Dealing With Threat of Drug-Resistant Tuberculosis: Background Information for Interpreting the Andrew Speaker and Related Cases

Abstract

Not since the threat of a potential SARS (severe acute respiratory syndrome) pandemic (in 2003) has medical news captured as much national media attention as in the recent few weeks. Tuberculosis (TB) has been in the public eye since news broke that Andrew Speaker, a 31-year-old US citizen and attorney from Atlanta, Ga, was a passenger on international commercial airline flights while infected with a very resistant strain of TB and that he has since been placed in isolation by US health authorities. This case has focused attention on important public health issues: the global TB epidemic and the risk of spread of infectious agents either knowingly or unknowingly via air travel. The purpose of this editorial is to provide background information on the epidemiology of TB in the world, the problem of drug-resistant TB, the risks of acquiring infections from air travel, and the role of health authorities in minimizing risk to the public. Among infectious diseases, TB is second only to the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome as the greatest contributor to adult mortality, causing approximately 2 million deaths per year worldwide. The World Health Organization (WHO) estimates that one third of the world's population is infected with Mycobacterium tuberculosis and that 1 in 8 deaths in the world today is due to tuberculosis.1Centers for Disease Control and Prevention (CDC) Trends in tuberculosis incidence—United States, 2006.MMWR Morb Mortal Wkly Rep. 2007; 56: 245-250PubMed Google Scholar After the discovery and introduction of antituberculosis medications in the late 1940s, there was hope that TB would soon be eliminated. However, after decades of steady decline, the number of reported TB cases began to increase in the late 1980s and early 1990s in the United States. This resurgence was fueled by several factors: the deterioration of the TB public health infrastructure, the onset of the HIV epidemic, increases in immigration of persons from countries where TB was common, and outbreaks in congregate settings such as hospitals and correctional institutions. Another important factor resulting in increasing numbers of TB cases is the increase in transmission of multidrug-resistant (MDR) strains of TB (Table 1). In the early 1990s, several outbreaks of MDR-TB occurred in hospitals and correctional facilities in Florida and New York, involving more than 250 MDR-TB cases.2Centers for Disease Control and Prevention (CDC) Epidemiologic notes and reports nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons—Florida and New York, 1988-1991.MMWR Morb Mortal Wkly Rep. 1991; 40: 585-591PubMed Google Scholar, 3Centers for Disease Control and Prevention (CDC) Nosocomial transmission of multidrug-resistant tuberculosis to health-care workers and HIV-infected patients in an urban hospital—Florida.MMWR Morb Mortal Wkly Rep. 1990; 39: 718-722PubMed Google Scholar Most patients in these outbreaks were coinfected with HIV. The mortality rate was approximately 80%, and the interval between TB diagnosis and death was short, ranging from 4 to 16 weeks. In addition to hospitalized patients and inmates, transmission of MDR-TB to health care workers and prison guards occurred; at least 9 of these workers developed active MDR-TB, and 5 died. Globally, 400,000 new cases of MDR-TB occur each year.4Zignol M Hosseini MS Wright A et al.Global incidence of multidrug-resistant tuberculosis.J Infect Dis. 2006 Aug; 194 (Epub 2006 Jul 12.): 479-485Crossref PubMed Scopus (439) Google Scholar Currently, drug-sensitive TB can be treated with first-line drugs for 6 to 9 months, and 95% of patients can be cured with these regimens. In contrast, MDR-TB requires treatment for 18 to 24 months with second-line drugs (Table 2)5American Thoracic Society, Centers for Disease Control and Prevention (CDC), Infectious Diseases Society of America Treatment of tuberculosis.MMWR Recomm Rep. 2003; 52: 1-77Google Scholar that are inherently less effective, often poorly tolerated by patients, and much more expensive. Under optimal conditions, the cure rate is 70% to 90% but is closer to 50% in diverse clinical practice.TABLE 1Definitions of Multidrug-Resistant Tuberculosis (TB) and Extensively Drug-Resistant TB Mutidrug-resistant TB TB resistant to at least rifampin and isoniazidExtensively drug-resistant TB TB resistant to isoniazid and rifampin plus resistant to any fluoroquinolone plus resistant to at least 1 of 3 injectable second-line drugs: amikacin, kanamycin and capreomycin Open table in a new tab TABLE 2Drugs for Tuberculosis Currently Used in the United StatesData from MMWR Recomm Rep.5American Thoracic Society, Centers for Disease Control and Prevention (CDC), Infectious Diseases Society of America Treatment of tuberculosis.MMWR Recomm Rep. 2003; 52: 1-77Google ScholarFirst-line drugsSecond-line drugs Isoniazid Cycloserine Rifampin Ethionamide Rifabutin Levofloxacin Rifapentene Gatifloxacin Ethambutol Moxifloxacin Pyrazinamide p-Aminosalicylic acid Amikacin or kanamycin Streptomycin Capreomycin Open table in a new tab Coincident with the increasing use of second-line drugs to treat the growing numbers of MDR-TB cases, the resistance pattern of TB continued to evolve, and TB that is resistant to both first- and second-line agents, termed extensively drug-resistant TB (XDR-TB), was born. In early 2005, physicians from KwaZulu-Natal in South Africa reported an outbreak of TB with an alarmingly high mortality rate.6Gandhi NR Moll A Sturm AW et al.Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa.Lancet. 2006; 368: 1575-1580Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar Of 221 patients with MDR-TB, 53 were found to have what is now known as XDR-TB; 52 of the 53 patients died, and the median survival was only 16 days from the time the first sputum sample was collected. Extensively drug-resistant TB is defined as TB that is resistant to isoniazid and rifampin (ie, MDR-TB) in addition to being resistant to any fluoroquinolone and at least 1 of the 3 injectable drugs: capreomycin, kanamycin, and amikacin7Centers for Disease Control and Prevention (CDC) Notice to readers: revised definition of extensively drug-resistant tuberculosis.MMWR Morb Mortal Wkly Rep. 2006; 55: 1176Google Scholar (Table 2). Recent reports suggest that XDR-TB is a global problem (Figure 1).8World Health Organization XDR-TB: extensively drug-resistant tuberculosis.Available at: www.who.int/tb/xdr/xdrmap_1may_en.pdfGoogle Scholar It has been identified in all regions of the world but is most frequent in the countries of the former Soviet Union and in Asia.9Centers for Disease Control and Prevention (CDC) Extensively drug-resistant tuberculosis—United States, 1993-2006.MMWR Morb Mortal Wkly Rep. 2007; 56: 250-253PubMed Google Scholar, 10US Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) Statement by Julie L. Gerberding, MD, MPH, on recent case of extensively drug resistant TB: CDC's public health response.Available at: www.hhs.gov/asl/testify/2007/06/t20070606a.htmlGoogle Scholar Estimates from the United States, the Republic of Korea, and Latvia show that 4%, 15%, and 19%, respectively, of MDR-TB isolates were XDR strains. Many developing nations lack the ability to test for drug resistance, and hence the number of cases reported thus far may represent only the tip of the iceberg. In the United States between 1993 and 2006, a total of 49 cases of XDR-TB were identified.9Centers for Disease Control and Prevention (CDC) Extensively drug-resistant tuberculosis—United States, 1993-2006.MMWR Morb Mortal Wkly Rep. 2007; 56: 250-253PubMed Google Scholar Of these 49 patients, 17 (35%) have completed treatment, 12 (24%) have diedduring treatment, and an alarming 12 patients (24%) were lost to follow-up. Multidrug-resistant TB and XDR-TB do not seem to be more contagious than other forms of TB. However, their danger lies in the fact that few or no drugs are available to treat these forms of TB. Persons who are infected with these strains and who develop active disease often undergo months to years of treatment with toxic medications plus possible surgical treatment, and they are at high risk of dying, especially if they have any form of immunosuppression. M tuberculosis acquires resistance primarily from incomplete or inadequate treatment courses, and the development of XDR-TB essentially points to the worldwide weaknesses in TB management. Improper use of antimicrobialtherapy for drug-susceptible TB inevitably leads to drug resistance. This improper use includes administration of inappropriate treatment regimens, failure to implement directly observed therapy, and incomplete adherence to or completion of the entire treatment course. The issues with treatment are compounded by the fact that the diagnosis of TB and detection of drug resistance can be challenging. Patients in whom the diagnosis of XDR-TB is delayed spread the infection to close contacts who then acquire primary XDR-TB. Areas of the world that have high HIV rates are especially at risk for XDR-TB outbreaks because HIV infection predicts extreme vulnerability to TB. Conventionally, TB is diagnosed by culturing the organism on liquid or solid media followed by identification of the species and then drug susceptibility testing. Since mycobacteria are slow growing, this process can take several weeks and can be technically challenging. This is high-lighted in the case of Speaker, in whom the initial diagnosis of TB was made in late March. However, he was identified as having only MDR-TB on May 10, and it was not until May 22 that the extent of drug resistance was realized.10US Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) Statement by Julie L. Gerberding, MD, MPH, on recent case of extensively drug resistant TB: CDC's public health response.Available at: www.hhs.gov/asl/testify/2007/06/t20070606a.htmlGoogle Scholar Recent advances in molecular biology and understanding of the molecular mechanisms of drug resistance in TB have led to newer diagnostic tools, some of which can provide information on susceptibility patterns in days.11Palomino JC Newer diagnostics for tuberculosis and multi-drug resistant tuberculosis.Curr Opin Pulm Med. 2006; 12: 172-178Crossref PubMed Scopus (46) Google Scholar A pilot study to evaluate some of these tests is currently under way in South Africa.12Wise J Fast action urged to halt deadly TB.Bull World Health Organ. 2007; 85: 328-329PubMed Google Scholar, 13Garwood P New tools for an old disease.Bull World Health Organ. 2007; 85: 331-332PubMed Google Scholar Speaker was smear negative (ie, no tuberculosis bacilli were visible on microscopic examination of his sputum); hence, the risk of TB transmission from him is low but not zero. Subsequently, the Centers for Disease Control and Prevention has recommended that all his copassengers on 2 international flights be tested for TB.14Centers for Disease Control and Prevention (CDC) CDC investigation of traveler with extensively drug-resistant tuberculosis (XDR TB): questions and answers for passengers and flight crew on affected flights.Available at: www.cdc.gov/tb/xdrtb/travellerfactsheet.htmGoogle Scholar This has caused a great deal of anxiety in the general public about the risk of infections related to air travel. Globally, more than 1 billion passengers travel by air annually. It is a common perception that airplanes are breeding grounds for microorganisms. Many people erroneously attribute upper respiratory tract symptoms after air travel to infections acquired on the airplane as a result of poor air quality. In reality, from a microbiologic standpoint, the quality of air on modern commercial aircraft is carefully controlled and is much better than that in similar enclosed places on the ground.15DeHart RL Health issues of air travel.Annu Rev Public Health. 2003; 24 (Epub 2002 Oct 23.): 133-151Crossref PubMed Scopus (97) Google Scholar Ventilation rates provide a total of 20 to 30 air exchanges per hour (the recommended rate for hospital isolation rooms for patients with TB is 6-12 exchanges per hour). Most modern aircraft have recirculation systems that recycle up to 50% of cabin air. However, this air is passed through high efficiency particulate air filters, similar to the ones used in hospitals, that remove 99.9% of particulate matter, bacteria, fungi, and viruses that are between 0.1 and 0.3 μm. The tubercle bacillus is approximately 0.5 to 1.0 μm and thus is removed by high efficiency particulate air filters.16Wick Jr, RL Irvine LA The microbiological composition of airliner cabin air.Aviat Space Environ Med. 1995; 66: 220-224PubMed Google Scholar Air enters and leaves the cabin at approximately the same seat row, and little front to back airflow occurs (Figure 2). This air circulation pattern means that essentially the cabin is divided into sections, and spread of airborne particles from a passenger is limited to the section in which he or she is seated. This is borne out by the fact that in reports of airborne disease transmission on aircraft, transmission has generally occurred to people close to a contagious passenger (within 2 rows) for a long time (>8 hours). Important exceptions are when flights are delayed, the aircraft is parked on the ground, and the aircraft ventilation system is not operating.18Moser MR Bender TR Margolis HS Noble GR Kendal AP Ritter DG An outbreak of influenza aboard a commercial airliner.Am J Epidemiol. 1979; 110: 1-6Crossref PubMed Scopus (466) Google Scholar According to the US Department of Transportation, “if the ventilation system is not operating, passengers should not stay aboard the plane for more than 30 minutes.” Transmission of TB on board a commercial aircraft during long-distance flights has been reported several times,19Centers for Disease Control and Prevention (CDC) Exposure of passengers and flight crew to Mycobacterium tuberculosis on commercial aircraft, 1992-1995 [published correction appears in MMWR Morb Mortal Wkly Rep. 1995;44:175].MMWR Morb Mortal Wkly Rep. 1995; 44: 137-140PubMed Google Scholar, 20Driver CR Valway SE Morgan WM Onorato IM Castro KG Transmission of Mycobacterium tuberculosis associated with air travel.JAMA. 1994; 272: 1031-1035Crossref PubMed Scopus (134) Google Scholar, 21Kenyon TA Valway SE Ihle WW Onorato IM Castro KG Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight.N Engl J Med. 1996; 334: 933-938Crossref PubMed Scopus (323) Google Scholar, 22McFarland JW Hickman C Osterholm M MacDonald KL Exposure to Mycobacterium tuberculosis during air travel [letter].Lancet. 1993; 342: 112-113Abstract PubMed Scopus (65) Google Scholar but no case of active TB disease resulting from exposure on board has been identified subsequently. In all instances, transmission occurred to passengers seated within 2 rows of the index case. The WHO first published guidelines regarding TB and air travel in 1998 and revised them in 2006 in response to increased concerns about resistant forms of TB and improved international collaboration in dealing with infectious disease risks.17World Health Organization Tuberculosis and Air Travel: Guidelines for Prevention and Control. 2nd ed. World Health Organization, Geneva, Switzerland2006Google Scholar The latest guidelines can be accessed at http://whqlibdoc.who.int/hq/2006/WHO_HTM_TB_2006.363_eng.pdf. These guidelines provide specific recommendations for passengers, airline crews, health authorities, and airlines and are applicable to all domestic and international airlines worldwide. Instances in which the risk of TB transmission on airplanes may be increased are listed in Table 3.TABLE 3Factors That Influence Risk of Tuberculosis (TB) Transmission on AirplanesData from the World Health Organization.17World Health Organization Tuberculosis and Air Travel: Guidelines for Prevention and Control. 2nd ed. World Health Organization, Geneva, Switzerland2006Google Scholar 1.Infectiousness of the patient with TB—Smear positivity increases the risk of transmission2.Duration of exposure—The total length of the flight, including time on the ground after boarding, flying time, and time on the ground after landing, must be taken into account. Evidence of transmission of TB has been found only when exposure to the person with TB exceeded 8 hours3.Proximity of an infectious passenger to other passengers— Passenger-to-passenger transmission has been documented only among people seated in the same section as the person with infectious TB Open table in a new tab Isolation and quarantine are public health strategies that aim to control exposure to infections. Isolation refers to the separation of persons who have a specific infectious illness from those who are healthy to stop the spread of that illness. In contrast, quarantine refers to the separation andrestriction of movement of persons who, although not yet ill, have been exposed to an infectious agent and therefore may become infectious. Local, state, and tribal jurisdictions are primarily responsible for isolation and quarantine within their borders. The federal government has the primary responsibility to prevent interstate spread of disease and to prevent the introduction of communicable diseases from foreign countries into the United States.23US Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) Fact Sheet: Legal authorities for isolation and quarantine. January 2006; Google Scholar The communicable diseases for which federal isolation and quarantine are authorized by presidential order are infectious TB, cholera, diphtheria, plague, smallpox, yellow fever, viral hemorrhagic fevers, SARS, and influenza with pandemic potential. This federal quarantine provision was last invoked in 1963 to deal with a patient infected with smallpox, but local public health authorities exercise the right to enforce isolation more frequently. In fact, a person with XDR-TB is currently incarcerated in a Phoenix jail for failing to comply with a physician's instructions to wear a mask in public.24Kahn C Man with drug-resistant TB locked up.USA Today. April 2, 2007; Google Scholar It remains unclear how Speaker became infected with XDR-TB. Additionally, it may never be known whether he understood the fact that he had a serious and potentially communicable form of TB and still chose to ignore medical advice or whether he simply did not understand all the implications of his diagnosis. His trans-Atlantic multicountry odyssey high-lights the fact yet again that spread of infectious agents via global air travel remains a very real threat and that international cooperation remains vital to limit the spread of infections. Moreover, this case draws attention to the fact that TB remains a great threat to humanity worldwide; in the words of US Representatives Eliot L. Engel and Gene Green “We'll get nowhere on TB till we tackle it everywhere.”25Engel EL Green G We'll get nowhere on TB till we tackle it everywhere.Houston Chronicle. June 8, 2007; Google Scholar