Michelle Towers

Reduced soluble receptor for advanced glycation end-products in COPD

The soluble receptor for advanced glycation end-products (sRAGE) has anti-inflammatory properties, and deficiency of circulating sRAGE is associated with various human diseases. Whether sRAGE concentrations are reduced in chronic obstructive pulmonary disease (COPD) has not been determined. The aim of this study was to determine plasma levels of sRAGE in COPD patients and establish whether sRAGE varies in relation to forced expiratory volume in 1 s (FEV1) and other inflammatory markers. 61 COPD patients and 42 healthy controls were recruited. Plasma sRAGE, C-reactive protein (CRP) and serum amyloid A (SAA) were measured in patients with stable COPD. A subgroup had measurements during acute exacerbations of COPD (AECOPD). sRAGE was significantly lower in stable COPD than in healthy controls (p<0.001), while CRP (p<0.001) and SAA (p = 0.015) were higher in stable COPD than in healthy controls. Multiple linear regression confirmed that COPD was negatively associated with sRAGE (p<0.001). Plasma sRAGE was positively correlated with FEV1 (r2 = 0.530, p<0.001), while CRP and SAA were inversely proportional to FEV1. Multiple linear regression analysis showed that only sRAGE was a strong predictor of FEV1. AECOPD were associated with even lower sRAGE levels that increased with convalescence. Circulating sRAGE is lower in COPD and shows a strong correlation to the degree of airflow limitation.

Budesonide and formoterol reduce early innate anti-viral immune responses in vitro.

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.

Subtropical grass pollen allergens are important for allergic respiratory diseases in subtropical regions

BackgroundGrass pollen allergens are a major cause of allergic respiratory disease but traditionally prescribing practice for grass pollen allergen-specific immunotherapy has favoured pollen extracts of temperate grasses. Here we aim to compare allergy to subtropical and temperate grass pollens in patients with allergic rhinitis from a subtropical region of Australia.MethodsSensitization to pollen extracts of the subtropical Bahia grass (Paspalum notatum), Johnson grass (Sorghum halepense) and Bermuda grass (Cynodon dactylon) as well as the temperate Ryegrass (Lolium perenne) were measured by skin prick in 233 subjects from Brisbane. Grass pollen-specific IgE reactivity was tested by ELISA and cross-inhibition ELISA.ResultsPatients with grass pollen allergy from a subtropical region showed higher skin prick diameters with subtropical Bahia grass and Bermuda grass pollens than with Johnson grass and Ryegrass pollens. IgE reactivity was higher with pollen of Bahia grass than Bermuda grass, Johnson grass and Ryegrass. Patients showed asymmetric cross-inhibition of IgE reactivity with subtropical grass pollens that was not blocked by temperate grass pollen allergens indicating the presence of species-specific IgE binding sites of subtropical grass pollen allergens that are not represented in temperate grass pollens.ConclusionsSubtropical grass pollens are more important allergen sources than temperate grass pollens for patients from a subtropical region. Targeting allergen-specific immunotherapy to subtropical grass pollen allergens in patients with allergic rhinitis in subtropical regions could improve treatment efficacy thereby reducing the burden of allergic rhinitis and asthma.

Reduced rhinovirus-specific antibodies are associated with acute exacerbations of chronic obstructive pulmonary disease requiring hospitalisation

BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are often linked to respiratory infections. However, it is unknown if COPD patients who experience frequent exacerbations have impaired humoral immunity. The aim of this study was to determine if antibodies specific for common respiratory pathogens are associated with AECOPD.MethodsPlasma was obtained from COPD patients when clinically stable. AECOPD requiring hospitalisation were recorded. IgG1 antibodies to H. Influenzae outer membrane protein 6 (P6), pneumococcal surface protein C (PspC) and the VP1 viral capsid protein of rhinovirus were measured.ResultsCOPD patients who had an AECOPD (n = 32) had significantly lower anti-VP1 IgG1 antibody levels when stable compared to COPD patients who did not have an AECOPD (n = 28, p = 0.024). Furthermore, the number of hospitalisations was inversely proportional to anti-VP1 antibody levels (r = −0.331, p = 0.011). In contrast, antibodies specific for P6 and PspC were present at similar concentrations between groups. Plasma IL-21, a cytokine important for B-cell development and antibody synthesis, was also lower in COPD patients who had an AECOPD, than in stable COPD patients (p = 0.046).ConclusionDeficient humoral immunity specific for rhinoviruses is associated with AECOPD requiring hospitalisation, and may partly explain why some COPD patients have an increased exacerbation risk following respiratory viral infections.

Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease

Background and objective Individuals with chronic obstructive pulmonary disease (COPD) are at a high risk of developing significant complications from infection with the influenza virus. It is therefore vital to ensure that prophylaxis with the influenza vaccine is effective in COPD. The aim of this study was to assess the immunogenicity of the 2010 trivalent influenza vaccine in persons with COPD compared to healthy subjects without lung disease, and to examine clinical factors associated with the serological response to the vaccine. Methods In this observational study, 34 subjects (20 COPD, 14 healthy) received the 2010 influenza vaccine. Antibody titers at baseline and 28 days post-vaccination were measured using the hemagglutination inhibition assay (HAI) assay. Primary endpoints included seroconversion (≥4-fold increase in antibody titers from baseline) and the fold increase in antibody titer after vaccination. Results Persons with COPD mounted a significantly lower humoral immune response to the influenza vaccine compared to healthy participants. Seroconversion occurred in 90% of healthy participants, but only in 43% of COPD patients (P=0.036). Increasing age and previous influenza vaccination were associated with lower antibody responses. Antibody titers did not vary significantly with cigarette smoking, presence of other comorbid diseases, or COPD severity. Conclusion The humoral immune response to the 2010 influenza vaccine was lower in persons with COPD compared to non-COPD controls. The antibody response also declined with increasing age and in those with a history of prior vaccination.

Evaluation of immune responses to influenza vaccination in chronic obstructive pulmonary disease

Background: Given that viral infections are common triggers for exacerbations of Chronic Obstructive Pulmonary Disease (COPD), current clinical guidelines recommend that all patients receive annual influenza vaccinations. A detailed examination of the immune response to vaccination in COPD has not previously been undertaken, so this study aimed to compare immune responses to influenza vaccination between COPD patients and healthy subjects. Methods: Twenty one COPD patients and fourteen healthy subjects were recruited and cellular immune function was assessed pre- and post- vaccination with trivalent inactivated influenza vaccine. Results: One month after vaccination, H1N1 specific antibody titres were significantly lower in COPD patients than in healthy controls (p=0.02). Multivariate analysis demonstrated that post vaccination antibody titres were independently associated with COPD, but not with age or smoking status. Innate immune responses to the vaccine preparation did not differ between the two populations. Serum concentrations of IL-21, a cytokine that is important for B cell development and antibody synthesis, were also lower in COPD patients than in healthy subjects (p<0.01). In vitro functional differences were also observed, with fewer proliferating B cells expressing CD27 (p=0.04) and reduced T-cell IFN-γ synthesis (p<0.01) in COPD patients, relative to healthy subjects. Conclusions: In conclusion, COPD was associated with altered immune responses to influenza vaccination compared to healthy controls with reductions in both T-cell and B-cell function. These findings provide a foundation for future research aimed at optimising the effectiveness of influenza vaccination in COPD.

Impaired immune response to influenza vaccination in chronic obstructive pulmonary disease

Idiopathic orbital myositis is a rare sporadic eye disease associated with extraocular eye muscle infl ammation. We report 3 new Australian cases of familial orbital myositis (FOM). The children extend one of only two reported families with FOM, and confi rm autosomal dominant inheritance. Cases: A girl aged 14, presented with ptosis, proptosis and diplopia in all positions of gaze except primary position. CT scan of orbits demonstrated swelling of her right medial and superior rectus muscles, consistent with orbital myositis. She was initially treated with oral prednisolone but has followed a refractory course with multiple relapses and bilateral involvement, requiring methotrexate as a steroid sparing agent. Her brother presented aged 11 with diplopia and a lateral gaze palsy of his right eye, with CT confi rming lateral rectus involvement. He responded to corticosteroids and has remained in remission for several years. A second cousin of the children, a boy, also presented with orbital myositis in childhood and has demonstrated a refractory course, again requiring initiation of a steroid sparing agent. Four cases of FOM in this family were originally reported in 1999, including the children’s mothers who both presented with orbital myositis in their teens. Both women have gone into remission in adult life. Conclusion: The family presented here is informative regarding severity, age of onset and prognosis of FOM. The idiopathic form of orbital myositis rarely presents before adulthood, whereas all 7 cases of FOM in this family presented in childhood. This indicates an earlier onset of disease in FOM. The sporadic form of orbital myositis usually follows a benign course, particularly in children, whereas two of these patients have required a steroid sparing agent, suggesting that FOM may be more aggressive than the sporadic form. Finally, the history of remission for their mothers may indicate a relatively benign long-term prognosis. P25 A CASE OF RECURRENT FEVERS Anthony Griffi ths, Karuna Keat Department of Clinical Immunology and Allergy, Campbelltown Hospital, Campbelltown, NSW 2560 University of Western Sydney Email: zzagriff@hotmail.com Introduction: We present the case of a 2 year 8 month old girl who presented to the paediatric clinical immunology clinic with multiple presentations of recurrent fever, pharyngitis, and lymphadenopathy. Case Presentation: MR was 2 years old at fi rst presentation. She was born full term, in an uncomplicated pregnancy and was breast fed for 6 months. From 6 months, she had multiple presentations to the Emergency Department and her GP with fevers up to 39°C, typically lasting 5 days, sometimes with accompanying tonsillitis, and bilateral axillary and cervical lymphadenopathy. The fevers usually responded to paracetamol or ibuprofen. She was well between episodes. She had normal developmental milestones. Both her parents were from Australia and of Caucasian ancestry. There was no symptoms of autoimmune disease. Infl ammatory markers were elevated during a few of these episodes. Blood, urine, and throat cultures and nasopharyngeal aspirates were repeatedly sterile. She was investigated for underlying autoinfl ammatory, autoimmune and immune defi ciency. Conclusion: This is a case of a young girl with recurrent fevers. Her results and differential diagnosis will be discussed. P26 A REVIEW OF THE EXPANDED SPECIALIST TRAINING PROGRAM IN ITS FIRST YEAR OF IMPLEMENTATION IN ADELAIDE Rory Hannah, Tahir Chaudry, Anthony Smith, William Smith, Frank Kette, Robert Heddle Clinical Immunology Unit, Royal Adelaide Hospital, Adelaide, Australia, Wesley private hospital, Brisbane, Australia, Respiratory, Allergy and Sleep Services, Flinders Medical Centre, Adelaide, Australia, Human Immunology, SA Pathology, Adelaide, Australia, Private Rooms, Email: rcshannah@hotmail.com In 2010 Adelaide put their fi rst advanced trainee through the Expanded Specialist Training Program (ESTP). This is a federally funded program with the stated aim enabling medical specialist trainees to undertake training rotations in an expanded range of settings outside traditional public teaching hospitals. This involves funding a trainee to attend clinics in areas including private rooms. The process of implementation was arduous but not insurmountable and the result was a federally funded advanced training position an addition to the traditional places available in Adelaide. This position is suitable for a trainee in their last year of training and provided a different experience and different patient mix to the Royal Adelaide Hospital job while still providing adequate breadth of patients and supervision for training. We illustrate our experience both in the implementation of the program and the experience of the supervisors and trainees with a view to aiding other centres whom may be considering the program. P27 A CONTROLLED STUDY OF DELTA-INULIN ADJUVANT IN HONEY BEE VENOM IMMUNOTHERAPY Rory Hannah, Nikolai Petrovsky, Anthony Smith, Robert Heddle Clinical Immunology Unit, Royal Adelaide Hospital, Adelaide, Australia, Endocrinology and Vaxxine Pty Ltd, Flinders Medical Centre and Flinders University, Adelaide, Australia, Respiratory, Allergy and Sleep Services, Flinders Medical Centre, Adelaide, Australia, Human Immunology, SA Pathology, Adelaide, Australia, Immunology, Flinders University, Adelaide, Australia, Email: rcshannah@hotmail. com Introduction: Honey bee (HB) venom (HBV) immunotherapy (HBVIT) reduces the frequency of immediate generalised allergic reactions (IGR) to subsequent sting by only about 80% and induces same in many subjects. Inulin has been used safely and extensively by intra-venous injection to study renal clearance and in studies involving infl uenza and hepatitis B vaccines has shown antigen sparing properties without evidence of activation of danger signal responses. In an ongoing, clinically double-blinded, study we have followed serological responses to HBVIT with and without inulin adjuvant. Methods: 23 subjects with a history of IGR to HB sting and specifi c IgE to HB venom have been randomised 2:1 to receive HBVIT by semi-rush regime with (group A) or without (group B) GMP inulin mixed with venom. Assays for HBV specifi c IgE (sIgE) used CAP system and for IgG and IgG4 (sIgG and sIgG4), ELISA assay. Results: Clinicians remain blinded. 2 subjects have withdrawn for personal reasons. There has been one IGR and one late systemic reaction to immunotherapy, both mild. The striking difference has been in sIgG4 responses to HBV. Both groups showed peak responses at 14 weeks (early maintenance HBVIT), group A at mean 33 units (SEM 6.2), group B at 13 units (SEM 4.9) and these levels were well maintained in both. The response was far earlier in group A with mean 19 units (SEM 6.1) at 5 weeks following maximum dose 25 mcg HBV vs 3.5 (SEM 1.8) Group B. Similar but less pronounced trends were seen with sIgG responses. sIgE responses show a wide scatter but peak rise from baseline was less in group A (144% vs 231%) and return to baseline earlier (month 3 vs month 9). Conclusions: With the caveat that only surrogate markers have yet been analysed, inulin appears to enhance wanted responses to HBVIT. ASCIA 2011 Poster Abstract

A Nurse-Led Omalizumab Clinic: the Princess Alexandra Hospital Experience

Despite the prevalence of acute cough in children (<2 weeks duration), the burden to parents and families is largely unknown. The objectives of this study were to determine the parental burden of children’s acute cough, and to evaluate psychological and other infl uences on the reported burden of acute cough in children. Methods Parents of children with a current acute cough (<2 weeks) at enrolment completed 4 questionnaires (state trait anxiety inventory (STAI); short form health survey (SF-8); depression, anxiety and stress 21-item scale (DASS21); and our preliminary 48-item parent acute cough specifi c quality of life (PAC-QOL48) questionnaire). In PAC-QOL48, lower scores refl ect worse QOL. Results Median age of the 104 children enrolled was 2.63 (IQR 1.42, 4.79) years, 54 were boys. Median length of cough at enrolment was 3 (IQR 2, 5) days. Median total PAC-QOL48 score of parents enrolled at presentation to the emergency department (n = 70) was signifi cantly worse than of parents enrolled through the community (n = 24) (p < 0.01). More than half (n = 55) had sought medical assistance more than once for the current acute coughing illness. PAC-QOL48 score was signifi cantly negatively correlated to verbal category descriptive and visual analogue scale cough scores (Spearman r = −0.26, p = 0.05 and r = −0.46, p = 0.01 respectively) and DASS21 total score (r = −0.36, p = 0.01), but not to child’s age. Conclusions Consistent with data on chronic cough, stress was the predominant factor of parental burden. This study highlights the ongoing need for clinicians to be cognizant of parental worries and concerns when their children are coughing, and for further research into safe and effective therapies for acute cough in children.

B cell responses to areoalllergens in patient with allergic disease

Idiopathic orbital myositis is a rare sporadic eye disease associated with extraocular eye muscle infl ammation. We report 3 new Australian cases of familial orbital myositis (FOM). The children extend one of only two reported families with FOM, and confi rm autosomal dominant inheritance. Cases: A girl aged 14, presented with ptosis, proptosis and diplopia in all positions of gaze except primary position. CT scan of orbits demonstrated swelling of her right medial and superior rectus muscles, consistent with orbital myositis. She was initially treated with oral prednisolone but has followed a refractory course with multiple relapses and bilateral involvement, requiring methotrexate as a steroid sparing agent. Her brother presented aged 11 with diplopia and a lateral gaze palsy of his right eye, with CT confi rming lateral rectus involvement. He responded to corticosteroids and has remained in remission for several years. A second cousin of the children, a boy, also presented with orbital myositis in childhood and has demonstrated a refractory course, again requiring initiation of a steroid sparing agent. Four cases of FOM in this family were originally reported in 1999, including the children’s mothers who both presented with orbital myositis in their teens. Both women have gone into remission in adult life. Conclusion: The family presented here is informative regarding severity, age of onset and prognosis of FOM. The idiopathic form of orbital myositis rarely presents before adulthood, whereas all 7 cases of FOM in this family presented in childhood. This indicates an earlier onset of disease in FOM. The sporadic form of orbital myositis usually follows a benign course, particularly in children, whereas two of these patients have required a steroid sparing agent, suggesting that FOM may be more aggressive than the sporadic form. Finally, the history of remission for their mothers may indicate a relatively benign long-term prognosis. P25 A CASE OF RECURRENT FEVERS Anthony Griffi ths, Karuna Keat Department of Clinical Immunology and Allergy, Campbelltown Hospital, Campbelltown, NSW 2560 University of Western Sydney Email: zzagriff@hotmail.com Introduction: We present the case of a 2 year 8 month old girl who presented to the paediatric clinical immunology clinic with multiple presentations of recurrent fever, pharyngitis, and lymphadenopathy. Case Presentation: MR was 2 years old at fi rst presentation. She was born full term, in an uncomplicated pregnancy and was breast fed for 6 months. From 6 months, she had multiple presentations to the Emergency Department and her GP with fevers up to 39°C, typically lasting 5 days, sometimes with accompanying tonsillitis, and bilateral axillary and cervical lymphadenopathy. The fevers usually responded to paracetamol or ibuprofen. She was well between episodes. She had normal developmental milestones. Both her parents were from Australia and of Caucasian ancestry. There was no symptoms of autoimmune disease. Infl ammatory markers were elevated during a few of these episodes. Blood, urine, and throat cultures and nasopharyngeal aspirates were repeatedly sterile. She was investigated for underlying autoinfl ammatory, autoimmune and immune defi ciency. Conclusion: This is a case of a young girl with recurrent fevers. Her results and differential diagnosis will be discussed. P26 A REVIEW OF THE EXPANDED SPECIALIST TRAINING PROGRAM IN ITS FIRST YEAR OF IMPLEMENTATION IN ADELAIDE Rory Hannah, Tahir Chaudry, Anthony Smith, William Smith, Frank Kette, Robert Heddle Clinical Immunology Unit, Royal Adelaide Hospital, Adelaide, Australia, Wesley private hospital, Brisbane, Australia, Respiratory, Allergy and Sleep Services, Flinders Medical Centre, Adelaide, Australia, Human Immunology, SA Pathology, Adelaide, Australia, Private Rooms, Email: rcshannah@hotmail.com In 2010 Adelaide put their fi rst advanced trainee through the Expanded Specialist Training Program (ESTP). This is a federally funded program with the stated aim enabling medical specialist trainees to undertake training rotations in an expanded range of settings outside traditional public teaching hospitals. This involves funding a trainee to attend clinics in areas including private rooms. The process of implementation was arduous but not insurmountable and the result was a federally funded advanced training position an addition to the traditional places available in Adelaide. This position is suitable for a trainee in their last year of training and provided a different experience and different patient mix to the Royal Adelaide Hospital job while still providing adequate breadth of patients and supervision for training. We illustrate our experience both in the implementation of the program and the experience of the supervisors and trainees with a view to aiding other centres whom may be considering the program. P27 A CONTROLLED STUDY OF DELTA-INULIN ADJUVANT IN HONEY BEE VENOM IMMUNOTHERAPY Rory Hannah, Nikolai Petrovsky, Anthony Smith, Robert Heddle Clinical Immunology Unit, Royal Adelaide Hospital, Adelaide, Australia, Endocrinology and Vaxxine Pty Ltd, Flinders Medical Centre and Flinders University, Adelaide, Australia, Respiratory, Allergy and Sleep Services, Flinders Medical Centre, Adelaide, Australia, Human Immunology, SA Pathology, Adelaide, Australia, Immunology, Flinders University, Adelaide, Australia, Email: rcshannah@hotmail. com Introduction: Honey bee (HB) venom (HBV) immunotherapy (HBVIT) reduces the frequency of immediate generalised allergic reactions (IGR) to subsequent sting by only about 80% and induces same in many subjects. Inulin has been used safely and extensively by intra-venous injection to study renal clearance and in studies involving infl uenza and hepatitis B vaccines has shown antigen sparing properties without evidence of activation of danger signal responses. In an ongoing, clinically double-blinded, study we have followed serological responses to HBVIT with and without inulin adjuvant. Methods: 23 subjects with a history of IGR to HB sting and specifi c IgE to HB venom have been randomised 2:1 to receive HBVIT by semi-rush regime with (group A) or without (group B) GMP inulin mixed with venom. Assays for HBV specifi c IgE (sIgE) used CAP system and for IgG and IgG4 (sIgG and sIgG4), ELISA assay. Results: Clinicians remain blinded. 2 subjects have withdrawn for personal reasons. There has been one IGR and one late systemic reaction to immunotherapy, both mild. The striking difference has been in sIgG4 responses to HBV. Both groups showed peak responses at 14 weeks (early maintenance HBVIT), group A at mean 33 units (SEM 6.2), group B at 13 units (SEM 4.9) and these levels were well maintained in both. The response was far earlier in group A with mean 19 units (SEM 6.1) at 5 weeks following maximum dose 25 mcg HBV vs 3.5 (SEM 1.8) Group B. Similar but less pronounced trends were seen with sIgG responses. sIgE responses show a wide scatter but peak rise from baseline was less in group A (144% vs 231%) and return to baseline earlier (month 3 vs month 9). Conclusions: With the caveat that only surrogate markers have yet been analysed, inulin appears to enhance wanted responses to HBVIT. ASCIA 2011 Poster Abstract