Dupilumab as a steroid-sparing treatment option in pediatric severe asthma and chronic rhinosinusitis with nasal polyps

Case report Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent comorbidity in severe asthma in adults. Both diseases share key pathophysiological mechanisms that can involve type-2 inflammatory pathways. However, this is an uncommon presentation in pediatric patients. Dupilumab, a fully human monoclonal antibody against IL-4Ralpha, inhibits IL-4/ IL-13 signaling, which are key drivers of type-2 inflammation and interfere with both eosinophilic and allergic pathways. It is approved for patients >= 12-year- old with moderate to severe uncontrolled asthma, but its approval in CRSwNP is limited to adults. We report a case of a 12-year- old boy with severe uncontrolled asthma and highly symptomatic CRSwNP referred to our center in May 2021. He was sensitized to house dust mite and pollens, and a specific immunotherapy had been tried previously. He was treated with high dose inhaled corticosteroid, long-acting beta agonist, long-acting muscarinic antagonist, montelukast and daily intra-nasal corticosteroids. Furthermore, a bilateral endoscopic sinus surgery with polypectomy was performed in April 2021. Despite adherence to medication and surgical treatment, both diseases were uncontrolled with frequent exacerbations requiring unscheduled visits and multiple systemic corticosteroid courses. This led to failure to thrive and several missed school days. Oral corticosteroid (OCS) tapering was unachieved due to symptoms rebound and so maintenance therapy with prednisolone 10mg daily was attempted, with only a slight improvement. High levels of eosinophils (1010 cells/muL), FeNO (122 ppb) and IgE (2255 kU/L) were present. Treatment with subcutaneous dupilumab was started in July 2021. A clinical and analytical improvement was evident at the 3-month evaluation (Table 1). He was able to stop prednisolone, and no clinically relevant exacerbations occurred. He also was fully vaccinated and had an asymptomatic COVID-19 infection in December 2021. Patients with CRSwNP and comorbid asthma have a higher disease burden than patients with each disease alone. In this adolescent, dupilumab was effective as an add-on treatment, for both severe asthma and CRSwNP. It led to disease control, OCS withdrawal, reduced eosinophilic inflammation, improved lung function, smell recovery and absence of exacerbations during follow-up. Dupilumab, targeting the type 2 inflammatory process, may allow a better management of pediatric patients >=12 years old with severe CRSwNP and comorbid asthma. (Table Presented).

Sublingual allergen immunotherapy: Safety, adherence, efficacy in adolescents during COVID-19 pandemic

Background: Allergic rhinitis, one of the most common chronic allergic diseases, commonly associated with asthma, has a disease modifying therapy, allergen-specific immunotherapy (AIT). AIT can play a significant role in the reduction of clinical and immunological reaction to the culprit allergen, decreasing the onset of new sensitizations, preventing the onset of asthma, and reducing use of pharmacological treatments. This latter aspect is highly relevant for adolescents, a category of patients that frequently prefer to use "as few drugs as possible". AIT continuation may be difficult in some situations, such as the COVID-19 pandemic. Difficulty in accessing hospitals was experienced by many leading to a discontinuation of therapies for chronic conditions, such as allergic rhinitis. Method(s): We report our experience on the management, safety and adherence to sublingual immunotherapy (SLIT) prescribed to 25 adolescents affected by allergic rhinitis (house dust mite (HDM) -8 patients, SLIT grass pollen -12 patients, SLIT parietaria -5 patients), during the COVID-19 pandemic, following EAACI recommendations. The first administration of SLIT was carried out under medical supervision. We used a personalized monitoring approach according to the type of SLIT prescribed and according to the needs presented by each patient, advising them how to recognize and manage a possible reaction. Result(s): No immediate severe adverse reactions were reported by patients. Between the 2nd and 5th day of SLIT, 4 patients in therapy with HDM SLIT, experienced an exacerbation of rhinitis symptoms, with resolution after the use of oral antihistamine and topical cortisone+antihistamine before taking the daily dose of SLIT (for 30 days). Two patients on grass pollen SLIT and 2 patients on HDM SLIT, with gastric upset after taking SLIT daily while fasting, presented a resolution of the symptom after we advised them to take the daily dose in the morning after breakfast. Five patients interrupted SLIT for COVID-19 infection, until complete resolution. To date, all 25 patients are continuing SLIT, with good tolerability, with an improvement of rhinitis symptoms. Conclusion(s): We have reported real-life SLIT adherence and safety in adolescents that started SLIT during the COVID-19 pandemic to confirm how SLIT is a winning strategy and the only modifying treatment for allergic conditions.

Duodenal Stricture as a Rare, Possible Complication of Eosinophilic Gastrointestinal Disease (Egid)

EGID is a recently described condition with an unknown etiology and pathogenesis. There are three case reports of duodenal stricture associated with EGID: one in an adult requiring pancreaticoduodenectomy due to the suspicion of malignancy and 2 cases in a child and a young adult, who responded to oral steroids. We report the case of a 10-year-old who presented to A&E with a 9-month history of epigastric abdominal pain and 1 episode of haematemesis, on a background of asthma. He was treated for Helicobacter pylori, based on a positive stool antigen. Abdominal pain and vomiting persisted, therefore an oesophago-gastro-duodenoscopy (OGD) was performed. This identified widespread white plaques throughout the oesophagus, erythema and nodularity of the gastric antrum and white nodules in the first part of the duodenum. Histology revealed changes of EGID and eosinophilic oesophagitis (EOE) and patient was commenced on Montelukast, oral viscous Budesonide (OVB), Cetirizine and continued proton pump inhibitor (PPI). After the allergy workup identified house dust mites, cat sensitisation and fish allergy, a 6-food elimination diet was initiated. During the next 2 years, symptoms subsided, and endoscopy changes improved, with only mild signs of active EOE while on OVB, PPI and diary/egg/fish free diet. However, the patient relapsed due to poor compliance to treatment. He became more unwell during the Covid pandemic with recurrent vomiting and static weight. A trial of dupilumab was considered, however his reassessment OGD had to be delayed due to restricted access to theatre. He was treated empirically with a reducing course of oral prednisolone, with temporary response. The endoscopic assessment performed subsequently showed erythema, erosions and white plaques in the distal oesophagus and gastric antrum with narrowing between the first and the second part of the duodenum (D2), that could not be entered. Histology identified mild upper oesophagitis (4 eosinophils (eos)/HPF), active middle and lower oesophagitis (20 eos/HPF and 12 eos/HPF, respectively), chronic gastritis (80 eos/HPF) and nonspecific reactive changes of the proximal duodenum. A barium meal confirmed a duodenal stricture. At this stage, we recommended a sloppy diet and a second weaning course of oral prednisolone, along with Montelukast. He was subsequently commenced on azathioprine for maintenance of remission. A repeat barium study and small bowel MRI performed post course of steroids and on azathioprine revealed stable appearances of the proximal duodenal stricture, excluding the presence of further strictures. While the patient has responded to the course of oral steroids and azathioprine, a repeat upper GI endoscopy is currently planned to dilate the duodenal stricture. The challenges posed by this case were the rarity of the condition, limited treatment options and access to endoscopy during the Covid pandemic and the fact that unlike previous case reports a sustained remission could not be obtained on steroids, and a maintenance immunosuppressive medication was required. We can conclude that this subgroup of patients should be monitored closely for signs of bowel obstruction and will require more intense treatment, including immunomodulators, endoscopic dilatation and or surgery.

ASTHMA, AIRWAY INFLAMMATION AND PTSD ASSOCIATION: RELEVANT MODELS AND A ROLE OF IL17A

Background: There is a growing interest in airway inflammation and mental health. Recent genetic and epidemiological evidence supports an association between PTSD and asthma however, contributory immune mediators/mechanisms are unclear. Recent work from our group employs mouse aeroallergen, house dust mite (HDM) models to examine the role of severe asthma linked inflammatory T helper cells, Th17 and interleukin 17 (IL-17A) in regulating PTSD-relevant behaviors. Methods: A combination of behavioral, immunological, transgenic and transcriptomic approaches were used. 1) BALBc-C5a receptor treatment that shifts Th2 mild asthma phenotype to Th17/IL17a expansion and robust airway inflammation;2) IL-17a receptor knockout mice and 3) RNAseq transcriptomics of cortical and blood brain barrier compromised area, subfornical organ (SFO) tissue was performed. Fear conditioning and extinction was assessed as a PTSD-relevant behavior. Results: Induction of Th17/IL-17 in the BALBc/anti-C5aR1 treated mice resulted in compromised fear extinction and increased fear reinstatement. Absence of IL-17 signaling in IL17Ra deficient mice attenuated HDM effects on fear extinction. Preliminary evidence suggests a potential of the SFO in translating HDM effects to the medial prefrontal cortex, an area regulating fear extinction. Transcriptomic analyses revealed modulation of immune T cell-targeted signaling pathways within the SFO in mice with Th17A expansion. Conclusion: Overall, our work provides novel insights on mechanisms by which mediators of severe airway inflammation, Th17/IL17A regulate fear memory of relevance to PTSD. Beyond asthma-PTSD, our findings have relevant implications for other pulmonary (e.g. COVID-19) and autoimmune inflammatory conditions and mental health.

LUNG ACE2 AND TMPRSS2 GENE EXPRESSION VARIES WITH ALLERGEN EXPOSURES IN MURINE MODELS OF ASTHMA

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2) for cell entry. Prior studies have reported that allergen exposure can downregulate ACE2 expression. Here, we sought to determine if exposure to distinct combinations of allergens results in the differential expression of ACE2 and TMPRSS2 in the mouse lung. Methods: We utilized three established murine models of asthma: 1. Alum/Ovalbumin (OVA) model;2. House dust mite (HDM)/OVA model;3. Mixed-allergen (MA) model using OVA, HDM, Aspergillus fumigatus and Alternaria alternata. Phosphate-buffered saline (PBS) treated mice were used as controls. Lung RNA was extracted using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s protocol, and complementary DNA was synthesized. Quantitative PCR (qPCR) was performed 24 hours after the last challenge utilizing validated primers for ACE2 and TMPRSS2. Analysis was performed using one-way ANOVA. Results: Here we report that ACE2 mRNA expression was lower in the MA and Alum/OVA-treated mice compared to the controls (p-value < 0.0001). No difference was seen in the ACE2 mRNA expression between HDM/OVA and PBS-treated mice. Furthermore, HDM/OVA-treated mice expressed higher levels of TMPRSS2 mRNA compared to controls (p-value < 0.01). No difference was seen in the TMPRSS2 mRNA expression between the MA or Alum/OVA, and the PBS-treated mice. Conclusion: The exposure to distinct combinations of allergens results in unique patterns of ACE2 and TMPRSS2 gene expression in the mouse lung. Further studies are required to evaluate the effects of allergen exposure with the susceptibility to SARS-CoV-2 infection.

Asthma and PTSD association: relevant models and a role of IL17AA

Background: Strong genetic and epidemiological evidence supports an asthma-PTSD association, however, contributory immune mediators/mechanisms are unclear. Here, we examined a direct role of severe asthma associated Th17/ IL-17A in regulating PTSD-relevant behaviors using mouse aeroallergen house dust mite (HDM) models. Methods: 3 strategies were used: 1) BALBc-C5a receptor treatment that shifts Th2 mild asthma phenotype to Th17/IL17a expansion;2) IL-17a receptor knockout mice and 3) sufficiency testing with intracerebroventricular (ICV) administration of recombinant IL17a effects on behavior. Fear conditioning and extinction, maze exploration and social behaviors were assessed. Results: Absence of IL-17 signaling attenuated HDM effects on fear extinction while induction of Th17/IL-17 in the BALBc/anti-C5aR1 treated mice resulted in compromised fear extinction. ICV IL-17a promoted an anxiogenic phenotype and impaired social behaviors. Preliminary evidence suggests a role of cortical mechanisms (under investigation). Conclusion: Overall, our work highlights severe asthma inflammatory mediator IL17a in regulating PTSD-relevant behaviors. Beyond asthma-PTSD, our findings have relevant implications for other pulmonary (e.g. COVID-19) and autoimmune inflammatory conditions and PTSD risk.

Terrific improvement of refractory atopic dermatitis with benralizumab (anti-IL5 receptor) therapy

In 2012 a 25-year-old man presented to our outpatient clinic for severe atopic dermatitis (AD) and severe allergic eosinophilic asthma in polisensitivity (house dust mite, cat, gramineous plants, birch, milk protein and, in particular, Alternaria). His clinical history was also characterized by gastro-esophageal reflux disease and chronic rhinitis without polyposis, with septal deviation and turbinate hypertrophy, worthy of surgical intervention. History taking revealed egg and cow milk protein allergy and severe asthma since the first months of life, with frequent hospital admissions due to exacerbations. AD was severe and diffuse, involving especially face, neck, back and superior limbs, often complicated by impetigo. The esthetic, social and psychological impact led him to quit his job as a barman. At presentation, the Eczema Area and Severity Index (EASI) score was 72/72. Laboratory tests showed eosinophilic count ranging between 1.060 and 2.140/mm3, and high serum levels of total Immunoglobulin E (5.939 kUI/L). Tryptase levels were normal and autoantibody analysis was negative. Parasite stool examination was negative. Nasal swab tested positive for Staphylococcus aureus, which was treated with Sulfamethoxazole-Trimethoprim. Asthma Control Test was 15/25, pulmonary function tests (PFTs) showed mild obstruction (FEV1 4.43 L, 103%, FEV1/FVC 69%), with positive bronchodilator testing (FEV1 5.12 L, + 670 mL, + 16%). Firstly, he was treated with topical steroids and sometimes with oral corticosteroids, with poor response. Then, in July 2019, he initiated therapy with cyclosporine 3-5 mg/kg. Soon, the drug had to be discontinued due to adverse effects (gastrointestinal symptoms and infections). In November 2019, at the age of 32 years, he started therapy with monoclonal antibody anti-IL-5 receptor alpha (benralizumab 30 mg 1 subcutaneous vial every 4 weeks for the first three administrations and then every 8 weeks), with a terrific clinical improvement of AD since the first administrations and with benefit on asthma control (ACT after the first administration increased up to 25/25;PFTs could not be performed, due to SARS-CoV-2 pandemic). This therapy has always been well tolerated. The eosinophilic count decreased to 0/mm3 after the first administration. At the moment, after one year of therapy, AD is almost fully disappeared (EASI SCORE 4/72), despite being in free diet, and the quality of life of the patient has definitely improved.