1. Jade Abudia
General Medicine Journal Club 11 November2016
BACKGROUND
Background Chronic obstructivepulmonarydisease (COPD)is characterizedby chronicairflowlimitationanda range ofpathological changes in
the lungandsome significant extra-pulmonaryeffects, remaining a majorpublic healthproblem. Manytimes,commoncolds in
COPD patients result in exacerbations due to the development oflower airway inflammation. Previously studies have foundthat the
dominant strain ofhumanrhinovirus, RV14, enters the cytoplasmof infectedcells afterbindingto its receptor intercellularadhesion
molecule-1 (ICAM-1); theories suggest that destabilizationfrom receptorbindingandendosomalacidification mediate the entryof
RV14’s ribonucleic acidinto theinfectedcell’s cytoplasm. Lansoprazole is a protonpump inhibitorwhich is usedfor gastroduodenal
ulcers andgastroesophageal reflux disease; it works by inhibitingH+
-K+
ATPase in gastric parietal cells. It is also theorizedthat it
may reduce the productionof ICAM-1in mononuclearcells andgastric mucosa.
Previous trials Trial Results
Rascon-aguilar IE, Pamer
M, Wludyka P, et al. Role
of gastroesophageal reflux
symptoms in exacerbations
of COPD.
The aims of this investigationwere todetermine theprevalence of gastroesophageal reflux (GER)
symptoms in COPD patients andthe effect ofGER on the rate ofexacerbations ofCOPDper year.
The study concludedthat thepresenceof GER symptoms appears to be associatedwith increased
exacerbations ofCOPD.
Sasaki T, Yamaya M,
Yasuda H, et al. The proton
pump inhibitor lansoprazole
inhibits rhinovirus infection
in culturedhuman tracheal
epithelial cells.
To examine theeffects of lansoprazole,a protonpumpinhibitor,on rhinovirus infection in airways,
human trachealepithelial cells were infectedwith a majorsubgroup of rhinoviruses, type 14
rhinovirus. Results suggest that lansoprazoleinhibits rhinovirus infectionby reducingICAM-1via
partly endogenous productionof interleukin-1β, andby blockingthe rhinovirus RNA entryinto the
endosomes. Lansoprazolemaymodulate airwayinflammation by reducingthe productionof
cytokines andICAM-1in rhinovirus infection.
GENERAL STUDY OVERVIEW
Title/Citation A Randomized, Single-BlindStudy of Lansoprazolefor thePreventionof Exacerbations ofChronicObstructive PulmonaryDisease
in Older Patients
Sasaki T, Nakayama K, Yasuda H, et al. A randomized, single-blindstudy oflansoprazole for the preventionof exacerbations of
chronic obstructive pulmonarydisease in older patients. J Am Geriatr Soc. 2009;57(8):1453-7.
Funding Research was partly supportedby HealthandLabour Sciences ResearchGrants, Labour andWelfare andthe RespiratoryFailure
Research Group formthe Ministry ofHealth, LabourandWelfare,Japan. Grants were also receivedfromGrant-in-Aidfor Scientific
Research from the Ministry ofEducation, Science,Culture, Sports, Science andTechnology. Finally, a grant was receivedfromthe
Japanese FoundationforAgingandHealth.
Objective To investigate whether protonpumpinhibitor (PPI) therapy reduces the frequencyofcommoncolds andexacerbations in patients
with chronic obstructive pulmonary disease (COPD).
Trial design  12-month, randomized, observer-blind, controlledtrial at a universityhospital andthree city hospitals in Miyagi prefecture in
Japan conductedfromOctober2005through March 2007.
 Patients were observedfor12 months, duringwhich time the following10 symptoms were recorded: sneezing, nasal discharge,
nasal congestion,malaise,headache,chills, feverishness, sorethroat, hoarseness, andcough.
 Symptoms were ratedforseverity ona scale from 0 to 3 andwere recordedon daily recordcards.
 A daily total of the symptoms scores couldvary from0 to30.
 A common coldwas definedas a total symptom score greaterthan5.
METHODS
Inclusion criteria  Fulfilledthe criteriaof the AmericanThoracic Society ofCOPD
Exclusion criteria  Obvious bronchial asthma, bronchiectasis, or diffuse panbronchiolitis
 Patients positiveforGERD, definedas a score of 6 or greater onthe Carlsson-Dent self-administeredquestionnaire(QUEST)
Interventions Patients were randomizedtoreceive either:
 Conventional therapyforCOPD, includingbronchodilators andsmokingcessation
 Lansoprazole15 mgdaily andconventional therapy for COPD, includingbronchodilators andsmokingcessation
Follow-up Patients were observedfor12 months, duringwhich time they filledout daily recordcards in which the 10symptoms were scored.
Patients also visitedthehospital every2 weeks, where theirdoctors evaluatedtheirphysical condition. It was also recommendedthat
they visit the hospital for investigator-initiatedchecks if theirtotal symptomscore was greaterthan5.
PrimaryEndpoint The primaryhypothesis was that the occurrenceof COPD exacerbationwouldbe lower in the PPIgroup than in thecontrol group. A
COPD exacerbation was definedas an acute and sustainedworseningof COPDsymptoms requiringchanges to regular treatment,
includingantimicrobial therapy andshort courses of systemic corticosteroids.
Statistical analyses  The original power calculationdeterminedthat a sample size of 44 participants in each armwouldresult in 80% power todetect a
twofolddifference in occurrence ofCOPDexacerbations between thetwo groups usinga two-tailedalpha level of 0.05.
 Two-tailedt-tests andchi square tests were usedto compare the demographic andclinical characteristics ofthe two groups at
baseline.
 Logistic regression was usedto examine theadjustedeffects ondevelopinga common coldandan exacerbation ofCOPDof age,
sex, influenza vaccination, treatment withinhaledcorticosteroid, COPD stage, anduse of PPI. Significance was acceptedat
P<0.05.

2. This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.
Page 2 of 2
RESULTS
Enrollment Out of 103 enrolledparticipants, 100 were consideredanalyzable; 50 in each arm. 51 patients were assignedto the PPIgroup and52
to the control group; duringthe study 1 patient in the PPI group refusedto continue the study because of occasional diarrhea,1 patient
in the control groupstoppedthe study because he moved, anda secondpatient in the control group droppedout because he hadan
acute myocardial infarction1 monthafterthe study enrollment.
Baseline characteristics Of the 50 PPIgroup completers: meanage = 74.9 +/- 8.9years; 47males (94%)and3 were females (6.0%)
Of the 50 control group completers: meanage = 74.8 +/- 7.5 years; 48males (96%)and2 were females (4.0%)
All participants were of Japanese ethnicity andformersmokers.
PrimaryOutcomes  The meannumber ofcommoncolds per person for 12months was lower, but not significantlyso, in thePPIgroup thanin
the control group(1.22+/- 2.09vs 2.04+/- 3.07; P = 0.12).
 The number ofCOPD exacerbations perpersonin 12 months was significantlylower in the PPI groupthanin the control
group (0.34 +/- 0.72vs 1.18+/- 1.40; P = 0.0003).
 Use of PPI was independently andsignificantly associatedwith less risk of developingfrequent common colds (≥3 times
per year), whereas the worst stage of COPD (stage IV) was independentlyandsignificantlyassociatedwith greaterrisk of
developingfrequent common colds (adjustedodds ratio (AOR) of developingfrequent commoncolds in the PPI groupvs
the control group= 0.28,95%confidence interval (CI) = 0.08-0.99, P=0.048; AOR of developingfrequent commoncolds
in patients with Stage IVCOPD vs Stage I COPD = 43.2, 95% CI = 2.7-703.2,P=0.008).
 Use of PPI was independently andsignificantly associatedwith less risk of exacerbations of COPD,whereas agingand
worse COPD were independentlyandsignificantlyassociatedwith greater riskof exacerbationof COPD (AOR of
developingexacerbations in thePPI group vs the control group= 0.23, 95% CI = 0.08-0.62, P=0.004; AOR of developing
exacerbation for eachyear ofage = 1.1, 95%CI 1.0-1.2,P=0.02; AOR ofdevelopingexacerbations in patients withStage
III of COPD vs Stage I = 3.9, 95% CI = 1.1-14.3, P=0.04; AOR of developingexacerbations in patients with Stage IVof
COPD vs Stage I = 45.6, 95% CI = 3.0-690.3,P=0.006).
AUTHORS’ CONCLUSIONS
 The result of the study foundthat treatment with lansoprazoleconsiderably reducedthe riskof catchingfrequent commoncolds (≥3 per year) in
patients with COPD.
 The study also foundthat treatment with lansoprazole significantly reduce the riskof exacerbations in patients with COPD.
 These findings suggest that the efficiency ofPPItreatment in inhibitingexacerbations of COPDseems tobe higher than that of inhibitingcatchingthe
commoncold.
 Acidreflux is a potential trigger of cough andmay be a complicatingfactor in difficult-to-control asthma; it has been reportedthat patients with COPD
are at significantlygreater riskof GERD than those without COPD.
 Adding low-dose, long-termlansoprazole to theconventional therapies wouldhave beneficial effects on reduction ofthe frequencyof catching
commoncolds andpreventionofexacerbations in patients with COPDwithout any severe adverse effects.
GENERALIZABILITY/CRITIQUE/DISCUSSION
Patient Population Inclusion parameters were appropriate but very small in samplesize, though it was technicallysufficient in power.
The populationchosenwas limitedtoJapanese ethnicity; this limits the generalizability to otherraces andethnicities. The gender of
the participants was almost ubiquitously male; again, theapplication ofthe study results are limitedbecause of this population
characteristic.
Intervention The study design was not placebocontrolled; this limits the degree of blindingandmayresult in bias. The ratingsystem seemed
inadequate; out of a possible scoreof 30, 5 was enough tobe considereda commoncold. Such a lowthresholdcouldleadto other
causes (i.e. allergies) beingmisclassifiedas a cold. This damages the validityof theresults because it appears that more colds
occurredandwere of shorter durationorhadless effect onthe patient’s COPD; in actuality, it mayhave not beena coldbut rather
allergic rhinitis.
Endpoints The study didnot explicitlystate endpoints but rathera primaryhypothesis. Without a statedendpoint, however, the durationof the
study anddefinitionof a commoncoldas a score ≥ 3 appeararbitrary withno empirical reasoning. It wouldhave benefitedthestudy
to explainwhy ≥ 3 points was definedas a coldwhen therewere 30 possible points.
Statistics The study was sufficientlypoweredto80%;appropriate statistical tests were usedfor both nominal andordinal data. Thestudy stated
that the worst stage ofCOPDwas independently andsignificantly associatedwith greaterrisk of developingfrequent commoncolds,
however theCI was very wide (2.7-703.2); wide confidence intervals mean that the sample size was too small to drawthis conclusion
with any precision. Number-needed-to-treat calculationyieldeda result of 2 patients; thus forevery 2 people withCOPD that you
treat with standardCOPD treatment inadditiontolansoprazole 15mg/day,youwill prevent an exacerbationin 1 ofthose patients
during a 12 month period.
PRESENTER’S CONCLUSIONS
Trial hadseveral limitations, includingno explicit endpoints, subjectivesymptom-ratingsystem,commoncolddefinedwith no empirical rationalization, and small
sample size. While results were encouraging, their best application would be to spur further, more-developed, larger studies.
STRENGTHS WEAKNESSES
 Appropriate statistical tests were performed
 Outside fundingwas limitedto educational grants,decreasingthelikelihood of
ulterior motivationtowarda set outcome
 LowNNT to see desiredoutcome
 Novel area of researchthat has great potential due to the scarcityof current data
available
 Duration oftrial was longenough toallowfor meaningful results
 Arbitrary definitionofcommoncold
 Bias: patient/clinicianbias couldbe present because of lackplacebo use
 Scoringsystem usedto define a commoncoldwere arbitraryandsubjective
based on patient’s tolerability ofeachsymptom
 Little tonopatient heterogenicityleavingresults tobe applicable to a narrow
population base
 Small sample size
APPLICATION TO CLINICAL PRACTICE
In the treatment ofChronic Obstructive PulmonaryDisease, add-onof lansoprazole 15mgdaily may prove to be beneficial forreductionof exacerbations in this patient
population. Furtherstudies in this area are warrantedboth due to inclusivityof current literature andencouragingpreliminaryfindings. Because lansoprazole should
not be used long-term without a definitive indication, I would not recommend adding on a PPI without further indications at this time.