SLEEP RESP

YEAR IN REVIEW

Year in review 2014: Interstitial lung disease, physiology, sleepand ventilation, acute respiratory distress syndrome, cystic

fibrosis, bronchiectasis and rare lung disease

TOBY M. MAHER,1,2 AMANDA PIPER,3,4 YUANLIN SONG,5 MARCOS I. RESTREPO6 AND NEIL D. EVES7

1National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton Hospital, and 2FibrosisResearch Group, Centre for Leukocyte Biology, National Heart Lung Institute, Imperial College, London, UK, and 3Department

of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, and 4Circadian Group, Woolcock Institute of MedicalResearch, University of Sydney, Sydney, New South Wales, Australia, 5Department of Pulmonary Medicine, Zhongshan Hos-pital, and Qingpu Branch, Fudan University, Shanghai, China, 6South Texas Veterans Health Care System, University of TexasHealth Science Center, San Antonio, Texas, USA, and 7Centre for Heart, Lung and Vascular Health, School of Health and Exer-cise Sciences, Faculty of Health and Social Development, University of British Columbia, Kelowna, British Columbia, Canada

Key words: acute respiratory distress syndrome, bronchiecta-sis, interstitial lung disease, lung function, obstructive sleepapnoea.

Abbreviations: BAL, bronchoalveolar lavage; BWAP, Burns WeanAssessment Program; CHF, chronic heart failure; CPAP, continu-ous positive airway pressure; CPEx, cardiopulmonary exercise;CPFE, combined emphysema and pulmonary fibrosis; CSA,central sleep apnoea; CT, computed tomography; CTD, connec-tive tissue disease; CXCL8, interleukin-8; FEV1, forced expiredvolume in 1 s; HCT, hypoxic challenge test; IgE, serum immuno-globulin E; ILD, interstitial lung disease; IPF, idiopathic pulmonaryfibrosis; iVAPS, intelligent volume assured pressure support; LCQ,Leicester Cough Questionnaire; LPS, lipopolysaccharide; MMP,matrix metalloproteinase; MSC, mesenchymal stromal cell;NCFB, non-cystic fibrosis bronchiectasis; NE, neutrophil elastase;NIPPV, non-invasive positive pressure ventilation; NIV, non-invasive ventilation; OHS, obesity hypoventilation syndrome;OSA, obstructive sleep apnoea; PAH, pulmonary artery hyperten-sion; PCD, primary ciliary dyskinesia; PDF, phosphodiesterase;PH, pulmonary hypertension; QoL, quality of life; RA-ILD, rheuma-toid arthritis-associated interstitial lung disease; RCT, randomizedcontrolled trial; SCC, Sputum Colour Chart; SGRQ, St George’sRespiratory Questionnaire; TLC, total lung capacity; TNF-α,tumour necrosis factor-α; VA, alveolar volume.

INTERSTITIAL LUNG DISEASE

Toby M. Maher

2014 was a seminal year for interstitial lung disease(ILD) with the announcement of three positive phase

III clinical trials assessing treatments for the mostdevastating of the ILDs, idiopathic pulmonary fibrosis(IPF).1,2 Both pirfenidone and nintedanib were shownto be effective in slowing the progression of IPF withthe consequence that both drugs have now beenapproved by the Federal Drugs Administration in theUnited States. While nintedanib is only now startingto be prescribed for patients, pirfenidone has beenlicensed in Europe since 2011 and Japan since 2008.3

With these new treatments, real-world experience ofprescribing together with long-term safety studieswill be important in defining the true costs and ben-efits of these first effective anti-fibrotic drugs. Withthis in mind, Valeyre et al. published an informativeanalysis of all patients treated to date in the CAPAC-ITY studies4 and the open-label, rollover RECAPstudies.5 This cohort included 789 subjects with amedian pirfenidone exposure of 2.6 years (range 7days to 7.7 years) and a cumulative exposure of 2059patient-years. The adverse events noted mirroredthose seen in shorter clinical trials with upper gastro-intestinal disturbance and photosensitive rash pre-dominating. Minor derangement of liver functiontests was observed in 2.7% of the study population.Reassuringly, no hitherto unrecognized, rare adverseevents were identified in this study population.

The advent of effective therapies for IPF, a diseasethat had until recently been considered by many to beuntreatable, has led to a considerable increase inclinical trial activity targeted at identifying novelapproaches to inhibiting fibroproliferation.6 Cham-bers et al. reported a phase 1b trial of placenta-derived mesenchymal stromal cells (MSC) in IPF.7

Eight subjects received escalating doses of MSCadministered via a peripheral vein. In general, thetreatment was well-tolerated and appeared to be safe.The study was not powered to determine efficacy, butat 6 months all subjects remained alive with stabledisease. As noted by Glassberg and Toonkel in theaccompanying editorial, the study raises at least asmany questions as it answers but it has, at least, paved

Correspondence: Toby M Maher, Fibrosis Research Group,Centre for Leukocyte Biology, National Heart Lung Institute, SirAlexander Fleming Building, Imperial College, London,SW7 2AZ, UK. Email: [email protected]

Conflict of Interest Statement: T.M.M. has received industry-academic funding from GlaxoSmithKline R&D, UCB and Novartisand has received consultancy or speakers fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla,GlaxoSmithKline R&D, Lanthio, InterMune, ProMetic, Roche,Sanofi-Aventis, Takeda and UCB.

Received 5 March 2015; accepted 6 March 2015.Article first published online: 30 March 2015

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© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 834–845doi: 10.1111/resp.12532

mailto:[email protected]

the way for larger and longer efficacy trials.8 ILD otherthan IPF are frequently characterized by progressive,life-threatening fibrosis. In contrast to IPF,9 many ofthese other ILDs are characterized by chronic inflam-mation or immune dysregulation, and it is this thatappears to drive the development of fibrosis.10 Assuch, the mainstay of treatment for conditions suchas connective tissue disease (CTD) associated ILD orchronic hypersensitivity pneumonitis is immunosup-pression. Following on from a smaller study,11 Keiret al. reported the potential beneficial effects of theanti-CD20 antibody, rituximab.12 Although a retro-spective report based on the open-label, clinical useof rituximab in a broad range of disorders, the resultsof treatment were sufficiently encouraging to supportthe funding and initiation of a double-blind clinicalcomparison of rituximab and cyclophosphamide asfirst-line treatment for CTD-ILD (NCT 01862926).

Another important aspect of treating progressivefibrotic ILD is managing disease complications; one ofthe most serious of which is pulmonary hypertension(PH). In IPF, the phosphodiesterase (PDF)-5 inhibitorsildenafil,13 but not the endothelin receptor antagonistbosentan,14 appears to be effective in alleviating thesymptoms of PH. Zimmermann et al., in a small studyof 10 patients with before and after cardiac catheterdata, were able to demonstrate that PDE-5 inhibitorsimprove pulmonary haemodynamics in individualswith ILD associated PH.15

Diagnosing and staging ILD

The advent of high-resolution computed tomography(CT) scanning and the introduction, at the turn of thiscentury, of international consensus diagnostic guide-lines were important factors leading to improvedclinical understanding of the natural history of manyof the ILD.16 However, improved collaborationbetween dedicated ILD centres continues to result inthe recognition of new disease entities (such aspleuroparenchymal fibroelastosis17) and has led to abetter appreciation of the clinical associationbetween chronic lung diseases such as emphysemaand progressive fibrosis. Whether combined emphy-sema and pulmonary fibrosis (CPFE) constitutes anovel disease syndrome remains hotly contested.However, as described by Sugino et al., the combina-tion of both emphysema and fibrosis confers a muchworse prognosis than either entity alone.18 In future,real-world registry data, such as that which will begenerated by the Australian IPF Registry, may helpanswer important questions about the nature ofCPFE, the occurrence of other disease complicationsand changes in survival following the introduction ofanti-fibrotic therapy.19

Despite the central role played by CT in the diagno-sis of ILD, there is sufficient diagnostic uncertainty towarrant some form of lung biopsy in upwards of 20%of patients. While an important diagnostic modality,surgical lung biopsy, even when undertakenlaparoscopically, carries an appreciable risk of mor-bidity and mortality. Cryobiopsy of lung parenchymahas recently been developed as a technique to try andobviate the need for surgical biopsy. The procedure,

undertaken bronchoscopically, entails freezing lungtissue with an ultra-low temperature cryoprobebefore removing a core of tissue with dedicatedbiopsy forceps. Cryobiopsy samples are significantlybigger than those obtained by trans-bronchial biopsy.Fruchter et al., in a study of 75 patients, were able todemonstrate that cryobiopsy can be safely under-taken in patients with ILD and was sufficient toenable a reliable diagnosis in at least 70% of sub-jects.20 In a separate study, Pajares et al. undertook arandomized assessment of cryobiopsy comparedwith transbronchial biopsy in patients with a range ofILD.21 Diagnostic yield was significantly better (74.4%compared with 34.1%, P < 0.001) in the cryobiopsygroup without any major increase in adverse events.Further studies are required to define the exact placeof cryobiopsy in the ILD diagnostic algorithm; none-theless, it can be hoped that the procedure may, in thefuture, prevent some patients from needing toundergo surgical lung biopsy.22,23

ILD comorbidities

While the impact of IPF has been increasingly recog-nized over the last decade, the importance of ILD andpulmonary fibrosis in other diseases is frequentlyoverlooked.24 Assayag et al. undertook a systematicreview of previous reports of rheumatoid arthritis-associated ILD (RA-ILD).25 They found that RA-ILDwas universally associated with a poor prognosis witha median survival from diagnosis ranging from 3.2–8.1 years. Predictors of mortality included malegender, age, extent of fibrosis and presence of a usualinterstitial pneumonia pattern. ILD, of whatevercause, is not only frequently life shortening, butimportantly it leads to significant curtailment ofphysical activity with consequent impairment ofquality of life (QoL). In separate studies, Holland et al.and de Boer et al. demonstrated a clear associationbetween dyspnoea and anxiety and depression inILD26 and health-related QoL and psychologicalfactors in sarcoidosis.27 Better recognition of the linkbetween dyspnoea and psychological morbidity canonly lead to improved delivery of care for both thesegroups of patients.28

Dyspnoea in ILD most commonly arises due to dif-fusion block associated with expansion of the inter-stitial space by either fibrosis or inflammation.However, in advanced disease the onset of PH (eitherdue to ablation of the vascular bed or in some subjectsdue to chronic hypoxia) inevitably exacerbates dysp-noea and further curtails exercise capacity.29 Tradi-tionally, invasive measurement of pulmonarypressure has been required to confirm a diagnosis ofPH in ILD. Non-invasive assessment of early PHwould, however, permit earlier treatment (or evenprevention).30 With this goal in mind, van der Plaset al. demonstrated that cardiopulmonary exercise(CPEx) parameters, especially ventilatory equivalentat anaerobic threshold, correlated well with invasivemeasures of pulmonary pressure and associate withan increased mortality risk.31,32 Although simpler thancardiac catheterization, CPEx still requires specializedequipment. For this reason, de Boer et al. compared

Year in review 2014 835

© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 834–845

the modified shuttle walk test with CPEx in patientswith sarcoidosis. Peak VO2 during CPEx correlatedstrongly with walk distance in a modified shuttlewalk.33 Whether this in turn enables simple, clinic-based prediction of the development of PH in thispatient cohort remains to be defined. The observationby Mendoza et al. that quadriceps strength and thusendurance is impaired in patients with fibrotic ILDsuggests that multiple comorbidities are likely to beinvolved in reducing walk distance in patients withchronic disease.34

Another comorbidity that has been linked to IPF isthat of lung cancer. Detection of cancer in individualswith progressive fibrotic lung disease is frequentlychallenging. Dai et al. assessed the relationshipbetween the serum cancer markers CEA and CA-125in a retrospective single-point-in-time study ofpatients with ILD.35 Interestingly, both markers wereincreased in ILD patients compared with control andwere further increased in those with coexistent ILDand cancer. The sensitivity and specificity for themarkers was, however, relatively low, thus limitingtheir clinical utility. In contrast to fibrotic ILD,Ungprasert et al. demonstrated in a systematic reviewthat patients with sarcoidosis do not appear to be atincreased risk of malignancy.36

PHYSIOLOGY

Neil D. Eves

Pulmonary function

Pulmonary function testing remains the cornerstoneof respiratory medicine and advances continue to bemade into how to improve the accuracy of diagnosis,while enhancing understanding of how lung functionchanges with age, disease and different comor-bidities. This year in Respirology saw the initiation ofan invited review series that brings together worldleaders in respiratory physiology and medicine toinvestigate the central question ‘what is the mostappropriate lung function test for a particular lungdisease’.37 Two initial reviews from this series werepublished in 2014.38,39 Fauroux and Khirani38 high-lighted the unique respiratory pathophysiology of avariety of neuromuscular diseases in children and therespiratory consequences of progressive neuro-muscular disorders when the respiratory muscles areaffected. The pros and cons of a host of invasive/non-invasive as well as volitional/non-volitional tests wereeloquently discussed. However, the authors clearlydemonstrate the importance and benefit of utilizinginvasive respiratory muscle assessments to guide theclinical diagnosis and management of these dis-eases.38 Similarly, in the second highly informativereview,39 Thompson and associates discuss the com-plexities of assessing the suitability of patients forlung transplantation and the importance of lungfunction testing for monitoring patients in the yearsfollowing transplantation. Not surprisingly, spirom-etry remains the primary diagnostic tool for the

evaluation of lung function following transplant andcan help discriminate between the different pheno-types of allograft dysfunction.39

Spirometry is the oldest and most widely usedmeasure of lung function testing, but how the meas-urements are performed and how we interpretspirometry data is constantly being refined.40 Forexample, while the effects of thoracic gas compres-sion on spirometry are well known,41 how thoracic gascompression affects spirometric measures in a varietyof disease states has been the focus of a number ofrecent studies.42,43 Pellegrino et al.44 reported thatairway responsiveness to methacholine was greaterusing forced expired volume in 1 s (FEV1) measuredby spirometry compared to plethysmograph in indi-viduals who had asthma with normal spirometry(n = 54) or airflow obstruction and a positivebronchodilatory response (n = 55). Additionally, thenumber of individuals diagnosed with a positivebronchodilatory response to salbutamol was largerusing FEV1 measured with spirometry than plethy-smography. These differences in bronchoconstrictorand bronchodilatory response were related to alveo-lar pressure generated during the forced expirationand the absolute lung volume. As such, the authorsconclude that spirometry tends to overestimate theairway responses to constrictor and dilator agents inindividuals with large lung volumes (i.e. taller males),and this should be taken into consideration wheninterpreting both clinical and research data.44

In another interesting study, Shin et al.45 visuallyinspected traditional flow volume loops from 1037individuals at ages 18, 26, 32 and 38 years old for thepresence of a convex inflection or ‘knee’ on theexpiratory limb of the flow-volume loop. It wasobserved that the knee pattern was found in approxi-mately two thirds of men and women aged 18 withprevalence decreasing with age, especially in males.Additionally, the knee pattern was associated withless airflow obstruction and was less common inthose with asthma. As it is believed that the appear-ance of the knee is due to a choke point limitingexpiratory flow at the level of the lower trachea,46,47 thedisappearance with increasing age may be due to lossof parenchymal elastic recoil or increased airwayresistance, which moves the choke point distallytoward the alveoli.45,47

Previous studies have reported that ventilatoryheterogeneity measured by a variety of techniques48–50

is associated with airway hyperresponsiveness inindividuals with asthma. Kaminsky et al.51 investi-gated whether a simple single-breath alveolar volume(VA) to plethysmographically determined totallung capacity (TLC) ratio, as a measure of globalventilatory heterogeneity, would correlate withairway hyperresponsiveness in 136 individuals whoperformed methacholine challenge testing. An asso-ciation was observed between airway hyper-responsiveness and VA/TLC suggesting that thosewith a low VA/TLC may have increased airwayhyperresponsiveness. As such, the authors suggestthat VA/TLC may also reflect the susceptibility forairway closure and narrowing during a methacholinechallenge.51

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© 2015 Asian Pacific Society of RespirologyRespirology (2015) 20, 834–845

Obesity and lung function

While obesity is a well-recognized problem affectingmillions around the globe,52 there is a still a consider-able amount to learn in regards to obesity as acomorbidity or cause of respiratory disease. Further-more, how dramatic weight loss due to obesity treat-ments (i.e. bariatric surgery) effects pulmonaryfunction is also poorly understood. In Respirology in2014, Chapman and colleagues53 phenotyped patientswith both asthma and obesity into two distinctgroups, those with early onset asthma and high serumimmunoglobulin E (IgE) (TH2-high) and those withlate onset asthma and low IgE (TH2-low). Twelvemonths following bariatric surgery, the TH2-low sub-jects had improved airway hyperresponsivenessrelated to airway closure but had no improvements inresting airway resistance. In contrast, in the TH2-highindividuals, weight loss improved airway resistancebut did not improve airway hyperresponsiveness.These findings clearly highlight the distinct effects ofobesity on small airway function and emphasize thecomplexity of how IgE status can affect asthma patho-physiology in the obese individual.53

Oxygen delivery and monitoring

The delivery and monitoring of oxygen levels is anessential part of medicine from neonatal care, toemergency and critical care medicine. In recent years,the potentially adverse effects of supplementaloxygen in a variety of acute care settings has madeclinicians highly aware of the need for more accuratedelivery of prescribed O2.54,55 Utilizing a novel tech-nique of inserting transtracheal catheter viabronchoscopy, O’Reilly and associates56 were able tocontinuously sample oxygen concentration, whichremoved the effects of local streaming and inadequatemixture of O2 and room air associated with samplingnearer to the mouth.56,57 It was confirmed with thistechnique that 2 L/min of O2 delivered via nasalcannula resulted in fractional tracheal O2 concentra-tions between 0.284 and 0.296, and that respiratoryrate, ventilation and whether breathing occurred withthe mouth open or closed all influenced the inspiredconcentration of O2. These findings are of significantclinical relevance, as all of these factors will affect theamount of O2 required via nasal cannula to achieve adesired prescription in different clinical scenarios.56,57

While the direct measure of arterial blood gasesremains the gold standard evaluation of bloodoxygen, carbon dioxide and acidity levels, it comeswith a number of risks and challenges. As such,there has been a growing interest to alternatively usearterialized58 or venous samples.59,60 However,whether the known differences between venous andarterial blood are constant and predictable are notknown. Byrne et al.61 performed a meta-analysis tocalculate the average difference and the limits ofagreements between standard arterial blood gasmeasures and peripheral venous blood gas. Whilethere was strong agreement between venous andarterial measures of pH, peripheral venous partialpressures of oxygen and carbon dioxide were not

comparable due to considerable variability observedfor both measures.61

While peripheral venous blood may not be optimalfor the accurate measurement of arterial blood gases,pulse oximetry for measuring oxygen saturations hasgrown in popularity due to its simplicity, non-invasiveness and ease of collection. This year saw theimportant and timely publication of the officialguidelines for the clinical use of pulse oximetry fromthe Thoracic Society of Australia and New Zealand,62

which offers excellent information on the advantages,limitations and technical considerations needed forthe accurate assessment of O2 saturation in a varietyof clinical settings.

Biomarkers in pulmonary artery hypertension

Biomarkers are an important and powerful approachto monitoring disease severity, helping design newdrugs, forecast responses to therapies and predictprognosis.63 Respiratory disease is no exception, andin recent years there has been considerable researchto identify and understand key biomarkers to assistclinicians in the diagnosis, treatment and manage-ment of their patients.64,65 Two original studies thisyear identified potentially important biomarkers thatmay be of important clinical relevance in pulmonaryartery hypertension (PAH).66,67 YKL-40 is an inflamma-tory glycoprotein that is associated with vascularinflammation, endothelial dysfunction68 and vascularremodelling.69 YKL-40 protein expression has alsobeen reported in macrophages from early atheroscle-rotic lesion and has been independently associatedwith the presence and extent of coronary arterydisease.70 Chen et al.66 investigated a potential role ofYKL-40 as a predictor of clinical outcomes in 82patients with idiopathic PAH. It was reported thatplasma YKL-40 was significantly elevated in thiscohort compared with healthy controls and was abetter predictor of both deteriorating clinical statusand death than N-terminal pro-brain natriureticpeptide and uric acid.66 Additionally, Fenster et al.67

reported that cystatin C, an endogenous biomarker ofrenal filtration and cardiovascular disease mortal-ity,71,72 was associated with right ventricular systolicpressure, function and morphology67 in a small cohortof patients with PAH (n = 14). The findings from thesetwo studies are promising for both cystatin C andYKL-40 as novel indicators of disease severity andprognosis in PAH, and further investigation appearswarranted.

Physical activity

The importance of physical activity for the primaryand secondary prevention of disease has been recog-nized and studied for decades. However, the impor-tance of physical activity for enhancing the healthof patients with respiratory disease is a relativelynew phenomenon that has received considerableattention in 2014 culminating with the release of theEuropean Respiratory Society statement on physicalactivity in chronic obstructive pulmonary disease.73

To assess the level of daily physical activity in smokers



without airflow obstruction and to examine the deter-minants of physical activity in this population,Furlanetto et al.74 undertook a study in 60 smokerscompared with 50 well-matched non-smokers. It wasreported that adult smokers had reduced levels ofphysical activity, which was related to functional exer-cise capacity, fatigue, motivation and the presence ofcardiac disease. Whether physical inactivity is thecause or the consequence of smoking cannot bedetermined, but the study highlights an importantconnection between two well-known risk factors ofcardiovascular disease whose interrelationshipclearly needs to be better understood.

SLEEP AND VENTILATION

Amanda J. Piper

Sleep disordered breathing and its impact on morbid-ity and mortality has gained increasing attention overthe past decade across a wide range of medical con-ditions. During 2014, Respirology published a numberof papers related to various aspects of the diagnosisand treatment of sleep disordered breathing.

Lui and colleagues75 examined the relationshipbetween mesenteric fat thickness and obstructivesleep apnoea (OSA). Previously, this group had shownmesenteric fat thickness correlated better with car-diovascular risk than visceral fat measured by mag-netic resonance imaging.76 In the current study,mesenteric fat thickness measured by ultrasound wasfound to be independently associated with OSA risk.Sonographic measurements of mesenteric fat thick-ness could provide a more clinically accessible andaccurate tool for unravelling the complex interrela-tionships between visceral fat, OSA and the metabolicsyndrome.

OSA may also occur in disorders associated withnasal obstruction and chronic mouth breathing.Primary ciliary dyskinesia (PCD) is one such disorder.Santamaria and colleague77 studied 16 children (aged5–17 years) with stable PCD, comparing parent-reported sleep quality and respiratory polygraphyfindings to 42 age- and gender-matched healthy con-trols. Eighty-one per cent of the PCD group had mod-erate or severe OSA. However, parent-reported sleepquality indicated less sleep disturbances in the PCDgroup than in the healthy controls. Importantly, theauthors found an association between nocturnaldesaturation and changes in lung function and struc-ture, suggesting a potential link between upper andlower airways disease in these individuals. As OSAcould contribute to pulmonary morbidity in PCD,objective investigation is needed to identify sleepbreathing problems in this population.

OSA is also associated with significant cardiovascu-lar morbidity and mortality. PH occurs in up to 40% ofOSA patients in the absence of other cardiopulmo-nary disorders, although the severity is usually mild.78

Nevertheless, prognosis is poorer in OSA patientswith PH.79 Although some studies have shown con-tinuous positive airway pressure (CPAP) reduces PH,the evidence is inconsistent. A meta-analysis con-

ducted by Sun and colleagues80 sought to clarify thisissue. The authors included six studies involving 181participants; five studies were before/after trials andone was a matched control trial. CPAP was associatedwith a small but statistically significant reduction inpulmonary artery pressure. However, the robustnessof these results was hindered by data quality. Norandomized studies could be included; duration ofCPAP use varied from 3 to 71 months, and compliancewith therapy was not reported in all studies. Further-more, five studies used Doppler echocardiography,which has been shown to be less accurate for meas-uring pulmonary artery pressure than right heartcatheterization.81 These findings highlight the needfor well-designed studies using robust outcomemeasures in patients with moderate to severe PH tobetter determine the impact of CPAP on mortality.

In patients with chronic heart failure (CHF) sleepdisordered breathing is prevalent. The presence ofsleep apnoea in CHF is associated with worse sur-vival, and CPAP is widely used to treat both obstruc-tive and central events. However, reports of the acutehaemodynamic effects of CPAP in this populationhave been contradictory. Schroll and colleagues82

tested the effects of incremental CPAP on blood pres-sure, heart rate and cardiac output in 37 stable nor-motensive CHF patients, most of whom hadpredominantly central apnoea. CPAP up to 10 cmH2Owas well tolerated and produced only small and clini-cally insignificant changes in haemodynamics in thevast majority of individuals. These results providereassurance about the acute safety of CPAP inpatients with CHF. However, as discussed in theaccompanying editorial by Hamilton et al.,83 care isstill needed when commencing CPAP in patients withmore severe heart failure or those with low fillingpressures, as acute haemodynamic compromise isstill possible. While CPAP has been shown to becardioprotective in patients with CHF and OSA,whether this is also true for those with central sleepapnoea (CSA) is less clear. There is now increasinginterest in adaptive servoventilation and whether it ismore effective in reducing morbidity and mortality inpatients with CHF with CSA. A multicentre trial(SERVE-HF) is currently underway and will helpclarify this issue.84

The high prevalence of OSA and increasing aware-ness of its significant health and social impact hasprompted the search for alternatives to the sleeplaboratory paradigm for diagnosing and initiatingCPAP therapy. In Australia, some pharmacy outletsare now involved in the delivery of CPAP services.Hanes and colleagues85 conducted a survey of thesepharmacies, providing the first overview of the rangeand quality of services currently offered. The investi-gators developed 23 criteria based on the AustralasianSleep Association’s position paper ‘Best practiceguidelines for provision of CPAP therapy’,86 group-ing criteria under subheadings of ‘infrastructure’,‘service-related processes’ and ‘patient-related moni-toring and follow-up’. Significant variability in theprovision of CPAP was noted, particularly in criteriaassociated with service-related processes. The ques-tion of service quality in the treatment of OSA is not

TM Maher et al.838


confined to pharmacy practices and is an issue thatshould be investigated in other CPAP providersettings.

Upper airway obstruction and CSA are not the onlyforms of sleep disordered breathing encountered bythe clinician. Sleep hypoventilation occurs commonlyin progressive neuromuscular disorders, chronic lungdisease and morbid obesity. If untreated, sleephypoventilation can progress to diurnal respiratoryfailure. In their excellent review, Hillman and col-leagues87 discussed the types of daytime respiratoryfunction tests that can be used to assist identifyingthose at risk of sleep hypoventilation. The goal is toflag these individuals early and institute appropriatetherapy, generally in the form of non-invasive venti-lation (NIV).

Hypoventilation secondary to obesity (the obesityhypoventilation syndrome—OHS) has become a sig-nificant issue over the past decade and not just inWestern countries. Harada and colleagues88 studiedsubjects presenting to a sleep clinic in Japan andfound the prevalence of OHS among obese individ-uals with OSA was 12.3%. This is similar to rates seenin Western populations.89 However, disease in theJapanese population occurred at a lower body massindex range (around 37 kg/m2). Even with effectivetherapy, patients with OHS may still exhibit an abnor-mal breathing response when the respiratory systemis challenged. Flying in a commercial aircraft is onesuch real-life challenge. Ali and colleagues90 studied13 patients with OHS effectively treated with long-term NIV. Although daytime resting SpO2 and arterialblood gases were within normal limits, 54% of thestudy group showed significant desaturation whenexposed to a hypoxic challenge test (HCT). Borderlinecontrol of chronic hypoventilation and severelyimpaired exercise capacity were two factors theauthors recommended should alert the clinician toarrange a HCT in NIV-treated OHS patients consider-ing air travel.

For the reasons outlined by Hillman et al.,87 sleephypoventilation commonly occurs in neuromusculardisorders. As with adults, nocturnal NIV is widelyused in children to relieve symptoms and improvedaytime blood gases, although data regarding efficacyis sparser. Using respiratory polygraphy and arterialblood gases prior to and during NIV therapy in 10consecutive children with progressive neuromusculardisease, Falsaperla and colleagues91 demonstratedsignificant improvements in nocturnal and awake gasexchange. Monitoring the efficacy of NIV during sleepis important. A growing number of studies have dem-onstrated how frequently issues such as leak andpatient-ventilator asynchrony occur, which canimpact on the efficacy of therapy. Improvements intechnology are opening up options for undertakingsuch monitoring outside of sleep laboratories.Devices for simultaneous measurement of transcuta-neous CO2 and SpO2 from a single probe are nowavailable and have been used in the patient’s home toidentify ongoing sleep hypoventilation despite NIV.92

There have also been advances in home ventilatorsoftware and data storage capacity, which are permit-ting more detailed analysis of ventilation on a breath-

by-breath basis without the need for externalmonitoring.93 Newer modes of ventilation that allowautomatic titration of settings to maintain target ven-tilation goals are also being developed. Kelly and col-leagues94 evaluated one such ‘intelligent’ bilevelventilation mode—intelligent volume assured pres-sure support (iVAPS). Improvements in nocturnal anddaytime gas exchange were similar to those achievedwith standard bilevel therapy, although mean nightlycompliance was better with iVAPS. The authors sug-gested that the automatic ventilator set up algorithmof the iVAPS could be advantageous in less experi-enced centres. However, more follow-up adjustmentswere required with iVAPS compared with standardbilevel therapy, highlighting the need for clinicalexpertise to optimise ventilation even with these‘intelligent’ modes. Nevertheless, an area where thismode of ventilation may be particularly useful is inpatients with progressive disorders in whom ventila-tory requirements are rapidly changing.

Predicting the likelihood of extubation success afterlong-term mechanical ventilation in intensive careunits is important. Extubation failure prolongs theneed for invasive ventilation and increases the risk ofmortality. The Burns Wean Assessment Program(BWAP) has been previously used to determine thereadiness to wean. Jiang and colleagues95 used a modi-fied BWAP tool to predict successful weaning andextubation in patients who had required long-termmechanical ventilation. They reported the tool wasmore sensitive and specific in predicting extubationsuccess than other traditional weaning parameters.The impact of this tool on clinical outcomes in pro-spective studies requires further evaluation.

ACUTE RESPIRATORYDISTRESS SYNDROME

Yuanlin Song

In 2014, research into acute respiratory distress syn-drome (ARDS) treatment delivered some promisingresults from pre-clinical studies and some negativeresults from clinical trials.

Pathogenesis

Ventilator-induced lung injury is a major concern inARDS ventilation. Using a cell culture stretch model,Kuhn et al. found that lipopolysaccharide (LPS) andcell stretching both activated nuclear factor κB andthat LPS-induced TLR4-mediated immunity intensi-fied cell damage caused by stretching while stretchingitself had no influence on cytokine secretion.96 Thisstudy suggests that mechanical ventilation has noapparent effects on TLR4-mediated innate immunity.

Considering inflammation is part of the lung’simmunity response to pathogen invasion and inflam-mation contributes to lung tissue damage, Galvãoet al. compared antibiotic treatment with/withoutantioxidant administration in a rat model of sepsis-induced lung injury. The results showed that therewas a survival benefit when antioxidants were admin-istered in addition to antibiotics.97 This result



highlights the potential of antioxidants in sepsis treat-ment although further exploration is warranted.

Treatment

Statin has been shown to modulate inflammatoryresponse. Two independent studies from the USA andIreland confirmed that neither rosuvastatin norsimvastatin improved 28-day survival of ARDS, androsuvastatin was even found to be associated withhepatic and renal dysfunction.98,99 Although the enrol-ment criteria were not exactly the same (therosuvastatin group consisted largely of sepsis-associated ARDS patients), the large study groups inboth randomized controlled trial (RCT) studies sug-gests the outcome was quite comparable and robust.

So far only very few treatment studies (e.g. low tidalvolume ventilation strategy) showed a survivalbenefit, with most clinical trials on ARDS treatmentshowing negative results no matter how promisingthe results from pre-clinical studies were. One expla-nation could be the heterogeneity of the enrolledARDS patients and the possibility that each of themanoeuvres used may not be beneficial to everyARDS patient. Calfee et al. analysed two randomizedcontrolled trials (including 1022 patients) and foundtwo sub-phenotypes within ARDS. One features moresevere inflammation, shock, and metabolic acidosisand worse clinical outcomes irrespective of the treat-ment strategy applied.100 This suggests that, in futureARDS clinical trial designs, stratifying patientsbased on different subphenotypes may show differentresponses.

Non-invasive positive pressure ventilation (NIPPV)has been proposed to treat early ARDS, but theoutcome was not consistent. Delayed intubation mayincrease mortality of ARDS. In 2014, Respirology pub-lished a meta-analysis evaluating whether NIPPV canprevent or reduce intubation of acute lung injury/ARDS patients. Six RCT were included in the analysis,and the results showed NIPPV reduced intubationrate but had no effects on survival.101 This suggeststhat NIPPV can be used for early ARDS treatment butdoes not change the disease progress.

CYSTIC FIBROSIS

Yuanlin Song

Evaluation

Due to the nature of chronic airway infection/inflammation and multiple organ dysfunctions incystic fibrosis (CF), it is essential to have an easy CFknowledge scale that can be used for self-recognitionand management in order to promote life qualityin CF patients. Balfour et al.102 proposed apsychological-educational-based CF knowledgescore that was validated in CF patients, patients withrespiratory disease, health-care providers and univer-sity students. The validation test showed consistentadherence among patients and health-care providers,suggesting that this scale could be used as an

outcome measure for educational intervention.102

Besides scale measurement, sensitive and specificlung function quantification is very useful in earlydetection of airway disease progress that usuallyoccurs in the preschool years. Careful interpretationof lung function changes in infants and young chil-dren is crucial given their lesser cooperation com-pared with adults.103

Treatment

In 2014, quite a few meta-analysis on cystic fibrosistreatment have been published, including but notlimited to inhalation of steroid, oral intake ofN-acetylcysteine as well as antibiotic strategy againstPseudomonas aeruginosa. As CF presents withchronic airway inflammation, anti-inflammationtherapy has been proposed with great hopes.N-acetylcysteine, a precursor of glutathione, hasshown beneficial effects on lung function without sig-nificant neutrophil activity reduction.104 Steroid inha-lation has been widely used in CF patients as anti-inflammation therapy, but it needs to be balancedagainst its side-effects. A meta-analysis by Conradet al. showed less power to evaluate the benefit oflong-term use of steroid inhalation, but it seemed safeto withdraw without obvious problems.105

Pseudomonas aeruginosa initiates colonization inairways of CF patients at an early age. Multiple clinicalstudies showed that nebulization of antibiotics(without or in combination with oral intake of antibi-otics) was better than non-antibiotics treatment forP. aeruginosa eradication, and this effect could last for2 years.106 However, it is too early to evaluate the long-term prognosis without sufficient randomized clinicaltrials. That being the case, adhering to the guide-lines107 is still one of the standard strategies in CFmanagement, although personalized medicine ishighly warranted in the CF field.

BRONCHIECTASIS

Marcos I. Restrepo

During 2014, Respirology published five manuscriptsrelated to non-cystic fibrosis bronchiectasis (NCFB),including two original manuscripts, with two relatededitorial, and one systematic review/meta-analysis.This is the summary of several key points that welearned from this interesting high level of evidence.

Goeminne et al.108 assessed in a case–control studythe value of sputum colour as a predictor of lunginflammation, proteolysis and damage in NCFB. Thesubjects were patients with NCFB and controls werehealthy subjects. All subjects were subjected tosputum induction testing. Sputum was then analysedfor several inflammatory parameters and markerssuch as total and differential cell count, interleukin-8(CXCL8), tumour necrosis factor-α (TNF-α) andproteolytic enzymes (neutrophil elastase (NE), gelatinzymography and total gelatinolytic activity (TGA)). Inaddition, each subject was assessed by spirometry,Leicester Cough Questionnaire (LCQ), Sputum

TM Maher et al.840


Colour Chart (SCC) and CT close to the time ofsputum induction date. The authors found thatpatients with NCFB had higher neutrophils, CXCL8,TNF-α, NE and TGA levels compared with healthycontrols. TGA subanalysis showed that the majority ofthe activity was NE. Residual activity was mainly zincion-dependent matrix metalloproteinase (MMP)activity. Subanalysis showed that patients withchronic P. aeruginosa colonization had more acti-vated MMP-9. Correlations were seen betweenproteolytic enzymes and inflammation and diseaseseverity (spirometry and CT score) but not with theLCQ. SCC was associated with increased markers ofinflammation, proteolytic enzymes and worse CTscores. The authors conclude that sputum purulenceassessment in daily clinical practice using the SCC is aquick and easy tool that reflects severity of inflamma-tion, destruction and proteolytic enzymatic activity/presence. In an editorial, Chalmers and Finchemphasize the significance of sputum colour as adirect measure of airway inflammation associatedwith proteolytic activity and bacterial infection.109 Inaddition, they suggest that sputum colour is the origi-nal biomarker that should be considered in the globalassessment of NCFB patients who require aggressivetreatment. The authors also recommend stratifyingNCFB patients to identify those at risk of disease pro-gression requiring prolonged antibiotic or anti-inflammatory therapies, balancing the potential side-effects associated with these treatments.

Lourdesamy Anthony and Muthukumaru110 evalu-ated the efficacy of a 12-week oral treatment withazithromycin in adult patients with NCFB. This studyfocused on the reduction in sputum volume,improvement of QoL and the long-term effects afterstopping azithromycin therapy. The authors rando-mized 78 subjects with confirmed high-resolutionCT bronchiectasis to receive 12 weeks of oralazithromycin (1 g/weekly) versus placebo. This treat-ment was followed by another 12 weeks of placebo inboth treatment groups. The end-points were meas-ured at baseline, 12 and 24 weeks and includedsputum volume, St George’s Respiratory Question-naire (SGRQ) score and spirometry. They analysed 68subjects and found that azithromycin was associatedwith lower mean 24-h sputum volume during theactive treatment phase, with persistent low volume inthe control phase. In addition, azithromycin-treatedpatients had lower SGRQ levels, with no differences inlung function testing by spirometry. Therefore, theauthors conclude that 12 weeks of therapy withazithromycin reduced mean sputum volume,improved health status by SGRQ and stabilized thelung function compared with placebo. Azithromycinadministration had a carry-over effect on sustaininglow sputum volume and improvement of QoL for 12weeks after cessation of azithromycin in NCFBpatients.

Wu et al.111 published a systematic review andmeta-analysis evaluating the long-term efficacy ofmacrolide therapy for the treatment of NCFB. Theauthors identified 9 RCT with 530 subjects and com-pared placebo and/or usual medical care versus long-term macrolide therapy. Long-term macrolide

therapy significantly reduced the risk of exacerba-tions, average exacerbations per participant, theSGRQ total scores, dyspnoea scale, 24-h sputumvolume and attenuated the decline in FEV1. In con-trast, eradication of pathogens, overall rate of adverseevents and emergence of new pathogens were notelevated, while gastrointestinal events increasedsignificantly with long-term macrolide therapy.Macrolide resistance increased, but a meta-analysiswas not possible due to the diversity of parameters.Long-term use of macrolides appears to be a treat-ment option for stable bronchiectasis. The results ofthis review justify further investigation in the additionof this intervention to the treatment regimens ofbronchiectasis. In an editorial, David J. Serisier112

elegantly emphasizes that the meta-analysis by Wuand collaborators strengthens the evidence and sup-ports the use of macrolides in NCFB. However, theeditorial balances this benefit with the potential risksof macrolide resistance if applied to a much broaderpopulation and recommends that this antibiotic classbe restricted to a more severe subgroup of patients. Inaddition, Dr Serisier has a provocative suggestion byrecommending erythromycin over azithromycinwhen macrolides are indicated for patients withNCFB. This recommendation focuses on a more eco-logically responsible choice in order to preventoveruse of macrolides and avoid selection of antimi-crobial resistance that may ultimately limit furtherbenefit of these medications in NCFB patients.

RARE LUNG DISEASE

Toby M. Maher

In the field of rare lung disease research, the use ofdisease biomarkers to stratify patients and guidetherapy was a theme that emerged during 2014. Ineosinophilic pneumonia Jhun et al. demonstratedthat a peripheral eosinophilia at diagnosis is associ-ated with milder disease and better outcomesfollowing treatment.113 In pulmonary alveolarproteinosis, Arai et al. found that the cytokeratinCYFRA 21-1 is elevated at diagnosis and that levelsrelated to disease severity and improve followingtreatment.114 In a study of bronchoalveolar lavage(BAL) in ILD patients, Papakosta et al. found thatnatural killer and natural killer T-like cells wereincreased in the BAL fluid of patients with crypto-genic organizing pneumonia when compared withhypersensitivity pneumonitis and IPF, suggestingboth a pathomechanistic and diagnostic role forthese cells.115 In sarcoidosis, BAL levels of the fungalantigen β-glycan were shown by Tercelj et al. to cor-relate with systemic levels of inflammation.116 Inhypersensitivity pneumonitis, Villar et al. establishedthat specific allergen challenge leads to measurablechanges in inflammatory cells and protein markersin induced sputum.117 Overall, these studies point atthe potential for utilizing novel serum and lung spe-cific measures of disease activity to provide betterunderstanding of disease behaviour and improvedtargeting of therapy.



AcknowledgementsM.I.R.’s time is partially protected by Award NumberK23HL096054 from the National Heart, Lung, and Blood Institute.The content is solely the responsibility of the authors and doesnot necessarily represent the official views of the National Heart,Lung, and Blood Institute or the National Institutes of Health, northe Department of Veteran Affairs.

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