We welcome the correspondence from Lavie and Amirav (1), highlighting the difficulties diagnosing primary ciliary dyskinesia (PCD) and the role of high-speed video analysis (HSVA). As members of the European Respiratory Society (ERS) PCD Diagnostic Task Force (2) and/or large PCD Centres, we agree that HSVA has an important role that is not recognized by the American Thoracic Society (ATS) PCD Diagnostic Guideline (3). This risks a large proportion of false-negative “missed” diagnoses and a sizable number of false-positive cases; we make additional important observations.</div

Haarman, Eric

Hirst, Robert A.

Hogg, Claire

Jackson, Claire L.

Lucas, Jane S.

Nielsen, Kim G.

Papon, Jean Francois

Robinson, Philip

Rubbo, Bruna

Shoemark, Amelia

Walker, Woolf T.

American Journal of Respiratory and Critical Care Medicine

English

Robinson, Phil

Lucas, Jane

Southampton (e-Prints Soton)

The controversies and difficulties of diagnosing Primary Ciliary Dyskinesia (PCD)

Discovery Research Portal

                                                                    University of DundeeThe Controversies and Difficulties of Diagnosing Primary Ciliary DyskinesiaShoemark, Amelia; Rubbo, Bruna; Haarman, Eric; Hirst, Robert A.; Hogg, Claire; Jackson,Claire L.Published in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201907-1334LEPublication date:2020Document VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Shoemark, A., Rubbo, B., Haarman, E., Hirst, R. A., Hogg, C., Jackson, C. L., ... Lucas, J. S. (2020). TheControversies and Difficulties of Diagnosing Primary Ciliary Dyskinesia. American Journal of Respiratory andCritical Care Medicine, 201(1), 120-122. https://doi.org/10.1164/rccm.201907-1334LEGeneral rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 23. Jan. 2020Jean Bourbeau, M.D., M.Sc.McGill University Health CentreMontreal, Quebec, CanadaandMcGill UniversityMontreal, Quebec, Canada*Corresponding author (e-mail: sebastien.gagnon3@mail.mcgill.ca).References1. Bhatt SP, Patel SB, Anderson EM, Baugh D, Givens T, Schumann C, et al.Video telehealth pulmonary rehabilitation intervention in COPD reduces30-day readmissions. Am J Respir Crit Care Med [online ahead of print]12 Apr 2019; DOI: 10.1164/rccm.201902-0314LE. Published in ﬁnal formas Am J Respir Crit Care Med 2019;200:511–513.2. Criner GJ, Bourbeau J, Diekemper RL, Ouellette DR, Goodridge D,Hernandez P, et al. Executive summary: prevention of acute exacerbationof COPD: American College of Chest Physicians and Canadian ThoracicSociety Guideline. Chest 2015;147:883–893.3. Harrison SL, Robertson N, Graham CD, Williams J, Steiner MC, MorganMD, et al. Can we identify patients with different illness schemafollowing an acute exacerbation of COPD: a cluster analysis. RespirMed 2014;108:319–328.4. Man WD, Puhan MA, Harrison SL, Jordan RE, Quint JK, Singh SJ.Pulmonary rehabilitation and severe exacerbations of COPD: solutionor white elephant? ERJ Open Res 2015;1:00050-2015.5. Czajkowski SM, Powell LH, Adler N, Naar-King S, Reynolds KD, Hunter CM,et al. From ideas to efﬁcacy: the ORBIT model for developing behavioraltreatments for chronic diseases. Health Psychol 2015;34:971–982.6. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al.; LookAHEAD Research Group. Cardiovascular effects of intensive lifestyleintervention in type 2 diabetes. N Engl J Med 2013;369:145–154.Copyright © 2020 by the American Thoracic SocietyReply to Gagnon et al.From the Authors:We thank Dr. Gagnon and colleagues for their interest andcomments. Because of the constraints of a research letter, we were notable to provide all the details of the telehealth intervention. Brieﬂy,each video session was designed to mimic the components of center-based pulmonary rehabilitation (PR) and lasted 45 to 60minutes. Thesessions included stretching and breathing exercises forapproximately 10 minutes; aerobic exercises using a foot peddler orwalking for 10 and 20 minutes in those with low and high baselinefunctional capacity, respectively; and strength training with stretchbands for 10minutes. Educational sessions were interspersed betweenthese exercise periods. We agree with Dr. Gagnon and colleagues thatthe interval between the initiation of PR and 30 days is short, and thuswe may not see meaningful changes in functional capacity. The 30-day time point was chosen based on our primary outcome of hospitalreadmission (1). We disagree that the higher proportion of patientson domiciliary oxygen in the group exposed to PR may havecontributed to improved outcomes, as this suggests more severe andperhaps less-responsive disease. We acknowledge that the study wasnot randomized and that we did not collect data on the number ofpatients approached and reasons for patient refusal to participate.These limitations in part underlie our call for well-conductedrandomized trials to test the efﬁcacy of our intervention. They alsomake a case that behavioral changes could have had a signiﬁcantimpact. Although we did not systematically study this in bothgroups, the emotional guardedness domain of the psychosocial riskfactor survey did improve with telehealth PR (2). nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Surya P. Bhatt, M.D., M.S.P.H.*Mark T. Dransﬁeld, M.D.University of Alabama at BirminghamBirmingham, AlabamaORCID ID: 0000-0002-8418-4497 (S.P.B.).*Corresponding author (e-mail: sbhatt@uabmc.edu).References1. Bhatt SP, Patel SB, Anderson EM, Baugh D, Givens T, Schumann C, et al.Video telehealth pulmonary rehabilitation intervention in COPD reduces30-day readmissions. Am J Respir Crit Care Med 2019;200:511–513.2. Eichenauer K, Feltz G, Wilson J, Brookings J. Measuring psychosocialrisk factors in cardiac rehabilitation: validation of the psychosocial riskfactor survey. J Cardiopulm Rehabil Prev 2010;30:309–318.Copyright © 2020 by the American Thoracic SocietyThe Controversies and Difﬁculties of DiagnosingPrimary Ciliary DyskinesiaTo the Editor:We welcome the correspondence from Lavie and Amirav(1), highlighting the difﬁculties diagnosing primary ciliarydyskinesia (PCD) and the role of high-speed video analysis(HSVA). As members of the European RespiratorySociety (ERS) PCD Diagnostic Task Force (2) and/or largePCD Centres, we agree that HSVA has an important rolethat is not recognized by the American Thoracic Society(ATS) PCD Diagnostic Guideline (3). This risks a largeThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by NIH grant K23HL133438 (S.P.B.).Originally Published in Press as DOI: 10.1164/rccm.201907-1486LE onAugust 6, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: A.S. and J.S.L. provided the concept and drafted thecorrespondence; all authors commented and approved the manuscript.The authors are members of European Respiratory Society Task Force (TF-2014-04) and BEAT-PCD network (COST Action BM 1407).Originally Published in Press as DOI: 10.1164/rccm.201907-1334LE onAugust 21, 2019CORRESPONDENCE120 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 1 | January 1 2020proportion of false-negative “missed” diagnoses and a sizablenumber of false-positive cases; we make additional importantobservations.We agree with Lavie and Amirav that nasal nitric oxide(nNO) should not be used in isolation to make a diagnosis orto exclude PCD. The risk for false-negatives is clearly describedin the literature (reviewed in Reference 2). The ERS Guidelinestherefore suggest that both nNO and HSVA should be entirelynormal before deciding that further investigation is notwarranted (2). We all have patients who proceeded to furthertesting because clinical history was strong or HSVA wasabnormal despite normal nNO, and then had a diagnosisconﬁrmed by transmission electron microscopy (TEM) orgenetics (e.g., CCDC103, DNAH9, or RSPH1 mutations).Contrary to Lavie and Amirav, neither ATS nor ERS guidelineswould exclude the diagnosis of PCD in patients with acompatible history and diagnostically low nNO despite normalHSVA, without proceeding to further tests including TEMand genetics.Similarly to Lavie and Amirav, we were surprised that theATS guideline speciﬁcally suggests not assessing ciliary beatpattern. Dyskinesia is a key feature of the condition andcan be accurately detected by HSVA (4). According to theERS Guidelines, repeatedly dyskinetic cilia or abnormalbeat pattern following reanalysis after culture, with normalgenetics and TEM, indicates PCD is “highly likely” (2),and patients should follow a PCD treatment plan (2).This recognizes that TEM and genetics will each be normalin 20–30% (2) of patients who truly have PCD (falsenegative), and that HSVA will detect most of these patientswho require specialist PCD care. Until HYDIN, DNAH11, andGAS8 were discovered as PCD genes, the patients wererecognized by abnormal HSVA, and until all genetic causes areidentiﬁed, HSVA is needed. It also acknowledges that evenrepeatedly abnormal HSVA may be falsely positive, andtherefore the ERS Guidelines recommend that patients are notlabeled as deﬁnitely having PCD based on HSVA alone (2, 4).Importantly, HSVA provides an accurate result on theday of testing that can be used to counsel patients andcommence treatment while awaiting conﬁrmatory TEMand genetics (4). HSVA also has an important researchvalue, assessing the ability of novel treatments to restorefunction.There are a large number of PCD genes, and becauseof their size, variants are common; not infrequently,patients without PCD have biallelic variants of unknownsigniﬁcance in PCD-related genes. The speciﬁcity of genetictesting is severely reduced, and many individuals couldbe incorrectly diagnosed with PCD (false positive) unlessthe mutations are conﬁrmed pathogenic. It is thereforeessential to ensure that the genotype is compatible withthe ciliary phenotype using HSVA, TEM, and/orimmunoﬂuorescence labeling, as well as with the clinicalphenotype (2).Importantly, there is no perfect way to identifypatients for diagnostic testing based on clinical assessment.Lavie and Amirav outline the approach proposed by the ATSGuideline, using a four-point clinical symptoms score.Having two of four clinical features provides speciﬁcity(0.72), ensuring that the diagnostic service only sees themost likely cases, but we suggest it has insufﬁcient sensitivityfor screening (0.8), meaning that 20% of patients withPCD are not tested and will therefore never be correctlydiagnosed (5). The ERS Guideline provides a ﬂexibleapproach (“patients with several typical features” [2]), orsuggests a clinical predictive score called Primary CiliaryDyskinesia Rule (PICADAR), which has good sensitivity andspeciﬁcity (cutoff, 4; 0.97, speciﬁcity, 0.48) (6). Therefore,PICADAR may correctly identify 97% of patients who requirefurther testing, while not inappropriately overwhelmingdiagnostic services, as approximately 50% of patients will turnout to have PCD. Both scores need validating in primarycare settings. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Amelia Shoemark, Ph.D.Royal Brompton HospitalLondon, United KingdomandUniversity of DundeeDundee, United KingdomBruna Rubbo, M.Sc.University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomEric Haarman, M.D.VU University Medical CenterAmsterdam, The NetherlandsRobert A. Hirst, Ph.D.University of Leicester, RKCSBLeicester, United KingdomClaire Hogg, M.D.Royal Brompton HospitalLondon, United KingdomandImperial College LondonLondon, United KingdomClaire L. Jackson, Ph.D.University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomKim G. Nielsen, M.D.Copenhagen University HospitalRigshospitalet, DenmarkJean-Francois Papon, M.D.Universite Paris-Sud, Faculte´ de Me´decineParis, FrancePhilip Robinson, M.D.Royal Children’s HospitalMelbourne, AustraliaCORRESPONDENCECorrespondence 121Woolf T. Walker, M.D., Ph.D.Jane S. Lucas, M.D., Ph.D.*University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomORCID IDs: 0000-0002-1629-8601 (B.R.); 0000-0003-1989-1790 (R.A.H.);0000-0002-8368-5994 (C.H.); 0000-0002-1200-0935 (C.L.J.);0000-0001-5906-9449 (K.G.N.); 0000-0001-6129-9075 (P.R.);0000-0001-8701-9975 (J.S.L.).*Corresponding author (e-mail: jlucas1@soton.ac.uk).References1. Lavie M, Amirav I. In defense of high-speed video microscopy inevaluating patients with suspected primary ciliary dyskinesia. Am JRespir Crit Care Med 2019;200:1181–1183.2. Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, et al.European Respiratory Society guidelines for the diagnosis of primaryciliary dyskinesia. Eur Respir J 2017;49:1601090.3. Shapiro AJ, Davis SD, Polineni D, Manion M, Rosenfeld M, Dell SD, et al.;American Thoracic Society Assembly on Pediatrics. Diagnosis ofprimary ciliary dyskinesia. An ofﬁcial American Thoracic Societyclinical practice guideline. Am J Respir Crit Care Med 2018;197:e24–e39.4. Rubbo B, Shoemark A, Jackson CL, Hirst R, Thompson J, Hayes J,et al.; National PCD Service, UK. Accuracy of high-speed videoanalysis to diagnose primary ciliary dyskinesia. Chest 2019;155:1008–1017.5. LeighMW, Ferkol TW, Davis SD, Lee HS, Rosenfeld M, Dell SD, et al. Clinicalfeatures and associated likelihood of primary ciliary dyskinesia inchildren and adolescents. Ann Am Thorac Soc 2016;13:1305–1313.6. Behan L, Dimitrov BD, Kuehni CE, Hogg C, Carroll M, Evans HJ, et al.PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia.Eur Respir J 2016;47:1103–1112.Copyright © 2020 by the American Thoracic SocietyHigh-Speed Videomicroscopy Analysis PresentsLimitations in Diagnosis of Primary Ciliary DyskinesiaTo the Editor:In response to the letter by Dr. Lavie and Dr. Amirav highlightingthe use of high-speed videomicroscopy analysis (HSVA) in a patientwith suspected primary ciliary dyskinesia (PCD) (1), we standby the American Thoracic Society (ATS) PCD diagnostic guidelinerecommendation. This recommendation speciﬁcally states thatclinicians should avoid using HSVA as a replacement diagnostictest for transmission electron microscopy (TEM) and/or extendedgenetic panel testing (2). Although we appreciate the authors’opinion and argument for the use of HSVA as a diagnostic tool inPCD, we have concerns about their anecdotal evidence andreference to publications with methodologic bias.First, they reference a publication reporting near-perfectsensitivity and speciﬁcity of HSVA testing for PCD (3). Inthis article, randomly selected HSVA case interpretations fromblinded experts, at three separate centers in England, areretrospectively analyzed for diagnostic accuracy. Thispublication has numerous methodologic biases (explained in arecently published letter [4]) that affect data interpretationand likely inﬂate the diagnostic accuracy. No otherpublication has examined the diagnostic accuracy of HSVAagainst PCD genetic testing. Thus, the true diagnosticaccuracy of HSVA in the era of PCD genomics remainsunclear, but it is likely lower than the values described in thatarticle.No single diagnostic test can exclude PCD. TEM and genetictesting individually miss approximately 30% of PCD diagnoses.The authors claim that in one case, normal HSVA “helped todetermine a diagnosis of PCD in this patient as being highlyunlikely,” even though the patient had a strong PCD phenotypeand repeatedly low nasal nitric oxide (nNO) values. Defects in atleast six known PCD-associated genes (HYDIN, CCDC164,DNAH9, GAS8, CCNO, and MCIDAS) result in normal ornondiagnostic HSVA, and more common genes (DYX1C1,RSPH1, and RSPH4A) have unexpected beat patterns for theircorresponding axonemal defects, making HSVA nondiagnostic inthese cases as well. Despite the well-recognized possibility ofPCD with normal HSVA, the authors do not present any TEM orgenetic testing results in their case and dismiss this patient fromfurther PCD therapies. Their decision to ignore the repeatedlylow nNO values as a consequence of sinus surgeries isconcerning, as nNO levels typically increase in non-PCDpatients after sinus surgery (5). The ATS PCD guidelines wereprioritized to avoid this scenario, in which patients with PCDare dismissed because of false-negative results on a singlediagnostic test.Finally, the authors claim the “simplicity of use andexpeditious results” of HSVA should prompt the ATS toreconsider its PCD diagnostic guidelines. However, there isnothing simple about HSVA studies, as they remainnonstandardized in both sample preparation and beat patterninterpretation. Moreover, to avoid secondary causes ofdyskinesia giving false-positive results, the European RespiratorySociety PCD guidelines also strongly recommend regrowth ofciliary samples at the air–liquid interface before HSVAanalysis (6). This arduous, weeks-long regrowth processrequires highly specialized laboratory expertise and refutes theclaim of “expeditious results,” leading to an immediate PCDdiagnosis. Most important, no studies have shown that HSVAcan be reliably and accurately performed outside of a few expertcenters (2).The ATS PCD diagnostic guidelines are rooted in science withrigorous methodology. Although not perfect, they represent themost rigorous review and analysis of scientiﬁc publications onPCD diagnosis and prioritize limiting false-negative diagnoses inwhich patients will suffer without proper, long-term PCDtherapies. Until prospective, well-designed, multicenter studiesare completed, the ATS guideline committee cannot recommendHSVA as a clinical diagnostic test for PCD. nThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contribution: All authors created and edited the manuscript.Originally Published in Press as DOI: 10.1164/rccm.201907-1366LE onAugust 21, 2019CORRESPONDENCE122 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 1 | January 1 2020

The Controversies and Difficulties of Diagnosing Primary Ciliary Dyskinesia

Hirst, Robert A

Jackson, Claire L

Nielsen, Kim G

Papon, Jean-Francois

Walker, Woolf T

Lucas, Jane S

Copenhagen University Research Information System

NARCIS 

Shoemark, A

Rubbo, B

Haarman, E

Hirst, RA

Hogg, C

Jackson, CL

Nielsen, KG

Papon, JF

Robinson, P

Walker, WT

Lucas, JS

University of Melbourne Institutional Repository

The controversies and difficulties of diagnosing primary ciliary dyskinesia

                                                                    University of DundeeThe Controversies and Difficulties of Diagnosing Primary Ciliary DyskinesiaShoemark, Amelia; Rubbo, Bruna; Haarman, Eric; Hirst, Robert A.; Hogg, Claire; Jackson,Claire L.Published in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201907-1334LEPublication date:2020Licence:CC BY-NC-NDDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Shoemark, A., Rubbo, B., Haarman, E., Hirst, R. A., Hogg, C., Jackson, C. L., Nielsen, K. G., Papon, J. F.,Robinson, P., Walker, W. T., & Lucas, J. S. (2020). The Controversies and Difficulties of Diagnosing PrimaryCiliary Dyskinesia. American Journal of Respiratory and Critical Care Medicine, 201(1), 120-122.https://doi.org/10.1164/rccm.201907-1334LEGeneral rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 31. Jul. 2023Jean Bourbeau, M.D., M.Sc.McGill University Health CentreMontreal, Quebec, CanadaandMcGill UniversityMontreal, Quebec, Canada*Corresponding author (e-mail: sebastien.gagnon3@mail.mcgill.ca).References1. Bhatt SP, Patel SB, Anderson EM, Baugh D, Givens T, Schumann C, et al.Video telehealth pulmonary rehabilitation intervention in COPD reduces30-day readmissions. Am J Respir Crit Care Med [online ahead of print]12 Apr 2019; DOI: 10.1164/rccm.201902-0314LE. Published in final formas Am J Respir Crit Care Med 2019;200:511–513.2. Criner GJ, Bourbeau J, Diekemper RL, Ouellette DR, Goodridge D,Hernandez P, et al. Executive summary: prevention of acute exacerbationof COPD: American College of Chest Physicians and Canadian ThoracicSociety Guideline. Chest 2015;147:883–893.3. Harrison SL, Robertson N, Graham CD, Williams J, Steiner MC, MorganMD, et al. Can we identify patients with different illness schemafollowing an acute exacerbation of COPD: a cluster analysis. RespirMed 2014;108:319–328.4. Man WD, Puhan MA, Harrison SL, Jordan RE, Quint JK, Singh SJ.Pulmonary rehabilitation and severe exacerbations of COPD: solutionor white elephant? ERJ Open Res 2015;1:00050-2015.5. Czajkowski SM, Powell LH, Adler N, Naar-King S, Reynolds KD, Hunter CM,et al. From ideas to efficacy: the ORBIT model for developing behavioraltreatments for chronic diseases. Health Psychol 2015;34:971–982.6. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al.; LookAHEAD Research Group. Cardiovascular effects of intensive lifestyleintervention in type 2 diabetes. N Engl J Med 2013;369:145–154.Copyright © 2020 by the American Thoracic SocietyReply to Gagnon et al.From the Authors:We thank Dr. Gagnon and colleagues for their interest andcomments. Because of the constraints of a research letter, we were notable to provide all the details of the telehealth intervention. Briefly,each video session was designed to mimic the components of center-based pulmonary rehabilitation (PR) and lasted 45 to 60minutes. Thesessions included stretching and breathing exercises forapproximately 10 minutes; aerobic exercises using a foot peddler orwalking for 10 and 20 minutes in those with low and high baselinefunctional capacity, respectively; and strength training with stretchbands for 10minutes. Educational sessions were interspersed betweenthese exercise periods. We agree with Dr. Gagnon and colleagues thatthe interval between the initiation of PR and 30 days is short, and thuswe may not see meaningful changes in functional capacity. The 30-day time point was chosen based on our primary outcome of hospitalreadmission (1). We disagree that the higher proportion of patientson domiciliary oxygen in the group exposed to PR may havecontributed to improved outcomes, as this suggests more severe andperhaps less-responsive disease. We acknowledge that the study wasnot randomized and that we did not collect data on the number ofpatients approached and reasons for patient refusal to participate.These limitations in part underlie our call for well-conductedrandomized trials to test the efficacy of our intervention. They alsomake a case that behavioral changes could have had a significantimpact. Although we did not systematically study this in bothgroups, the emotional guardedness domain of the psychosocial riskfactor survey did improve with telehealth PR (2). nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Surya P. Bhatt, M.D., M.S.P.H.*Mark T. Dransfield, M.D.University of Alabama at BirminghamBirmingham, AlabamaORCID ID: 0000-0002-8418-4497 (S.P.B.).*Corresponding author (e-mail: sbhatt@uabmc.edu).References1. Bhatt SP, Patel SB, Anderson EM, Baugh D, Givens T, Schumann C, et al.Video telehealth pulmonary rehabilitation intervention in COPD reduces30-day readmissions. Am J Respir Crit Care Med 2019;200:511–513.2. Eichenauer K, Feltz G, Wilson J, Brookings J. Measuring psychosocialrisk factors in cardiac rehabilitation: validation of the psychosocial riskfactor survey. J Cardiopulm Rehabil Prev 2010;30:309–318.Copyright © 2020 by the American Thoracic SocietyThe Controversies and Difficulties of DiagnosingPrimary Ciliary DyskinesiaTo the Editor:We welcome the correspondence from Lavie and Amirav(1), highlighting the difficulties diagnosing primary ciliarydyskinesia (PCD) and the role of high-speed video analysis(HSVA). As members of the European RespiratorySociety (ERS) PCD Diagnostic Task Force (2) and/or largePCD Centres, we agree that HSVA has an important rolethat is not recognized by the American Thoracic Society(ATS) PCD Diagnostic Guideline (3). This risks a largeThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by NIH grant K23HL133438 (S.P.B.).Originally Published in Press as DOI: 10.1164/rccm.201907-1486LE onAugust 6, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: A.S. and J.S.L. provided the concept and drafted thecorrespondence; all authors commented and approved the manuscript.The authors are members of European Respiratory Society Task Force (TF-2014-04) and BEAT-PCD network (COST Action BM 1407).Originally Published in Press as DOI: 10.1164/rccm.201907-1334LE onAugust 21, 2019CORRESPONDENCE120 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 1 | January 1 2020proportion of false-negative “missed” diagnoses and a sizablenumber of false-positive cases; we make additional importantobservations.We agree with Lavie and Amirav that nasal nitric oxide(nNO) should not be used in isolation to make a diagnosis orto exclude PCD. The risk for false-negatives is clearly describedin the literature (reviewed in Reference 2). The ERS Guidelinestherefore suggest that both nNO and HSVA should be entirelynormal before deciding that further investigation is notwarranted (2). We all have patients who proceeded to furthertesting because clinical history was strong or HSVA wasabnormal despite normal nNO, and then had a diagnosisconfirmed by transmission electron microscopy (TEM) orgenetics (e.g., CCDC103, DNAH9, or RSPH1 mutations).Contrary to Lavie and Amirav, neither ATS nor ERS guidelineswould exclude the diagnosis of PCD in patients with acompatible history and diagnostically low nNO despite normalHSVA, without proceeding to further tests including TEMand genetics.Similarly to Lavie and Amirav, we were surprised that theATS guideline specifically suggests not assessing ciliary beatpattern. Dyskinesia is a key feature of the condition andcan be accurately detected by HSVA (4). According to theERS Guidelines, repeatedly dyskinetic cilia or abnormalbeat pattern following reanalysis after culture, with normalgenetics and TEM, indicates PCD is “highly likely” (2),and patients should follow a PCD treatment plan (2).This recognizes that TEM and genetics will each be normalin 20–30% (2) of patients who truly have PCD (falsenegative), and that HSVA will detect most of these patientswho require specialist PCD care. Until HYDIN, DNAH11, andGAS8 were discovered as PCD genes, the patients wererecognized by abnormal HSVA, and until all genetic causes areidentified, HSVA is needed. It also acknowledges that evenrepeatedly abnormal HSVA may be falsely positive, andtherefore the ERS Guidelines recommend that patients are notlabeled as definitely having PCD based on HSVA alone (2, 4).Importantly, HSVA provides an accurate result on theday of testing that can be used to counsel patients andcommence treatment while awaiting confirmatory TEMand genetics (4). HSVA also has an important researchvalue, assessing the ability of novel treatments to restorefunction.There are a large number of PCD genes, and becauseof their size, variants are common; not infrequently,patients without PCD have biallelic variants of unknownsignificance in PCD-related genes. The specificity of genetictesting is severely reduced, and many individuals couldbe incorrectly diagnosed with PCD (false positive) unlessthe mutations are confirmed pathogenic. It is thereforeessential to ensure that the genotype is compatible withthe ciliary phenotype using HSVA, TEM, and/orimmunofluorescence labeling, as well as with the clinicalphenotype (2).Importantly, there is no perfect way to identifypatients for diagnostic testing based on clinical assessment.Lavie and Amirav outline the approach proposed by the ATSGuideline, using a four-point clinical symptoms score.Having two of four clinical features provides specificity(0.72), ensuring that the diagnostic service only sees themost likely cases, but we suggest it has insufficient sensitivityfor screening (0.8), meaning that 20% of patients withPCD are not tested and will therefore never be correctlydiagnosed (5). The ERS Guideline provides a flexibleapproach (“patients with several typical features” [2]), orsuggests a clinical predictive score called Primary CiliaryDyskinesia Rule (PICADAR), which has good sensitivity andspecificity (cutoff, 4; 0.97, specificity, 0.48) (6). Therefore,PICADAR may correctly identify 97% of patients who requirefurther testing, while not inappropriately overwhelmingdiagnostic services, as approximately 50% of patients will turnout to have PCD. Both scores need validating in primarycare settings. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Amelia Shoemark, Ph.D.Royal Brompton HospitalLondon, United KingdomandUniversity of DundeeDundee, United KingdomBruna Rubbo, M.Sc.University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomEric Haarman, M.D.VU University Medical CenterAmsterdam, The NetherlandsRobert A. Hirst, Ph.D.University of Leicester, RKCSBLeicester, United KingdomClaire Hogg, M.D.Royal Brompton HospitalLondon, United KingdomandImperial College LondonLondon, United KingdomClaire L. Jackson, Ph.D.University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomKim G. Nielsen, M.D.Copenhagen University HospitalRigshospitalet, DenmarkJean-Francois Papon, M.D.Universite Paris-Sud, Faculté de MédecineParis, FrancePhilip Robinson, M.D.Royal Children’s HospitalMelbourne, AustraliaCORRESPONDENCECorrespondence 121Woolf T. Walker, M.D., Ph.D.Jane S. Lucas, M.D., Ph.D.*University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomORCID IDs: 0000-0002-1629-8601 (B.R.); 0000-0003-1989-1790 (R.A.H.);0000-0002-8368-5994 (C.H.); 0000-0002-1200-0935 (C.L.J.);0000-0001-5906-9449 (K.G.N.); 0000-0001-6129-9075 (P.R.);0000-0001-8701-9975 (J.S.L.).*Corresponding author (e-mail: jlucas1@soton.ac.uk).References1. Lavie M, Amirav I. In defense of high-speed video microscopy inevaluating patients with suspected primary ciliary dyskinesia. Am JRespir Crit Care Med 2019;200:1181–1183.2. Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, et al.European Respiratory Society guidelines for the diagnosis of primaryciliary dyskinesia. Eur Respir J 2017;49:1601090.3. Shapiro AJ, Davis SD, Polineni D, Manion M, Rosenfeld M, Dell SD, et al.;American Thoracic Society Assembly on Pediatrics. Diagnosis ofprimary ciliary dyskinesia. An official American Thoracic Societyclinical practice guideline. Am J Respir Crit Care Med 2018;197:e24–e39.4. Rubbo B, Shoemark A, Jackson CL, Hirst R, Thompson J, Hayes J,et al.; National PCD Service, UK. Accuracy of high-speed videoanalysis to diagnose primary ciliary dyskinesia. Chest 2019;155:1008–1017.5. LeighMW, Ferkol TW, Davis SD, Lee HS, Rosenfeld M, Dell SD, et al. Clinicalfeatures and associated likelihood of primary ciliary dyskinesia inchildren and adolescents. Ann Am Thorac Soc 2016;13:1305–1313.6. Behan L, Dimitrov BD, Kuehni CE, Hogg C, Carroll M, Evans HJ, et al.PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia.Eur Respir J 2016;47:1103–1112.Copyright © 2020 by the American Thoracic SocietyHigh-Speed Videomicroscopy Analysis PresentsLimitations in Diagnosis of Primary Ciliary DyskinesiaTo the Editor:In response to the letter by Dr. Lavie and Dr. Amirav highlightingthe use of high-speed videomicroscopy analysis (HSVA) in a patientwith suspected primary ciliary dyskinesia (PCD) (1), we standby the American Thoracic Society (ATS) PCD diagnostic guidelinerecommendation. This recommendation specifically states thatclinicians should avoid using HSVA as a replacement diagnostictest for transmission electron microscopy (TEM) and/or extendedgenetic panel testing (2). Although we appreciate the authors’opinion and argument for the use of HSVA as a diagnostic tool inPCD, we have concerns about their anecdotal evidence andreference to publications with methodologic bias.First, they reference a publication reporting near-perfectsensitivity and specificity of HSVA testing for PCD (3). Inthis article, randomly selected HSVA case interpretations fromblinded experts, at three separate centers in England, areretrospectively analyzed for diagnostic accuracy. Thispublication has numerous methodologic biases (explained in arecently published letter [4]) that affect data interpretationand likely inflate the diagnostic accuracy. No otherpublication has examined the diagnostic accuracy of HSVAagainst PCD genetic testing. Thus, the true diagnosticaccuracy of HSVA in the era of PCD genomics remainsunclear, but it is likely lower than the values described in thatarticle.No single diagnostic test can exclude PCD. TEM and genetictesting individually miss approximately 30% of PCD diagnoses.The authors claim that in one case, normal HSVA “helped todetermine a diagnosis of PCD in this patient as being highlyunlikely,” even though the patient had a strong PCD phenotypeand repeatedly low nasal nitric oxide (nNO) values. Defects in atleast six known PCD-associated genes (HYDIN, CCDC164,DNAH9, GAS8, CCNO, and MCIDAS) result in normal ornondiagnostic HSVA, and more common genes (DYX1C1,RSPH1, and RSPH4A) have unexpected beat patterns for theircorresponding axonemal defects, making HSVA nondiagnostic inthese cases as well. Despite the well-recognized possibility ofPCD with normal HSVA, the authors do not present any TEM orgenetic testing results in their case and dismiss this patient fromfurther PCD therapies. Their decision to ignore the repeatedlylow nNO values as a consequence of sinus surgeries isconcerning, as nNO levels typically increase in non-PCDpatients after sinus surgery (5). The ATS PCD guidelines wereprioritized to avoid this scenario, in which patients with PCDare dismissed because of false-negative results on a singlediagnostic test.Finally, the authors claim the “simplicity of use andexpeditious results” of HSVA should prompt the ATS toreconsider its PCD diagnostic guidelines. However, there isnothing simple about HSVA studies, as they remainnonstandardized in both sample preparation and beat patterninterpretation. Moreover, to avoid secondary causes ofdyskinesia giving false-positive results, the European RespiratorySociety PCD guidelines also strongly recommend regrowth ofciliary samples at the air–liquid interface before HSVAanalysis (6). This arduous, weeks-long regrowth processrequires highly specialized laboratory expertise and refutes theclaim of “expeditious results,” leading to an immediate PCDdiagnosis. Most important, no studies have shown that HSVAcan be reliably and accurately performed outside of a few expertcenters (2).The ATS PCD diagnostic guidelines are rooted in science withrigorous methodology. Although not perfect, they represent themost rigorous review and analysis of scientific publications onPCD diagnosis and prioritize limiting false-negative diagnoses inwhich patients will suffer without proper, long-term PCDtherapies. Until prospective, well-designed, multicenter studiesare completed, the ATS guideline committee cannot recommendHSVA as a clinical diagnostic test for PCD. nThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contribution: All authors created and edited the manuscript.Originally Published in Press as DOI: 10.1164/rccm.201907-1366LE onAugust 21, 2019CORRESPONDENCE122 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 1 | January 1 2020

Amelia Shoemark (631175)

Bruna Rubbo (287422)

Eric Haarman (7401878)

Robert A Hirst (8413239)

Claire Hogg (4913242)

Claire L Jackson (8413242)

Kim G Nielsen (8413245)

Jean-Francois Papon (8413248)

Philip Robinson (17437)

Woolf T Walker (8413251)

Jane S Lucas (8413254)

Leicester Research Archive

                                                                    University of DundeeThe Controversies and Difficulties of Diagnosing Primary Ciliary DyskinesiaShoemark, Amelia; Rubbo, Bruna; Haarman, Eric; Hirst, Robert A.; Hogg, Claire; Jackson,Claire L.Published in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201907-1334LEPublication date:2020Licence:CC BY-NC-NDDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Shoemark, A., Rubbo, B., Haarman, E., Hirst, R. A., Hogg, C., Jackson, C. L., Nielsen, K. G., Papon, J. F.,Robinson, P., Walker, W. T., & Lucas, J. S. (2020). The Controversies and Difficulties of Diagnosing PrimaryCiliary Dyskinesia. American Journal of Respiratory and Critical Care Medicine, 201(1), 120-122.https://doi.org/10.1164/rccm.201907-1334LEGeneral rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 24. Sep. 2025Jean Bourbeau, M.D., M.Sc.McGill University Health CentreMontreal, Quebec, CanadaandMcGill UniversityMontreal, Quebec, Canada*Corresponding author (e-mail: sebastien.gagnon3@mail.mcgill.ca).References1. Bhatt SP, Patel SB, Anderson EM, Baugh D, Givens T, Schumann C, et al.Video telehealth pulmonary rehabilitation intervention in COPD reduces30-day readmissions. Am J Respir Crit Care Med [online ahead of print]12 Apr 2019; DOI: 10.1164/rccm.201902-0314LE. Published in final formas Am J Respir Crit Care Med 2019;200:511–513.2. Criner GJ, Bourbeau J, Diekemper RL, Ouellette DR, Goodridge D,Hernandez P, et al. Executive summary: prevention of acute exacerbationof COPD: American College of Chest Physicians and Canadian ThoracicSociety Guideline. Chest 2015;147:883–893.3. Harrison SL, Robertson N, Graham CD, Williams J, Steiner MC, MorganMD, et al. Can we identify patients with different illness schemafollowing an acute exacerbation of COPD: a cluster analysis. RespirMed 2014;108:319–328.4. Man WD, Puhan MA, Harrison SL, Jordan RE, Quint JK, Singh SJ.Pulmonary rehabilitation and severe exacerbations of COPD: solutionor white elephant? ERJ Open Res 2015;1:00050-2015.5. Czajkowski SM, Powell LH, Adler N, Naar-King S, Reynolds KD, Hunter CM,et al. From ideas to efficacy: the ORBIT model for developing behavioraltreatments for chronic diseases. Health Psychol 2015;34:971–982.6. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al.; LookAHEAD Research Group. Cardiovascular effects of intensive lifestyleintervention in type 2 diabetes. N Engl J Med 2013;369:145–154.Copyright © 2020 by the American Thoracic SocietyReply to Gagnon et al.From the Authors:We thank Dr. Gagnon and colleagues for their interest andcomments. Because of the constraints of a research letter, we were notable to provide all the details of the telehealth intervention. Briefly,each video session was designed to mimic the components of center-based pulmonary rehabilitation (PR) and lasted 45 to 60minutes. Thesessions included stretching and breathing exercises forapproximately 10 minutes; aerobic exercises using a foot peddler orwalking for 10 and 20 minutes in those with low and high baselinefunctional capacity, respectively; and strength training with stretchbands for 10minutes. Educational sessions were interspersed betweenthese exercise periods. We agree with Dr. Gagnon and colleagues thatthe interval between the initiation of PR and 30 days is short, and thuswe may not see meaningful changes in functional capacity. The 30-day time point was chosen based on our primary outcome of hospitalreadmission (1). We disagree that the higher proportion of patientson domiciliary oxygen in the group exposed to PR may havecontributed to improved outcomes, as this suggests more severe andperhaps less-responsive disease. We acknowledge that the study wasnot randomized and that we did not collect data on the number ofpatients approached and reasons for patient refusal to participate.These limitations in part underlie our call for well-conductedrandomized trials to test the efficacy of our intervention. They alsomake a case that behavioral changes could have had a significantimpact. Although we did not systematically study this in bothgroups, the emotional guardedness domain of the psychosocial riskfactor survey did improve with telehealth PR (2). nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Surya P. Bhatt, M.D., M.S.P.H.*Mark T. Dransfield, M.D.University of Alabama at BirminghamBirmingham, AlabamaORCID ID: 0000-0002-8418-4497 (S.P.B.).*Corresponding author (e-mail: sbhatt@uabmc.edu).References1. Bhatt SP, Patel SB, Anderson EM, Baugh D, Givens T, Schumann C, et al.Video telehealth pulmonary rehabilitation intervention in COPD reduces30-day readmissions. Am J Respir Crit Care Med 2019;200:511–513.2. Eichenauer K, Feltz G, Wilson J, Brookings J. Measuring psychosocialrisk factors in cardiac rehabilitation: validation of the psychosocial riskfactor survey. J Cardiopulm Rehabil Prev 2010;30:309–318.Copyright © 2020 by the American Thoracic SocietyThe Controversies and Difficulties of DiagnosingPrimary Ciliary DyskinesiaTo the Editor:We welcome the correspondence from Lavie and Amirav(1), highlighting the difficulties diagnosing primary ciliarydyskinesia (PCD) and the role of high-speed video analysis(HSVA). As members of the European RespiratorySociety (ERS) PCD Diagnostic Task Force (2) and/or largePCD Centres, we agree that HSVA has an important rolethat is not recognized by the American Thoracic Society(ATS) PCD Diagnostic Guideline (3). This risks a largeThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by NIH grant K23HL133438 (S.P.B.).Originally Published in Press as DOI: 10.1164/rccm.201907-1486LE onAugust 6, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: A.S. and J.S.L. provided the concept and drafted thecorrespondence; all authors commented and approved the manuscript.The authors are members of European Respiratory Society Task Force (TF-2014-04) and BEAT-PCD network (COST Action BM 1407).Originally Published in Press as DOI: 10.1164/rccm.201907-1334LE onAugust 21, 2019CORRESPONDENCE120 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 1 | January 1 2020proportion of false-negative “missed” diagnoses and a sizablenumber of false-positive cases; we make additional importantobservations.We agree with Lavie and Amirav that nasal nitric oxide(nNO) should not be used in isolation to make a diagnosis orto exclude PCD. The risk for false-negatives is clearly describedin the literature (reviewed in Reference 2). The ERS Guidelinestherefore suggest that both nNO and HSVA should be entirelynormal before deciding that further investigation is notwarranted (2). We all have patients who proceeded to furthertesting because clinical history was strong or HSVA wasabnormal despite normal nNO, and then had a diagnosisconfirmed by transmission electron microscopy (TEM) orgenetics (e.g., CCDC103, DNAH9, or RSPH1 mutations).Contrary to Lavie and Amirav, neither ATS nor ERS guidelineswould exclude the diagnosis of PCD in patients with acompatible history and diagnostically low nNO despite normalHSVA, without proceeding to further tests including TEMand genetics.Similarly to Lavie and Amirav, we were surprised that theATS guideline specifically suggests not assessing ciliary beatpattern. Dyskinesia is a key feature of the condition andcan be accurately detected by HSVA (4). According to theERS Guidelines, repeatedly dyskinetic cilia or abnormalbeat pattern following reanalysis after culture, with normalgenetics and TEM, indicates PCD is “highly likely” (2),and patients should follow a PCD treatment plan (2).This recognizes that TEM and genetics will each be normalin 20–30% (2) of patients who truly have PCD (falsenegative), and that HSVA will detect most of these patientswho require specialist PCD care. Until HYDIN, DNAH11, andGAS8 were discovered as PCD genes, the patients wererecognized by abnormal HSVA, and until all genetic causes areidentified, HSVA is needed. It also acknowledges that evenrepeatedly abnormal HSVA may be falsely positive, andtherefore the ERS Guidelines recommend that patients are notlabeled as definitely having PCD based on HSVA alone (2, 4).Importantly, HSVA provides an accurate result on theday of testing that can be used to counsel patients andcommence treatment while awaiting confirmatory TEMand genetics (4). HSVA also has an important researchvalue, assessing the ability of novel treatments to restorefunction.There are a large number of PCD genes, and becauseof their size, variants are common; not infrequently,patients without PCD have biallelic variants of unknownsignificance in PCD-related genes. The specificity of genetictesting is severely reduced, and many individuals couldbe incorrectly diagnosed with PCD (false positive) unlessthe mutations are confirmed pathogenic. It is thereforeessential to ensure that the genotype is compatible withthe ciliary phenotype using HSVA, TEM, and/orimmunofluorescence labeling, as well as with the clinicalphenotype (2).Importantly, there is no perfect way to identifypatients for diagnostic testing based on clinical assessment.Lavie and Amirav outline the approach proposed by the ATSGuideline, using a four-point clinical symptoms score.Having two of four clinical features provides specificity(0.72), ensuring that the diagnostic service only sees themost likely cases, but we suggest it has insufficient sensitivityfor screening (0.8), meaning that 20% of patients withPCD are not tested and will therefore never be correctlydiagnosed (5). The ERS Guideline provides a flexibleapproach (“patients with several typical features” [2]), orsuggests a clinical predictive score called Primary CiliaryDyskinesia Rule (PICADAR), which has good sensitivity andspecificity (cutoff, 4; 0.97, specificity, 0.48) (6). Therefore,PICADAR may correctly identify 97% of patients who requirefurther testing, while not inappropriately overwhelmingdiagnostic services, as approximately 50% of patients will turnout to have PCD. Both scores need validating in primarycare settings. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Amelia Shoemark, Ph.D.Royal Brompton HospitalLondon, United KingdomandUniversity of DundeeDundee, United KingdomBruna Rubbo, M.Sc.University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomEric Haarman, M.D.VU University Medical CenterAmsterdam, The NetherlandsRobert A. Hirst, Ph.D.University of Leicester, RKCSBLeicester, United KingdomClaire Hogg, M.D.Royal Brompton HospitalLondon, United KingdomandImperial College LondonLondon, United KingdomClaire L. Jackson, Ph.D.University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomKim G. Nielsen, M.D.Copenhagen University HospitalRigshospitalet, DenmarkJean-Francois Papon, M.D.Universite Paris-Sud, Faculté de MédecineParis, FrancePhilip Robinson, M.D.Royal Children’s HospitalMelbourne, AustraliaCORRESPONDENCECorrespondence 121Woolf T. Walker, M.D., Ph.D.Jane S. Lucas, M.D., Ph.D.*University Hospital Southampton NHS Foundation TrustSouthampton, United KingdomandUniversity of Southampton Faculty of MedicineSouthampton, United KingdomORCID IDs: 0000-0002-1629-8601 (B.R.); 0000-0003-1989-1790 (R.A.H.);0000-0002-8368-5994 (C.H.); 0000-0002-1200-0935 (C.L.J.);0000-0001-5906-9449 (K.G.N.); 0000-0001-6129-9075 (P.R.);0000-0001-8701-9975 (J.S.L.).*Corresponding author (e-mail: jlucas1@soton.ac.uk).References1. Lavie M, Amirav I. In defense of high-speed video microscopy inevaluating patients with suspected primary ciliary dyskinesia. Am JRespir Crit Care Med 2019;200:1181–1183.2. Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, et al.European Respiratory Society guidelines for the diagnosis of primaryciliary dyskinesia. Eur Respir J 2017;49:1601090.3. Shapiro AJ, Davis SD, Polineni D, Manion M, Rosenfeld M, Dell SD, et al.;American Thoracic Society Assembly on Pediatrics. Diagnosis ofprimary ciliary dyskinesia. An official American Thoracic Societyclinical practice guideline. Am J Respir Crit Care Med 2018;197:e24–e39.4. Rubbo B, Shoemark A, Jackson CL, Hirst R, Thompson J, Hayes J,et al.; National PCD Service, UK. Accuracy of high-speed videoanalysis to diagnose primary ciliary dyskinesia. Chest 2019;155:1008–1017.5. LeighMW, Ferkol TW, Davis SD, Lee HS, Rosenfeld M, Dell SD, et al. Clinicalfeatures and associated likelihood of primary ciliary dyskinesia inchildren and adolescents. Ann Am Thorac Soc 2016;13:1305–1313.6. Behan L, Dimitrov BD, Kuehni CE, Hogg C, Carroll M, Evans HJ, et al.PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia.Eur Respir J 2016;47:1103–1112.Copyright © 2020 by the American Thoracic SocietyHigh-Speed Videomicroscopy Analysis PresentsLimitations in Diagnosis of Primary Ciliary DyskinesiaTo the Editor:In response to the letter by Dr. Lavie and Dr. Amirav highlightingthe use of high-speed videomicroscopy analysis (HSVA) in a patientwith suspected primary ciliary dyskinesia (PCD) (1), we standby the American Thoracic Society (ATS) PCD diagnostic guidelinerecommendation. This recommendation specifically states thatclinicians should avoid using HSVA as a replacement diagnostictest for transmission electron microscopy (TEM) and/or extendedgenetic panel testing (2). Although we appreciate the authors’opinion and argument for the use of HSVA as a diagnostic tool inPCD, we have concerns about their anecdotal evidence andreference to publications with methodologic bias.First, they reference a publication reporting near-perfectsensitivity and specificity of HSVA testing for PCD (3). Inthis article, randomly selected HSVA case interpretations fromblinded experts, at three separate centers in England, areretrospectively analyzed for diagnostic accuracy. Thispublication has numerous methodologic biases (explained in arecently published letter [4]) that affect data interpretationand likely inflate the diagnostic accuracy. No otherpublication has examined the diagnostic accuracy of HSVAagainst PCD genetic testing. Thus, the true diagnosticaccuracy of HSVA in the era of PCD genomics remainsunclear, but it is likely lower than the values described in thatarticle.No single diagnostic test can exclude PCD. TEM and genetictesting individually miss approximately 30% of PCD diagnoses.The authors claim that in one case, normal HSVA “helped todetermine a diagnosis of PCD in this patient as being highlyunlikely,” even though the patient had a strong PCD phenotypeand repeatedly low nasal nitric oxide (nNO) values. Defects in atleast six known PCD-associated genes (HYDIN, CCDC164,DNAH9, GAS8, CCNO, and MCIDAS) result in normal ornondiagnostic HSVA, and more common genes (DYX1C1,RSPH1, and RSPH4A) have unexpected beat patterns for theircorresponding axonemal defects, making HSVA nondiagnostic inthese cases as well. Despite the well-recognized possibility ofPCD with normal HSVA, the authors do not present any TEM orgenetic testing results in their case and dismiss this patient fromfurther PCD therapies. Their decision to ignore the repeatedlylow nNO values as a consequence of sinus surgeries isconcerning, as nNO levels typically increase in non-PCDpatients after sinus surgery (5). The ATS PCD guidelines wereprioritized to avoid this scenario, in which patients with PCDare dismissed because of false-negative results on a singlediagnostic test.Finally, the authors claim the “simplicity of use andexpeditious results” of HSVA should prompt the ATS toreconsider its PCD diagnostic guidelines. However, there isnothing simple about HSVA studies, as they remainnonstandardized in both sample preparation and beat patterninterpretation. Moreover, to avoid secondary causes ofdyskinesia giving false-positive results, the European RespiratorySociety PCD guidelines also strongly recommend regrowth ofciliary samples at the air–liquid interface before HSVAanalysis (6). This arduous, weeks-long regrowth processrequires highly specialized laboratory expertise and refutes theclaim of “expeditious results,” leading to an immediate PCDdiagnosis. Most important, no studies have shown that HSVAcan be reliably and accurately performed outside of a few expertcenters (2).The ATS PCD diagnostic guidelines are rooted in science withrigorous methodology. Although not perfect, they represent themost rigorous review and analysis of scientific publications onPCD diagnosis and prioritize limiting false-negative diagnoses inwhich patients will suffer without proper, long-term PCDtherapies. Until prospective, well-designed, multicenter studiesare completed, the ATS guideline committee cannot recommendHSVA as a clinical diagnostic test for PCD. nThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contribution: All authors created and edited the manuscript.Originally Published in Press as DOI: 10.1164/rccm.201907-1366LE onAugust 21, 2019CORRESPONDENCE122 American Journal of Respiratory and Critical Care Medicine Volume 201 Number 1 | January 1 2020

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The Controversies and Difficulties of Diagnosing Primary Ciliary Dyskinesia

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