Clinical profiling of subgroups of women with chronic pelvic pain (preprint)

Study question Do subgroups of women with chronic pelvic pain (CPP) report different clinical symptoms and differing impact of pain on their quality of life? Summary answer Clinical profiles of women with CPP show variability of clinical symptoms both within and between subgroups. However, there is an obvious negative impact of pain on the patients’ lives across all subgroups with the comorbid endometriosis and bladder pain symptoms group (EABP) presenting with the higher pain intensities and the lower quality of life. What is known already CPP is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. The clinical presentation of CPP is varied and there are frequently comorbid conditions both within and outside the pelvis. Evidence from the literature show that there is an overlap of symptoms in chronic pain conditions whatever the underlying cause which suggests that chronic pain could be a condition itself. Study design, size, duration The study is part of The Translational Research in Pelvic Pain (TRiPP) project ( https://www.imi-paincare.eu/PROJECT/TRIPP/ ) which is a cross-sectional observational cohort study. The present study includes 769 female participants sampled from two existing endometriosis-focused cohort studies in Oxford, UK and Boston, MA, USA and newly recruited from the Instituto de Biologia Molecular e Celular (IBMC)) in Porto. The participants completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this study population we defined a control group (reporting no pelvic pain, no bladder pain syndrome (BPS), and no endometriosis diagnosis, N=230) and four pain groups: endometriosis-associated pain (EAP, N=237), (BPS, N=72), comorbid endometriosis-associated pain and BPS (EABP, N=120), and pelvic pain only (PP, N=127). Participants/materials, setting, methods All participants were women of reproductive age (13-50 years) and were recruited at three different sites: Oxford (University of Oxford), Boston (Boston Center for Endometriosis (BCE)) and Porto (Instituto de Biologia Molecular e Celular (IBMC)). The questionnaire included: demographics; reproductive history; pelvic pain intensity assessed using 10-point numerical rating scales (NRS) for dysmenorrhoea, non-cyclical pain, dyspareunia and bladder pain; medical comorbidities; factors relieving and worsening pain; quality of life assessed using the SF-36 questionnaire; and pain catastrophising. Main results and the role of chance The EAP (Mean:7.37) and EABP (Mean:7.88) groups scored higher on the pain intensity scales for non-cyclical pelvic pain than the PP (Mean:6.82) group (p<0.001) and higher on the dysmenorrhoea scale than both the BPS and PP groups (p<0.001). The EABP (Mean:6.61) and BPS (Mean:6.52) groups had significantly higher bladder pain scores than the EAP (Mean:0.95) and PP (Mean:0.78) (p<0.001). The EABP group also had significantly higher pain scores for dyspareunia (p<0.001), even though more than 50% of participants (who were sexually active) in each of the pain groups reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Exploring the factors reported to worsen or relieve pain found that across the pain groups the three most reported factors for worsening pelvic pain were: stress (23.6%), full bladder/urinating (23.3%) and exercising (20.2%). The most common factors for relieving pelvic pain were: pain medication (31.4%), lying down (31.0%), and use of a heat pad (29.5%). Analysis of the quality-of-life questionnaire (SF-36) subscales revealed significant differences between the study groups across all SF-36 subscales (p<0.001). In line with the pain results the EABP group reported the negative highest impact across all the health measures while the PP group’s profile was closest to the control group’s profile. Significant effects were also observed between the pain groups for pain interference with their work (F(3,209)=9.76, p<0.001) and daily lives (F(3,244)=10.51, p<0.001), with the EABP suffering more compared to the EAP and PP groups (p<0.001). Limitations, reasons for caution Data for this study were derived predominantly from existing cohorts where data have been collected over time and thus different versions of questionnaires have been used. Thus, for some questions only a subgroup may have had an opportunity to complete the measure of interest. Recruitment of participants was impacted due to the COVID-19 pandemic. As a result, sample sizes overall were smaller than originally designed, and our BPS group was predominantly identified from gynaecological rather than urological clinics making it potentially different from other published BPS cohorts. Wider implications of the findings Overall, our results demonstrate the negative impact that chronic pain has on CPP patients’ quality of life and suggests that further exploration of interventions targeting quality of more broadly is important. Furthermore, it demonstrates the importance of dyspareunia in women with CPP, highlighting the need for more research in this area. Importantly, we show significant differences between the sub-groups of CPP suggesting the need for better patient stratification in future clinical studies and trials. However, the marked variability both within and between CPP sub-groups raises the question whether subgrouping on the basis of clinical diagnosis is the most appropriate strategy or whether alternative approaches could be identified allowing prioritisation of treatments better suited to the individual patient. Study funding/competing interest(s) This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777500. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA Companies. Financial support was provided by the J. Willard and Alice S. Marriott Foundation for establishment of and baseline data collection within the A2A cohort - from which the Boston-based TRiPP population was sampled. Trial registration number NCT04001244

Using social media to crowdsource collection of urine samples during a national pandemic.

The COVID-19 pandemic and subsequent lockdown had a substantial impact on normal research operations. Researchers needed to adapt their methods to engage at-home participants. One method is crowdsourcing, in which researchers use social media to recruit participants, gather data, and collect samples. We utilized this method to develop a diagnostic test for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). Participants were recruited via posts on popular social-media platforms, and enrolled via a website. Participants received and returned a mail kit containing bladder symptom surveys and a urine sample cup containing room-temperature preservative. Using this method, we collected 1254 IC/BPS and control samples in 3 months from all 50 United States. Our data demonstrate that crowdsourcing is a viable alternative to traditional research, with the ability to reach a broad patient population rapidly. Crowdsourcing is a powerful tool for at-home participation in research, particularly during the lockdown caused by the COVID-19 pandemic.

Pentosan polysulfate inhibits attachment and infection by SARS-CoV-2 in vitro: insights into structural requirements for binding. (preprint)

Two years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.

Web-mediated counseling to counteract the emotional impact of COVID-19 for women with interstitial cystitis/bladder pain syndrome.

OBJECTIVE: Interstitial Cystitis (IC) is a chronic and rare disease, more frequent in women. Symptoms of continuous pain can produce psychological disorders, such as anxiety and depression. The spread of COVID-19 pandemic added to distress experienced by patients with IC emotions, such as fear, sadness, boredom, frustration and anger. MATERIALS AND METHODS: A research on very recent literature outlines the necessity for patients facing the complexity of IC during the COVID-19 outbreak to prevent the temporary crisis, to broaden perspectives, to deal with confusion, to support in struggling with unpleasant and unexpected events. CONCLUSIONS: People affected by IC have a psychological vulnerability that needs tailored support interventions, particularly in the COVID era. A multidisciplinary approach offers a personalized treatment through a web-mediated counseling intervention for patients and their caregivers: a space for continuous discussion and reflection can favour a relationship-based process of change aimed at an improvement in quality of life.

COVID-19 inflammation results in urine cytokine elevation and causes COVID-19 associated cystitis (CAC).

Coronavirus disease 2019 (COVID-19) causes a wide range of symptoms, including several unexpected symptoms such as loss of taste, skin changes, and eye problems. We recently observed patients with documented COVID-19 develop de novo severe genitourinary symptoms, most notably urinary frequency of ≥ 13 episodes/24 h and nocturia ≥ 4 episodes/night. We call these associated urinary symptoms COVID-19 associate cystitis (CAC). COVID-19 severity is associated with inflammation. We collected urine samples from COVID-19 patients, including patients with CAC, and found elevation of proinflammatory cytokines also in the urine. It has been previously shown that patients with urinary incontinence and ulcerative interstitial cystitis/bladder pain syndrome have elevated urinary inflammatory cytokines compared to normal controls. We therefore hypothesize that CAC, with presentation of de novo severe urinary symptoms, can occur in COVID-19 and is caused by increased inflammatory cytokines that are released into the urine and/or expressed in the bladder. The most important implications of our hypothesis are: 1) Physician caring for COVID-19 patients should be aware of COVID-19 associate cystitis (CAC); 2) De novo urinary symptoms should be included in the symptom complex associated with COVID-19; and 3) COVID-19 inflammation may result in bladder dysfunction.

Management of Female and Functional Urology Patients During the COVID Pandemic.

CONTEXT: Coronavirus disease 19 (COVID-19) has changed standard urology practice around the world. The situation is affecting not only uro-oncological patients but also patients with benign and disabling conditions who are suffering delays in medical attention that impact their quality of life. OBJECTIVE: To propose, based on expert advice and current evidence where available, a strategy to reorganize female and functional urological (FFU) activity (diagnosis and treatment). EVIDENCE ACQUISITION: The present document is based on a narrative review of the limited data available in the urological literature on SARS-Cov-2 and the experience of FFU experts from several countries around the world. EVIDENCE SYNTHESIS: In all the treatment schemes proposed in the literature on the COVID-19 pandemic, FFU surgery is not adequately covered and usually grouped into the category that is not urgent or can be delayed, but in a sustained pandemic scenario there are cases that cannot be delayed that should be considered for surgery as a priority. The aim of this document is to provide a detailed management plan for noninvasive and invasive FFU consultations, investigations, and operations. A classification of FFU surgical activity by indication and urgency is proposed, as well as recommendations adopted from the literature for good surgical practice and by surgical approach in FFU in the COVID-19 era. CONCLUSIONS: Functional, benign, and pelvic floor conditions have often been considered suitable for delay in challenging times. The long-term implications of this reduction in functional urology clinical activity are currently unknown. This document will help functional urology departments to reorganize their activity to best serve their patients. PATIENT SUMMARY: Many patients will suffer delays in urology treatment because of COVID-19, with consequent impairment of their physical and psychological health and deterioration of their quality of life. Efforts should be made to minimize the burden for this patient group, without endangering patients and health care workers.