key: cord-0770634-7x3b1hzd
authors: Akan, Serkan; Ediz, Caner; Kızılkan, Yunus Emre; Alcin, Adem; Tavukcu, Hasan Huseyin; Yilmaz, Omer
title: Covid‐19 Threat in Patients with High‐Risk Non‐Muscle Invasive Bladder Cancer Receiving Intravesical BCG Therapy
date: 2020-10-16
journal: Int J Clin Pract
DOI: 10.1111/ijcp.13752
sha: aace9b8bba04b50919957d641522048a045e0415
doc_id: 770634
cord_uid: 7x3b1hzd

AIM: We evaluated the COVID‐19 infection threat in patients receiving intravesical BCG therapy which has immunotherapeutic effects and is of vital importance in most of the individuals with high‐risk non‐muscle‐invasive bladder cancer (NMIBC) and investigated the need for postponement of this therapy. METHODS: A total of 71 patients, who were diagnosed with high‐risk NMIBC and on intravesical BCG treatment regularly (induction or maintenance), were enrolled in the study. The patients were classified into two groups depending on whether they were diagnosed with COVID‐19 during the pandemic period or not. RESULTS: Of 71 patients, 26 underwent a COVID‐19 polymerase chain reaction test with clinical suspicion during the pandemic period. Of these 26 patients, 4 were diagnosed with COVID‐19. Age of the patients, working status (working/retired), compliance with containment measures against the pandemic, number of BCG courses, adverse effects after BCG therapy, and systemic immune‐inflammation index, which is an inflammation‐related parameter, were not different between groups (p>0.05). Neutrophil/lymphocyte ratio was significantly higher in the COVID‐19 positive group (p<0.05). COVID‐19 positivity was higher in age groups 50‐64 (6.6%) and 65‐80 (5.8%) years than that in similar age groups of the normal population. CONCLUSION: Every effort should be made to administer intravesical BCG treatment in high‐risk NMIBC patients even during the pandemic period. However, increased risk of COVID‐19 transmission should be kept in mind and protective measures against COVID‐19 for healthcare providers and patients before the procedure should be taken optimally. The procedure should be postponed in patients with lymphopenia in recent complete blood count.

Coronavirus disease 2019 (COVID- 19) , which was first reported on January 7 th in 2020 as a result of investigations from pneumonia cases of unknown etiology in Wuhan, China's Hubei province, caused a pandemic all over the World (1) . The disease is transmitted mainly through droplets. Asymptomatic individuals might be infectious, because the virus could be detected in their respiratory secretions. First COVID-19 case was announced on March 13 th in Turkey and over 200.000 laboratory confirmed cases were reported until June 6 th (2). COVID-19 pandemic resulted in postponement of lots of medical and surgical procedures.

The rationale behind this approach was decreasing the risk of COVID-19 transmission, increasing bed availability for COVID-19 in wards and intensive care units, relieving the health care providers of workload except COVID-19, and limiting the aerosol generating procedures. Several guidelines stratifying urological procedures into risk groups developed recommendations about which procedure should be carried out or postponed (3, 4) .

Postponement of intravesical bacillus Calmette-Guérin (BCG) therapy in patients with highrisk non-muscle invasive bladder cancer (NMIBC) is recommended in present studies (5,6).

This article is protected by copyright. All rights reserved reported, there are no sufficient studies to compare risk of transmissions among treatment receiving patients and normal population. In this study, COVID-19 threat is evaluated in patients receiving intravesical BCG therapy which has immunotherapeutic effects and is of vital importance in most of the individuals with high-risk non-muscle invasive bladder cancer (NMIBC) and the need for postponement of this therapy is investigated.

This study was approved by the local Ethics Committee (Hamidiye-BAEK 20/299) and In Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey, patients who were diagnosed with high-risk NMIBC from 2018 to 2020 and on intravesical BCG treatment regularly (induction or maintenance), were enrolled in the study. Up-to-date data of the most patients were obtained by the Uro-oncology outpatient clinic checks in July 2020 and the rest by telephone conversation retrospectively. Exclusion criteria were having any missing data in records or analyses, refusal to enroll in the study, not receiving intravesical BCG therapy regularly, incompleteness of at least 6-week intravesical BCG induction, having chronical lung diseases which increases COVID-19 risk, and being immunosuppressed due to a systemic disease or a medical treatment. 

This article is protected by copyright. All rights reserved Data analyses were performed using SPSS Statistics 20.0 software (SPSS Inc., Chicago, IL, USA The patients were classified into two groups depending on whether they were diagnosed with COVID-19 or not. Age of the patients, working status (working/retired), compliance with containment measures against pandemic, number of BCG courses, adverse effects after BCG therapy, and SII, which is an inflammation related parameter, were not different between groups (p>0.05). NLR was significantly higher in COVID-19 positive group (p<0.05) ( Table   2 ).

In subgroups analyses by age, COVID-19 positivity was higher in our patients in 50-64 and 65-80 years subgroups (6.6% and 5.8%, respectively) in comparisons with the incidences of

This article is protected by copyright. All rights reserved the corresponding age groups of the normal population demonstrated in COVID-19 Daily Situation Report Turkey (June 29 th , 2020) provided by Ministry of Health (Table 3) .

(ACE-2) receptor and entering to host cells (7) . Patients on ACE inhibitors have greater expression of ACE-2 receptors which is shown to be the entry point into human cells for COVID-19 virus. This leads to the corollary that any drug or vaccine which has the potential to increase the level of ACE may help down regulate the expression of ACE-2 receptors, thereby having some beneficial effect on the host immune system against COVID-19. Earlier animal studies have shown that ACE-like activity increased with inflammation induced by BCG suppressed the induction of the inflammatory response in both lungs and spleen (8) .

Consequently, the BCG vaccine does not directly protect against the coronavirus but provides a boost to the immune system which may lead to improved protection and a milder infection (9) .

Countries which have universal long-standing policies of BCG vaccination were less severely affected from COVID-19 compared with those without universal policies of BCG vaccination (ie, Italy, the Netherlands, and the United States) (10) . Countries which have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population (8) . Therefore, recently, researchers hypothesized that BCG vaccination might also combat COVID-19 because of its broad ability to stimulate the immune system. However, it should be emphasized that the causality is not yet proven; there is only one study predicting an association (11) .

Intravesical BCG treatment (application of attenuated Mycobacterium Bovis vaccine through urethra into the bladder) acts by massive local immune response. Adhesion of BCG to the urothelium including malignant cells induces secretion of cytokines and chemokines which results in migration of different immune system cells to the bladder wall (12) . By cellular immunity, phagocyte activation and new cytokine environment, and by humoral immunity direct immune response of CD4+ T cells with differentiation to TH1 and/or TH2 cells are stimulated (13) . Beside the local immunotherapeutic effects of intravesical BCG, systemic immunological effects are also shown (14) . Intravesical BCG induces an important systemic impact as humoral response and increases IgG level binding to tuberculin and mycobacterial heat shock proteins (HSPs) (15, 16) . Although these findings are in favor of intravesical BCG therapy for patients with NMIBC during COVID-19 pandemic, our results are contrary.

This article is protected by copyright. All rights reserved It is supposed that patients, who sustained cancer or are being treated for cancer, are in risky group for COVID-19 (17, 18) . Of cases until January 31 st , 2020 in China, 1590 (1%) had a cancer diagnosis and this rate was higher than that of general population in China (0.29%) (19) . The most important parameter with a five-fold increased risk in this study was receiving chemotherapy or undergoing surgery in last month. In a study from 14 centers from China comparing 105 patients, who had cancer, with 536 patients without cancer, increased risk with cancer especially hematologic malignancies, lung cancer, and metastatic cancer is reported (20). To the best of our knowledge, there is no study regarding COVID-19 incidence in patients with early stage bladder cancer in English literature. COVID-19 incidence in our patients receiving intravesical BCG due to high-risk NMIBC was 5.6% and higher than that of general population. Among parameters which might increase the risk, NLR was significantly higher in COVID-19 positive group. In our 3 hospitalized patients due to COVID-19, lymphocyte levels were below 1.5 10 3 /mm 3 . However, this result might be due to small patient group of our single-center study. Intravesical chemotherapy, which is advised for low-and some intermediate-risk NMIBC and has lower complication rates than BCG therapy, is not recommended during pandemics because it could increase the complication rates in the postoperative period and prolong the length of hospital stay (21, 22) . However, according to recent uro-oncology guidelines for COVID-19 pandemic period, intravesical BCG treatment should not be postponed providing that the clinic has adequate conditions considering the potential benefits to patients regarding high-risk NMIBC vs. probable complications (3, 4) . Teoh and colleagues advocated that for patients with high-risk NMIBC, benefit of continuing BCG for a better cancer control outweighed the potential risk of COVID-19 infection along the treatment course, in their article published in Word J Urol (5).

In the same article, they concluded that it can be interrupted during pandemic period in highrisk NMIBC patients who completed minimum one-year BCG treatment and in intermediaterisk ones, despite the lack of relative oncological data. We think every effort should be made to administer intravesical BCG treatment, which is the most effective therapy for preventing recurrence and progression of the disease in patients with high-risk NMIBC, even during COVID-19 pandemic. However, increased risk of COVID-19 transmission should be kept in mind and protective measures for COVID-19 for healthcare providers and patients before the procedure should be taken optimally. The procedure should be postponed in patients with lymphopenia in recent complete blood count.

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progress, role of BCG vaccine in alleviation of the disease is put forward. In this study, we recommend being aware of increased risk of COVID-19 transmission in high-risk NMIBC patients receiving intravesical BCG, taking protective measures against COVID-19 for healthcare providers and patients before the procedure optimally, and postponement of the procedure in patients with lymphopenia in recent complete blood count.

This prospective descriptive study was approved by the University of Health Sciences Hamidiye Scientific Research Ethics Committee (Hamidiye-BAEK 20/299).

Informed consent is not obtained from patients to publish the data concerning this study.

Authors declared no conflict of interest.

This article is protected by copyright. All rights reserved