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INVITED REVIEW SERIES: TUBERCULOSISSERIES EDITORS: WING WAI YEW, GIOVANNI B. MIGLIORI AND CHRISTOPH LANGE

Tuberculosis, bronchiectasis and chronic airflow obstructionTONI S. JORDAN, ELSPETH M. SPENCER AND PETER DAVIES

TB Unit, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool, UK

ABSTRACT

Both tuberculosis and bronchiectasis carry a signifi-cant burden worldwide in terms of morbidity and mor-tality, as well as financial, especially in the developingworld. Epidemiological data for tuberculosis are now

more readily available since the World Health Organi-sation declared it a global emergency in 1993. Theglobal prevalence of bronchiectasis, a recognizedsequel of tuberculosis, is unknown, but is by no meansinsignificant. The pathophysiology of chronic airflowobstruction in both of these diseases is poorly under-stood, but it is associated with an accelerated rate ofloss in pulmonary function. This article examines theglobal burden of tuberculosis and bronchiectasis, andfocuses on the interrelation with chronic airflowobstruction.

Key words: bronchiectasis, chronic airflow obstruction,mycobacteria, tuberculosis.

INTRODUCTION resp_1749 623..628

Despite many advances in modern medicine, bothtuberculosis and bronchiectasis remain significant

public health problems in developed countries andthe developing world. A significant proportion ofpatients with pulmonary tuberculosis may developbronchiectasis as a sequel to the disease. These dis-eases carry a significant burden worldwide in terms ofmorbidity and mortality, as well as financially to theaffected population. In addition, they are associatedwith chronic airflow obstruction, regardless ofsmoking status. This article focuses on the develop-ment of chronic airflow obstruction associated withtuberculosis and bronchiectasis, reviewing longitudi-nal changes in pulmonary function and outcome.

TUBERCULOSIS ANDBRONCHIECTASISTHE BURDENOF DISEASE

Tuberculosis has been known to man for many cen-

turies and is caused by the bacillus Mycobacteriumtuberculosis, a member of the mycobacterium family.It has made a re-emergence in recent decades to suchan extent that in 1993 the World Health Organisationdeclared tuberculosis as a global emergency.1 Themode of transmission in humans is by inhalation ofinfected aerosol droplets, and usually causes diseasein the lungs. However, any system in the body may beaffected. Only the pulmonary form is infectious. Everyyear it is estimated that nine million new cases oftuberculosis and nearly two million deaths fromtuberculosis occur around the world. Tuberculosisremains the leading cause of death among curableinfectious disease.2 Globally, there were an estimated9.27 million incident cases of tuberculosis in 2007,which equates to 137 cases per 100 000 population.This is an increase from 9.24 million cases in 2006 andin turn 8.3 million cases in 2000 and 6.6 million casesin 1990. Most of the cases in 2007 were in Asia (55%)and Africa (31%), with a fewer number in the EasternMediterranean Region (6%), the European Region(5%) and the America Regions (3%). An estimated511 000 cases reported were multi-drug-resistanttuberculosis.2 In the UK, 8417 cases of tuberculosiswere reported in 2007, equivalent to 13.8 per 100 000population.3 Most cases were in England (92%),mainly in the major cities. Of these 55% had pulmo-nary disease, a decrease since 2000, when 60% were

Professor Peter Davies qualified at Oxford and St Tomass

Hospital in 1973. He was appointed a Consultant Respiratory

Physician to Fazakerly Hospital (now Aintree University Hospital)

and the Cardiothoracic Centre Trusts, Liverpool in 1988. In 1990

he set up the Tuberculosis Research and Resources Unit

(TBRRU), which he is Director of and from where he has con-

ducted research into many epidemiological aspects of TB in

Liverpool and other parts of the world. He is the editor of Clinical

Tuberculosis, now in its fourth edition and the only international

standard reference book on clinical aspects of TB published

outside the USA. In 2004 he was appointed Honorary Professor

to Liverpool University. Dr Toni Jordan qualified from Liverpool

School of Medicine in 2001. She is a Specialist Registrar in res-

piratory medicine, currently based at the Liverpool Heart and

Chest Hospital, where she is working with Professor Davies in his

TB unit. Dr Elspeth Spencer qualified at Liverpool Medical School

in 2001. She is a Specialist Registrar in respiratory medicine in

the Mersey deanery. Earlier in 2009 she worked with Professor

Davies at Liverpool Heart & Chest Hospital and is now continuing

her training at the Royal Liverpool University Hospital.

Correspondence: Toni S. Jordan, TB Unit, Liverpool Heart and

Chest Hospital, Thomas Drive, Liverpool, L14 3PE, UK. Email:

t.jordan@nhs.net

Received 16 November 2009; Invited to revise 18 November

2009; Revised 26 November 2009; Accepted 27 November 2009.

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reported to have pulmonary involvement. In the UK,there has been a gradual increase in exclusively extra-pulmonary tuberculosis, rising by 5% over the past5 years to the current 45%.

Worldwide, in 2007, an estimated 1.32 million (19.7per 100 000 population) tuberculosis deaths werein HIV-negative people.2 There were an additional456 000 deaths in HIV-positive individuals,2 which

accounted for23% of HIVdeaths that occurred in 2007globally.4 In people with latent tuberculosis, the risk ofdeveloping tuberculosis disease is between 10% and20%.5,6 This risk may increase if people are coinfectedwith HIV.710 The incidence of tuberculosis is stronglyassociated withadultHIV prevalence; hence countrieswith epidemic levels of HIV will also experience a sig-nificantly greater burden of tuberculosis.10

The association between pulmonary tuberculosisand bronchiectasis was first noted by Laennec (theinventor of the stethoscope) in 1819 when he noticedcrackles in the lungs of patients with tuberculosisand pneumonia. This association was supported byGrancher in 1878, who recognized bronchiectasis

as a sequel to pulmonary tuberculosis,11

which waslater confirmed by several post-mortem studies ofpeople who had died from tuberculosis.12,13 Thesestudies found the incidence of bronchiectasis torange between 19% and 65%, with a higher incidencein the fibroid stage of the disease.13 Childhood studiessuggest bronchiectasis associated with tuberculosis isthe result of protracted bronchial obstruction by com-pression from enlarged hilar and interlobar lymphnodes or by infiltration of bronchial walls by caseouslymph nodes.14 In the aetiology of bronchiectasis,pulmonary infections are a significant cause account-ing for approximately one-third of cases.1519 Theproportion attributable to tuberculosis is highly vari-

able, ranging from 1% to 32%.

13,16,17,1921

The cause isunknown in a sizeable percentage of cases, in someseries, in excess of 50%.17,20,22 Other associationsinclude cystic fibrosis, primary and secondary ciliarydyskinesia, immunodeficiency syndromes and rheu-matoid arthritis (Table 1).

Bronchiectasis is manifested by irreversible dilata-tion of bronchi with destruction of elastic andmuscular elements of bronchial walls. The term bron-chiectasis is derived from the Greek bronchionmeaning windpipe and ektasismeaning stretched. It ischaracterized by recurrent respiratory infections, pro-ductive cough, breathlessness and at times haemop-tysis. Chronic airflow obstruction is also a feature.

The worldwide incidence of bronchiectasis isunknown. It appears to have declined in recentdecades, especially in developed countries of theworld, possibly because of effective anti-tuberculosistherapy and immunization against pertussis andmeasles.15,23 However, bronchiectasis remains a sig-nificant cause of chronic lung disease.2426 IntheUK,ithas been estimated to have an incidence rate at 1.061.3 per 100 000 population.27 High rates have beenobserved in Turkey, where there is believed to be agenetic predisposition within sections of the popula-tion, and people of Polynesian and Alaskan Nativeancestory.28 It is a chronic disease, so prevalence ismuch higher. In the USA, the prevalence of non-cystic

fibrosis bronchiectasis was estimated at 32.3 per100 000 population in 2005 with the prevalenceincreasing with advancing age.26 A higher prevalencehas also been reported in relatively isolated popula-

tions where access to health care is limited.

2830

Theestimated prognosis for patients with bronchiectasisis better than for those with COPD, but poorer thanfor patients with asthma.31 Keistinenet al. estimatedthe risk of death at 1.25 (95% CI: 1.151.36) for COPDpatients and 0.79 (95% CI: 0.710.87) for asthmaticsrelative to patients with bronchiecatasis. The risk ofdeath was increased by a factor of 1.25 with tubercu-losis coinfection in patients with bronchiectasis.

In terms of health economics, respiratory diseasewas the third most commonly reported chronic illnessin Great Britain in 2004, with an estimated cost tothe NHS of 6600m ($11 815m).32 Over 6% of peoplereported having a chronic respiratory illness withhigher rates in older age groups. Respiratory diseasewas the reason for more consultations with a generalpractitioner than any other type of long-term illness.In 2002/2003, 25 million working days were lost due toincapacity from respiratory disease, equating to anestimated 1728m ($9537m) in lost production.

In the USA, people with non-cystic fibrosis bron-chiectasis had on average an additional 2 days in hos-pital, 6.1 extra outpatient visits and 27.2 more days ofantibiotic therapy than those without the disease in2001.26 The annual treatment costs are estimated to be$630m. A report on the burden of lung disease inHong Kong in 2005 by the Hong Kong ThoracicSociety ranked bronchiectasis as the 5th highest

Table 1 Causes of and associations with bronchiectasis

Post-infection

Bacterial pneumonia

Virusesmeasles, pertussis

Allergic bronchopulmonary aspergillosis

Pulmonary tuberculosis

Congenital

Cystic fibrosisPrimary ciliary dyskinesia

Alpha1 antitrypsin deficiency

Pulmonary sequestration

Marfans syndrome

Immunodeficiency syndromes

Hypogammaglobinaemia

Secondary, e.g. chemotherapy

Aspiration

Gastro-oesophageal reflux disease

Foreign body

Rheumatological disorders

Rheumatoid arthritis

SLE

Sjogrens syndrome

Relapsing polychondritis

Other causes

Secondary ciliary dyskinesia (Youngs syndrome)

Yellow nail syndrome

Inflammatory bowel disease

SLE, systemic lupus erythematosus.

TS Jordanet al.624

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cause of respiratory mortality and the 6th highestcause of hospitalization for a respiratory illness thataccounted for 1.75% of all hospital inpatient days. 25

The rate of hospitalization increased considerablywith older age, yet a significant proportion of theseadmissions occurred in people of working age.

The economic impact of tuberculosis is significantwith the greatest impact of tuberculosis in developing

countries.2 This is even more marked where there isa high prevalence of HIV10 where it predominantlyaffects a young working population. Many lack accessto health-care facilities and anti-tuberculosis medica-tions. The result may be a significant financial burdento the population,33 especially low-income families.34

Tuberculosis was ranked 7th in the leading causes ofdeath and disability globally in 1990 and is projectedto remain so by 2020, contributing up to 42.5 milliondisability adjusted life years.35,36

CHRONIC AIRFLOW OBSTRUCTIONIN BRONCHIECTASIS

AND TUBERCULOSIS

Progressive airflow obstruction causes disability andsymptoms such as cough, wheeze and breathlessnessthat occur initially on exertion and then ultimatelyat rest. Pulmonary tuberculosis, particularly in thedeveloping world,37 is a recognized risk factor for thedevelopment of chronic airflow obstruction.

The pathophysiology of airflow obstruction intuberculosis is multifactorial in nature.38,39 Endobron-chial involvement may produce localized bronchialobstruction and fibrosis, while tuberculous lymphad-enopathy can cause extrinsic bronchial compression.Parenchymal lung destruction can affect pulmonary

compliance resulting in an increased tendency forperipheral airways collapse and subsequent airtrapping.

In India, a study of 268 patients in a tertiary healthcentre showed that obliterative bronchiolitis was thecause of chronic airflow obstruction in 13% ofpatients, of which 78% were post-tuberculosis.40

Chronic airflow obstruction may be found at timeof diagnosis of tuberculosis or as a sequel, even fol-lowing successful treatment of the disease. In the1960s, of 1403 patients admitted to the ChicagoMunicipal TB Sanatorium, 23% had airflow obstruc-tion.39 Chronic airflow obstruction may developfollowing tuberculosis, particularly if disease is long-standing and there is extensive parenchymal involve-ment. This is seen more in developing countrieswhere patients are more likely to present with exten-sive parenchymal lung destruction secondary to inad-equately treated tuberculosis in addition to the highincidence of cigarette smoking.

Chronic airflow obstruction is also associated withpulmonary tuberculosis even after treatment hasended. A cohort of 74 Black Africans with severetuberculosis was studied. Thirteen patients had HIV,those with multi-drug-resistant tuberculosis wereexcluded.41 Treatment comprised standard modernanti-tuberculosis drugs for 6 months. Lung functionwas measured before and 6 months after treatment.

All patients improved symptomatically on treatmentand bacteriological eradication was confirmed.Lung function improved in 54% of patients (meanFEV1% predicted before treatment 69.6, after treat-ment 76.4) but in the remainder it deteriorated orwas unchanged despite radiological improvement.Improvement in lung function did not appear to beaffected by smoking habit. The HIV group failed to

demonstrate any improvement in lung function aftertreatment. At the end of treatment, 47% of patientshad normal lung function, 24% showed a restrictivepattern and 28% had airflow limitation.

The prevalence of airflow obstruction in patientswith pulmonary tuberculosis varies from 28%41 to68%.42 The prevalence of obstructive airways disease(FEV1/FVC < 70%) in 100 patients fully treated for pul-monary tuberculosis in a tertiary care teaching hospi-tal in India was 46%. Severity was mild (FEV1 >60%) in75%, moderate (FEV1 4059%) in 10% and severe(FEV1 < 40%) in 15%. The prevalence increased withduration since treatment completion.43

In a national survey of 13 826 adults in South Africa,

the strongest predictor of chronic bronchitis (definedas chronic productive cough) was a history of tuber-culosis: odds ratio (OR) 4.9 (95% CI: 2.69.2) for menand 6.6 (95% CI: 3.711.9) for women.44 The studyused self-reported symptoms and did not measurelung function. The risk of chronic bronchitis wasfound to be more strongly associated with previoustuberculosis than with smoking. A later study, whichdid use spirometry, confirmed the stronger associa-tion of chronic airflow obstruction with a history ofpulmonary tuberculosis.45 A large cross-sectional,population-based observational study of five LatinAmerican cities involving 5539 people found theoverall prevalence of COPD (defined as post-

bronchodilator FEV1/FVC