Title PageYELLOW NAIL SYNDROME: a case reportIntroductionYellow Nail Syndrome (YNS) is a rare disorder characterised by the triad of yellow and thickened nails, respiratory manifestations and lower limbs lymphedema. Two out of three clinical characteristics are required to diagnosis [1]. Less than 400 cases are described in literature with a prevalence of < 1/1.000.000. The diagnosis is clinical, particularly based on nail abnormalities, pulmonary manifestations, lymphedema and sinusitis. YNS is a condition of unknown aetiology, usually sporadic or presenting as a paraneoplastic syndrome, associated with cancer. To date there is not a specific treatment for YNS [1]. Resolution has been observed in up to 30% of patients, either spontaneously, or after cancer treatments in case of a paraneoplastic condition [1]. Herein we present a paraneoplastic case of YNS in a 67-years old never-smoker female, complaining chronic productive purulent cough for the last two years, after diagnosis of breast cancer.Key Clinical MessageYellow nail syndrome is a rare disorder affecting multiple districts. The diagnosis is clinical, based on nail abnormalities, pulmonary manifestations and lymphedema.The aetiology is unknown, usually presenting spontaneously or as a paraneoplastic syndrome.There is not an established treatment, while resolution is scarce.Case ReportCase History . A 67-years old never-smoker female was referred to a Respiratory outpatient clinic complaining productive purulent cough for the last two years despite treatments with mucolytic and antitussive. Two years before, following a diagnosis of left ductal mucinous breast cancer (G2 pT1No), she underwent quadrant surgery and local radiotherapy. Since then in remission and currently receiving hormonal therapy with anastrozole. She has a history of atrial fibrillation treated with warfarin and she refers otitis and sinusitis of recent onset (3 months). The high resolution thoracic CT scan highlighted bronchiectasis in the lower right inferior bronchus with mucus plugs. Spirometry was performed in stable conditions showing mild obstruction. A short course of oral clarithromycin was not effective in reducing respiratory symptoms. The thoracic CT scan performed after 6 months showed a parenchymal consolidation (organising pneumonia) in the lower right lobe (Fig 1A). She was then referred to our Outpatient clinic.Methods . She reported that during the last year her nails turned yellow, thicker and frail with slowed growth of both finger and toenails (Fig. 1B). Onychomycosis was excluded by a Dermatologic evaluation and Wood’s lamp test. No history of lower limb lymphedema was reported. Due to persistent respiratory symptoms resistant to antibiotic therapy a bronchoscopy was performed showing purulent material dripping from the nasal districts and mucous-purulent secretions in the lower right bronchus, in the absence of sign of malignancy. Based on xantonychia, bronchiectasis and sinusitis a diagnosis of yellow nail syndrome was performed.Conclusion and Results . A short course of azithromycin was started although the bronchoscopy culture resulted negative, with partial remission of the productive cough. The patient was subsequently chronically treated with low dose azithromycin (500 mg twice/week), a cycling combination of N-Acetyl-L-Cysteine + Lactoferrin + Resveratrol; cycling oral Vitamin E and inhaled umeclidinium. After six-months the patients referred remission of the chronic productive cough, otitis and sinusitis; the yellow nails condition remained unchanged. She is continuing the regular oncologist follow up, still in remission.DiscussionYellow Nail Syndrome (YNS) - OMIM 153300; ORPHA662 - is a rare disorder characterised by the triad of yellow and thickened nails, respiratory manifestations and primary lymphedema [1]. Two out of three clinical characteristics are required to diagnose YNS [1]. First described in 1927, the current definition dates back to 1966 [2]. There are less than 400 cases described in literature with a prevalence < 1/1.000.000. YNS is a condition of unknown aetiology, usually sporadic and affecting adults over 50 years worldwide, with no gender predominance [1] The completed triad is present only in 27-60% of cases, with nail chromonychia being the main clinical manifestation, as shown in Table 1. The diagnosis is clinical, particularly based on nail abnormalities, pulmonary manifestations, lymphedema and sinusitis. Chromonychia (nail discoloration), together with xantonychia (yellow nail coloration), progressive thickening and hardening of the nail plate and a slow growth (reduced by half), are the main characteristics of the YNS [1]. Respiratory manifestations occur in 60-70% of patients, with chronic cough as the most frequent symptom [3, 4]. Pleural effusion presents in up to 46% of cases, usually bilateral with a lattescent appearance (chylothorax); bronchiectasis in 44% [1, 4]. Both chronic and acute rhinosinusitis are common, presenting in 14-83% of cases with daily mucopurulent rhinorrhea and nasal obstruction [1]. Lower limbs lymphedema is present in 29-80% of cases, usually bilateral [1]. A lymphatic disorder with defective lymphatic drainage has been hypothesised as a possible cause of lymphedema, pleural effusion and subungual tissue sclerosis with nail alterations [1]. Another hypothesis considers microvasculopathy and protein leakage [3, 5]. YNS may present as a paraneoplastic syndrome, associated with malignant diseases, such as lung and breast cancer or non-Hodgkin lymphoma [1]. The paraneoplastic presentation could be due to lymphatic micro-obstruction, possibly correlated with circulating tumour microemboli [6], or due to cancer histopathology. Other diseases described associated with YNS are autoimmune and immunodeficiency [1]. Differential diagnosis is broad and involves: asbestos-related disease, heart failure, connective tissue diseases, malignancies and onychomycosis are the main ones [4]. To date there is not a specific treatment for YNS. Resolution has been observed in up to 30% of patients, either spontaneously, or after cancer treatments in case of a paraneoplastic condition [1]. Oral α-tocopherol (vitamin E) at 1000-1200 IU/day, is considered the only partially effective agent nail alterations [1]. Regular antifungal treatment (itraconazole or fluconazole) and oral zinc sulphate were also tried, with scarce evidence [1]. A randomised study using topic vitamin E preparation showed no difference versus placebo [7]. Acute exacerbations of bronchiectasis and sinusitis can be treated with antibiotics and symptomatic drugs, whereas for recurrent flares up or poor symptom control, low dose oral azithromycin (250 mg 3 times/week), and a physiotherapy program should be prescribed. Flu and pneumococcal vaccinations are recommended [1]. Surgical intervention for recurrent or large pleural effusions can be useful, while somatostatin analogues as octreotide for chylothorax can be tried [1]. Complete decongestive therapy is an option for lymphedema volume reduction [1].

Background: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins 4/13, key and central drivers of type 2 inflammation. The LIBERTY ASTHMA TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who had participated in a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Methods: This analysis includes patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose inhaled corticosteroids (ICS) at parent study baseline (PSBL) and enrolled in TRAVERSE. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (pre-BD) FEV 1 (L), asthma control (5-item asthma control questionnaire), and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Results: Of patients with type 2 asthma (n=1,666) in this analysis, 891 (53.5%) were receiving high‑dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab vs placebo were 0.517 vs. 1.883 (phase 2b) and 0.571 vs. 1.300 (QUEST) over 52 weeks of the parent study, and remained low throughout TRAVERSE (0.313–0.494). Improvements in pre-BD FEV 1 from PSBL were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Conclusions: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

To the Editor Since the end of February 2020 Italy, first non- Asian Country, has reported an ever increasing number of COronaVIrus Disease 19 (COVID-19) patients, which has reached over 200,000 confirmed Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected subjects and resulted in more than 34000 deaths (data updated to June 19th, 20201).Patients with asthma are potentially more severely affected by by SARS-CoV-2 infection 2 and it is well established that respiratory viral infections are associated with severe adverse outcomes in patients with asthma, including increased risk of asthma exacerbation episodes 3. Nonetheless, according to the epidemiological studies published so far, chronic pulmonary diseases are not amongst the most common clinical conditions in COVID-19 patients4About 5-10% of entire asthma population, are severe asthmatics5 and one would expect increased vulnerability to SARS-CoV-2 infection, but no data is so fare available ti confirm this hypothesis.We investigated the incidence of COVID-19, describing its clinical course, in the population of the Severe Asthma Network in Italy (SANI), one of the largest registry for severe asthma worldwide6, and in an additional Center (Azienda Ospedaliero Univeristaria di Ferrara, Ferrara, Italy). All centers, have been contacted and inquired to report confirmed (i.e. patients with positive test result for the virus SARS-CoV-2 from analysis of nasopharyngeal or oropharyngeal swab specimens) or highly suspect cases of COVID-19 (i.e. patients with symptoms, laboratory findings and lung imaging typical of COVID-19 but without access to nasopharyngeal or oropharyngeal swab specimens because of clinical contingencies/emergency) among their cohorts of severe asthma. Demographic and clinical data of the entire cohort of severe asthmatics enrolled in the study and all reported cases of confirmed or suspect cases of COVID-19, have been obtained from the registry platform and collected from the additional Center. Additional data about COVID-19 symptoms, treatment and clinical course have been collected for all cases reported.Ethical issues and statistical analysis are reported in the online supplementary material.Twenty-six (1.73%) out of 1504 severe asthmatics had confirmed (11 out of 26) or highly suspect COVID-19 (15 out 26); eighteen (69.2%) were females and mean age was 56.2 ± 10 years. The geographical distribution of COVID-19 cases is presented in Figure 1.Nine (34.6%) infected patients experienced worsening of asthma during the COVID-19 symptomatic period; four of them needed a short course of oral corticosteroids for controlling asthma exacerbation symptoms.The most frequent COVID-19 symptoms reported were fever (100% of patients), malaise (84.6%), cough (80.8%), dyspnea (80.8%), headache (42.3%) and loss of smell (42.3%). Four patients (15.3%) have been hospitalized, one of which in intensive care unit; among hospitalized patients, two (7.7%) died for COVID-19 interstitial pneumonia. No deaths have been reported among the non-hospitalized patients.Severe asthmatics affected by COVID-19, had a significantly higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) compared to non-infected severe asthma patients (15.4% vs 3.8%, p=0.002; odds ratio: 4.7). No difference was found in other comorbidities (including rhinitis, chronic rhinosinusitis with or without nasal polyps, bronchiectasis, obesity, gastroesophageal reflux, arterial hypertension, cardiovascular diseases).Twenty-one patients with COVID-19 were on biological treatments: 15 (71%) were on anti-IL-5 or anti-IL5R agents (Mepolizumab n= 13; Benralizumab n=2 - counting for the 2.9% of all severe asthmatics treated with anti-IL5 in our study population) and 6 (29%) were on anti IgE (Omalizumab - 1.3% of all severe asthmatics treated with omalizumab in our study population).Table I summarizes demographic and clinical characteristics of the 26 COVID-19 patients.In conclusion, in our large cohort of severe asthmatics, COVID-19 was infrequent, not supporting the concept of asthma as a particularly susceptible condition to SARS-COV2 infection 2. This is in line with the first published large epidemiological data on COVID-19 patients, in which asthma is under-reported as comorbidity4. The COVID-19 related mortality rate in our cohort of patients was 7.7%, lower than the COVID-19 mortality rate in the general population (14.5% in Italy 1). These findings suggest that severe asthmatics are not at high risk of the SARS-CoV-2 infection and of severe forms of COVID-19. There are potentially different reasons for this. Self-containment is the first, because of the awareness of virus infections acting as a trigger for exacerbations, and therefore they could have acted with greater caution, scrupulously respecting social distancing, lockdown and hygiene rules of prevention, and being more careful in regularly taking asthma medications.Another possible explanation stands in the intrinsic features of type-2 inflammation, that characterizes a great proportion of severe asthmatics. Respiratory allergies and controlled allergen exposures are associated with significant reduction in angiotensin-converting enzyme 2 (ACE2) expression 7, the cellular receptor for SARS-CoV-2. Interestingly, ACE2 and Transmembrane Serine Protease 2 (TMPRSS2) (another protein mediating SARS-CoV-2 cell entry) have been found highly expressed in asthmatics with concomitant NIDDM8, the only comorbidity that was more frequent reported in our COVID-19 severe asthmatics.The third possible explanation refers to the possibility that inhaled corticosteroids (ICS) might prevent or mitigate the development of Coronaviruses infections. By definition, patients with severe asthma are treated with high doses of ICS 5 and this may have had a protective effect for SARS-CoV-2 infection.Noteworthy, among the patients of our case-series of severe asthmatics with COVID-19, the proportion of those treated anti-IL5 biologics was higher (71%) compared to the number of patients treated with anti-IgE (29%). Although the number of cases is too small to draw any conclusion, it is tempting to speculate that different biological treatments can have specific and different impact on antiviral immune response. In addition we may speculate of the consequence of blood eosinophils reduction: eosinopenia has been reported in 52-90% of COVID-19 patients worldwide and it has been suggested as a risk factor for more severe COVID-19 9.In conclusion, in our large cohort of severe asthmatics only a small minority experienced symptoms consistent with COVID-19, and these patients had peculiar clinical features including high prevalence of NIDDM as comorbidity. Further real-life registry-based studies are needed to confirm our findings and to extend the evidence that severe asthmatics are at low risk of developing COVID-19.

BACKGROUND: COronaVIrus Disease 19 (COVID-19) pandemic is affecting almost the entire world since February 2020. Patients with chronic pulmonary diseases, such as asthma and chronic obstructive lung disease potentially and theoretically may be more vulnerable and therefore seriously ill if infected by SARS-CoV-2; however, according to the first epidemiological studies published so far, chronic pulmonary diseases are under-reported. No data is available, so far, about the incidence of COVID-19 in severe asthmatics and about which are the COVID-19 outcomes in this subgroup of patients. METHODS:: In this study, we investigated the incidence of COVID-19 cases in a large population of severe asthmatics in Italy, describing their clinical characteristics and clinical course of COVID-19 disease. RESULTS: Twenty-six (1.73%) out of 1504 severe asthmatics were identified as confirmed or highly suspect with COVID-19. Nine (34.6%) of infected patients experienced worsening of asthma during the COVID-19 symptomatic period. Severe asthmatics affected by COVID-19, compared to those who did not contracted the infection, had a significantly higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) (15.4% vs 3.8%, p=0.002); among COVID-19 patients the proportion of those treated anti-IL5 biologic agents was higher (71%) compared to the number of patients treated with anti-IgE (29%). CONCLUSIONS: In our large cohort of severe asthmatics, the incidence of COVID-19 was particularly low, with higher prevalence of NIDDM as comorbidity, suggesting that NIDDM might be a risk factor for COVID-19 in severe asthmatics.