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A Woman With Dyspnea and Bronchiectasis
Leonard Riley, MD; Mark Brantly, MD; Ali Ataya, MD
A 41-year-old woman with an 8–p...
distribution and severity of this patient’s bronchiectasis and em-
physema(predominantlyupperlobesincysticfibrosisvslowerl...
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Antitrypsin deficiency

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AATD is an underdiagnosed genetic condition attributable to an inherited mutation in the α1-antitrypsin protease inhibitor of the proteolytic enzyme elastase, with an increased risk of pulmonary and hepatic disease.1 Individuals with AATD commonly present in
the fourth or fifth decade of life with symptoms of dyspnea and
cough with or without sputum production. AATD may also involve other organs and present with liver cirrhosis, panniculitis, or granulomatosis with polyangiitis.2,3 AATD classically produces a panlobular emphysema disproportionally affecting the lung bases, in contrast
to COPD related to tobacco smoke, which typically affects the
upper lobes.3 In the United States, the prevalence of AATD has been reported to be 1 in 5097 individuals and is responsible for 1% to 2%of COPD cases.2,4

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Antitrypsin deficiency

  1. 1. A Woman With Dyspnea and Bronchiectasis Leonard Riley, MD; Mark Brantly, MD; Ali Ataya, MD A 41-year-old woman with an 8–pack-year history of tobacco use presented for progres- sivecoughanddyspneaof4years’duration.Hercoughwasproductiveofyellow-greenspu- tumandtreatedwithantibioticsonmultipleoccasions,whichprovidedsomealleviationof her symptoms. She had no history of neonatal respiratory distress, nasal congestion, per- sistent urticaria, joint laxity, or illicit drug use. She denied a family history of liver cirrhosis, chronicobstructivepulmonarydisease(COPD),orcysticfibrosis.Examinationrevealedscat- tered wheezes and rhonchi on auscultation. Pulmonary function testing demonstrated a severe obstruction with a forced expiratory volume at 1 second (FEV1) of 0.79 L (28% of predicted),forcedvitalcapacity(FVC)of1.64L(47%ofpredicted),FEV1:FVCratioof48%, and a reduced diffusing capacity for carbon monoxide of 8.74 mL/min per mm Hg (23.75% of predicted), which was consistent with emphysema. Chest radiography followed by computed tomography (CT) of the chest showed lower lobe predominant emphysema and bronchiectasis (Figure). Diagnosis α1-Antitrypsin deficiency (AATD) What to Do Next B. Assess serum α1-antitrypsin level and genotype The key to the correct diagnosis in this case is the severe ob- structivepatternonpulmonaryfunctiontesting,CTofthechestdem- onstrating lower lobe predominant emphysema and bronchiecta- sis, and presentation during the fourth decade of life. Bronchoscopy with bronchoalveolar lavage and transbron- chial biopsy may be reasonable in pursuit of an infectious or ciliary dyskinesiaetiologyrelatedtothispatient’sbronchiectasisbutisun- likely to provide a unifying diagnosis with her emphysema. Inhaled nasal nitric oxide and ciliary dyskinesia genetic testing can be used toevaluateforciliarydyskinesia,buttheabsenceofneonatalrespi- ratorydistress,year-rounddailycoughandnasalcongestionbegin- ning before age 6 months, and situs inversus makes this diagnosis unlikely. A diagnosis of cystic fibrosis is also unlikely, given the Figure. Computed tomography of the chest. Left, Transverse view. Right, Coronal view. WHAT WOULD YOU DO NEXT? A. Order bronchoscopy with bronchoalveolar lavage and transbronchial biopsy B. Assess serum α1-antitrypsin level and genotype C. Order inhaled nasal nitric oxide and ciliary dyskinesia genetic testing D. Assess sweat chloride and cystic fibrosis genetic screening Clinical Review & Education JAMA Clinical Challenge jama.com (Reprinted) JAMA Published online July 5, 2019 E1 © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ AIIMS – Bhubaneswar by Ramachandra Barik on 07/06/2019
  2. 2. distribution and severity of this patient’s bronchiectasis and em- physema(predominantlyupperlobesincysticfibrosisvslowerlobes in AATD) without extrapulmonary manifestations or family history. Discussion AATD is an underdiagnosed genetic condition attributable to an inherited mutation in the α1-antitrypsin protease inhibitor of the proteolytic enzyme elastase, with an increased risk of pulmonary and hepatic disease.1 Individuals with AATD commonly present in the fourth or fifth decade of life with symptoms of dyspnea and cough with or without sputum production. AATD may also involve other organs and present with liver cirrhosis, panniculitis, or granu- lomatosis with polyangiitis.2,3 AATD classically produces a panlobu- lar emphysema disproportionally affecting the lung bases, in con- trast to COPD related to tobacco smoke, which typically affects the upper lobes.3 In the United States, the prevalence of AATD has been reported to be 1 in 5097 individuals and is responsible for 1% to 2% of COPD cases.2,4 The World Health Organization, American Thoracic Society, European Respiratory Society, and the COPD Foundation recom- mend testing of all individuals with COPD for AATD. However, there is significant cost associated with testing more than an estimated 174 million persons globally, and there is low uptake of this recommendation in clinical practice.3,5-7 Testing for AATD should be strongly considered when symptoms of emphysema occur in younger patients (<50 years), when there is a rapid decline in FEV1, or when there is a strong family history of COPD or liver cirrhosis.3,5,6 Common pathologic allele variations for α1-antitrypsin prote- ase inhibitor are named the “Z” allele and “S” allele.2 The allelic homozygous variation PI*ZZ accounts for approximately 95% of AATD and significantly increases the risk for severe lung disease.2 According to the National Heart, Lung, and Blood Institute Regis- try of AATD, which is composed of 97.3% of patients with PI*ZZ genotype, the mean FEV1:FVC ratio is 43%, with 83.9% individu- als reporting shortness of breath.8 One study showed that bron- chiectasis was a common phenotype in 95% of patients with PI*ZZ genotype; however, only 27% had symptoms of regular sputum production.9 As directed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD, treatment for AATD follows conventional therapy and includes inhaled long-acting muscarinic agonists, long-acting β-agonists, and corticosteroids. An option for additional therapy specifically for AATD is purified α1-antitrypsin infusion, termed “augmentation therapy.”10 Mul- tiple studies conducted to evaluate the efficacy of augmentation therapy suggest that it may slow the decline of lung function evaluated by pulmonary function testing or CT densitometry.1,2 Definitive randomized studies are lacking; however, based on concordant observational studies the American Thoracic Society recommends augmentation therapy for individuals with estab- lished airflow obstruction.6 Patient Outcome Testingrevealedaserumα1-antitrypsinlevelof18mg/dL(3.3μmol/L) (reference range, 100-300 mg/dL [18.4-55.2 μmol/L]) with a PI*ZZ genotype.Thepatientwasprovidedcounselingonavoidanceofto- baccosmokeaswellasotherinhaledirritantsandmaintainingpneu- mococcal and influenza immunizations. She initiated GOLD- directedbronchodilatortherapyandaugmentationtherapy,andher symptoms and results of pulmonary function testing have im- proved over the last 6 years. ARTICLE INFORMATION Author Affiliations: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, College of Medicine, University of Florida, Gainesville. Corresponding Author: Ali Ataya, MD, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, 1600 SW Archer Rd, M452, Gainesville, FL 32610 (AliAtaya@gmail.com). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Published Online: July 5, 2019. doi:10.1001/jama.2019.8606 Conflict of Interest Disclosures: None reported. Additional Contributions: We thank the patient for providing permission to share her information. Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Challenge. Please contact Dr McDermott at mdm608@northwestern.edu. REFERENCES 1. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. doi:10.1164/rccm.201108- 1428CI 2. Greene CM, Marciniak SJ, Teckman J, et al. α1-Antitrypsin deficiency. Nat Rev Dis Primers. 2016;2:16051. doi:10.1038/nrdp.2016.51 3. Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016;3(3):668-682. 4. O’Brien ML, Buist NRM, Murphey WH. Neonatal screening for alpha1-antitrypsin deficiency. J Pediatr. 1978;92(6):1006-1010. doi:10.1016/S0022-3476(78) 80388-6 5. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415. 6. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10. 1164/rccm.168.7.818 7. Soriano JB, Abajobir AA, Abate KH, et al; GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691-706. doi:10.1016/S2213- 2600(17)30293-X 8. McElvaney NG, Stoller JK, Buist AS, et al; α1-Antitrypsin Deficiency Registry Study Group. Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of α1-antitrypsin deficiency. Chest. 1997;111(2):394-403. doi:10.1378/chest.111.2.394 9. Parr DG, Guest PG, Reynolds JH, Dowson LJ, Stockley RA. Prevalence and impact of bronchiectasis in α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2007;176(12):1215-1221. doi:10. 1164/rccm.200703-489OC 10. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Am J Respir Crit Care Med. 2017;195(5):557-582. doi:10.1164/ rccm.201701-0218PP Clinical Review & Education JAMA Clinical Challenge E2 JAMA Published online July 5, 2019 (Reprinted) jama.com © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ AIIMS – Bhubaneswar by Ramachandra Barik on 07/06/2019

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