1. Oral Immunotherapy With Inactivated Nontypeable Haemophilus influenzae Reduces Severity of Acute Exacerbations in Severe COPD Maharaj Kishore Tandon, MD ; Martin Phillips, MBBS ; Grant Waterer, MD, PhD, MBBS, FCCP ; Margaret Dunkley, PhD ; Phillip Comans, PhD ; and Robert Clancy, PhD, MBBS CHEST 2010; 137(4):805– 811 R1 Chihyeok Oh, M.D.

2. Introduction COPD –major cause of morbidity and mortality –New management strategies are needed to reduce the human and economic costs of this disease –The underlying pathology of COPD an inflammatory process due at least in part to bacterial colonization of the bronchus mucosa, which has been damaged by inhalation of toxic material Acute exacerbations of COPD –intense intrabronchial inflammation –inappropriate excessive inflammatory response to colonizing bacteria, precipitated by an intercurrent virus infection –recurrent exacerbations worsening of air-flow obstruction and health status OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

3. Host containment of colonizing bacteria –control of neutrophil activation and recruitment into the bronchus lumen by T lymphocytes generated from the gut-associated lymphoid tissue –Immunotherapy the oral administration of nontypeable Haemophilus influenzae (NTHi), which stimulates specific T lymphocytes within Peyer patches →traffic to the bronchus mucosa where they recruit and activate phagocytes, which reduce the load of colonizing bacteria →significant 3 log reduction in colonization with NTHi

4. Materials and Methods multicenter, double-blind, placebo-controlled trial –Clinical Research Organization (Novotech Pty Ltd) Hollywood Private Hospital, Perth, WA (M. K. T.) Sir Charles Gairdner Hospital, Perth, WA (M. P.) Royal Perth Hospital, Perth, WA (G. W.) the University of Newcastle, Newcastle, NSW (R. C.), Australia The study tested the efficacy of HI-164OV in reducing the number and severity of acute episodes (defined as increase in volume and purulence of sputum) in subjects with two or more episodes per year for 2 consecutive years with severe COPD. HI-164OV tablets that contained 45 mg of formalin-inactivated NTHi, provided as enteric-coated tablets, or enteric-coated placebo tablets At all visits acute episodes and their characteristics were documented with the aid of a respiratory questionnaire Sputum and pharyngeal swabs –were collected to monitor bacterial colonization, blood samples –were collected to monitor antibodies (serum and saliva IgG and IgA anti-NTHi outer membrane protein antibody by enzyme-linked immunosorbent assay)and for safety parameters OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

5. Major variables 1.the number of exacerbations 2.the proportion experiencing one or more exacerbations 3.the mean duration of exacerbations 4.the number of antibiotic courses prescribed for exacerbations. The secondary variables –immune markers –pharyngeal and sputum bacteriology –severity of acute episodes (including hospitalization), and safety parameters.

6. The requirement of repeated episodes over consecutive previous years proved a major impediment to recruitment, with a total of 38 complying with admission criteria being enrolled. No significant differences in demographics between the active and placebo groups were found. Bronchiectasis was also present in two subjects in the active group and four subjects in the placebo group. All subjects were stable at the onset of study. The percentage of 16% never-smokers is similar to other studies. Background therapy included broncho-active drugs; in particular, all subjects took regular inhaled beta–agonist therapy, with 84% taking an inhaled corticosteroid.

7. Results - Number of Acute Exacerbations there were 22 episodes in the active group compared with 29 episodes in the placebo group (event rate/subject 1.22 and 1.45, respectively), with a risk ratio of 0.83 (95% CI, 0.47, 1.46), which was not significant(NS). The absolute numbers for, respectively, placebo and active groups –no exacerbations, seven and five –one exacerbation, two and seven –two exacerbations, six and four –three exacerbations, five and one –four exacerbations, zero and one. With analysis by 3-month periods, the event rate/100 days was the same in both groups at 0.82 for the first 3 months, but reduced in the active group compared with placebo in the remaining months (0.6 vs 0.85), which represented a 29% reduction in incidence (NS). An additional analysis using more current definitions that incorporate a therapeutic decision showed for antibiotic-treated episodes there was a 28% level of protection (NS), whereas protection in corticosteroid-treated episodes was 63% ( P=.05). g OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

8. Results - Proportion With Acute Exacerbations The proportion with any acute exacerbation defined as an increase in volume and purulence of sputum was unchanged with immunotherapy. Additional more appropriate analyses –for corticosteroid-treated exacerbations, there was a 56% reduction in the proportion with acute exacerbations ( P=.07) with treatment –for all episodes the proportion with recurrent exacerbations was less in the treated group(0.33/subject compared with 0.55/subject, a 40%reduction [NS]). OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

9. Results - Duration of Episodes The mean duration of episodes was less in active compared with placebo groups (14.3 compared with 22.7 days; P=.01). The range in duration of episodes was similar in active and placebo groups. OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

10. Results - Prescribed Courses of Antibiotics A significant reduction in the number of prescribed courses of antibiotics following active treatment was noted (56%; P=.03). Additional analysis –a significant reduction in the total number of days of antibiotic usage (72%; P=.01) and in the number of subjects receiving three or more courses of antibiotics during the course of the study (80%;P=.01). OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

11. Results - Admission to Hospital The rate of hospital admission for exacerbation of COPD was high, with 11 admissions in seven patients in the placebo group (20 subjects) reflecting the greater severity of disease in those with frequent exacerbations. Protection against admission to hospital due to an exacerbation of COPD was 90%, which was significant ( P=.04). A significant difference in hospitalization for all causes was detected ( P<.05) with 75% protection. It is unclear if any additional protection occurred for other than an acute exacerbation. OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

12. Results - Bacteriology Specimens of sputum collected at regular visits following the onset of the study were valid. The overall positive cultures were twice as high in the placebo group( P=.05); reduced numbers of positive cultures in the active group applied to all pathogens. the lower level of positive cultures in the active group is a direct outcome of immunotherapy. The detection rate of NTHi in pharyngeal washings was similar in both groups, reflecting environmental exposure (active: 17 positive cultures in 4 subjects; placebo: 22 positive cultures in 8 subjects). OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

13. Results - Anti-NTHi Antibody A small increase in serum IgG anti-NTHi antibody following active treatment was significant (in enzyme-linked immunosorbent assay units: 0.15log 10, P=.004). A similar increase in saliva was not significant. There was no significant difference in serum or saliva IgA anti-NTHi antibody levels. OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae Results - Adverse Effects OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae No significant difference in incidence in adverse effects was noted between the active and placebo groups, except for the incidence of hospitalization judged as a severe adverse event. Four of the reported mild-to-moderate adverse events were considered to be possibly related to treatment (one in HI-164OV group with gastroenteritis; three in placebo group: rash, hot flush, nausea). One subject died (placebo group; from an acute exacerbation of COPD).

14. Immunotherapy with a novel NTHi isolate –safe and significant efficacy in subjects with severe COPD and recurrent acute exacerbations –reduction in level of severity of exacerbations (with episodes of shorter duration that required less antibiotic therapy and fewer admissions to hospital) –A reduction in incidence and recurrence of exacerbations was short of statistical significance –the protocol definition of an increase in volume and purulence of sputum A reduction in incidence and recurrence of exacerbations –short of statistical significance –The protocol definition of corticosteroid-treated acute exacerbations a reduction in frequency and recurrence –borderline statistical significance Discussion OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

15. Acute exacerbations of COPD –key events in the natural history of COPD –particular targets for intervention therapy –potentially life-threatening and associated with significant reductions in quality of life, faster rates of decline in FEV 1, and substantial economic costs. –Using a classic definition of acute episodes (ie, an increase in volume and purulence of sputum) –16% fewer episodes in actively treated subjects were recorded 1.85% of subjects used combination inhaled corticosteroid/beta-agonist therapy –by its own action of reducing the incidence of acute episodes, makes more difficult detection of any additional benefit 2.the higher event rate in the active group in the first months of the study with 29% reduction in the second 3 months –suggests a delayed benefit due to the time taken to activate mucosal protection

16. 3.those with frequent infections have more intense and continuous intra-bronchial inflammation –over the winter period, making complete abolition of episodes more difficult 4.preferential reduction in incidence of more severe episodes –defined as requiring corticosteroid treatment –a 63% reduction in number of episodes –a 56% reduction in the proportion with exacerbations the dominant effect of immunotherapy is to reduce the severity of episodes This is further supported by the findings of shorter episodes requiring less antibiotic therapy following treatment.

17. HI-164OV offers a clinical benefit to subjects with severe COPD –reducing the number and severity of acute exacerbations –through its impact on immunologic networks the results of this study show a potential to improve health and reduce the economic burden of acute exacerbations in COPD. Conclusion OralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzaeReducesSeverityofAcuteExacerbationsinSevereCOPDOralImmunotherapyWithInactivatedNontypeableHaemophilusinfluenzae

18. Current therapy has limited value –a significant reduction in moderate-to-severe exacerbations (defined as requiring corticosteroid therapy) of about 40%, –less clear reduction of severe exacerbations (defined as reduction in hospital admission) recorded at 0 and 17%, respectively –the incidence of antibiotic-treated episodes increased in the treated groups infection linked to long-term inhalation of corticosteroids?? –the current study population was small and only included those with recurrent exacerbations significant protection against severe exacerbations requiring admission to hospital