosis, 35, 38 one with hospital admission, 28 one with fever remission, 34 and one study beginning with consecutive negative test results. 39 Symptoms did not evolve in a predictable way with increasing follow-up time.

The case-control study examined serum immunological changes in peripheral blood mononuclear cellsat various timepoints from first diagnosis (median 112 days, range 60-136 days)in 49 patients with previous mild or moderate COVID-19 compared with 27 matched participants without SARS-CoV-2 infection. 32 The patients with past COVID-19 had lower numbers of invariant natural killer T (NKT) cells and NKT-like cells compared with the control group without past SARS-CoV-2 infection. In addition, these patients had greater numbers of regulatory T-cells, increased T-cell immunoglobulin and mucin domain-3 expression on CD4 and CD8 T cells, increased programmed death-ligand 1 expression on B cells, and decreased cytotoxic potential of T cells and NKTlike cells. However, CD4 and CD8 T-cells showed increased Ki67 expression and were able to produce effector cytokines on T-cell receptor stimulation.

Only one study directly investigated the effect of past SARS-CoV-2 infection on postoperative outcomes. 44 This was a subgroup analysis of the COVIDSurg-Cancer study of patients undergoing curative elective cancer surgery. The study examined patients in which SARS-CoV-2 RNA had been detected in a respiratory swab but who were not suspected of active infection at the time of surgery. The study found that past COVID-19 was associated with increased odds of pulmonary complications compared to no prior infection, and when analysed by time from positive swab to surgery, both pulmonary complications and mortality were lowest 4 weeks after the swab. Nevertheless, more than 70% of included patients had had their surgeries within 4 weeks of confirmed SARS-CoV-2 infection.

In addition to this study, five expert consensus guidance documents also provided data around alterations to surgical management for surgical patients who had recovered from COVID-19. [45] [46] [47] [48] [49] Within these guidelines, there was notable heterogeneity in the advice provided. Some stated that after a positive SARS-CoV-2 test, surgery should be delayed until patients are no longer infectious and have demonstrated recovery from COVID-19. 47,48 Some advised deferral for at least 2-4 weeks, 49 while others recommended a minimum of 8 weeks without symptoms before all but minor elective procedures. 45 There was consensus; however, [45] [46] [47] For patients experiencing ongoing symptoms after laboratory recovery from acute SARS-CoV-2 infection, it was advised that a multisystem and multidisciplinary approach is taken to assessment and rehabilitation. 50 

This study evaluates the long-term effects after SARS-CoV-2 infection that have been reported so far in the literature, in addition to potential impacts on surgery and perioperative care. On the basis of Ongoing lymphopenia 2% † (n = 110; median 83 days) 37 C-reactive protein >10 mg/L 2% † (n = 110; median 83 days) 37 †Non-refereed data.

CT, computed tomography; MRI, magnetic resonance imaging. 39 †Non-refereed data. a rapid review, evidence-based recommendations have been produced regarding the period of delay necessary to allow for adequate recovery of surgical patients after COVID-19 (Table 5 ). 20 Articles were sourced from peer-reviewed, non-refereed and grey literature, given the uniqueness of the topic. Lower levels of evidence predominated. Case-series studies formed the majority of the literature around the long-term clinical characteristics associated with COVID-19. The sole case-control study described immune signatures in patients recovering from SARS-CoV-2 infection, and found that the cellular immune systems of these patients may be impacted for multiple months after laboratory confirmation of infection. 32 Only one study directly investigated the effect of past COVID-19 on postoperative outcomes, suggesting that care of cancer patients with past SARS-CoV-2 infection may be optimized by delaying elective curative surgery by at least 4 weeks after a positive swab. 44 

Preoperative assessment of surgical patients can improve outcomes, identify potential anaesthetic difficulties and determine surgical risk. 51 During preoperative evaluation, increased surgical risks associated with perioperative SARS-CoV-2 infection need to be considered against the risks of delaying surgery for individual patients. 3 There is strong evidence demonstrating an association between surgery on COVID-19 patients and significant rates of postoperative complications, particularly of a pulmonary or thrombotic nature. 2, 3 The difficulty of this decision-making process is further compounded by the fact that COVID-19 may be more important than other surgical risk factors in preoperative evaluation. 2 Conditions such as diabetes and obesity that may affect surgical risk and worsen outcomes after acute illness, must still be considered in the presence of SARS-CoV-2 infection. This review provides the best available evidence on the persistent clinical manifestations and immunological dysregulation associated with COVID-19. It recommends that a complex risk-benefit deliberation should be undertaken within 4 weeks of laboratory confirmation of SARS-CoV-2 infection when considering patients for minor surgery, and from 8-12 weeks when considering patients for major surgery (Table 5) . For patients who have severe illness during either the acute phase of SARS-CoV-2 infection or the ongoing disease process, it is advised that they are reviewed preoperatively by a physician and undergo investigations including stress echocardiography, respiratory function tests, and immune and clotting status review. For certain patients with severe disease, admission to high dependency or critical care units in the immediate postoperative period may be required. Further, given some studies reported lasting issues with cognition and memory, 28,39 preoperative processes of ensuring adequate informed consent may also need to be considered, such as the preoperative provision of written information or obtaining consent in the presence of a patient's next of kin.

The findings from this study have direct implications for systems of surgical and perioperative care. Delay of non-urgent operations to minimize transmission of SARS-CoV-2 in the early stages of the pandemic resulted in long-lasting disruption to surgical systems worldwide. 5 To avoid similar effects arising from the need to delay surgery in patients recovering from COVID-19, cases must be considered on an individual basis using a data-driven approach incorporating resource supply and local COVID-19 prevalence. 1 More intensive surveillance must occur for patients with both COVID-19 and cancer 52 to ensure clinical decision-making accounts for current circumstances and unnecessary delay is avoided. Where possible, if surgery is delayed after confirmation of SARS-CoV-2 infection, nonoperative management strategies that do not worsen patient outcomes should be considered by the treating surgical team. 1

The primary limitation of this study was the inclusion of evidence from non-refereed and grey literature. Given the novelty of the topic; however, widely accepted methods 21,23 were used to rigorously evaluate this literature along with peer-reviewed sources, which allowed us to extract data that may otherwise have been missed. The rapid evolution of the evidence base associated with the increased data-sharing during the COVID-19 pandemic 53 means that new relevant data may soon be available. 8 The process of selecting relevant studies and data extraction was conducted by a single reviewer, leading to potential selection bias; however, all synthesized data were reviewed by a working group of clinical experts prior to the formulation of the evidence-based recommendations. Collaboration between researchers and expert clinicians also ensured enhanced clinical relevance of the evidence presented within the final report. Not all included studies provided baseline measures of patient quality of life or symptoms existing prior to SARS-CoV-2 infection, which added a degree of bias to the association of certain clinical profiles with the long-term effects of COVID-19. Similarly, the symptoms outlined, particularly those of a psychological nature, rely on subjective patient reports, thus carrying the possibility of misestimation. Likewise, symptom aetiology may be attributed to COVID-19 when in reality it may be multifactorial, with many of the lifestyle changes associated with the pandemic also playing a role. 8 

This rapid review synthesizes the available data around the longterm clinical manifestations of COVID-19 and associated impacts on postoperative care. Utilizing these findings alongside input from a working group of clinical experts, evidence-based guidance regarding delaying surgery for patients recovering from COVID-19 was developed. Given persistent clinical manifestations and immunological dysregulation, minor surgery should be delayed for at least 4 weeks and major surgery for 8-12 weeks after laboratory confirmation of SARS-CoV-2 infection, where it does not compromise patient outcome. Methods must be implemented to ensure adequate informed consent if COVID-19 results in ongoing issues with memory or cognition. Comprehensive preoperative and ongoing assessment must be carried out to ensure optimal clinical decision-making. As SARS-CoV-2 does not conform to previous knowledge of respiratory viruses, future research of COVID-19 via studies of strong design is required to clarify the direct, long-term effects of SARS-CoV-2 infection on both preoperative risk profile and postoperative outcomes.

Conceptualization; investigation; writing-original draft; writing-review and editing. N. Ann Scott: Data curation; formal analysis

Tivey: Conceptualization; investigation; methodology; supervision; writing-review and editing. Wendy Babidge: Conceptualization; formal analysis; investigation; supervision; writing-review and editing. David Scott: Conceptualization; investigation; supervision; writing-review and editing

Kok: Conceptualization; investigation; supervision; writing-review and editing. Conceptualization; investigation; supervision; writing-review and editing. R Padbury: Conceptualization; investigation; supervision; writing-review and editing. Thomas Hugh: Conceptualization; investigation; supervision; writing-review and editing. Peter Hewett: Conceptualization; investigation; supervision; writing-review and editing. Trevor Collinson: Conceptualization; investigation; supervision; writingreview and editing. Guy Maddern: Conceptualization

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The authors would like to thank Kaitryn Campbell for assistance with the literature searches and Kristin Weidenbach for copyediting the final version of this report. Funding was provided by Royal Australasian College of Surgeons, Research Audit and Academic Surgery.