Tuberculosis. The Comeback of a Killer
Tuberculosis, the single largest cause of death worldwide in the 19th and first half of the 20th century by an infectious agent, was considered a controllable disease in the 1950’s after the discovery of streptomycin, PAS and isoniazid. The incidence of tuberculosis began to decline in the United States and in Western Europe in the 1960’s and 1970’s resulting in the closing of sanatoria and clinics devoted to the treatment of this dread disease. This paper will deal with some of the myths related to TB including the one that, like small pox, for which a vaccine had been developed, TB could be totally eradicated. In the late 1970’s and the 1980’s, a gradual increase in TB began to re-emerge and reached epidemic proportions in the late 1980’s in New York City and other urban areas of the United States. This upsurge was alarming and mysterious. In 1990, the WHO convened a meeting in Geneva where the conclusions drawn by representatives of TB programs from all over the world were alarming: 2.9 million deaths were caused by tuberculosis in 1990, “making this disease the largest cause of death from a single pathogen in the world”. In June, 1992, the WHO issued a press release about the rise of tuberculosis in industrialized countries including the United Kingdom and Italy in addition to the United States. It seemed evident that there must be a common factor. Although socioeconomic factors such as crowding, homelessness and poor nutrition were contributing factors, the main factor for this global threat was the human immunodeficiency virus (HIV).
In consideration of the large number of intravenous drug users who have become HIV+, (many of whom have developed AIDS), this paper will deal with the role that substance abuse treatment programs (particularly Methadone Maintenance Programs) are playing in the identification, treatment and prophylaxis of tuberculosis. Patients are being tested and identified and environmental protection is being introduced into the clinics. While these programs cannot address the socioeconomic factors that have always played a role in the transmission of tuberculosis, efforts are made to improve the living conditions of the patients enrolled in their clinics. A major factor that has enhanced the seriousness of the medical aspects of tuberculosis today is the emergence of multidrug resistant (MDR) TB. Although non-compliance has contributed to the development of MDR TB, it has long been recognized that the drugs most effective in treating TB result in resistance even when taken as directed. To the extent that time permits this paper will attempt to deal with the above issues and the efforts being made to reduce the risks inherent in a world where co-existing tuberculosis and HIV are so prevalent.
Infectious diseases have been and remain the leading cause of death world wide, and tuberculosis heads the list as the single pathogen responsible for the largest number of deaths. It is responsible for more deaths world wide than cancer or cardiovascular disease. Annually there are eight million new cases of tuberculosis, and 2.9 million deaths. The greatest killer in history, tuberculosis has claimed more than a billion lives world wide. One third of the world’s population harbors the tubercle bacillus, and in some developing countries as many as 67% of the deaths are caused by tuberculosis.
From the earliest days of recorded medical history going back to Hippocrates, tuberculosis has been the most dreaded scourge. Many of the most creative people, such as Keats, Byron and Chopin among others, have fallen victim to this disease at a very young age and at the height of their creative talents (1).
As AIDS is now, it was feared by people of all classes and eluded the efforts of the best scientists to find an effective treatment.
Today we are confronted with the deadly dyad of HIV and TB. The synergism of these two pathogens has created a public health problem that threatens every segment of our society.
DOUBLE TROUBLE… This is the issue with which we are concerned here today, but first let’s briefly review the history of tuberculosis.
In general, tuberculosis was viewed as a weakness of the spirit. In 16th century Italy, Fracastora included phthisis (as tuberculosis was then known and which is the Greek word for wasting) in a work on contagion. Then the Decree of Lucca, promulgated in 1699, required physicians to notify the General Sanitary Council of the names of patients with phthisis. And it was Villemin in 1865 who formally demonstrated that TB was contagious by infecting rabbits with pus from a human tubercle. In 1882 Robert Koch, a German country doctor, shook up the medical world with his isolation of bacterial rods from “tubercles” or freshly developed abscesses, from human beings who had died from tuberculosis. With this discovery, it was finally established that TB was in fact a bacterial disease (2).
There ensued a feverish search in Europe and America to discover a cure for this disease which killed one in seven people world wide. Decades would pass before Albert Shatz, a young assistant in Selman Waksman’s laboratory at Rutgers University would discover in 1943 that streptomycin was effective in inhibiting in vitro the growth of the Mycobacterium bacillus (3).
In 1944 the first trial of parenteral streptomycin in human tubercular patients led to a dramatic improvement of symptoms even though sputa failed to turn negative and resistance developed in most cases. (Adding PAS to the medical regimen for a period of 4 months did result in negative sputa).
In 1952 the first trial of isoniazid taken orally appeared promising. Symptoms cleared but in only 8 of 44 patients did sputa turn negative. Moreover, resistance developed frequently and rapidly. It soon became evident that no single drug in the pharmacopoeia was a miracle drug capable of eradicating a patient’s infection--and the same holds true today. A combination of drugs was recognized as necessary.
In 1963 Rifampin was added to the armamentarium of anti-tuberculosis medications. As powerful as isoniazid and less toxic than streptomycin, it could also be taken orally. Further studies showed that a combination of INH and Rifampin yielded even better results than either taken separately; with the introduction of additional anti-TB drugs in the 1960’s (e.g. ethambutol, pyrazinamide and others), the hope (and illusion) that tuberculosis could be eradicated led to a spirit of optimism (4). In the United States, a decline in the incidence of tuberculosis had actually begun well before the discovery of chemotherapeutic agents.
Improved living conditions, better housing and less crowding seemed to be factors contributing to this reduction in the number of active cases. As a result of this dramatic decline in the US and in other industrial nations, the need for sanatoria and special hospital beds and clinics was questioned and they were closed. Even the sanatorium in Davos made famous by Thomas Mann in The Magic Mountain was closed and faded into history. Many experts in the field questioned the wisdom of these moves and expressed the idea that, although tuberculosis appeared to be waning, we could expect a resurgence of this deadly disease.
Beginning in the late 1970’s, there was a gradual increase in the number of cases of tuberculosis in the United States and strains resistant to more than one chemotherapeutic agent began to emerge with increasing frequency. Pulmonary physicians as early as 1978 (Lee Reichman et al.) warned that tuberculosis was on the increase but their words fell on deaf ears. In reality, although the incidence of tuberculosis had dramatically diminished by the 1960’s, it had never disappeared (5).
In 1990, articles in the daily newspapers reflected the recognition by the news media that there was indeed a deadly strain of tuberculosis reaching epidemic proportions in New York City. That same year the World Health Organization convened a summit meeting in Geneva to address the growing number of TB cases in developing nations, especially the subSaharan countries. There was a widespread fear that Africa was lost. In 1992, the WHO added at least 10 European countries (including the Netherlands, Sweden, Finland and Italy) to the list of those regions where TB had re-emerged. Although the increase was now observed to be primarily associated with the HIV epidemic, there was general recognition that poverty and a growing homeless population were also significant contributory factors.
In New York City in 1991, the number of tubercular cases continued to rise. Case rates which had been rising since 1979, were then 50.2 per 100,000 population. There were 3,673 new cases of tuberculosis that year. The case rate in 1991 was the highest in two decades, having risen 143% since 1980. One third of all NYC cases reported in 1991 were resistant to two or more drugs, and nearly one in five were resistant to both INH and Rifampin, the two most effective oral anti-TB drugs.
Patients with a previous history of treatment for TB were more likely to have resistant strains than those who had never been treated: 44% had strains resistant to one or more anti-TB drugs, 36% had strains resistant to INH and 30% demonstrated resistance to both INH and Rifampin (6).
The fatality rate for multiple drug resistant MDR-TB in some series is between 40% and 60% in HIV- individuals and up to 80% in HIV+s. In 1990 and 1991, 3 outbreaks of MDR-TB in NYC hospitals were investigated by the CDC and the NYC Department of Health. Eighty-two (82) cases of MDR-TB were identified as probably occurring due to transmission within these institutions. At least 85% of the patients were HIV positive.
The pool of prevalent latent infections is a major source of new cases occurring in individuals whose immune systems can no longer contain their infection. The extent to which recently acquired infection contributes to the incidence of new cases is uncertain, but may be greater than previously recognized.
Prior to the era of HIV, it was known that the risk of progression from infection to disease is greatest in the two years following infection and tends to decline with the passage of time. The lifetime risk of disease is about one in ten unless preventive therapy is given, and prophylaxis with isoniazid is about 90% effective in preventing the disease. However, the course of TB in HIV+ individuals is dramatically different. Tuberculosis is an AIDS-defining disease in HIV infected patients and is often the first indication of HIV infection. While the lifetime risk of developing tuberculosis in the average healthy person is 10% over a lifetime, it is 8% a year in an HIV+ individual. In view of the fact that cure rates can be as high for HIV+ patients as for those who are HIV-, it is essential to start drug treatment without delay. Recognizing the synergism between tuberculosis and HIV infection, and the high percentage of co-infection among methadone patients, all methadone patients must be evaluated for tuberculosis infection and disease.
Although not all patients enrolled in methadone treatment are at equal risk for acquiring infection with HIV or tuberculosis, all patients should be screened for tuberculosis infection and disease. The Mantoux skin test is used to detect tuberculosis infection. A reaction of 5 mm or more is considered positive in HIV infected individuals; 10 mm or greater induration is considered positive in patients with a history of intravenous drug use and other risks for TB infection, and 15 mm or more is considered positive for patients without other risk factors for tuberculosis infection (7).
All patients except those who tested positive for tuberculosis infection in the past should undergo testing upon admission to the program and annually or semi-annually thereafter. HIV-infected drug users with cutaneous anergy have been shown to be at high risk of developing tuberculosis. Anergy testing is therefore recommended for HIV+ and HIV-serostatus unknown patients in methadone treatment. At Montefiore, anergy tests are placed simultaneously with the PPD for all patients regardless of HIV serologic status to eliminate the need for additional patient visits (8–9). A negative PPD together with a reactive anergy panel make the diagnosis of tuberculosis infection unlikely. It is important to point out that skin testing identifies tuberculosis infection. It does not diagnose active tuberculosis which requires radiologic tests and culture of the bacillus from the patient. Therefore all patients with reactive skin tests or who are HIV+ or HIV-unknown and anergic warrant evaluation for active disease with a chest xray.
The classical radiologic appearance of pulmonary TB is of the upper lobe infiltration with cavitation. In HIV+ patients the xray pattern is frequently atypical; infiltrates in any lung field may be found, and cavitation is uncommon. All too often this has led to a delay in the diagnosis of TB in HIV infected patients. Culturing M. TB sputum specimens can be a slow and tedious process, usually taking 3 to 8 weeks. Subsequently, determining susceptibility to a wide range of anti-TB drugs can be equally daunting. When in vitro sensitivity is not known, which is generally the case at the outset of therapy, treatment of patients with active TB should be started in a hospital on a 4 drug regimen, consisting of INH, Rifampin, pyrazinamide and streptomycin or ethambutol. This regimen is usually effective even against INH resistant strains and can be administered twice a week after an eight-week induction period of daily therapy. Sputum conversion is achieved more rapidly with this 4 drug regimen than with a 3-drug regimen of INH, Rifampin and PZA, and a patient who is treated with the 4 drug regimen is more likely to be cured and not relapse when compared with a patient treated for the same length of time with the 3 drug regimen.
It is well known that Rifampin decreases serum levels of methadone when the two medicines are taken concurrently. In this age of epidemic tuberculosis, with drug users bearing a disproportionate burden of active disease, more and more methadone-maintained patients are being started on Rifampin.
It is imperative that clinicians be prepared to work closely with methadone-maintained patients being started on potentially life saving medication. Patients must be advised in advance of the probable decrease in efficacy of their current methadone dose, and reassured that the clinician will raise the patient’s methadone dose as rapidly as the patient feels it is necessary.
Only in this manner will patients be able to tolerate this critical drug, thereby increasing the likelihood that they will be compliant with the regimen and that they will complete their course of therapy. The risk of progression to disease in newly infected individuals is greatest in the two years following infection and tends to decline with the passage of time.
The risk of infection is about one in ten unless preventive therapy is given, and the successful results of prophylaxis is high. The drug of choice for prophylaxis is isoniazid given daily in a dose of 300 mg. Unlike treatment of active disease, isoniazid ideally should be given daily for prevention as there are no good studies showing effective prophylaxis unless the medication is taken daily. The most effective treatment outcome is associated with 300 mgs given daily under observation, and that is the regimen we try to follow at Einstein and Montefiore. However, because of fiscal and other constraints some groups give isoniazid two or three times weekly in appropriately higher doses.
Regardless of the regimen, the medication should be taken under direct observation. The reduction in the number of visits per week makes it possible for the staff to observe the administration of the medication. Otherwise it may be necessary to find a family member who will supervise the patient.
One of the greatest challenges in controlling tuberculosis is achieving compliance. Compliance can be increased by administering the anti-TB drugs when patients come in for their methadone, offering an opportunity for directly observed therapy (DOT) and directly observed prophylactic therapy (DOPT). This gives staff the opportunity to educate patients about the personal and public health benefits of taking the medication as prescribed, and to motivate the patient.
Methadone maintenance treatment clinics are ideal sites to accomplish multiple goals. When this treatment modality was originally developed by Dole and Nyswander in the 1960’s, their main purpose was the rehabilitation of patients, to help them develop or rebuild normal lives. In the past three decades the patients have presented with increasingly difficult problems and now the clinics play a crucial role in the treatment of HIV infection, AIDS, and tuberculosis. Unlike AIDS for which there is no known cure at the present, tuberculosis is not only treatable but it is also preventable in a large percentage of these who are infected. One of the greatest challenges in controlling tuberculosis is achieving compliance.
Methadone maintenance clinics can play a crucial role in achieving compliance and other goals essential to a successful outcome.
Given the known synergism between HIV and TB, and the high percentage of HIV infection among many of the patients who are former intravenous drug users, the guidelines which have been issued by the CDC can be implemented in methadone clinics.
Compliance can be achieved by administering the anti-TB drugs when patients come in for their methadone offering an opportunity for directly observed therapy (DOT) and directly observed prophylactic therapy (DOPT). They also give staff the opportunity to educate patients about the personal and public health benefits of their taking the medication as prescribed, and to motivate the patients (10).
Treatment of subclinical infections in the general population is critical since 5 to 10% will develop active disease over their lifetime. The development of disease is significantly greater in HIV infected patients--and the greatest risk among this group seems to be in present (and past) intravenous drug users. HIV-positive patients progress from the infected to the active state at the rate of 8% per year and at a more rapid rate than the otherwise healthy individual. If treatment is started early enough in an HIV+ patient, the cure rate is usually high.
Van Etten History.
It might be of some interest to review the first pilot program where methadone was used to treat tubercular addicts in 1966 at Einstein in the Van Etten Hospital for Chest Diseases. Prior to the introduction of methadone, 95% of these patients signed out A.M.A. One year after the pilot was started, the figure was reversed; not only did the patients remain in the hospital until their sputa turned negative, but they returned to the hospital after discharge where they received their anti-TB medications and methadone. The irony of this successful experiment is that the results contributed to the closing down of special beds for tubercular patients.
The resurgent tuberculosis epidemic reflects a failure to maintain a public health infrastructure focused on treating active tuberculous patients until cured and on preventing active disease in high risk populations. Directing public health resources into targeted programs that enhance compliance with treatment regimens and expanding chemoprophylaxis among HIV+ individuals is not only possible but essential.
To achieve success in controlling tuberculosis, a sustained commitment to fund an adequate public health infrastructure is needed. There are multiple problems which include the need for better and more rapid diagnostic techniques to determine drug susceptibility, improved social conditions with the elimination of homelessness and crowded living conditions, the introduction of environmental controls especially in long term living facilities such as prisons and nursing homes, and the ability to ensure that patients complete their course of therapy.
Sheldon Landsman expressed it very effectively in a recent issue of the American Journal of Public Health when he suggested that the tuberculosis epidemic in New York City can be seen “as the superimposition of a biologic process--HIV infection-- upon a social and political landscape of inadequate policies, planning and funding (11).” The large number of HIV+ patients with active TB has increased the caseload of patients requiring active supervision, but there has not been a concomitant increase in programs or personnel to provide the supervision. And completion of therapy is the first and central priority of tuberculosis control.
KeywordsHuman Immunodeficiency Virus Tuberculosis Infection Methadone Maintenance Treatment Intravenous Drug User Directly Observe Therapy
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