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Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection
Gowan views gout as a problem of the kidneys not being able to excrete enough uric acid to prevent a buildup, rather than simply a matter of excessive protein intake. Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide. Now you will start your assessment of the risks in taking on this patient. Thus, although pyrazinamide may be considered after the first trimester in women with HIV infection , it should otherwise be avoided. They will need to wean themselves off, and eventually stop, the use of these substances. Therefore, there has been interest in the development of shorter, rifampin-based regimens as alternatives to isoniazid for the treatment of LTBI. Over time, Lila vowed to achieve the perfect body thus erasing nagging self-doubts about her appearance.

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The 2-mo daily regimen of rifampin and pyrazinamide is recommended on the basis of a prospective randomized trial of treatment of LTBI in HIV-infected persons that showed the 2-mo regimen to be similar in safety and efficacy to a mo regimen of isoniazid.

Twice-weekly treatment with rifampin and pyrazinamide for 2 or 3 mo may be considered when alternative regimens cannot be given. This intermittent regimen should always be administered as DOT. Some experts recommend that the 2-mo regimen of daily rifampin and pyrazinamide also be given by DOT, which can consist of five observed and two self-administered doses each week.

In situations in which rifampin cannot be used e. Rifampin given daily for 4 mo is recommended on the basis of the efficacy of a similar regimen in a a prospective randomized trial of tuberculin-positive persons with silicosis and b a nonrandomized trial in persons exposed to individuals with isoniazid-resistant TB. This option may be especially useful for patients who cannot tolerate isoniazid or pyrazinamide.

Before beginning treatment of LTBI, active TB should be ruled out by history, physical examination, chest radiography, and, when indicated, bacteriologic studies. Special considerations for treatment of LTBI apply to the following populations: For pregnant, HIV-negative women, isoniazid given daily or twice weekly for 9 or 6 mo is recommended. For women at risk for progression of LTBI to disease, especially those who are infected with HIV or who have likely been infected recently, initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester.

For women whose risk for active TB is lower, some experts recommend waiting until after delivery to start treatment.

For children and adolescents, isoniazid given either daily or twice weekly for 9 mo is the recommended regimen. For contacts of patients with isoniazid-resistant, rifampin-susceptible TB, rifampin and pyrazinamide given daily for 2 mo is recommended, and for patients with intolerance to pyrazinamide, rifampin given daily for 4 mo is recommended. For persons who are likely to be infected with isoniazid- and rifampin-resistant multidrug TB and who are at high risk for developing TB, pyrazinamide and ethambutol or pyrazinamide and a quinolone i.

Immunocompetent contacts may be observed or treated for at least 6 mo, and immunocompromised contacts e. Clinical and Laboratory Monitoring Once patients have been identified and then tested for LTBI, they should receive an initial clinical evaluation. They should also receive follow-up evaluations at least monthly if receiving isoniazid alone or rifampin alone and at 2, 4, and 8 wk if receiving rifampin and pyrazinamide.

This evaluation should include questioning about side effects and a brief physical assessment checking for signs of hepatitis. Patients should be educated about the side effects associated with treatment of LTBI and advised to stop treatment and promptly seek medical evaluation when they occur. Baseline laboratory testing is not routinely indicated for all patients at the start of treatment for LTBI see Table 8. Patients whose initial evaluation suggests a liver disorder should have baseline hepatic measurements of serum aspartate aminotransferase serum glutamic oxaloacetic transaminase AST [SGOT] or alanine aminotransferase serum glutamic pyruvic transaminase ALT [SGPT] and bilirubin.

Baseline testing is also indicated for patients with HIV infection, pregnant women, and women in the im mediate postpartum period i. Baseline testing is not routinely indicated in older persons.

However, such testing may be considered on an individual basis, particularly for patients who are taking other medications for chronic medical conditions. Active hepatitis and end-stage liver disease are relative contraindications to the use of isoniazid or pyrazinamide for treatment of LTBI. Routine laboratory monitoring during treatment of LTBI is indicated for persons whose baseline liver function tests are abnormal and other persons at risk for hepatic disease.

Laboratory testing may also be indicated for the evaluation of possible adverse effects that occur during the course of treatment e. Some experts recommend that isoniazid should be withheld if transaminase levels exceed three times the upper limit of normal if associated with symptoms and five times the upper limit of normal if the patient is asymptomatic. In the United States and other countries with a low incidence of TB, most new, active cases have occurred among persons who were once infected, contained this infection, and then later developed active TB 5.

The identification and treatment of infected persons at highest risk for developing disease benefit both infected persons and susceptible persons in their communities. Until recently, isoniazid was the only drug proven effective and thus recommended for treatment of LTBI. Shortly after isoniazid was found to be effective for the treatment of TB, clinical trials were begun to assess the ability of the drug to prevent progression of primary disease in children.

When it was found that this intervention was highly effective, larger trials were begun to evaluate the drug for treatment of infected contacts of TB patients and of other persons at high risk e. This initial statement recommended isoniazid for persons with evidence of previously untreated TB and persons with recent tuberculin skin test conversions, including all children younger than 3 yr of age with a positive tuberculin skin test.

The recommendations stated that chemoprophylaxis is mandatory for a persons with inactive cases of TB who were not previously treated and their contacts, b persons with tuberculin skin test conversions, c persons with specified medical conditions, and d all persons younger than 20 yr of age who had had positive tuberculin skin tests 8.

With widespread use of such an inexpensive drug that had "virtually no side effects," it was believed that "chemoprophylaxis [could] reduce future morbidity from TB in high risk groups by some 50 to 75 percent" 8. However, despite this belief, the goal of reducing TB morbidity by such a substantial percentage through the administration of isoniazid was never reached.

In , among several thousand persons who began isoniazid treatment as a result of an outbreak of TB on Capitol Hill in the District of Columbia, 19 persons developed clinical signs of liver disease and two persons died of hepatic failure attributed to isoniazid 9. The recognition that isoniazid was associated with potentially fatal hepatitis led to the development of guidelines regarding pretreatment screening and monitoring to minimize the risk for severe complications In , following a study to quantify the risk for isoniazid-related hepatitis 11 , guidelines for treatment of LTBI were updated.

The revised guidelines excluded low-risk persons aged older than 35 yr of age as candidates for treatment Subsequent controversy over the appropriate age cut-off for these low-risk, tuberculin-positive persons ensued, with one group concluding that the risks of treatment of LTBI outweighed the benefits for young adults This controversy and resulting confusion led to a decrease in the use of isoniazid for treating persons with LTBIeven persons at high risk for whom treatment was indicated In , the guidelines were further revised to recommend routine clinical and laboratory monitoring for persons aged older than 35 yr of age and other persons at risk for hepatotoxicity Recent studies have suggested that since the advent of routine monitoring, the risk for severe hepatotoxicity has been substantially reduced Because widespread use and the potential impact of isoniazid treatment of LTBI became limited by actual and perceived toxicity and patient nonadherence because of the relatively long period of treatment required, alternatives to isoniazid were suggested The introduction of rifampin, which appeared to be a better sterilizing agent than isoniazid, suggested the possibility that rifampin-based regimens might be safer, more effective, and shorter.

The results of these studies have recently become available and have contributed substantially to guidelines on treatment of LTBI in persons with HIV infection 3. Because testing persons for infection and provision of treatment are interrelated, these recommendations include sections on program activities aimed at identifying high-risk infected persons and tuberculin skin testing, as well as recommendations on the use of new, short-course treatment regimens.

Identification of persons with LTBI has previously been accomplished by widespread tuberculin skin testing of individuals or groups at variable risk for TB. In many situations, this screening was done with limited consideration of the risk for TB in the population s being tested. To focus on groups at the highest risk for TB, the term "targeted tuberculin testing" is used in these guidelines to encourage directed program activities.

Although the terms "preventive therapy" and "chemoprophylaxis" have been used for decades, they have also been confusing. To describe the intended intervention more accurately, this report uses the terminology "treatment of LTBI" rather than "preventive therapy" or "chemoprophylaxis.

Persons at high risk for TB i. Screening of low-risk persons and testing for administrative purposes e. Persons or groups with presumed recent M.

Persons infected with M. In two controlled trials examining the efficacy of treatment of LTBI among contacts of persons with active TB and among patients in mental hospitals, the tuberculin skin tests of participants in the placebo groups of the trials converted from negative to positive.

Among persons whose tests converted, 19 developed disease in the first year of follow-up In a study of TB vaccines given to British schoolchildren, unvaccinated participants' tuberculin skin tests converted. Of these, 4. In designing and planning targeted testing programs, several groups of persons can be identified as being at increased risk for being recently infected with M. A high prevalence of either LTBI or active TB has been documented among close contacts of persons with infectious pulmonary TB 21 ; both of these characteristics are likely attributable to recent contact with infectious persons.

Likewise, persons whose tuberculin skin tests convert from negative to positive within a period of 2 yr are presumed to have been infected recently. Persons who have immigrated from areas of the world with high rates of TB have incidence rates that approach those of their countries of origin for the first several years after arrival in the United States This high rate likely results from infection with M.

This hypothesis is supported by a DNA fingerprinting studies with restriction fragment length polymorphism RFLP interpreted to correlate with low rates of recent transmission of TB among foreign-born case patients in the United States 23 and b other data indicating that with time, the incidence of TB in foreign-born persons declines to approach that of the U.

Children, especially those younger than 5 yr of age, who have a positive tuberculin skin test are likely to be in the early stage of LTBI and are at high risk for progression to active disease, with the potential for disseminated TB The risk for developing active TB is also increased in adolescents and young adults In addition, persons who reside or work in institutional settings e.

However, the risk for transmission varies greatly, and the likelihood that a specific institution is a site of transmission of M. Clinical conditions associated with progression to active tuberculosis. Rates of progression to TB among HIV-infected persons have ranged from 35 to per person-years of observation Table 2 In a prospective cohort study of persons with HIV infection in the United States, the annual risk of active-TB among persons with a positive tuberculin test was 45 cases per person-years Injection drug users also have an increased risk for progressing to active TB 10 cases per person-years 30 , and this risk is even greater for injection drug users coinfected with HIV and TB 76 cases per person-years These higher rates may reflect increased transmission, more recent infection in this population, and the increased risk associated with injection drug use and HIV infection.

The risk for active TB is also increased in a persons with pulmonary fibrotic lesions seen on chest radiographs presumed to be from prior, untreated TB and b underweight persons. Persons with fibrotic lesions on chest radiographs consistent with prior, healed TB have a risk for progression to active TB of 2.

A study of 23, U. Studies indicate that several other clinical conditions increase the risk for active TB, although participants in these studies were not stratified by tuberculin-test status Table 3. Tuberculin-positive persons with silicosis have an approximately fold greater risk for developing TB Persons with chronic renal failure who are on hemodialysis also have an increased risk: Persons with diabetes mellitus have a risk for developing active TB that is twofold to fourfold greater than persons without diabetes mellitus, and this risk is likely greater in persons with insulin-dependent or poorly controlled diabetes Other clinical conditions that have been associated with active TB include gastrectomy with attendant weight loss and malabsorption , jejunoileal bypass 48,49 , renal 50 and cardiac 51,52 transplantation, carcinoma of the head or neck 53 , and other neoplasms e.

Persons receiving prolonged therapy with corticosteroids and other immunosuppressive agents may be at risk for reactivation of TB, but the exact risk is unknown 1. Reactivation of TB is more likely to occur in persons receiving higher doses of corticosteroids for prolonged periods of time, especially in populations at high risk for TB, but specific thresholds of dose and duration that could increase the risk for TB are unknown Persons who use alcohol may be at increased risk for acquiring or developing TB, but given the many other potential risk factors that commonly occur among such persons, alcohol use has been difficult to identify as a separate risk factor for TB 2,42,59, At that time, the administration of skin tests, interpretation of test results, and intensive follow-up required to ensure adherence with and to prevent side effects of isoniazid treatment were believed to be beyond the scope of most private health care providers.

However, in , CDC published recommendations on targeted testing and treatment of LTBI that emphasized the importance of health departments in assisting local providers in the development, implementation, and evaluation of TB screening programs appropriate for their communities 2. This recommendation was based on the recognition that changes in the organization, delivery, and financing of health care in the United States have led to most routine tuberculin testing being done outside of the public health system For example, populations that previously received clinical services, including diagnosis of LTBI, at public health clinics are now increasingly being enrolled as members of managed care organizations.

Because health departments might lack access to high-risk populations and the resources necessary to undertake targeted testing programs, the participation of other health care providers is essential to ensure the successful implementation of community efforts to prevent TB in high-risk groups.

The tuberculin skin test is the only proven method for identifying infection with M. Proper use of the tuberculin skin test requires knowledge of the antigen used tuberculin , the immunologic basis for the reaction to this antigen, the technique s of administering and reading the test, and the results of epidemiologic and clinical experience with the test. Immunologic basis for the tuberculin reaction. Purified protein derivative PPD tuberculin, which is used for most skin testing, is isolated from culture filtrate by protein precipitation.

The reaction to intracutaneously injected tuberculin is a delayed-type cellular hypersensitivity DTH reaction, and infection by M. Delayed hypersensitivity reactions to tuberculin usually begin 56 h after injection, reach a maximum at h, and subside over a period of a few days, although positive reactions often persist for up to 1 wk Sensitivity and specificity of skin-test reactions.

Knowledge of tuberculin-test sensitivity and specificity, as well as positive predictive value, is required to interpret skin-test reactions properly. However, false-positive tuberculin tests occur in persons who have been infected with nontuberculous mycobacteria and in persons who have received BCG vaccine. These false-positive reactions result in a lower specificity and a low positive predictive value in persons who have a low probability of LTBI.

However, the specificity of the test is also dependent on the criterion used to define a "positive" test. The specificity can be improved by progressively increasing the reaction size that separates positive from negative reactors at the expense of decreasing test sensitivity Intracutaneous inoculation with BCG is currently used in many parts of the world as a vaccine against tuberculosis.

Tuberculin reactivity caused by BCG vaccination generally wanes with the passage of time but can be boosted by the tuberculin skin test. Periodic skin testing may prolong reactivity to tuberculin in vaccinated persons HIV infection and anergy testing. HIV-infected persons may have a compromised ability to react to tuberculin skin tests because of cutaneous anergy associated with progressive HIV immunosuppression However, the usefulness of anergy testing in selecting tuberculin-negative, HIV-infected persons who might benefit from treatment of LTBI has not been demonstrated In persons with LTBI, the chest radiograph is usually normal, although it may show abnormalities suggestive of prior TB.

Previous, healed TB can produce various radiographic findings that usually differ from those associated with active TB. Dense pulmonary nodules, with or without visible calcification, may be seen in the hilar area or upper lobes. Smaller nodules, with or without fibrotic scars, are often seen in the upper lobes, and upper-lobe volume loss often accompanies these scars.

Nodules and fibrotic lesions of previous, healed TB have well-demarcated, sharp margins and are often described as "hard. Pleural scarring may be caused by prior TB but is more commonly caused by trauma or other infections.

Nodules and fibrotic scars may contain slowly multiplying tubercle bacilli with substantial potential for future progression to active TB Conversely, calcified nodular lesions calcified granulomas and apical or basal pleural thickening pose a lower risk for future progression to active TB.

The presumptive diagnosis of active pulmonary TB is often made on the basis of microscopic examination of a stained sputum smear for acid-fast bacilli AFB. Confirmation of the diagnosis usually requires identification of M. In asymptomatic persons with normal chest radiographs, AFB are rarely seen on sputum smear examination, and tubercle bacilli are not found in cultures of respiratory specimens.

However, some HIV-infected persons with sputum culture-positive TB have been described as having normal chest radiographs. Treatment of Latent Tuberculosis Infection Isoniazid. Before clinical trials of isoniazid for the treatment of LTBI were begun in the United States, its efficacy was demonstrated in guinea pigs. In a study conducted by PHS, guinea pigs receiving varying doses of isoniazid were challenged with virulent tubercle bacilli Clinical trials in HIV-negative persons.

Many randomized, controlled clinical trials of isoniazid for the treatment of LTBI were conducted in the s and s 6. These trials were conducted in seven countries, both industrialized and developing, and involved more than , participants at risk for TB, including children with primary TB, contacts of active case patients, persons who had had tuberculin skin reactions, institutionalized patients with mental disease, and persons with inactive TB.

Most studies compared 12 mo of isoniazid with placebo. The outcomes measured in these studies included progression of primary TB, tuberculin conversion in uninfected contacts, prevention of TB in infected persons, and recurrence of disease. Substantial protection was conferred even if pill taking was irregular but sustained, suggesting the possibility that intermittent treatment may be efficacious.

In this trial, a placebo regimen was compared with isoniazid regimens lasting for 3, 6, and 12 mo among persons with fibrotic pulmonary lesions consistent with inactive TB. The 5-yr incidence rates of tuberculosis were 1. The mo regimen provided a substantial reduction in risk compared with the 6-mo regimen among compliant persons with small lesions Table 4. Additional information on the efficacy and effectiveness of different lengths of therapy with isoniazid for the treatment of LTBI has been derived from a randomized study of household contacts conducted by PHS The same data can be further examined to determine whether reduction in the rate of TB was affected more by duration of therapy or the amount of medication.

Effectiveness data from the IUAT study, published data on isoniazid-associated hepatitis, and cost information obtained from a survey of U. TB programs were used to assess the cost effectiveness of various durations of isoniazid The cost per case of TB prevented with the 6-mo regimen was determined to be half of the cost as either the 3-mo or mo regimens.

This cost-effectiveness analysis was largely responsible for the widespread adoption of the 6-mo regimen of isoniazid for the treatment of LTBI in HIV-seronegative persons with normal chest radiographs However, the protection conferred by taking at least 9 mo of isoniazid is greater than that conferred by taking 6 mo; it is not likely that further protection is conferred by extending the duration of treatment from 9 to 12 mo Clinical trials in HIV-positive persons.

Five of these studies evaluated isoniazid regimens using comparison groups that either received a placebo or were not actively treated. Protection was constant over the 4 yr of follow-up after treatment.

Two other studies, which evaluated 6 mo of isoniazid taken daily by tuberculin-positive persons, had differing results: A fourth study evaluated a 6-mo, twice-weekly regimen of isoniazid in both tuberculin-positive and - negative persons in Zambia The Uganda study also evaluated the 6-mo regimen of daily isoniazid in anergic persons, as did the fifth study conducted in the United States In both studies, the level of protection against TB was low, and neither study demonstrated a significant level of protection.

Additional evaluations of isoniazid were conducted in tuberculin-negative persons who were not assessed for anergy 83,85, The level of protection provided by isoniazid among this population was not significant in any of the studies. Thus, for HIV-infected persons, treatment should be targeted at tuberculin-positive persons. A recently published metaanalysis of these trials supports this conclusion In , when isoniazid was first recommended in the United States for treatment of LTBI, it was not thought to cause severe toxicity.

In the PHS studies conducted among TB contacts, the percentage of persons stopping treatment because of suspected drug reactions was low and approximately equivalent for the placebo and isoniazid groups The occurrence of hepatitis was rare and was not assumed to be caused by isoniazid. However, studies conducted in the late s suggested that isoniazid did cause hepatitis and indicated that asymptomatic increase in hepatic transaminases occurred among persons receiving the drug It was not until the s, when several persons receiving isoniazid for LTBI died from hepatitis, that the likelihood of isoniazid hepatitis was understood 9.

The largest and most comprehensive study of isoniazid hepatitis was conducted by PHS during In this survey, nearly 14, persons who received isoniazid were monitored for the development of hepatitis. An association of hepatitis also was found with alcohol consumption, with rates being fourfold higher among persons consuming alcohol daily than among those who did not drink alcohol. Rates among males and females were equivalent and were lower among black males and higher among Asian males compared with rates among white males.

Hepatitis rates were lower among participants in the IUAT trial, although the same positive association with age was observed In the PHS surveillance study, eight deaths from hepatitis occurred among the participants, seven of which were among persons living in Baltimore.

Several years after completion of the study, a review of death certificates showed a marked increase in deaths from cirrhosis during in Baltimore and surrounding counties, suggesting that another cofactor may have been associated with the cluster of deaths observed in the study A comprehensive analysis of deaths from isoniazid-associated hepatitis in the United States found that women may be at increased risk of death Other reports have suggested that the risk for isoniazid-associated hepatitis may be increased by the administration of the drug to pregnant women in the third trimester and the immediate postpartum period 92 or by the concomitant administration of acetaminophen Although experimental evidence suggests that acetaminophen hepatotoxicity is potentiated by isoniazid 94 , a more detailed study of deaths from isoniazid-associated hepatitis did not implicate acetaminophen as a factor Isoniazid-related deaths continue to be reported.

However, the likelihood of this occurrence can be greatly reduced by careful monthly monitoring and stopping of medication if symptoms occur In a recent study, seven of eight patients receiving a liver transplant following the development of fulminant, isoniazid-related hepatitis continued to take the drug for a least 10 d after onset of symptoms of hepatotoxicity Following the PHS surveillance study, guidelines on the use of isoniazid for the treatment of LTBI were revised to recommend that low-risk persons older than 35 year of age with reactive tuberculin skin tests not be treated, that no more than 1 mo drug supply be issued at a time, and that monthly questioning and education about signs and symptoms of hepatitis should be routine The guidelines were further revised to recommend baseline and periodic liver-function tests for persons at risk for hepatotoxicity, including persons aged 35 yr of age or older More recently, a survey found that many public health TB clinics now use clinical, rather than biochemical, monitoring for hepatotoxicity during treatment of LTBI Clinical monitoring is based on educating patients about the symptoms of hepatotoxicity and instructing them to stop treatment immediately if such symptoms occur and to report to the clinician for evaluation.

After using clinical monitoring exclusively, one public health TB clinic reported only 11 cases of clinical hepatotoxicity one of which required hospitalization and no deaths among more than 11, persons with LTBI during isoniazid treatment over a 7-yr period Recent studies of isoniazid treatment of LTBI in HIV-infected persons have demonstrated that the medication was well tolerated and not associated with substantial increases in hepatic side effects.

In a recent meta-analysis of placebo-controlled trials, adverse drug reactions were slightly but not significantly more common among persons receiving isoniazid Despite the high efficacy and relative safety of isoniazid treatment for LTBI, its use has been frequently debated; much literature has been published regarding whether and when to prescribe isoniazid 13, However, because the arguments em bodied in that literature emerged more than two decades ago, in a different environmental context with different risks and contingencies, its appropriateness to current circumstances is uncertain.

Although the likelihood that a patient treated with isoniazid would develop hepatitis was low, it presented a valid argument against the use of isoniazid among persons who had no increased risk for developing active TB. Most of the arguments concerning the use of this drug, which appeared from the s through the early s, focused on persons at low risk for reacting to tuberculin, primarily those 35 yr of age or older who were likely at higher risk for isoniazid-associated hepatitis than younger patients.

Because the debate over whether to prescribe or withhold isoniazid for persons older than 35 yr of age at low risk for reacting to tuberculin involved a trade-off between risk for developing active TB versus risk for developing isoniazid-induced hepatitis, decision analysis was used by most investigators Despite many analyses, the decision to treat persons at low risk for reacting to tuberculin at any age continued to be controversial.

Although various analyses supported both sides of the debate, none of the calculated benefits of isoniazid was substantial. Experimental studies in animals. Because of high rates of nonadherence with the long duration of isoniazid i. The studies evaluating rifampin were based on data from several studies in mouse models of chronic TB. One study compared isoniazid with regimens of rifampin alone; rifampin and pyrazinamide; and isoniazid, rifampin, and pyrazinamide The rifampin-only regimen sterilized lung and spleen tissues within 4 mo, and the combination of rifampin and pyrazinamide sterilized tissues within 2 mo.

The isoniazid, rifampin, and pyrazinamide regimen was of intermediate efficacy, taking longer than the rifampin and pyrazinamide regimen to sterilize tissues. The isoniazid regimen had not sterilized tissues by the end of 6 mo. The apparent superiority of the rifampin--pyrazinamide regimen over the regimen containing the same two drugs plus isoniazid might be explained by impaired absorption of rifampin when given simultaneously with other drugs in mice Support for this hypothesis came from a study using a Cornell mouse model that compared 6-wk regimens of rifampin, rifampin--isoniazid, rifampin--pyrazinamide, and rifampin-- pyrazinamide--isoniazid, with delayed administration of rifampin when given with other drugs.

The efficacy of all three regimens was similar, with trend toward a lower colony count in spleens of animals given more drugs, and lower colony counts in the lungs of mice given rifampin--isoniazid.

Experimental studies have also suggested that rifabutin alone, taken daily, and rifabutin--isoniazid, taken twice weekly, may effectively treat LTBI in 3 mo The only randomized clinical trial to evaluate rifampin-containing regimens among HIV-seronegative persons was conducted in tuberculin-positive persons with silicosis in Hong Kong In this study, daily regimens of 6 mo of isoniazid, 3 mo of rifampin, or 3 mo of isoniazid and rifampin were compared with a 6-mo placebo control.

All of these differences were significantly different from the placebo regimen but were not statistically different from each other. The largest programmatic experience using rifampin-based treatment of LTBI comes from Blackburn, England, where children at increased risk of TB have been treated with daily rifampin--isoniazid since Although not a controlled clinical trial, these data suggest that this intervention has been highly effective in reducing the rate of childhood TB in this city.

Thus, this regimen is currently recommended for the treatment of both adults and children with LTBI in the United Kingdom The Uganda study also evaluated regimens of isoniazid--rifampin and isoniazid--rifampin--pyrazinamide taken daily for 3 mo in tuberculin-positive persons The Zambia study also evaluated a self-administered regimen of rifampin and pyrazinamide taken twice weekly for 3 mo In two trials, rifampin and pyrazinamide regimens have been compared with regimens of isoniazid alone in tuberculin-positive persons.

A second study conducted in Haiti during compared twice-weekly regimens of 6 mo of isoniazid and 2 mo of rifampin and pyrazinamide, with half of the doses directly observed A multinational study comparing a mo regimen of isoniazid taken daily with a 2-mo regimen of rifampin and pyrazinamide taken daily was conducted in the United States, Haiti, Brazil, and Mexico A total of patients were enrolled and followed for an average of 3 yr.

The annual risk of culture-confirmed TB was 0. In conclusion, as evidenced by the large multinational study, a 2-mo regimen of rifampin and pyrazinamide taken daily provides protection against TB equivalent to a mo regimen of isoniazid taken daily. The data supporting the use of a twice-weekly rifampin and pyrazinamide treatment regimen are less conclusive.

The only study that has evaluated a rifampin-alone regimen, the Hong Kong study in persons with silicosis, suggests that daily rifampin for 3 mo provides similar protection to that conferred from 6 mo of isoniazid In the Uganda study, 3-mo regimens of a isoniazid and rifampin and b isoniazid, rifampin, and pyrazinamide provided protection equivalent to that of 6 mo of isoniazid In the earlier Haiti study, isoniazid likely conferred protection against progression of HIV disease among tuberculin-positive sub jects In the multinational study, persons receiving the 2-mo regimen had lower mortality rates and less progression of HIV disease, although these differences were not statistically significant In none of the other studies was active treatment protective against death or HIV progression.

Before the conduct of the studies in HIV-infected persons, a pilot study to assess the safety and tolerability of short-course regimens was conducted in HIV-seronegative adults in North America , Participants were randomized to receive either 2 mo of rifampin and pyrazinamide, 4 mo of rifampin only, or 6 mo of isoniazid.

The rates of adverse reactions and abnormal AST elevations were higher than those reported in studies involving HIV-positive populations and those described in a clinical trial of isoniazid, rifampin, and pyrazinamide for the treatment of active TB in HIV-seronegative persons Two smaller pilot studies of rifampin and pyrazinamide treatment of LTBI using identical protocols were conducted in adults in Poland and children in Germany The results of the study in Poland were similar to those in the study in North America; the children in Germany tolerated the regimens well and did not experience changes in hepatic function.

In the Hong Kong study of patients with silicosis, no significant differences were noted in the occurrence of severe adverse reactions in the three drug regimens studied However, patients receiving isoniazid had a higher incidence of abnormal liver function tests during treatment. In the clinical trials involving HIV-infected persons, a trend of increased adverse reactions occurred among persons taking a daily regimen that included pyrazinamide.

The Uganda study reported that persons taking the three-drug, pyrazinamide-containing regimen had higher rates of paresthesias, arthralgias, and significant increases in serum AST The multinational study reported minimal increases in the number of persons receiving the 2-mo rifampin and pyrazinamide regimen who had the drugs permanently discontinued, most commonly because of nausea and vomiting and narcotic withdrawal However, abnormal liver function tests were more common among patients taking isoniazid.

In the Haiti study conducted during and the Zambia study, regimens of twice-weekly rifampin and pyrazinamide were well tolerated. Biochemical hepatitis was more frequent in the isoniazid group, whereas rash was more common in persons receiving rifampin and pyrazinamide. Testing for and treating LTBI requires several steps, including administering the test, reading the test, medically evaluating infected persons, initiating treatment, and completing therapy.

Because persons with LTBI are not clinically ill and may not be motivated to undergo treatment, nonadherence occurs commonly in all steps of the treatment process. The health care system can compromise patient adherence to testing and treatment of LTBI A lengthy referral process may discourage patients from being evaluated for a positive tuberculin test or initiating treatment for LTBI.

Long waiting times in the clinic may also discourage patients from attending follow-up visits. Other factors that may affect adherence with testing and treatment include the clinic's hours of operation, distance of the clinic from the patient's home, the cleanliness of the clinic, and the attitude of clinic staff.

Since the advent of effective chemotherapy for active TB, adherence to treatment regimens has been recognized as a substantial problem for TB controlespecially for treatment of LTBI. Adherence to treatment decreases with time, whereas the efficacy of the regimen increases with the length of therapy Patients may be more adherent to the 2-mo regimen of rifampin and pyrazinamide because of the shorter length of therapy; however, this regimen also involves taking multiple medications, and patients may not tolerate this regimen as well as isoniazid, thus potentially resulting in nonadherence.

The Haiti study of rifampin and pyrazinamide taken twice weekly and the multinational study both reported better adherence with the shorter, 2-mo regimens. Nonadherence was similar during the first 2 mo of therapy for both groups. However, overall completion rates were lower for the isoniazid regimen because of continued nonadherence during the last 4 mo of therapy.

For example, demographic factors are not reliable predictors of adherence. However, culturally influenced beliefs and attitudes may result in misinformation about TB and may adversely affect adherence The intervention most likely to improve adherence for treatment of LTBI has been DOT, which requires direct observation of the patient ingesting each dose of medication and usually includes the provision of comprehensive services that attempt to meet the patient's basic needs and the use of incentives and enablers Although randomized trials have yet to be reported, available information suggests that DOT leads to higher rates of completion than self-supervised therapy, and, under certain circumstances, is more cost effective Targeted tuberculin testing programs should be designed for one purpose: Following that principle, targeted tuberculin testing programs should be conducted among groups at risk for recent infection with M.

With the exception of initial testing of persons at low risk whose future activity will place them at increased risk of exposure e. In addition, a substantial proportion of tuberculin-test-positive persons from low-risk populations may have false-positive skin tests Testing is also discouraged unless a plan has been developed to complete a course of treatment in persons found to have LTBI.

Such planning should include arrangements for medical evaluation e. A flexible approach to identifying high-risk groups is recommended, and state and local public health agencies are encouraged to analyze their TB case reports and data obtained from tuberculin skin testing to identify high-risk groups based on local trends in the epidemiology of TB.

Thus designing and conducting skin-test-screening surveys to determine whether population groups are at high risk for TB may be desirable. Populations at risk can be accessed at HIV treatment facilities, drug treatment centers, homeless shelters, community health centers and schools serving foreign-born persons, and selected community-based organizations. Mandated skin-testing programs e. In this community-based approach to targeted testing and treatment of LTBI, the health department TB program should be instrumental in planning and coordination, setting performance standards, and overseeing quality of service.

The health department is responsible for assessing the community's TB problem, identifying high-risk groups based on the local epidemiology of TB, and ascertaining the sites of most convenient access to those groups.

In addition, the health department should assume responsibility for organizing the community-based approach, recruiting health professionals, educating such professionals about TB, and motivating them to institute targeted testing and treatment programs.

Please check with individual clinic if you have questions. Active Physical Therapy provides state of the art treatment throughout the state of Maryland. Our experienced and dedicated physical therapists and certified hand therapists work closely with our diverse clinical team to design individualized treatment plans to achieve specific goals for each patient. We look forward to helping you make your appointment. Please contact the office nearest you: Our dedicated staff aims to provide you the best physical therapy in MD.

Recommendations from local active athletics encouraged me go to Active Physical Therapy for lingering knee pain. After my diagnosis by Lynn, my treatment by Lucas, who has incredible credibility as an accomplished athlete, went the extra mile with advice on bicycle seat positioning and pedal stroke. Bottom line after roughly 6 weeks of treatment, commitment to their recommended fitness routine, and suggestion that I keep active while I heal, allowed me to keep my fitness level while losing the knee pain.

I started going to Active Physical Therapy in January of Being underweight can also derail intake and absorption of vital nutrients, including amino acids, vitamins, and minerals, leading to increased risk of osteoporosis and anemia. In addition, underweight women are prone to amenorrhea and possible pregnancy complications. There is a plethora of reasons why people may become underweight, and there are as many treatment courses as there are causes.

Being underweight, whether or not weight is lost intentionally, results from a variety of factors, some psychological, some physiological. Physical origins of underweight include genetics and illness. Some bouts with the flu or other viruses can cause unprompted weight loss, and many medications can suppress appetite or actually cause weight loss. Patients should check with their pharmacist if they have recently started a new medication and are now experiencing otherwise unexplained weight loss.

Anorexia likely comes to mind when considering underweight, but excessive stress may not. Yet many people under stress experience weight loss due to a lack of appetite or nausea. Another major psychological cause of underweight is depression. Individuals suffering from depression often present with a reduced appetite and rapid weight loss; in these cases, advice from a psychologist or counselor should be sought in addition to guidance from a dietitian.

Wasting Diseases Several major illnesses foster pronounced weight loss and underweight, including hyperthyroidism and—perhaps surprisingly, since it is often related to obesity and overweight—diabetes. These conditions are called wasting diseases because patients literally shrink away. Patients with wasting generally lose muscle mass, not fat, as the body burns up muscle tissue for the protein needed to fight inflammation in those with heart conditions and cancer.

Since wasting can be a sign of disease progression, it should be a red flag for clinicians. While not completely understood, the correlation between disease and wasting has many causes, including drug- or illness-associated side effects such as nausea and appetite loss; infections, which increase calorie needs; oral infections, which complicate eating or swallowing; and debilitating fatigue, which makes daily chores such as shopping and cooking difficult.

Intestinal malfunction may lead to an inability to absorb nutrients and can contribute to weight loss. Metabolic changes, including the number of calories patients expend at rest or during physical activity, also affect weight loss. Successful weight gain comes down to the age-old tactic of pairing a structured diet with regular physical activity. Healthy weight gain, like healthy weight loss, requires guidance and determined effort. As with weight loss, 1 to 2 pounds per week is a healthy target, says Blanco-Schumacher, when it comes to putting on weight.

Similarly, realistic goals are also essential for proper weight gain, Grotto says.

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