Diseases of the Airway: A Clinical Perspective

Educational Objectives

The goal of this program is to improve screening and treatment of tuberculosis (TB) and pinpoint causes of chronic cough. After hearing and assimilating this program, the clinician will be better able to:

1.   Review risk factors for Mycobacterium tuberculosis exposure and infection, as well as factors that cause

reactivation of latent TB.

2.   Screen patients for TB using the tuberculin skin test or interferon-release assays.

3.   Describe the treatment and monitoring of patients with active TB.

4.   Discuss common and unusual causes of chronic cough, and methods to diagnose them.

5.   Treat chronic cough using multidrug approaches and speech pathology.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. However, in her lecture, Dr. Rees does present information that is related to off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Jasmer was recorded at the University of California, San Francisco, School of Medicine’s 30th Annual Advances in Infectious Diseases: New Directions for Primary Care, held May 6-8, 2009, in San Francisco, CA. Dr. Rees was recorded at the 29th Annual James A. Harrill Lecture, presented by the Department of Otolaryngology of Wake For­est University School of Medicine, and held April 24-25, 2009, in Winston-Salem, NC. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

What’s New in Tuberculosis

Robert M. Jasmer, MD, Associate Clinical Professor of Medicine, University of California, San Francisco, School of Medicine, and Staff Member, San Francisco General Hospital, San Francisco, CA  

Epidemiology of tuberculosis (TB): in 2008, 4.2 cases per 100,000 people in United States (lowest since 1950s); however, growing pool of infected individuals (due to influx of immigrants); among United States-born  —  number of cases decreasing; among foreign-born  —  increasing; San Francisco Bay area  —  »80% of cases occur in foreign-born

Screening for TB

Overview: perform symptom review to rule out active TB; if tests negative, rule out TB; exception  —  if patient in contact with recent active case, then consider treatment; retest after 8 wk; if positive  —chest x-ray; if chest x-ray ab­normal, consider active TB

Who should be screened? those in contact with infectious cases (»3 people infected for every TB case); people from TB-endemic countries (most countries outside United States, Canada, and Western Europe); places  —  hospitals, correctional facilities, nursing homes, renal dialysis units; populations  —homeless, migrant workers (seasonal basis), hotel dwellers, street drug-users, certain racial and ethnic minorities, and children of parents with TB

Risk factors for immune compromise: cause latent TB to become active TB at higher rate; HIV  —  common for pa­tients to have abnormal x-ray consistent with previous TB (upper lobe scarring with volume loss); often asymp­tomatic; 10% per year develop TB (much higher than average 10% lifetime risk); certain medical therapies  —  patients on steroids, chemotherapy, insulin, or dialysis; tumor necrosis factor-a inhibitors  —among patients not appropriately screened, significant number of TB-related deaths; relative risk similar to that of HIV

Abnormal x-rays: calcified granuloma  —  typical; does not increase risk for TB; may result from TB or other previ­ous infection; does not contain viable bacteria; asymptomatic stable fibrotic lesion  —  frequently seen in immi­grants; no definite cavities; increased markings and volume loss; right diaphragm and hilum pulled up; 10% grow Mycobacterium tuberculosis from sputum

Screening for Latent TB Infection (LTBI)

Tuberculin skin test (TST): inject 5 tuberculin units of purified protein derivative (PPD); delayed-type hypersensi­tivity reaction  —  read 2 to 3 days later for area of induration (not erythema); major limitation  —  patients who re­ceived Bacillus Calmette-Guérin (BCG) vaccine (strain of Mycobacterium bovis) test positive; most common vaccine worldwide; protects against childhood TB and disseminated TB, but not adult reactivation TB; other false positives  —  from nontuberculous mycobacteria (eg, Mycobacterium avium, Mycobacterium szulgai, Myco­bacterium marinum); interpretation of positive result depends on TB risk factors

TST interpretation:  ³5 mm induration  —  conclude positive if patient in high-risk category, eg, HIV coinfection, immune compromise, recent contact with TB, suspected disease; ³10 mm  —population categories, eg, foreign-born, health care workers, drug-users without HIV, children <4 yr of age; ³15 mm  —  with no risk factors, proba­bly did not need screen

Interferon-g (IFN-g) release assay (IGRA): blood-based; eg, QuantiFERON-TB and T-SPOT.TB tests; both mea­sure release of IFN-g from infected mononuclear cells after blood drawn and incubated with antigens; quantitative in vitro version of PPD; advantages over TST  —  minimal interreader variability; one patient visit (vs 2 for TST); antigens  —  relatively (not 100%) TB-specific; eg, ESAT-6 (early secretory antigenic target-6 kDa), CFP-10 (culture filtrate protein-10 kDa) not included in vaccines; Mycobacterium africanum, M bovis (not vaccine strain), and My­cobacterium kansasii test positive

Question: choose best way to rule out active TB (pre-nursing home); a) tuberculin; b) IGRA; c) chest x-ray; d) symp­toms (eg, cough, sweating, weight loss)

Answer: chest x-ray; TST and IGRA test for latent TB; if chest x-ray normal  —  can rule out pulmonary TB; laryngeal TB highly unlikely; symptom screening  —  also insensitive

Efficacy and cost: QuantiFERON-TB Gold  —  sensitivity 75% (same as TST); studies show specificity better than that of TST; T-SPOT.TB  —  requires extra purification of blood cells; more expensive but sensitivity better (90%) than Quanti-FERON-TB; current Centers for Disease Control and Prevention (CDC) guidelines  —  TST and IGRA effective for same populations; for frequent testing  —  speaker finds Quanti-FERON-TB easier to establish baseline blood values; costs  —$29 for QuantiFERON-TB Gold, including equipment and staff time; »$60 for T-SPOT.TB (requires more laboratory resources); cost of TST equivalent to that of IGRA if accounting for missed follow-ups

Other uses of IGRA: to monitor treatment efficacy for, eg, difficult to culture TB (extrapulmonary); not optimal to measure reversal of active TB

LTBI Treatment

Overview: treatment has not changed; 1st choice  —  isonicotinic acid hydrazide (INH) for 9 mo; 2nd choice  —  rifampin for 4 mo (few studies); rifampin and pyrazinamide for 2 mo  —  no longer recommended because of liver toxicity and death; age  —  treat regardless of age; duration of INH therapy  —  1982 study of »28,000 patients showed 75% reduction in TB with INH 12 mo vs 65% for 6 mo (not statistically significant); in compliant patients, 93% for 12 mo vs 69% for 6 mo; 12 mo better on individual basis (but higher rate of liver toxicity); Comstock (1999, Inter­national Journal of Tuberculosis and Lung Disease)  —  threshold at 9 mo based on extrapolation; no other evidence supporting 9 mo duration

Monitoring treatment: baseline liver enzymes  —  not recommended, except in patients who have HIV, are pregnant or immediately postpartum, or have history of liver disease or heavy alcohol use; standard of care  —  evaluate pa­tient monthly for adherence and symptoms of hepatitis

INH therapy-induced hepatitis: older studies  —  hepatitis in »2.5% patients on INH therapy; age and alcohol-re­lated; Nolan (1999) study  —  in Seattle patients, hepatitis risk 1 in 1000 (instead of 1 in 100)

Case example: man 71 yr of age presented with intermittent hemoptysis; history of TB (treated in Philippines >25 yr ago); abnormal x-ray (in left upper lobe); 3 sputum smears  —negative for acid-fast bacilli

Question: how to manage this patient? a) check IGRA; b) begin treatment for LTBI with INH; c) begin multidrug therapy for TB; d) repeat x-ray in 4 mo

Answer: c) begin multidrug therapy; signs consistent with TB; first, put patient in isolation; collect sputum for smears, and start treatment; TB class 5 (ie, high suspicion for TB); IGRA does not matter

Case update: 3 cultures tested negative for all mycobacteria; intermittent hemoptysis persists; received 3 mo of di­rectly observed therapy (INH, rifampin, ethambutol, and pyrazinamide)

Question: next step?; a) continue with same drugs for 3 mo; b) continue with 2 drugs (INH and rifampin) for 3 mo; c) obtain computed tomography (CT); d) stop drugs and obtain x-ray in 3 mo

Answer: c) obtain CT; if not active TB, drugs do not help determine cause

Case conclusion: final diagnosis  —  mycetoma; collection of fungus that grows and colonizes preexisting cavity; possible complication of TB; treatment surgery; at-risk patient with abnormal x-ray  —  treat patient and take re­peat x-ray; if x-ray does not improve, rule out TB; if patient and x-ray improve  —  treat for 4 mo (INH and ri­fampin); fibrotic scarring with no hemoptysis  —  treatment can be delayed (if patient high-risk for hepatitis); cultures and repeat x-ray at 2 mo; can wait 4 or 9 mo, depending on level of suspicion; varies by case

Special situations: INH  —  900 mg twice weekly considered equivalent to 300 mg/day; rifampin  —  interacts with many drugs (eg, oral contraceptives, methadone); more costly than INH; not recommended for patients on protease inhibitors (use rifabutin); rifapentine  —  potential alternative drug (being tested); approved for active TB; taken once weekly; long-acting form of rifampin and rifabutin; ongoing study of high-risk groups comparing effectiveness of weekly rifapentine and INH for 3 mo to INH alone for 9 mo

Chronic Cough

Catherine J. Rees, MD, Assistant Professor, Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, NC

Overview: chronic cough lasts >8 wk; <8 wk  —  subacute cough, usually from viral infection; typical patient  —  has normal x-ray; immunocompetent; nonsmoker and not exposed to smoke; not taking angiotensin-converting enzyme (ACE)-inhibitors; impact  —  costly for health care system (most common symptom in United States for which peo­ple seek medical attention); causes dyspnea, fatigue, disturbed sleep, vomiting, social limitations, rib fractures, in­continence (particularly in older women), and depression

Causes of Cough

Antihypertensives: ACE-inhibitors  —  particularly problematic; work by decreasing cough threshold; try taking pa­tient off for several weeks; can replace ACE-inhibitor with angiotensin II receptor blocker; if on >1 antihypertensive  —  send patient to primary care physician for blood pressure management; main causes for those not on ACE-inhibitors  —  allergy or postnasal drip syndrome, reactive airway disease, and reflux (or combinations of these)

Allergic rhinitis: test all patients for allergy, except for those with clear history; consider longer trial of allergy drugs (>1-2 wk); most patients have other allergy and sinonasal symptoms (eg, itchy watery eyes, sneezing)

Postnasal drip syndrome: common in pulmonary literature; also called “upper airway cough syndrome”; related to sinonasal disease and allergy; often, patient has history of recent cold; treatment  —  similar to that used for acute cold or allergies; cough symptom  —  21% of patients with acute sinus infection; sinus CT  —  useful in cough work-up, if all else normal

Asthma and reactive airway disease: common cause of cough; usually causes chronic, nonproductive cough, dys­pnea, and wheezing; often worse at night and in early morning; spirometry tests  —  helpful if negative, particu­larly with positive methacholine challenge test (MCT)

Cough-variant asthma: normal spirometry and pulmonary function studies; reduced or no response to MCT; cough only symptom

Nonasthmatic eosinophilic bronchitis (NAEB): normal spirometry and MCT; can be diagnosed with deep sputum (counting number of eosinophils); trial of inhaled corticosteroid for 1 mo (not many respond); not many clues (eg, normal examination and chest x-ray, nonsmoking patient)

Gastroesophageal reflux disease (GERD): possible mechanism  —  direct irritation of airways by reflux (probably not majority of cases); activation of esophageal sensory nerves and stretch receptors (likely responsible for majority of reflux-related cough cases); esophageal motility disorder; cough sensitivity study (capsaicin test)  —  if patients do not have cough reflux, cough sensitivity does not change when acid placed in esophagus; people with reflux have heightened sensitivity in response to acid; cat model  —acidified esophagus; tracheal mucus levels increased in 10 min; ruling out GERD  —  try proton pump inhibitor (PPI) or 24-hr pH impedance testing

Nonacid reflux: cough despite PPI use; some propose impedance testing (for reflux occurring at pH >4.0); treatments  —alginate; bethanechol (increases lower esophageal sphincter [LES] pressure); baclofen (in some small studies decreases transient LES relaxation); promotility agents (some have side effects); tricyclic antidepressants decrease visceral sensitivity; fundoplication surgery may work for some patients; theories about cause  —  direct esophageal stimulation (of  stretch receptors) and direct pharyngeal stimulation; may be reflux-mediated; likely varies from person to person

Esophageal adenocarcinoma (EA): retrospective study  —cough largest independent risk factor for EA; however, some participants had other risk factors; change practice to include esophagoscopy; consider EA when no other ex­planation exists (especially in high-risk age groups)

Unusual causes of cough: aspiration  —  can be silent, possibly from chronic low-level pneumonitis; consider swal­low evaluation, particularly in elderly or neurologically impaired patients; consider endoscopic evaluation of swallowing; Zenker’s diverticulum  —  aspiration cough may be only symptom; TB  —  patients sometimes have normal chest x-ray; ask patient if PPD up-to-date and about any known exposures

Pertussis: adolescents and adults at risk (from waning immunogenicity after pertussis vaccine); £ 60,000 cases per year in United States; increasing in adults, but still most common in infants (<1 yr) before vaccination; booster infections; stage 1  —  looks like upper respiratory infection (URI); most infectious phase; infectiousness lasts for »3 wk; paroxysmal (whooping) phase  —  paroxysms of intense coughing; whooping more common in children than adults; convalescent stage  —  chronic cough that lasts weeks to months; consider pertussis  —  if patient coughing <1 yr; symptoms include uninterrupted and constant coughing, vomiting, and headaches; diagnosis  —  nasopharyngeal culture (not sensitive if patient coughing >3 wk); polymerase chain reaction shows more prom­ise but may not be positive in later disease stages; treatment  —  erythromycin or clarithromycin; symptoms usu­ally improve after 10 days (if not, pertussis ruled out)

Other causes: 1) chronic obstructive pulmonary disease  —  usually caused by smoking, but look for other causes; 2) bronchiectasis  —confirmed by CT; chest x-ray may be