COVID-19 as a trigger of irritable bowel syndrome: A review of potential mechanisms

In December 2019 a novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), started spreading from Wuhan city of Chinese Hubei province and rapidly became a global pandemic. Clinical symptoms of the disease range from paucisymptomatic disease to a much more severe disease. Typical symptoms of the initial phase include fever and cough, with possible progression to acute respiratory distress syndrome. Gastrointestinal manifestations such as diarrhoea, vomiting and abdominal pain are reported in a considerable number of affected individuals and may be due to the SARS-CoV-2 tropism for the peptidase angiotensin receptor 2. The intestinal homeostasis and microenvironment appear to play a major role in the pathogenesis of COVID-19 and in the enhancement of the systemic inflammatory responses. Long-term consequences of COVID-19 include respiratory disturbances and other disabling manifestations, such as fatigue and psychological impairment. To date, there is a paucity of data on the gastrointestinal sequelae of SARS-CoV-2 infection. Since COVID-19 can directly or indirectly affect the gut physiology in different ways, it is plausible that functional bowel diseases may occur after the recovery because of potential pathophysiological alterations (dysbiosis, disruption of the intestinal barrier, mucosal microinflammation, post-infectious states, immune dysregulation and psychological stress). In this review we speculate that COVID-19 can trigger irritable bowel syndrome and we discuss the potential mechanisms.     

Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients With COVID‐19

Conflicting evidence regarding the use of hydroxychloroquine (HCQ) and azithromycin for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection do exist. We performed a retrospective single‐center cohort study including 377 consecutive patients admitted for pneumonia related to coronavirus disease 2019 (COVID‐19). Of these, 297 were in combination treatment, 17 were on HCQ alone, and 63 did not receive either of these 2 drugs because of contraindications. The primary end point was in‐hospital death. Mean age was 71.8 ± 13.4 years and 34.2% were women. We recorded 146 deaths: 35 in no treatment, 7 in HCQ treatment group, and 102 in HCQ + azithromycin treatment group (log rank test for Kaplan–Meier curve P < 0.001). At multivariable Cox proportional hazard regression analysis, age (hazard ratio (HR) 1.057, 95% confidence interval (CI) 1.035–1.079, P < 0.001), mechanical ventilation/continuous positive airway pressure (HR 2.726, 95% CI 1.823–4.074, P < 0.001), and C reactive protein above the median (HR 2.191, 95% CI 1.479–3.246, P < 0.001) were directly associated with death, whereas use of HCQ + azithromycin (vs. no treatment; HR 0.265, 95% CI 0.171–0.412, P < 0.001) was inversely associated. In this study, we found a reduced in‐hospital mortality in patients treated with a combination of HCQ and azithromycin after adjustment for comorbidities. A large randomized trial is necessary to confirm these findings.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is spreading worldwide since December 2019 and still no proven effective therapy has been found. First therapy proposed to treat coronavirus disease 2019 (COVID‐19) has been the association of lopinavir‐ritonavir, a protease inhibitor approved for HIV infection. However, Cao et al. observed no benefit comparing lopinavir‐ritonavir treatment of hospitalized patients with severe COVID‐19, ¹ and this treatment is currently not recommended. Currently, only remdesivir has been approved for COVID‐19 treatment, as it reduced recovery time by 4 days in 1,063 patients randomized to either remdesivir 200 mg loading dose followed by 100 mg daily or placebo for up to 10 days ² with a similar rate of adverse events between the 2 groups. ³ However, no effect on in‐hospital mortality was found.Chloroquine and its derivative hydroxychloroquine (HCQ), based on few preclinical studies, have also been proposed as therapies for COVID‐19. A Chinese randomized trial in patients with mild disease showed a significantly shorter recovery time in the group treated with HCQ vs. the standard of care along with a radiological improvement. ⁴ Differently, a retrospective study performed in the United States Veterans Health Administration medical centers found an increased mortality associated with the treatment with HCQ. ⁵ Moreover, an observational study has shown no significant association between HCQ use and risk of intubation or death. ⁶ Furthermore, a recent randomized controlled trial has found no differences between patients treated with HCQ plus the standard of care vs. the standard of care alone in terms of virus elimination. ⁷ On the basis of a very small nonrandomized study, azithromycin has been proposed as possible treatment in association with HCQ. ⁸ Azithromycin, is an antibiotic belonging to the class of macrolides, with some proven efficacy in acute respiratory distress syndrome. ⁹ , ¹⁰ It is known to have immunomodulatory properties through the polarization of macrophages toward the reparative state ¹¹ and the reduction in the production of pro‐inflammatory cytokines, such as IL‐8, IL‐6, TNF alpha, ¹² and iNOS expression. ¹³ Recently, two large retrospective studies evaluating in‐hospital mortality associated with the use of the combination of HCQ and azithromycin (or another macrolide, such as clarithromycin), have shown no benefits. ¹⁴ Despite the lack of a proven clinical efficacy and some concerns regarding the possible QT prolongations caused by the association of HCQ and azithromycin, ¹⁵ given the low price and the wide availability, the association of these two drugs has become the most used treatment in patients with moderate‐severe COVID‐19.Because of the urgent need to find answers to the many questions posed by the fight to SARS‐CoV2 infection and some negative evidences regarding the use of HCQ, we here propose a retrospective observational study to assess the efficacy of the combination of HCQ plus azithromycin for hospitalized patients with medium‐severe COVID‐19.     

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (p_homogeneity = 0.42). This risk increased linearly with duration of use (p_trend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (p_homogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.     

Ocular Alterations in a Rare Case of Segmental Neurofibromatosis Type 1 with a Non-Classified Mutational Variant of the NF-1 Gene

Background: Neurofibromatosis type 1 (NF-1) is an autsomal dominant disorder which can occasionally result from somatic mosaicism and manifest as segmental forms of the disease.

Methods: A 37-year-old woman with ascertained NF-1, based on clinical diagnostic criteria and genetic analysis, was referred for ophthalmological evaluation. Genetic analysis, magnetic resonance imaging (MRI), complete ophthalmological examination, and near infrared reflectance (NIR) images at 815?nm of the retina were obtained.

Results: Genetic analysis revealed a non-classified mutational variant of the NF-1 gene identified as NM_000267.3:c2084T?>?C (p.Leu695Pro.T). MRI demonstrated non-symptomatic bilateral optic nerve gliomas. The only cutaneous sign was a subcutaneous neurofibroma of the posterior cervical region. Slit-lamp examination showed bilateral Lisch nodules. NIR images of the retina did not show any choroidal hamartomas.

Discussion: We report a rare case of segmental neurofibromatosis with a non-classified mutational variant of the NF-1 gene described in only one previous case in the literature. The patient presented with clinical features of NF-1 localized to the head and neck region, compatible with diagnosis of segmental NF-1. Interestingly, ocular manifestations included bilateral optic nerve gliomas and Lisch nodules, but no choroidal hamartomas.