The Challenge of Multidrug-Resistant Tuberculosis
The Clinical Features, Diagnosis, and Treatment of TB in Patients With HIV Infection
Tuberculosis is the most common cause of death among HIV-infected patients throughout the world. Since the introduction of effective tuberculosis chemotherapy in the 1950s, the prevalence of strains of Mycobacterium tuberculosis resistant to one or more anti-tuberculous drugs has steadily increased. These resistant strains of tuberculosis have resulted in outbreaks of disease that are difficult to treat and are associated with significant morbidity and mortality.
Tuberculosis that is resistant to two or more first-line anti-tuberculous drugs -- that is, TB resistant to isoniazid and rifampin, with or without resistance to either pyrazinamide, ethambutol, or streptomycin -- is known as multidrug-resistant tuberculosis, or MDR-TB. It is an especially formidable problem among HIV-infected patients, in whom mortality from MDR-TB can be as high as 80%.(1-2) Moreover, MDR-TB is the only AIDS-related opportunistic infection that presents a threat to the general population, because unlike PCP, CMV, and other AIDS-related OIs, MDR-TB can be transmitted to otherwise healthy people who live with, care for, or simply come into intimate contact with infected individuals.
The clinical presentation of MDR-TB does not differ substantially from that of tuberculosis caused by drug-susceptible bacilli. The epidemiologic risk factors for tuberculosis include a history of incarceration, homelessness, and/or substance abuse (alcohol or drugs). Country of origin is another risk factor: patients born in countries with a high prevalence of tuberculosis run an increased risk of infection because of exposure to TB in their homeland prior to immigration. Infection is also more likely to occur in the eastern United States than in the Midwest or Far West, according to data from a cohort of HIV-infected individuals followed for several years (see "Predictors of TB infection" in the Newsline section of this issue).
Tuberculosis in HIV-infected patients, as in other populations, is primarily a pulmonary infection, although extrapulmonary disease occurs in up to 40% of patients coinfected with HIV and TB. Tuberculosis can occur at any CD4 cell count, but as the CD4 cell count decreases, the incidence of mycobacteremia and disseminated tuberculosis increases. In HIV-infected patients with MDR-TB, the most common presenting symptoms are fever, night sweats, cough, and dyspnea.(2) These symptoms tend to be present for several weeks to months prior to evaluation, in contrast to the often more acute presentation of bacterial pneumonia (Table 1). Constitutional symptoms, such as weight loss, anorexia, and chills, are also frequently reported. Symptoms suggestive of extrapulmonary disease, such as back pain or headache, are frequently present in patients with extrapulmonary tuberculosis (Table 2).
Physical examination of patients with MDR-TB does not usually reveal specific findings. Fever, tachycardia, tachypnea, and generalized or regional lymphadenopathy may be present. Examination of the chest often discloses signs of localized consolidation, rales, or dullness, although frequently no abnormalities are found. Laboratory studies, including complete blood count and serum chemistries, are often abnormal, but these abnormalities are not specific for tuberculosis. Because the symptoms and signs of tuberculosis in HIV-infected patients are so nonspecific, a high degree of suspicion -- and the inclusion of tuberculosis in the differential diagnosis -- is the key to accurate diagnosis of TB in these patients.
|Chest radiograph of an HIV-infected patient with a CD4 count of < 50 cells/mm3 showing a focal alveolar consolidation diagnosed as tuberculosis by sputum culture. The key to diagnosis was recognition that seropositive patients with severe immunosuppression may present with a wide range of radiographic findings -- including such atypical features as diffuse infiltrates, focal alveolar consolidation, and intrathoracic lymphadenopathy.|
Chest radiographs can provide additional information in HIV-infected patients suspected of having tuberculosis (Figure), and they should be performed on all patients with HIV disease who present with respiratory or constitutional symptoms. Studies of HIV-infected patients with MDR-TB have found many different radiographic patterns. Alveolar infiltrates (especially in the upper lobes), intrathoracic lymphadenopathy, and interstitial infiltrates with a reticular pattern have been the most commonly reported findings.(2)
Many other radiographic features have been found as well, including cavitation, pleural effusion, and even normal chest radiographs.(3) However, all of these findings have also been reported in HIV-infected patients with drug-susceptible tuberculosis. Thus, there are no specific chest X-ray findings that distinguish HIV-infected patients with MDR-TB from those with drug-susceptible tuberculosis.
In fact, the radiographic appearance of tuberculosis in HIV-infected patients correlates more closely with the degree of immunosuppression than with whether the bacteria are drug-resistant or drug-susceptible. Chest radiographs of patients with less advanced HIV disease tend to show more "classic" changes, such as upper-lobe disease and cavitation, whereas patients with more advanced HIV-induced immunosuppression tend to have diffuse infiltrates and intrathoracic lymphadenopathy.
Diagnosing drug-resistant TB
Since there are no specific clinical or radiographic features to distinguish HIV-infected patients with MDR-TB from those with drug-susceptible tuberculosis, the key to diagnosing MDR-TB is a high index of suspicion. Given the variability in the clinical and radiographic presentation of tuberculosis in HIV-infected patients, tuberculosis should always be included in the differential diagnosis of all pulmonary disease processes in such patients, and the work-up should include tests to detect M. tuberculosis. Sputum and other clinical specimens -- such as pleural or bronchoalveolar lavage fluid and tissue from transbronchial biopsy -- should be stained and cultured for acid-fast bacilli. Blood cultures for acid-fast bacilli should also be obtained. Since M. tuberculosis is never part of a patient's normal flora, the finding of even one acid-fast organism should lead to empiric treatment for tuberculosis in essentially all clinical situations.
The single most powerful predictor of the presence of MDR-TB is a history of previous treatment for tuberculosis. Inadequate therapy, due to either poor prescribing practices by physicians or poor compliance by patients, is the most common route by which resistant organisms are acquired. This leads to the most common form of microbial resistance to anti-tuberculous drugs, acquired (or secondary) drug resistance. In contrast, initial resistance occurs in patients who have not had previous treatment for tuberculosis. Risk factors for initial resistance include exposure to a patient with MDR-TB, being from a country with a high prevalence of MDR-TB (such as the Philippines), and living in a community with greater than 4% resistance to isoniazid.(4) In the U.S., the highest rates of MDR-TB have been found in large urban areas such as New York City, Washington, D.C., and Miami.(5)
The determination of whether a strain of tuberculosis is resistant to anti-tuberculous drugs can only be accomplished by in vitro drug susceptibility testing. This test should be performed on all new isolates of M. tuberculosis. With modern laboratory techniques for identifying drug-resistant strains of TB, diagnosis of MDR-TB can usually be made within three to six weeks after specimens have been sent to the laboratory. As our understanding of the genetic basis of drug resistance increases, more rapid diagnostic tests, based on DNA amplification, will become available. In the case of rifampin resistance, we already know that the vast majority of resistant bacterial isolates have mutations limited to a specific part of the bacterial genome.
Given the extremely high mortality of MDR-TB in HIV-infected patients, it is imperative that treatment occur under the supervision of persons expert in the management of tuberculosis. Primary providers should consult tuberculosis specialists as soon as drug resistance is discovered. Because treatment varies depending upon the specific in vitro resistance pattern and history of previous treatment regimens, all therapy is highly individualized. Several principles do apply to treating MDR-TB in all HIV-infected patients, however.
The single most important principle in the treatment of MDR-TB is to administer at least two drugs to which there is documented susceptibility. (4) The corollary to this principle is: Never administer only one drug to a patient who is failing a TB regimen. This was the most common error noted in a study reviewing management practices among a group of patients with MDR-TB.(6) In fact, not adhering to this principle is responsible in part for the very existence of strains of MDR-TB, since therapy with only one active drug will inevitably lead to the development of resistant organisms.
It is currently recommended that initial treatment of tuberculosis in all patients, irrespective of serostatus, consist of all four first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin). The only exceptions to this recommendation are: if there is less than 4% primary resistance to isoniazid in the community and if the patient has had no previous treatment with anti-tuberculous drugs, is not from a country with a high prevalence of drug resistance, and has no known exposure to a person with drug-resistant TB.(4) From a practical point of view, all HIV-infected persons should be initially treated with the four-drug regimen until drug-susceptibility data become available.
Another important issue involves the duration of treatment of MDR-TB. Treatment of MDR-TB requires at least nine months of therapy, and often as much as 24 months. As a general rule, if rifampin is one of the drugs to which a patient's isolate is resistant, treatment will often require up to 24 months of therapy after the sputum culture becomes negative.(7)
In addition, all HIV-infected patients with MDR-TB should be given directly observed therapy (DOT) -- that is, each dose should be taken under the direct supervision of a care provider or health department official. Given the high mortality of MDR-TB in HIV-infected patients and the potential for spread to others, it is essential that patients take their prescribed medications. DOT programs have been shown to prolong survival in HIV-infected patients with MDR-TB (see "Aggressive treatment programs defuse a global TB crisis," AIDS Care, Vol. 1., No. 2), and they are now considered to be the standard of care for all patients with MDR-TB, HIV-infected or not.(8)
Diagnosing and treating MDR-TB in HIV-infected patients can be a significant clinical challenge. The key to diagnosis is to maintain a high level of suspicion, especially in persons with epidemiologic risk factors for tuberculosis, and to order appropriate diagnostic studies whenever TB is suspected. Treatment of MDR-TB should ideally be handled by persons with expertise in the management of tuberculosis. Given the extraordinarily high mortality of this disease, and the risk it presents to those who come into close contact with infected individuals, we cannot afford to make its treatment less than a top priority.
1. Frieden TR, Sterling T, Pablos-Mendez A, et al. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 1993; 328: 521-6.
2. Fischl MA, Daikos GL, Uttamchandani RB, et al. Clinical presentation and outcome of patients with HIV infection and tuberculosis caused by multiple-drug-resistant bacilli. Ann Intern Med 1992; 117: 184-90.
3. Lessnau K-D, Gorla M, Talavera W. Radiographic findings in HIV-positive patients with sensitive and resistant tuberculosis. Chest 1994; 106: 687-9.
4. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149: 1359-74.
5. Bloch AR, Cauthen GM, Onorato IM, et al. Nationwide survey of drug-resistant tuberculosis in the United States. JAMA 1994; 271: 665-71.
6. Mahmoudi A, Iseman MD. Pitfalls in the care of patients with tuberculosis. Common errors and their association with the acquisition of drug resistance. JAMA 1993; 270: 65-8.
7. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329; 784-91.
8. Park MM, Davis AL, Schluger NW, et al. Outcome of MDR-TB patients, 1983-1993. Prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996; 153: 317-24.
Robert M. Jasmer, M.D., is Senior Fellow, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco.
Laurence Huang, M.D., is Assistant Professor of Medicine, UCSF; Medical Director, Inpatient AIDS Unit, San Francisco General Hospital; and Chief, San Francisco General Hospital.