eMedicine Specialties > Emergency Medicine > Infectious Diseases

Tuberculosis

Author: Erica Bang, MD, BS, Clinical Assistant Instructor, State University of New York Downstate Health Center, Brooklyn/Kings County Hospital
Coauthor(s): Richard H Sinert, DO, Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center; James Li, MD, Former Assistant Professor, Division of Emergency Medicine, Harvard Medical School; Board of Directors, Remote Medicine
Contributor Information and Disclosures

Updated: Jan 26, 2009

Introduction

Background

Tuberculosis (TB) is a well-known entity encountered in emergency departments (ED) by the emergency physician (EP). The incidence of suspected TB is significant with the undifferentiated patient. It is common to initiate respiratory isolation and deliver treatment to patients with suspected TB in the ED. A large percentage of patients who enter the ED are those that are high risk such as homeless or shelter-dwelling patients, those from endemic areas or those with HIV, health care workers, and incarcerated patients. Therefore, it is imperative for EPs to understand the management and treatment of TB as a critical public health measure in prevention of a new epidemic.

On a national level, the incidence of tuberculosis is at an all time low. Between 1993 and 2003, the incidence of TB has decreased 44%, and it is currently at a historic low, 13,767 cases (4.6 per 100,000 population) in 2006.^1,2 These current statistics indicate the success of early TB treatment and management since 1985 when TB was rampant. TB had resurfaced in inner-city EDs due to the HIV epidemic and growing indigent population. TB infectious control can be mainly attributed to uniformity in health care globally, with the standardization and implementation of organizations and public health policies such as the World Health Organization (WHO) tuberculosis control strategy.^3,4  

The WHO initiated directly observed treatment short-course (DOTS), which consists of 5 components introducing the administration of standardized short-course chemotherapy regimens with first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol and/or streptomycin) under direct observation regardless of drug susceptibility. This strategy has been considered by the World Bank as one of the most cost-effective interventions in human health and has now been adopted by 119 countries worldwide.

However, though statistically the number of new cases of tuberculosis is low since 1991, the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis as reported by the Centers for Disease Control and Prevention (CDC) are on the rise.² MDR-TB is defined as resistance to either isoniazid and/or rifampin, which is managed by second-line drugs that have more side effects, require longer treatment, and are more expensive. XDR-TB is defined as resistance to at least isoniazid and rifampin among first-line anti-TB drugs, resistance to any fluoroquinolone, and resistance to at least one second-line injectable drug (amikacin, capreomycin, or kanamycin). This can occur with treatments for MDR-TB when second-line drugs are misused, mismanaged, or even ineffective causing limited options of management. 

In 2005, 124 cases of MDR-TB were reported to the CDC in high-risk populations such as foreign-born persons from areas including Russia, Kazakhstan, China, Ecuador, and Israel. These countries alone account for 81.5% of the 124 MDR-TB cases. Although the incidence of TB has decreased in both the general population and foreign-born persons, the rate of decline has slowed and the proportion of TB cases among foreign-born persons has increased. According to the WHO, the prevalence of MDR-TB alone has been 1.1% in newly diagnosed patients; it is reportedly even higher, 7%, in patients who have previously received anti-TB treatment. MDR-TB and XDR-TB not only produce fulminant and fatal disease among patients infected with HIV (time from TB exposure to death averages 2-7 mo) but also are proven highly infectious (conversion rates of up to 50% in exposed health care workers).
 
Because of the prevalence of MDR-TB and XDR-TB strains, recommendations for pharmacologic management as well as exposure prophylaxis have evolved over the past decade.5,6 To avoid selecting drug-resistant organisms, treatment should begin with at least 4 medications (isoniazid, rifampin, pyrazinamide, ethambutol) until drug susceptibilities are known for approximately 6-9 months. (One in 106 tuberculous bacilli mutate and become isoniazid [INH] resistant.) In contrast, MDR-TB is typically treated with second-line drugs such as levofloxacin, aminoglycosides, pyrazinamide, ethambutol, and thioamides for an extended period of time, 18-24 months, with an increase in costs and adverse reactions. 

In 2006, with the advent of MDR-TB and XDR-TB, the need for newer anti-TB drugs is now pressing. Six agents in 5 different drug classes are currently being tested in humans—TMC-207, OPC 67683, SQ109, PA824, moxifloxacin, and gatifloxacin. With the help of the Global Alliance for TB Drug Development and the CDC’s TB Trials Consortium, these medications (ie, moxifloxacin and rifapentine-based treatment) will create the groundwork for defining MDR-TB treatment.

The potential for catastrophic outbreaks resulting from MDR-TB and XDR-TB has led to national efforts for both surveillance and control with a goal-oriented approach toward eradicating TB globally. The low incidence of TB has rejuvenated many organizations such as the Advisory Council for Elimination to renew their commitment in eliminating TB in the United States altogether. The Institute of Medicine has recently published a detailed plan for achieving this goal. As a united front, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and the Infectious Disease Society of America (IDSA) are constantly updating recommendations for early recognition. They are targeting high-risk populations, managing MDR-TB and XDR-TB, and reducing barriers to TB elimination. Efficiently run TB control programs based on directly observed treatment and short-course DOTS are essential in the prevention of MDR-TB and XDR-TB. 

In the ED, triage protocols are being introduced for judicious respiratory isolation. Moran et al showed that among patients with active TB in the ED, TB was often unsuspected and isolation measures are often unused.⁷  Through retrospective analysis, it had been shown that of those who had active tuberculosis in similar high-risk populations, only 50% were isolated and universal triage protocols were needed for implementation for public health measures and safety for health care providers.

Overall, TB research and active outreach has enabled a steady decline in TB; however, there is a need for improvement in terms of identification of high-risk populations, intensification of outreach and testing within high-risk populations, appropriate implementation of medication management, and collaborative measures with other nations globally to unify our efforts to reduce TB incidence. Currently, many clinical studies are investigating the expansion of the role of the EP in recognition and infection control to quell the rise of TB.⁸ It is feasible to manage and prevent TB if aggressive measures are widely implemented, including judicious use of drugs with supervised standardized treatment and focused clinical, radiologic, and bacteriologic follow-up.

To contribute to early intervention, the EP may be the patients’ best opportunity for recognition of mycobacterial infection by sheer influx of high-risk patients throughout the ED. It is in the ED where the implementation of isolation, hospitalization, and drug treatment can be initiated and achieved.

Pathophysiology

Transmission is spread through air droplets (ie, coughing, sneezing, speaking, and even singing). These particles are 1-5 micrometers in diameter and contain Mycoplasma tuberculosis. A single cough can generate 3000 infective droplets. Fewer than 10 mycobacterial bacilli may initiate a pulmonary infection. 

Four factors contribute to the likelihood of transmission: (1) number of organisms expelled, (2) concentration of organisms, (3) length of time of exposure breathing in contaminated air, and (4) immune status of the exposed individual. Those who are immunocompromised, such as HIV patients, are more likely to develop active TB. The organisms grow for 2-12 weeks until they reach 1000 to 10,000 in number, which is sufficient to elicit a cellular immune response that can be detected by a reaction to the tuberculin skin test. The organisms spread via the lymphatics to the hilar lymph nodes and then through the bloodstream to more distant sites such as the bone marrow, liver, spleen, kidneys, bones, and brain.

Recently, it has been shown that multidrug resistance can be attributed to molecular changes and genetic mutations. Spontaneous chromosomally borne mutations occur at a predictable rate.  A TB cavity typically contains 10⁷ to 10⁹ bacilli; if mutations causing resistance to isoniazid occur in about 1 in 10⁶ replications of bacteria and the mutations causing resistance to rifampin occur in about 1 in 10⁸, the probability of spontaneous mutations causing resistance to both isoniazid and rifampin would be 1 in 10¹⁴.

Drug resistance of M tuberculosis has been implicated in many etiologies such as incomplete and inadequate treatment; inadequate treatment adherence, which resulted in directly observed treatment; short-course (DOTS) strategy endorsed by the WHO; logistic issues; virulence of the organism; multidrug transporters; host genetic factors; and HIV. Rifampin resistance is attributed to an alteration of the β subunit of RNA polymerase, which is encoded by the rpo β gene. More than 95% of rifampin-resistant strains are associated with mutations within an 81-base pair region of the rpo β gene, which is called the rifampin resistance determinant region. In contrast, isoniazid resistance is more complex and is multifactorial involving the enoyl acyl carrier protein (acp) reductase.

Frequency

United States

• In 2006, 13,767 TB cases (4.6 per 100,000 population) were reported in United States, indicating a 3.2% decline from 2005 and, more significantly, a 68.6% decline since 1993.  
• The TB rate in 2006 was the lowest recorded rate since the national reporting began in 1953, but the rate of decline has slowed since 2000. 
• The population disproportionately at risk are foreign-born and racial/ethnic minority populations such as blacks, Asians, and Hispanics.
• Foreign-born TB cases have risen; however, the rate has declined: 21.9 per 100,000 population, representing a 0.5% decline since 2006 and a 35.8% decline since 1993. Most cases are from 5 countries: Mexico, Philippines, Vietnam, India, and China. 
• The TB rate for foreign-born persons in the United States is 9.5 times greater than those born in the United States.
• The majority of TB cases reported (60%) came from 7 states: California, Florida, Illinois, New York, New Jersey, Georgia, and Texas. 
• In 2006, the CDC issued new guidelines recommending that all patients initiating treatment of TB be routinely screened for HIV. Patients with HIV are a population vulnerable to TB due to immune suppression. Being HIV positive also increases the likelihood of rapid progression from TB infection to TB disease. HIV is the most important known risk factor for rapid progression from latent TB to active TB. Patients with TB and HIV are 5 times more likely to die during anti-TB treatment than patients not infected with HIV.
• According to the World Health Organization and the International Union Against Tuberculosis and Lung Disease, the median prevalence of MDR-TB is 1.1% in newly diagnosed patients and is even higher at 7% in previously treated patients who had received anti-TB treatment. 
• According to the US National TB Surveillance System (NTSS) during 1993-2006, a total of 49 cases (3% of evaluable MDR-TB cases) met the revised case definition for XDR-TB.  Of these, 17 (35%) were reported during 2000-2006. Compared with 1993-1999, cases from 2000-2006 were more likely to be in persons who were foreign-born than those with HIV infection. The largest numbers were found in New York City and California, and high mortality rates were found in HIV-infected patients.
• The success rate of treatment with standard short-course chemotherapy (SCC) is less than 60% in patients with MDR-TB compared with a success rate of more than 85% in patients with drug-susceptible TB.
• Of all new TB cases in adults aged 15-29 years, 9% were attributable to HIV infection, but the proportion was much greater in the WHO African sub-Saharan region (31%) and in the United States (26%).
• An estimated 1.8 million deaths were due to TB, of which 2% were attributable to HIV; tuberculosis was the cause of 11% of all adult AIDS deaths. 
• The prevalence of TB co-infection with HIV is 0.36%, globally; co-infection is highest in South Africa, India, and Nigeria.
• The risk for persons with HIV is 200-400 times greater than those without HIV. Other high-risk populations include hospital employees, inner-city residents, nursing home residents, persons with alcoholism, persons who use illicit drugs, and prisoners.

International

• TB is on the top 10 list for all-cause, all-age worldwide mortality; 95% of all TB cases occur in developing countries where resources are limited and HIV is common. An estimated 9-43% of the world’s population is infected with TB.
• TB prevalence is about 2 billion persons. New cases number about 8 million yearly, and annual mortality worldwide is estimated at 3 million, accounting for 7% of total worldwide mortality rate.
• The vast majority of the world burden of TB is in developing countries; only 23% of the prevalent active cases are currently estimated to receive appropriate anti-TB treatment due to either inappropriate therapy or patient noncompliance.
• Recent estimates from 184 countries indicate 438,000 new cases of MDR-TB worldwide in 2003, with 60% from high burden countries such as China, India, Soviet Union, Israel, and Ecuador.
• The African sub-Saharan regions had the highest annual incidence rates of MDR-TB, while the South East Asia region had the largest number of cases overall.
• The global burden of TB is growing; the total number of new TB cases has been rising at a rate of 0.4% per year, most rapidly in the Soviet Union and sub-Saharan African region.

Mortality/Morbidity

Historically, prior to the advent of antibiotics, active TB was fatal for up to 50% of untreated patients. The mortality rate in 1953 was 12.4 deaths per 100,000 persons. Currently, the US mortality rate from TB is 0.3 deaths per 100,000 persons—approximately 800 deaths per year. This represents an annual mortality rate of approximately 6% of newly identified cases.

Globally, 1.84 millions deaths from TB occurred in 2000, in which 12% were attributable to HIV. MDR-TB cases have a reported fatality rate of more than 70%. In early reports of outbreaks of MDR-TB in HIV–co-infected patients in hospitals and prisons, the mortality rate was very high, 72-89%. However, further studies have documented decreased mortality and improvement in clinical outcomes in both HIV-positive and HIV-negative patients with MDR-TB. Poor prognostic markers include extrapulmonary involvement, immunocompromised state (eg, HIV), older age, and history of previous treatment.

Race

In the United States, two thirds of TB cases occur among minorities. In 2006, more TB and latent TB cases were reported among Hispanics than any other racial/ethnic group. Overall, in descending order of prevalence, Asians constitute the number one group at high risk, followed by Hispanics, blacks, and whites.

Sex

In the United States, overall incidence rates are twice as high for men as for women.

Age

Most TB cases are found in the 25- to 44-year-old age group. In minority populations, the median age of onset is approximately 39 years. In nonminorities, the median age of onset is 62 years.

Clinical

History

It is critical to inquire about demographic elements to risk stratify the patient (ie, indigent, shelters, incarceration, HIV, travel to endemic area); these risk factors have been shown to increase a patient's risk of acquiring TB.
 
Risk factors

• HIV
• History of positive purified protein derivative (PPD) test result
• History of prior TB treatment
• TB exposure
• Travel or emigration from a TB endemic area
• Homelessness, shelter-dwelling, incarceration

• Classic symptoms are often absent particularly in patients who are immunocompromised or elderly. Up to 20% of patients with active TB may be asymptomatic. Classic features associated with active TB are as follows:
  • Cough
  • Weight loss/anorexia
  • Fever
  • Night sweats
  • Hemoptysis
  • Chest pain: Dull aching consistent with pericardial tuberculosis can lead to cardiac tamponade or constriction and presents similarly to congestive heart failure.
  • Genitourinary symptoms: These symptoms are less common. In women,  dysuria, hematuria, and frequent urination may be present. In men, painful scrotal mass, prostatitis, orchitis, and epididymitis may be present.
  • Joint pain and swelling: Osteoporosis, sclerosis, and bone involvement is more common in children. The epiphyseal bones can be involved due to their high vascularity. If vertebral involvement (Pott disease) or brain involvement is suspected, delay of treatment can be severe because of compression of the spinal cord and/or paraplegia; further evaluation is necessary with CT scan or MRI. 
  • CNS: Altered mental status, neck stiffness, decreased level of consciousness, increased intracranial pressure, and cranial nerve involvement can indicate tuberculosis meningitis or tuberculoma. TB can directly seed the meninges and, if suspected, performing a lumbar puncture for evaluation of the cerebrospinal fluid is necessary. In addition, a tuberculoma can be substantiated with an increase in intracranial pressure (ICP) and CT scan/MRI.
• Signs and symptoms of extrapulmonary tuberculosis may be nonspecific. They can include leukocytosis, anemia, and hyponatremia due to the release of ADH-like hormone release from affected lung tissue.

Physical

Physical findings of tuberculosis are typically nonspecific.

• Fever
• Cachexia
• Hypoxia
• Tachycardia
• Lymphadenopathy: Painless swelling of >1 lymph nodes usually bilaterally and typically anterior or posterior cervical chain or supraclavicular may be present.
• Abnormal lung sounds: Rales or bronchial breath signs may be noted, indicating lung consolidation.
• Choroidal tubercle: Granuloma in the choroid of the retina strongly indicates disseminated disease.
• Note: The absence of any significant physical findings does not exclude active disease. In high-risk patients, respiratory isolation and sputum sampling are essential.

Causes

Tuberculosis is caused primarily by direct inhalation of infective droplet nuclei. Transdermal and gastrointestinal (GI) transmission have also been reported. Infected patients living in crowded or closed environments pose a particular risk for noninfected persons.

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