Background: Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen ( Phleum pratense and Dactylis glomerata) administered via either the subcutaneous or sublingual route. Methods: A randomized, double-blind, placebo-controlled trial with a double-dummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed. Results: Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required. Conclusions: Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL.

To the Editor:COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 of the genus Betacoronavirus (SARS-CoV-2). It was first described in Wuhan (China) on December 2019 and has spread to become a pandemic. Its clinical presentation is mainly characterized by cough, fever and dyspnea, although many other symptoms have been described within its presentation pattern. In some cases, it causes an acute respiratory distress that has lead to the death of thousands of people around the world. Furthermore, different type of skin lesions have been described during the infection period of illness due to SARS-CoV-2.1 The first report of cutaneous manifestations described different forms of skin lesions such as erythematous rash, urticaria and chicken-pox-like vesicles.2 In this exceptional situation of global health emergency, physicians are undertaking research work in order to achieve notions on the etiopathogenesis of these skin lesions. Acro-ischaemic lesions have also been notified and attributed to disseminated intravascular coagulation and to the expression of secondary microthrombosis due to endotelial damage.3-5However, to date, there is no clear understanding on whether the skin lesions are secondary to the viral infection nor why there are different presentations of skin lesions for the same viral infection.We present 4 patients with COVID-19, confirmed by positive polymerase chain reaction, who were referred to our service due to the appearance of skin lesions. Two of them developed skin lesions during hospitalization whilst presenting respiratory symptoms and the other two developed skin lesions many days after hospital discharge. Demographic data, description and histology of skin lesions, blood parameters, clinical symptoms and drugs administered are shown in table I. The algorithm of the spanish pharmacovigilance system (ASPS), which evaluates the possible implication of a drug reaction as a cause of the skin lesions6 was also applied. The ASPS analizes: i) the interval between drug administration and the aparition of skin lesions, ii) the degree of knowledge of the relationship between the drug and the effect described in literature, iii) the evaluation of drug withdrawal, iv) the rechallenge effect, and v) alternative causes. Each item receives and individual subscore, and a total sum ≥ 6 indicates a probable causality.6As mentioned above, skin lesions appear to be a sign within patients suffering from COVID-19. To date, no hypothesis has been proposed to explain if the lesions (including the different types) are attributable to the virus, to drug adverse reactions or to any other clinical condition. In our series, small enough to draw conclusions, we have found no differences between the multiple types of skin lesions and analytical or clinical features. Even in lesions with apparent vascular involvement, which have been associated with alterations in coagulation,3-5 the values detected do not differ from those with other types of skin lesions. Regarding drug involvement, since all the patients were exposed to multiple drugs at the same time, the ASPS was not able to differentiate the possibility of drug implication nor the immune mechanisms involved. Thus, further assays with selective (in vitro or in vivo ) tests for each drug seem necessary in order to completely rule out drug involvement. In addition, since many patients worldwide are being infected with SARS-Cov-2, and many of them present similar medical history and receive the same treatments, it seems necessary to investigate the existence of an individual predisposition that facilitates the developement of skin lesions. In this new scenario that we are facing in these last months, providing light on these still unresolved questions, can contribute to prevent or to manage the symptoms in an early way.