The Relationship of Chronic Sputum Expectoration to Physiologic, Radiologic, and Health Status Characteristics in α1-Antitrypsin Deficiency (PiZ)

doi:10.1378/chest.122.4.1247

Chest

Volume 122, Issue 4, October 2002, Pages 1247-1255

https://doi.org/10.1378/chest.122.4.1247 Get rights and content

Study objectives

First, to determine the relationships among chronic sputum expectoration (CSE), exacerbations, airflow obstruction, and emphysema in patients with α₁-antitrypsin deficiency (α₁-ATD) [PiZ]. Second, to use multivariate analysis to determine how these factors influence health status.

Design

Cross-sectional, single-center.

Setting

UK center for α₁-ATD, university teaching hospital.

Patients

One hundred seventeen nonsmoking patients underwent lung function testing, high-resolution CT (HRCT) scanning with density mask analysis, and health status assessment using the St. George's Respiratory Questionnaire (SGRQ) and short form 36 (SF-36) health survey questionnaire.

Results

Patients with CSE (n = 50) had worse postbronchodilator airflow obstruction than those who did not (p = 0.03), with a median FEV₁ of 1.15 L (interquartile range [IQR], 0.76 to 1.82) vs 1.44 L (IQR, 0.99 to 2.93), respectively, and higher HRCT scan voxel index (VI) values indicating more extensive emphysema (patients with CSE: median lower zone VI, 50; IQR, 28 to 61; patients without CSE: median lower zone VI, 41; IQR, 5 to 53; p = 0.04). Patients with CSE also had worse health status, as assessed by the SGRQ (p < 0.01 for all domains) and SF-36 questionnaire (p < 0.05 for seven of nine domains). Exacerbation frequency was greater in those patients with CSE (p < 0.001), with a median of two episodes per year (IQR, 1 to 3) vs 0.66 episodes per year (IQR, 0 to 2) for those without CSE. Stepwise linear regression analysis revealed FEV₁, exacerbation frequency, and lower zone VI to be the most important predictors of health status.

Conclusions

Among patients with α₁-ATD, those with CSE expectoration exhibit greater physiologic impairment and more extensive emphysema than those without. This is reflected in an inferior health status, which is also influenced independently by an increased exacerbation frequency in those with CSE.

Section snippets

Subjects

The group of study subjects consisted of the first 127 patients attending our department for assessment. All patients had a serum α₁-antitrypsin (α₁-AT) concentration of < 10 μM, and the phenotype was confirmed as PiZ (inferring a genotype PiZZ or PiZnull) by isoelectric focusing in a central US laboratory (Salt Lake City, UT). Augmentation therapy with α₁-AT is not licensed within the United Kingdom and, therefore, was not received by any of the study participants. Investigations and data

Results

The 117 nonsmoking PiZ patients displayed a wide range of lung function, although the median data indicated severe airflow obstruction (median FEV₁, 32% predicted; total range, 10 to 130% predicted) and reduced gas transfer (median Dlco/Va ratio, 71% predicted; total range, 4 to 148% predicted), which are conditions that are consistent with the presence of emphysema. This was confirmed by HRCT scan, and the VI values demonstrated lower zone predominance (p < 0.001), which is characteristic of α₁

Discussion

In this group of patients with α₁-ATD, CSE was associated with more severe airflow obstruction and emphysema. In addition, these patients demonstrated worse health status, as assessed by both disease-specific and generic instruments, and the initial analysis indicated that this relationship was independent of the degree of physiologic impairment, smoking history, and age.

Of importance in our study, sputum expectoration was neither sensitive nor specific for the presence of bronchiectasis on

References (30)

T Hajiro et al.
A comparison of the level of dyspnea vs disease severity in indicating the health-related quality of life of patients with COPD
Chest
(1999)
NL Muller et al.
“Density mask”: an objective method to quantitate emphysema using computed tomography
Chest
(1988)
C Yamamoto et al.
Airway inflammation in COPD assessed by sputum levels of interleukin-8
Chest
(1997)
B Foxman et al.
Chronic bronchitis: prevalence, smoking habits, impact, and antismoking advice
Prev Med
(1986)
AD Morgan et al.
Psychological factors contributing to disproportionate disability in chronic bronchitis
J Psychosom Res
(1983)
TL Petty
The National Mucolytic Study: results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis
Chest
(1990)
J Lieberman
Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency: a new hypothesis with supporting data
Chest
(2000)
JB Mullen et al.
Reassessment of inflammation of airways in chronic bronchitis
BMJ
(1985)
JB Mullen et al.
Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function
Thorax
(1987)
TR Martin et al.
The effects of chronic bronchitis and chronic air-flow obstruction on lung cell populations recovered by bronchoalveolar lavage
Am Rev Respir Dis
(1985)

D Stanescu et al.

Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils

Thorax

(1996)

C Fletcher et al.

The natural history of chronic airflow obstruction

BMJ

(1977)

J Vestbo et al.

Association of chronic mucus hypersecretion with FEV₁ decline and chronic obstructive pulmonary disease morbidity: Copenhagen City Heart Study Group

Am J Respir Crit Care Med

(1996)

P Lange et al.

Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes

Thorax

(1990)

TA Seemungal et al.

Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

(1998)

Cited by (40)

Thoracic CT Imaging in AATD
2017, Alpha-1-antitrypsin Deficiency: Biology, Diagnosis, Clinical Significance, and Emerging Therapies
Computed tomography (CT) has shown variability in the lung disease that occurs with alpha-1-antitrypsin deficiency (AATD). Basal emphysema has been the predominant recognized classical phenotype. CT has demonstrated that the pattern of emphysema is more varied and often involves the upper areas of the lung, thus a mixed phenotype is more common in AATD. Bronchiectasis has also been identified by CT in a proportion of AATD subjects suggesting that this is unlikely to be a coincidental finding. CT lung densitometry is also a useful parameter for a quantitative assessment of emphysema and is being used in clinical trials to measure responses to therapy.
α-1-Antitrypsin deficiency: Clinical variability, assessment, and treatment
2014, Trends in Molecular Medicine
Citation Excerpt :
Again, longitudinal follow-up of the Swedish birth cohort may provide further insight into whether asthma plays a role in the natural history of lung disease. Chronic bronchitis has been recognised as an important feature of usual COPD and is also a feature of AATD, affecting up to 40% of patients [26]. Chronic bronchitis is certainly associated with more evidence of neutrophilic inflammation in the airways [27], and this is greater than in usual COPD.
The recognition of α-1-antitrypsin deficiency, its function, and its role in predisposition to the development of severe emphysema was a watershed in our understanding of the pathophysiology of the condition. This led to the concept and development of intravenous replacement therapy used worldwide to protect against lung damage induced by neutrophil elastase. Nevertheless, much remained unknown about the deficiency and its impact, although in recent years the genetic and clinical variations in manifestation have provided new insights into assessing impact, efficacy of therapy, and development of new therapeutic strategies, including gene therapy, and outcome measures, such as biomarkers and computed tomography. The current article reviews this progress over the preceding 50 years.
COPD and alpha-1-antitrypsin deficiency
2010, Archivos de Bronconeumologia
El déficit de alfa-1-antitripsina (DAAT) es el primer factor genético relacionado con el desarrollo de enfisema. Esta proteína tiene numerosa variantes, algunas de las cuales tienen relevancia clínica porque su conformación anómala implica que no alcanzan los órganos diana por polimerizar en el hepatocito. La principal variante deficitaria es la PiZ. La acumulación de polímeros Z en el hígado condiciona la aparición de hepatopatía en un pequeño porcentaje de individuos. La falta de AAT en el pulmón favorece el desarrollo de enfisema al no contrarrestarse el efecto proteolítico de las elastasas, que es la principal función biológica de la AAT. En España, el número de casos diagnosticados de déficit grave de AAT es de aproximadamente 400 individuos, lo que representa menos del 10% de los esperados por los estudios epidemiológicos. El principal factor pronóstico en estos pacientes es el volumen espiratorio máximo en el primer segundo, condicionado principalmente por la exposición al tabaco, de manera que los individuos no fumadores tienen una esperanza de vida similar a la población general, mientras que los fumadores tienen una caída de la función pulmonar más acelerada que el resto de afectados por la enfermedad pulmonar obstructiva crónica (EPOC). El tratamiento de la enfermedad pulmonar es el mismo, aunque está indicado el tratamiento sustitutivo con AAT exógena cuando la función pulmonar se deteriora.
Alpha-1-antitrypsin deficiency (AATD) is the main genetic factor related to the development of emphysema. This protein has numerous variants, some of which are clinically relevant because their anomalous conformation implies that they fail to reach the target organs as they are polymerized in the hepatocyte. The main abnormal variant is PiZ. In a small percentage of individuals, the accumulation of Z polymers in the liver leads to the development of liver disease. The lack of AATD in the lung favors the development of emphysema, since the proteolytic effect of elastases – the main biological function of AATD – is not counteracted. In Spain, approximately 400 persons are diagnosed with severe AATD deficiency, representing less than 10 % of those expected by epidemiological studies. The principal prognostic factor in these patients is forced expiratory volume in one second (FEV₁), which is affected mainly by exposure to tobacco smoke. Thus, life expectancy in nonsmokers is similar to that in the general population while lung function decreases faster in smokers than in other patients with chronic obstructive pulmonary disease (COPD). The treatment of the lung disease is the same, although exogenous AATD augmentation is indicated when lung function deteriorates.
CT scan appearance, densitometry, and health status in protease inhibitor SZ α<inf>1</inf>-antitrypsin deficiency
2009, Chest
The aim of this study was to uniquely describe CT scan appearance, densitometry, and health status in subjects with protease inhibitor SZ phenotype (PiSZ) α₁-antitrypsin deficiency (AATD) compared with matched subjects with protease inhibitor ZZ phenotype (PiZZ).
The presence and type of emphysema seen on CT scan, upper and lower zone densitometry, health status, physiology, and symptoms were compared for 126 subjects (63 with PiSZ, 63 with PiZZ) from the UK AATD registry, matched for age, gender, and smoking status. Similar analyses were performed for lung index and nonindex subgroups.
A lower proportion of PiSZ index (46%) and non-PiSZ index (15%) subgroup case patients showed visible emphysema on CT scans compared with matched PiZZ index (91%; p < 0.001) and non-PiZZ index (61%; p = 0.011) case patients. Sixty-five percent of subjects with PiSZ and 74% with PiZZ had panacinar emphysema (p = 0.54); however, a greater proportion (p = 0.005) of the PiSZ group (39%) had upper zone-predominant emphysema compared with the PiZZ group (12%). Densitometric analysis revealed less extensive emphysema in the lower zones, but not the upper zones, of subjects with PiSZ than those with PiZZ. When subjects were matched for ascertainment method, health status was similar between the two phenotypes, despite the differences in CT scan and densitometry findings, and more abnormal respiratory physiology test results in subjects with PiZZ.
Subjects with PiSZ showed less emphysema on CT scans, more apical predominance, less abnormal respiratory physiology test results, but similar health status impairment compared with matched subjects with PiZZ.
Alpha-1 antitrypsin deficiency: Clinical differences and treatment of children and adults
2008, Anales de Pediatria Continuada
Nine controversial questions about augmentation therapy for alpha-1 antitrypsin deficiency: a viewpoint
2023, European Respiratory Review

View all citing articles on Scopus

: The Antitrypsin Deficiency Assessment and Programme for Treatment (ADAPT) project is supported by a noncommercial grant from Bayer plc. Dr. Stockley is a member of the α₁ International Registry (AIR).

View full text

Chest

Clinical InvestigationsThe Relationship of Chronic Sputum Expectoration to Physiologic, Radiologic, and Health Status Characteristics in α1-Antitrypsin Deficiency (PiZ)

Study objectives

Design

Setting

Patients

Results

Conclusions

Section snippets

Subjects

Results

Discussion

Chest

Chest

Chest

Prev Med

J Psychosom Res

Chest

Chest

Reassessment of inflammation of airways in chronic bronchitis

BMJ

Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function

Thorax

The effects of chronic bronchitis and chronic air-flow obstruction on lung cell populations recovered by bronchoalveolar lavage

Am Rev Respir Dis

Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils

Thorax

The natural history of chronic airflow obstruction

BMJ

Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity: Copenhagen City Heart Study Group

Am J Respir Crit Care Med

Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes

Thorax

Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Clinical Investigations
The Relationship of Chronic Sputum Expectoration to Physiologic, Radiologic, and Health Status Characteristics in α₁-Antitrypsin Deficiency (PiZ)

Association of chronic mucus hypersecretion with FEV₁ decline and chronic obstructive pulmonary disease morbidity: Copenhagen City Heart Study Group