CSF Rhinorrhea After Endonasal Intervention to the Skull Base (CRANIAL) — Part 2: Impact of COVID-19

Background During the coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised regarding the increased risk of perioperative mortality for patients with COVID-19, and the transmission risk to healthcare workers, especially during endonasal neurosurgical operations. The Pituitary Society has produced recommendations to guide management during this era. We sought to assess contemporary neurosurgical practice and the effects of COVID-19. Methods A multicenter prospective observational cohort study was conducted at 12 tertiary neurosurgical units (United Kingdom and Ireland). Data were collected from March 23 to July 31, 2020, inclusive. The data points collected included patient demographics, preoperative COVID-19 test results, operative modifications, and 30-day COVID-19 infection rates. Results A total of 124 patients were included. Of the 124 patients, 116 (94%) had undergone COVID-19 testing preoperatively (transsphenoidal approach, 97 of 105 [92%]; expanded endoscopic endonasal approach, 19 of 19 [100%]). One patient (1 of 116 [0.9%]) had tested positive for COVID-19 preoperatively, requiring a delay in surgery until the infection had been confirmed as resolved. Other than transient diabetes insipidus, no other complications were reported for this patient. All operating room staff had worn at least level 2 personal protective equipment. Adaptations to surgical techniques included minimizing drilling, draping modifications, and the use of a nasal iodine wash. At 30 days postoperatively, no evidence of COVID-19 infection (symptoms or positive formal testing results) were found in our cohort and no mortality had occurred. Conclusions Preoperative screening protocols and operative modifications have facilitated endonasal neurosurgery during the COVID-19 pandemic, with the Pituitary Society guidelines followed for most of these operations. We found no evidence of COVID-19 infection in our cohort and no mortality, supporting the use of risk mitigation strategies to continue endonasal neurosurgery in subsequent pandemic waves.


INTRODUCTION
T he coronavirus disease 2019 (COVID- 19) pandemic is an ongoing global pandemic caused by a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). 1,2 Measures were enacted to mitigate the spread of the virus and, thereby, prevent national healthcare systems from being overwhelmed. These measures included reenlisting retired healthcare workers 3 and redeploying surgeons to provide out-ofspecialty care. 4,5 As a secondary consequence of this reallocation of resources in healthcare services globally, it proved increasingly challenging to continue providing existing services for other diseases and conditions, including a noticeable reduction in surgical activity. [6][7][8] This reduction was likely compounded by the initial concern that patients undergoing surgery would be an especially vulnerable group owing to their risk of exposure 9 and, as such, a more cautious approach was taken regarding surgery.
One such specialty that has seen their normal services disrupted is neurosurgery, 10 with some countries reporting the cancellation of more than one half of all their indicated neurosurgical operations. 11 This has been especially so for pituitary surgery. 12,13 One factor that played a role in the reduction of pituitary surgery was the need to protect healthcare workers (HCWs). 10,12 The transmission of the SARS-CoV-2 virus occurs primarily via large respiratory droplets containing the virus. Therefore, HCWs working in certain specialties and subspecialties were considered to have a high risk owing to their frequent exposure to oronasal secretions. 14 These HCWs include those involved in pituitary surgery, given the number of procedures for which access is via the nasal cavity and sphenoid sinus. 15 To manage the risk to HCWs involved in such procedures, the Professional Education Committee of the Pituitary Society produced a set of comprehensive guidelines for international guidance. 12 These included advising all patients to undergo COVID-19 screening preoperatively, the use of nondrill techniques, considerations for alternative approaches (e.g., transcranial), and for operating room staff involved in endoscopic or microscopic endonasal approach surgeries to wear at least level 2 personal protective equipment (PPE). 16,17 Although the caseloads in neurosurgery have decreased, some operations have been performed during the course of the pandemic. 18,19 These operations were most likely performed for patients requiring urgent or emergency surgery, 20 including patients presenting with pituitary apoplexy, visual loss, malignant pathology, or significant endocrine disorders. However, reported data are lacking regarding the number of neurosurgical operations performed, their indications, and the postoperative complications for the patients who had undergone neurosurgical operations during the COVID-19 pandemic. These data are essential, especially to quantify the effects on those who have undergone an endonasal operation in the context of a respiratory virus. The timeline of a prospective multicenter pilot study in the United Kingdom and Republic of Ireland-CRANIAL (CSF [cerebrospinal fluid] rhinorrhea after endonasal intervention to the skull base) 21 -coincided with the start of the COVID-19 pandemic. This provided a unique opportunity to assess the effects of the COVID-19 pandemic on endonasal surgery practices in the United Kingdom in real time. Therefore, in the present report, our primary aim was to determine whether the advice regarding COVID-19 testing and the use of PPE had been followed, and to investigate the intraoperative adaptations used to minimize the risk of COVID-19, the 30-day postoperative COVID-19 infection rate, and the mortality rate.

Study Design
A multicenter prospective observational cohort study design was implemented 21  . The project was registered as a service evaluation at each center, with approval received from the audit department of each institution (and Caldicott guardians when required). The local team consisted of consultant lead(s) with overall project responsibility, trainee lead(s) in charge of data collection, and, on occasion, student lead(s) for additional support. The STROBE (strengthening the reporting of observational studies in epidemiology) statement was used in the preparation of this report. 22 The eligible cases included patients of all ages who had undergone the transsphenoidal approach (TSA) for sellar tumors or the expanded endonasal approach (EEA) for skull base tumors. 21 The exclusion criteria were transcranial surgery and a history of preoperative CSF rhinorrhea. Case selection was limited to patients who had presented from March 23 to July 31, 2020, inclusive. Before March 23, 2020, pauses had occurred in data collection owing to data pro forma amendments and attaining additional approvals (e.g., information governance approvals where requested). This also allowed for our data to coincide with when the first lockdown had begun in the United Kingdom. 23

Data Collection
The data points collected included the patient demographics, preoperative COVID-19 status, operative modifications, and postoperative COVID-19 data. The primary outcomes of interest were as follows: 1) the COVID-19 preoperative screening method used; 2) the precautions taken to reduce the risk of airborne pathogen transmission; and 3) the 30-day COVID-19 infection rate for patients postoperatively. The secondary outcomes of interest were the length of hospital stay and the mortality rate.
The local teams submitted data to a secure web-based central database hosted by Castor Electronic Data Capture (Amsterdam, The Netherlands; available at: https://www.castoredc.com/). All initial data were collected within 30 days of surgery, followed by a 30-day follow-up window. The data points collected by medical students or junior trainees were confirmed with the operating surgeons or senior members of the team before final submission to the Castor Electronic Data Capture system. 21

Data Validation
Data validation was performed in all centers to audit quantitative data accuracy. 21 This involved an independent data validator (who had not collected the local data) who reviewed the datasets for several enrolled cases, selected randomly. Each data validator was from the hospital in which the data had been collected. The targets for validation were a secure and accurate record of the Castor identification records with corresponding medical record numbers, no case or data duplication, and data accuracy of >95%.

Statistical Analysis
The pooled quantitative data were analyzed using Microsoft Excel, version 16.41 (Microsoft, Redmond, Washington, USA), to present descriptive statistics. If a data point was missing from a case, the denominator was adjusted to account for the missing data. The data were used to create tables summarizing the demographic characteristics, tumor characteristics, operative characteristics, and methods used to reduce COVID-19 transmission. For 3 centers, data were available before the lockdown had begun (November 1, 2019 to March 22, 2020). The Mann-Whitney U test was used for comparative analysis (pre-lockdown vs. during lockdown) of patient age and hospital length of stay for the patients from these 3 centers. The Fisher exact test was for comparative analysis (pre-lockdown vs. during lockdown) of the remaining data points for patients from these 3 centers. Statistical analysis was performed using Prism, version 5 (GraphPad, San Diego, California, USA), with statistical significance set at P 0.05.

General Data
Data were collected for 124 patients across the 12 tertiary neurosurgical centers. The neurosurgical centers had contributed data for 2 to 21 patients. No duplicates in the cases or data were found in the records audited for data validation. All centers had fulfilled the >95% accuracy target per case.

Patient Characteristics
The median patient age in the present study was 50.5 years (range, 7e82 years). Of the 124 patients, 65 were male and 59 were female. At presentation, the body mass index had been recorded for 118 patients (95% ). These data are summarized in Table 1. Comparing the preoperative factors from before and during the lockdown at the 3 pilot centers, a larger proportion of patients who had undergone surgery during the lockdown had had visual compromise preoperatively compared with those treated before the lockdown (P 0.01; Table 2).

COVID-19 Screening Preoperatively
Preoperatively, 2 of the 124 patients (2%) had presented with symptoms associated with COVID-19: 1 with a new cough and 1 with shortness of breath. Neither of these patients had tested positive for COVID-19 when screened and both had eventually undergone endoscopic surgery with the TSA-1 patient after 2 weeks self-isolation and negative swab results and 1 after computed tomography of the thorax and swab testing were negative (without isolation owing to clinical urgency

ORIGINAL ARTICLE
of the thorax (0.9%). Of these 116 patients, 1 (0.9%) had tested positive for COVID-19 via the swab test preoperatively. The patient who had tested positive (a 52-year-old man) underwent selfisolation for 2 weeks and re-screening preoperatively. He subsequently had an endoscopic TSA for pituitary macroadenoma resection after a re-screening swab test result was negative. The swab types used were examined at the initial pilot centers (n ¼ 4) and were either RNA polymerase chain reaction tests (n ¼ 2 of 4) or RNA transcription-mediated amplification tests (n ¼ 2 of 4).
The  Table 4.

Postoperative Complications and Screening
The median length of patient stay was 4 days (range, 1e32 days) for the entire group and was 3.5 days (range, 1e32 days) for the TSA group and 7 days (range, 1e20 days) for the EEA group.

Principal Findings
To the best of our knowledge, the present study is the first multicenter study reporting data of contemporaneous endonasal skull base operative practice during the COVID-19 pandemic. As expected, the operative caseload was lowest at the peak of the pandemic (March) and increased over time as operative protocols were established and infection rates reduced. Most of these endonasal neurosurgical cases were for pituitary adenoma (n ¼ 88 of 124 [71%]), and most patients were symptomatic preoperatively: visual loss in 83 of 121 patients (69%), anterior pituitary deficiency requiring hydrocortisone in 30 of 124 patients (24%), and/or posterior pituitary deficiency requiring desmopressin in 5 patients (4%). The most common approach used was the TSA (n ¼ 102 of 124; 82%). The operating room staff involved in these operations adhered to international guidance by wearing at least level 2 PPE. 12 Considerable heterogeneity was present in the PPE worn; however, the PPE items worn in most cases were FFP3 masks (n ¼ 99 of 124; 80%) and eyeglasses (n ¼ 74 of 124; 60%). Adaptations to surgical techniques included minimizing drilling, draping modifications, and using nasal iodine wash.
At 30 days postoperatively, no evidence was found of COVID-19 infection (no symptoms and no positive test results) in our cohort and no mortality had occured. One of the 116 patients had tested positive for COVID-19 preoperatively and was isolated for 2 weeks, with negative swab screening results before the patient underwent surgery. This patient had developed transient diabetes insipidus postoperatively; however no other complications had been reported at 30 days postoperatively.

Findings in the Context of the Reported Data
Few studies have provided data on patients who have undergone pituitary surgery during the COVID-19 pandemic. One case report from Wuhan, China, described a patient developing COVID-19 within the first week after endoscopic endonasal pituitary surgery. However, the use of a preoperative swab screening test was not reported; thus, it was unclear whether the patient had had COVID-19 preoperatively or had developed a postoperative infection. 19 Additionally, a case series from Cambridge, United Kingdom, reported that none of 9 consecutive patients who had undergone pituitary surgery or skull base surgery from March 30 to April 28, 2020, had contracted COVID-19 after the adoption of a risk-mitigation protocol. 12,18 Similar risk-mitigation strategies were subsequently advocated by the Professional Education Committee of the Pituitary Society. The results from our international, multicenter study support the findings of the latter study, because we did not find a greater risk to patients of acquiring COVID-19 if they underwent endonasal surgery during the pandemic. Our results also suggest that a standardized, risk-mitigation strategy that accounts for earlier guidance might allow for normalization of activity. Our results join an increasing body of data showing that surgery is safe for patients with negative SARS-CoV-2 test results preoperatively in a COVID-19efree surgical pathway. 24,25 The preoperative swab tests used in our series were RNA polymerase chain reaction and transcription-mediated amplification via nasopharyngeal swabs. The use of a single swab is estimated to have a sensitivity of 70% and specificity of

ORIGINAL ARTICLE
95%-with the true predictive value determined by factors such as symptoms and disease prevalence. 12,26,27 However, the resumption of full elective workloads will depend on wider national and international factors that protect patients from becoming infected with SARS-CoV-2 and, thereby, avoid delays in surgery. The noneCOVID-19 morbidity of patients with pituitary pathology is an increasing concern, and our results could help alleviate concerns about performing surgery during the pandemic.

Study Limitations
The present study had several limitations, which require a tempered assessment of the findings. Firstly, because of the reduced caseloads aimed at mitigating the effects of COVID-19, we had a moderate sample size, especially with respect to EEA. Owing to the recency of cases and the urgency to inform policymakers about the risks to surgical patients, the follow-up period was limited to the 30-day postoperative period. In addition, because the present study was a prospective cohort study, the data points were purely observational and across the context of multiple centers. Also, owing to the observational nature, not all patients had been screened postoperatively for COVID-19, and we were reliant on these patients self-reporting any COVID-19 symptoms if and when they had developed. Similarly, robust and consistent data regarding the symptoms or infection rates of the surgical team were lacking. The most significant limitation was the paucity of baseline data to compare against the postoperative findings.
The prepandemic dataset used in the present study for limited comparative analysis was not consecutive and was small in size.
The main CRANIAL study is ongoing and should provide the baseline data with which to correlate our findings once the study has been completed. 21

CONCLUSIONS
As operative protocols were established and infection rates reduced, the number of endonasal operations increased. Guidelines reported by the Professional Education Committee of the Pituitary Society were followed. No postoperative COVID-19 infections occurred; therefore, the patients who had undergone surgery had not experienced any COVID-19erelated morbidity or mortality. This suggests that a risk mitigation approach can enable timely pituitary surgery to continue safely during the COVID-19 pandemic.