[Downloaded free from http://www.saudiannals.

net on Saturday, January 23, 2010]

guidelines
Saudi guidelines for testing and treatment of
latent tuberculosis infection
Joint Statement of the Saudi Thoracic Society, the Saudi Society of Medical
Microbiology and Infectious Diseases, the Saudi Association of Public
Health, and the Society of Family and Community Medicine

Hamdan H. Al Jahdali,a Salim Baharoon,a Abdullah A. Abba,b Ziad A. Memish,a Abdulrahman A.
Alrajhi,c Ali AlBarrak,d Qais A. Haddad,e Mohammad Al Hajjaj,b Madhukar Pai,f Dick Menziesf

From the aDepartment of Medicine, King Saud University for Health Sciences, King Abdulaziz Medical City, bKing Khalid University Hospital and
College of Medicine, King Saud University, cKing Faisal Specialist Hospital and Research Centre, dRiyadh Armed Forces Hospital, eSecurity Forces
Hospital, Riyadh, fMontreal Chest Institute & Department of Epidemiology & Biostatistics, McGill University, Montreal, Canada

Correspondence: Dr. Hamdan Al Jahdali •Division of Pulmonology, Department of Medicine, King Saud University for Health Sciences, King
Abdulaziz Medical City, Riyadh •T: +96612520088 Ext 17597 . +966505224271 •jahdali@yahoo.com •Accepted for publication November
2009

Ann Saudi Med 2010;30(1): 38-49
PMID: **** DOI: 10.4103/0256-4947.59373

Pulmonary tuberculosis is a common disease in Saudi Arabia. As most cases of tuberculosis are due to
reactivation of latent infection, identification of individuals with latent tuberculosis infection (LTBI) who
are at increased risk of progression to active disease, is a key element of tuberculosis control programs.
Whereas general screening of individuals for LTBI is not cost-effective, targeted testing of individuals at
high risk of disease progression is the right approach. Treatment of those patients with LTBI can diminish
the risk of progression to active tuberculosis disease in the majority of treated patients. This statement is
the first Saudi guideline for testing and treatment of LTBI and is a result of the cooperative efforts of four
local Saudi scientific societies. This Guideline is intended to provide physicians and allied health workers
in Saudi Arabia with the standard of care for testing and treatment of LTBI.

O
ver the last century, the tuberculin skin test not be distinguished with absolute certainty from those
(TST) has been used extensively in epide- caused by latent TB infection. However, the wealth of
miological surveys and as a clinical test for the epidemiological information has allowed the formulation
diagnosis of latent Mycobacterium tuberculosis (MTB) of recommendations for informed interpretation of the
infection (LTBI) in different populations throughout TST in most clinical situations.4,8 We believe, however,
the world.1-4 It is mainly used for the identification and that many practitioners remain reluctant to use the TST,
treatment of persons infected by MTB, who are at high and therefore, do not give therapy for latent TB infection
risk of progression to active disease.4 This strategy has even to patients at high risk of reactivation.
proved to be effective in tuberculosis (TB) control be- This statement provides the first set of national rec-
cause preventive treatment of latently infected people ommendations for targeted tuberculin testing and treat-
diminishes the risk of subsequent development of active ment regimens for persons with latent tuberculosis infec-
TB by about 90%.4-7 tion. We strongly believe that targeted testing and treat-
The TST uses a relatively crude mix of antigens from ment of individuals with latent tuberculosis infection,
MTB. As a result, false-positive reactions can occur be- who are at increased risk of progression to active disease,
cause of previous Bacillus Calmette-Guérin (BCG) vac- is a key component of tuberculosis control. Infected per-
cination or sensitization to nontuberculous mycobacteria sons who are considered to be at high risk for developing
(NTM). This complicates the interpretation of the TST active TB should be offered treatment of LTBI, unless
as tuberculin reactions caused by BCG or NTM can- there are absolute contraindications for therapy.

38 Ann Saudi Med 30(1)  January-February 2010  www.saudiannals.net

This means that the reac- tion/year. and Saudi Association area of the skin selected for testing should be free of of Public Health (SAPH) and Society of Family and any cutaneous or subcutaneous lesion that could inter- Community Medicine. is maximal between 48 and comprehensive and nationwide tuberculin survey in the 72 hours after injection. although there is no evidence of their ef- the prevalence of LTBI at 10 and 20 years is 3. is demarcated using the ball-point technique. The induration is measured and recorded in millime- ulations. Reading is done between 48 and 72 hours af- stratification. kept protected from light. quently given.[Downloaded free from http://www. The Infectious Disease (SSMMID).net on Saturday. The transverse diameter of the induration. the estimated incidence of active TB (all forms) has also been observed. sorbed by glass and plastics.10 Using the Stabylo9 calculation. If there is no reaction.2/100 000. The blistered area should be covered with a dry 6. A ment regimens for person with latent tuberculosis in. TB not Tuberculosis in Saudi never be transferred to secondary containers. eter should be elicited at the time of injection. WHO 2007 estimation of the most importantly. The injection should be ommendation for targeted tuberculin testing and treat. sensitivity immune reaction.4% and ficacy. and then wanes over the next Saudi Arabian general population with urban/rural few days. for which topical steroids are fre- of infection of 0. small wheal measuring approximately 5 mm in diam- fection in Saudi Arabia. the size should be recorded of a TST is the expected prevalence of true latent TB as 0 mm and not simply as “negative”. Using a definition of a positive tuberculin ter administration. Severe TB is 21 cases per 100 000.7% respectively. It should Arabia affects mainly young and middle-aged individu.11 to scratch it. placing Saudi Arabia in the interme.8/100 000. and 8. delayed type. and neither too deep nor too shallow. be administered as soon as feasible after filling the sy- als.10 Al Kassimi et al in 19939 conducted the first tion begins within 24 hours. The ringe. Tuberculin ma- the incidence of smear-positive tuberculosis was terial should be kept refrigerated but not frozen. The incidence of smear-positive cases of pul. The most important Ann Saudi Med 30(1)  January-February 2010  www. a second test dose can Prevalence of LTBI in Saudi Arabia be given immediately at a site that is at least 5 cm away The total number of reported tuberculosis cases in from the first one. Similarly readings infection. but not tive TST. which gives an annual risk blistering is possible. of “doubtful” or “positive” are discouraged. In Saudi ally in the form of a rash on the arm. Many factors can cause false-negative tests including vi- berculin units of purified protein derivative (PPD) or ral. These reactions begin shortly is 46 per 100 000 and the incidence of smear-positive after injection and disappear within 24 hours. that false positive reactions can occur in almost all pop. (STS). and 56% were aged 45 years and older. the incidence of new smear positive cases was Reading the TST 21/100 000 population/year and the estimated preva. Generalized rash Arabia.net 39 .saudiannals.saudiannals. incidence of TB new cases was 46/100 000 popula- tion/year.4 between the incidence of smear-positive pulmonary Adverse reactions to tuberculin skin testing are un- TB and the annual risk of TB infection (ARI). ideally within 20 minutes. or fungal infections.4 As a result of its tendency to be ad- the year 2008 was 3 918 cases in a population of ap. intradermal. test of 10 mm or more. one can common. Usually. provides the first national rec. 33% of the subjects had a posi. most of them aged between 15 and 44 years old. However. bacterial. hyper- lence of all forms of TB cases was 65/100 000 popula.35%. A standard tuberculin syringe False-negative TST with a 27-gauge needle should be used to inject five tu. Long-term storage of incidence of all cases was estimated at 15. prefilled syringes is not recommended. the Saudi Society of Medical Microbiology and the volar or inner surface of the forearm is used. in individuals in whom repeated testing is done (see Based on the observation by Styblo9 of the relationship below). dressing and the patient advised to keep it clean and not diate prevalence (2%-14%) category. the most important determinant of the utility ters. 2010] GUIDELINES FOR LTBI guidelines This statement by the Saudi Thoracic Society two tuberculin units of RT-23 intradermally. Local allergic reactions to tuberculin or its calculate the ARI based on the expected prevalence of components can occur in 2% to 3% of those tested usu- latent TB infection in persons of a given age. If incor- rect administration is suspected. particularly monary tuberculosis varies widely between countries.4 Administrative technique for the TST Interpretation of the TST The administration of TST requires proper technique by trained professionals. January 23. The tuberculin reaction is a classic. tuberculin materials should proximately 24 807 273. fere with any interpretation. Given erythema.

4 nocompromised because of the evidence that this test- ing is unreliable. tuberculin reactivity was seen to wane rapid- mon at CD4 counts above 500/mL. 2010] guidelines GUIDELINES FOR LTBI cause of a false-negative TST is HIV infection. Causes of false-negative tuberculin skin testing tive TST. hospital-based studies in Kuwait and Saudi Arabia es. There are few studies of the and a 95. terial exposure.Injection of too little tuberculin. severe malnutrition.29 stress (surgery. those vaccinated at a later age have Arabia has a low prevalence of HIV infection of less larger TST reactions that wane more slowly. However. . in infancy. to 25% of the reactions persisting beyond ten years. nontuberculous mycobac- .Viral. protein depletion. such as mumps and was given later in life.Contamination. .13 HIV infection is therefore not an im.Inexperienced or biased reader absence of any obvious exposure.Diseases of lymphoid organs: (lymphoma. developing active tuberculosis in persons who manifest sarcoidosis) the “boosting” phenomenon is actually lower than those 40 Ann Saudi Med 30(1)  January-February 2010  www. Japan study from Saudi Arabia gave an intermediate figure of laboratory Tokyo).23 Most of the international can have true. In HIV.or false-negative tuberculin reactions.4 Other causes of false-negative TSTs Nontuberculous mycobacteria are presented in Table 1. the likelihood of a false-negative TST In several other studies following BCG vaccination is inversely proportional to the CD4 count: it is uncom.4.saudiannals. respectively. improper dilution When repeated tuberculin testing has been performed. [Downloaded free from http://www. guidelines recommend ignoring BCG’s effect on the However.26 An earlier similar same BCG strain (freeze-dried glutamate BCG.4.5%) specimens. there was testing with control antigens to which most normal ad. protective effect in the 5-14-year-old age group. Two recent BCG vaccine is given at birth without any booster dos.27 A nationwide population-based survey. such as during the primary or sec- Candida. or remote infection with MTB. BCG vaccination was started in 1964 in Saudi Arabia and even within countries.Metabolic derangement. This is because the risk of .9%) and 70 of 286 the protective effect of the BCG vaccine using the (24. with 15% than 0. or too superficial.01%.9 A recent me- ta-analysis involving more than 18 studies found that NTM is not a clinically important cause of false-posi- Table 1. but no revealed a much lower figure of 0. However.Error in recording this reflects an anamnestic response representing the re- stimulation of previously acquired immunity from ear- Biological factors: (not correctable) lier exposure.HIV (especially if CD4 count <200) ing remote BCG vaccination.24 The prevalence of False-positive TST NTM varies considerably between regions. burns) It is important to distinguish boosting from the phe- . bacterial. developing active TB.net on Saturday. protective effect 25 years after vaccination. chronic renal failure.12.Live virus vaccination within the past two months .Defective antigens because of improper storage (exposure to light or heat) or boosting) manufacturing .28 Technical factors: (potentially correctable) Serial tuberculin testing (conversion or . A case-control study in Saudi Arabia determined identified NTM in 18 of 325 (5. and nomenon of tuberculin conversion which occurs after others) . or too deeply (should be a substantial number of individuals may manifest an in- intradermal) creased tuberculin reaction on their second test in the .Very young <6 months or elder an initial tuberculin infection. particularly in areas of high TB prevalence. however.saudiannals.14 The prevalence of NTM in the Middle East.4 Anergy ten years after BCG vaccination.Concurrent use of immunosuppressive drugs: (corticosteroids. a greater and more long-lasting effect on TST if BCG olescents and adults should react. A meta-analysis including more than 24 stud- It is important to note that patients with active TB ies found that only 1% of patients who received BCG can have false-negative tests at the time of diagnosis. or fungal infections results from a previous mycobacterial exposure.net .9% coverage rate was achieved by 2007. chronic lymphocytic leukemia. termed “boosting”.004%. and almost uni. ly so that there was little discernible effect by the age of versal when the CD4 count is less than 200/mL. January 23. TNF inhibitors. includ- .Prolonged storage within the syringe before administration (more than 20 minutes) . anergy testing is not routinely recommended interpretation of TST in persons at increased risk of in persons who are HIV-infected or otherwise immu. during infancy were TST positive if tested more than particularly those with more advanced disease. It is now realized that .20.29 This phenomenon. countries.16-22 portant cause of a false-negative TST in Saudi Arabia.25.15 This study demonstrated an 82% 9%.15 infected persons. Nontuberculous mycobacteria (NTM) are another ma- jor cause of false-positive TST. Saudi five years. have been used to determine whether people ondary school-going years.

regardless of age. NTM is not a clinically important cause of false- sitive to detect conversion.31 The risk-benefit ratio for treating LTBI to test for LTBI.33. then a sec. if infected. The principle indications and precautions in tical. Treatment for LTBI is contraindi- the booster phenomenon. 3. ing is not generally indicated). on hemodialysis. The in various conditions. persons entering professions or facilities with an ≥10 mm is considered positive in moderate-risk indi- increased risk of occupational exposure such as health viduals. If the second tuberculin test is negative (<10 mm). and should not be considered in the interpretation of Indications for TST and who should be treated TST. then the cause than for normal. vaccination should not be considered when deciding year period.36-44 Moderate-risk individuals are to years after the first. dividuals are those at slightly increased risk for reac- version. latent tuberculosis testing and treatment the individual can be considered to be truly negative. Therefore.4 Boosting can be seen after cated in patients with active TB disease and in patients intervals as long as two years. If the second test is performed months healthy individuals. Furthermore. For persons at low risk for TB and with high care or prisons). 1. January 23. although the annual risk of disease. the IDSA definition of conversion requires an increase of effects of BCG on TST should be ignored in high- 10 mm or more from the previous TST result. and a shorter interval is always more prac. reaction is dependent on the size of the TST: ≥5 mm ronment where there might be a risk of exposure to TB is considered positive in high-risk individuals whereas (e.saudiannals. and much lower than in infection. A history of BCG induration from the previous TST results within a two. TST screening for LTBI should 5. This is fection. positive TST. Patient age is of some importance in the decision ommended. the tuberculin test is posi.4.[Downloaded free from http://www. An initial two-step estimated risks for TB relative to healthy individuals testing protocol is recommended in this situation.56 TB disease. A TST conversion is defined as a TST reaction of 2.29. indicating TB infection. or who are at high risk of progression from persons with tuberculin conversion.7 This risk individuals. and there has been exposure to those whose risk for reactivation is 3 to 6 times higher MTB (such as contacts of active cases).29 In persons with LTBI to TB disease as outlined in Tables 2 and 3.5 to 3 times higher than In some clinical situations.29 tivation and whose risk is 1. this can be considered as a true conversion. but this phenomenon with severe liver disease. Testing is not recommended for depends principally on whether the individual is truly individuals ≥65 years unless they are at high risk for infected and is at substantial risk of developing active reactivation.1% (1 per 1000) of developing active It is difficult to distinguish the phenomena of boost. Defining a positive tuberculin most common situation is when persons enter an envi.53-55 Table 4 shows the peat the TST on a periodic basis. the risk of disease is between 5% and 20% Normal healthy individuals with LTBI have an over the next two years alone.30 The ATS/CDC/ whether to perform TST or not. If the second TST is performed soon (with. It is essential to exclude active TB disease in persons be reserved for those groups with a high risk of recent with newly detected latent TB infection. it may be necessary to re. then boosting is most likely the cause for a activation is at least six times higher than for normal. healthy individuals.4. ing and conversion simply on the basis of size.saudiannals. more stringent criteria will be more specific but less sen. TB.32 Depending on the individual’s clinical condition.33-35 in two weeks) after the first and there is no intervening High-risk individuals are those whose risk for re- exposure. can range from if the second reaction is >15 mm. Treatment Ann Saudi Med 30(1)  January-February 2010  www. healthy individuals. for normal.9.4. 4. is to identify individuals who are at risk of new in- tive.29 risk of exposure to NTM (for whom tuberculin test- If the initial TST is negative (<10 mm).net 41 .29 Table 1. positive TST. annual risk of 0.. regardless of BCG history.g. ≥15 mm of induration is ond test should be performed 1 to 4 weeks later to elicit considered positive. particularly in Saudi Arabia. and to identify individuals at increased risk strong evidence of new infection and should therefore of reactivation due to the biological factors listed in be treated. it is most likely to be more than 10% for HIV patients to 1 to 2% for patients conversion.45-52 Low-risk in- for a positive TST is considered to be recent TST con.4.25-28 Routine screening of asymptomatic subjects is not rec. All people who are considered high risk should be 10 mm or more plus as an increase of 6 mm or more of tested.net on Saturday. 2010] GUIDELINES FOR LTBI guidelines with an initial positive TST. The goal of testing for latent tuberculosis infection If on subsequent retesting.4 is maximal if the two tests are between one and four weeks apart. conversion.

. leukemia chemotherapy should be delayed until active TB has been ruled out. Moderate risk (only patients less than 65 years of age should be tested) 5. and that there is Persons at increased risk of developing active tuberculosis: effective treatment available for this infection. treatment persons receiving the equivalent of 15 mg/day of prednisone for at least 30 days or more) The term. Indications for tuberculin skin testing. Aim of treatment jejunoileal bypass Treatment of LTBI is intended to prevent the develop- Children younger than four years of age ment of active TB disease.4 If a radiograph is abnormal but was taken more than three months prior to evaluation. test reaction size. use of a single antituberculosis agent is sufficient for the treat- ment of latent infection. hospitals.g.g. a new Table 3.Persons who never received antituberculosis therapy with abnormal chest x-ray 5. Target for tuberculin skin testing and who should be considered for treatment. In most of the cases.net .Close contacts of persons with active pulmonary TB .g. this has been TST≥15 mm Persons with no risk factors for tuberculosis referred to as ‘chemoprophylaxis’ or ‘preventive therapy’. weight loss of more than 10% of ideal body weight. B. chronic renal failure. Low risk: test not indicated therapy. Individuals with increased risk for new infection: (all patients should be tested ease has been excluded.Persons whose tuberculin skin tests have converted to positive (≥10 mm induration positive test.net on Saturday. blockers) Starting treatment pending the culture results . lymphoma. High risk (all patients should be tested regardless of age) no symptoms or physical findings consistent with TB. ‘treatment of LTBI’ has been adopted to highlight the fact that the patient is considered to be in- TST≥10 mm Injection drug use fected with live (although dormant) bacilli. nursing homes. diabetes mellitus.Persons receiving immunosuppressive therapy (e. gastrectomy. Situation in which reaction is considered positive 5.5 If the abnormality on the chest radiograph is of (mm induration) questionable significance. 2010] guidelines GUIDELINES FOR LTBI Table 2. consultation with an TST≥5 mm HIV seropositive expert is recommended. Individuals with clinical conditions associated with increased risk of reactivation: 5.Diabetes mellitus with TB. Medical examination and regardless of age) chest x-ray should be done to rule out tuberculosis disease for any individual with a newly identified . neck or lung.1 If the radiograph is normal and the patient has 1. lymphoma. but not for active disease. 42 Ann Saudi Med 30(1)  January-February 2010  www. 2. therefore..Persons with certain medical conditions (e.Persons who live or work in clinical or institutional settings where TB exposure may undergo sputum smear microscopy and culture to be likely (e. 5. In the past. prolonged corticosteroid therapy [the equivalent of >15 mg/day of prednisone for one month or more]. or bacteriological evidence of TB for treatment disease burden of organisms. [Downloaded free from http://www.saudiannals. Persons with radiographic signs or and >6 mm increase) within the past two years symptoms that are suggestive of active TB should .. treatment of latent in- fection requires fewer drugs than active disease to de- crease the risk of developing active tuberculosis without creating drug resistance. microbiology labs) rule out active TB. which could Residents and employees in high-risk settings: nursing homes.Children four years of age or waiting for culture results before starting 3. 1. leukemia. those with silicosis. specimens of sputum (using sputum . cancer of the head.Persons with HIV infection . Latent tuberculosis infection is associated with a low Contraindications Any clinical. treatment of LTBI may be indicated. prisons. is a clinical judgment dependent on benefit-risk considerations.2 If the radiograph is normal but the patient has with apical fibronodular changes typical of healed TB (not including granuloma) a clinical presentation consistent with TB. TNF-α induction if necessary) should be obtained. fur- .Transplant.3 If the radiograph is abnormal and consistent .saudiannals. Close contact with positive AFB in the sputum Fibrotic changes on chest radiograph consistent with prior untreated tuberculosis Aims of and recommended regimens for LTBI Organ transplants and other immunosuppressed patients (e. January 23. for LTBI should not be initiated until active dis- A. hospitals cause active TB disease in the future. and other long-term care facilities. radiograph should be performed at the time of Tuberculin skin evaluation.g. chronic renal failure on dialysis ther workup is indicated and treatment of LTBI .. radiological.. silicosis.

Monitoring of treatment be monitored clinically for symptoms and signs of • Education about adverse effects associated with the adverse drug reactions.60 Cigarette smoker (1 pack/day) 2-3 54. 55 • Rifabutin (RFB) may be substituted for rifampin Chest x-ray with solitary granuloma 2 94.6 48-51 This regimen should be reserved for those individuals Young age when infected (≤4 years) 2. 72. effects. 94 tion but is considered to be an acceptable alternative. including This regimen is not recommended due to fatal hepato. with advice to stop treatment and promptly seek medical evaluation if serious ad- d. but susceptible to RIF. this is equivalent to body • Rifampin alone for six months is generally recom. it should generally NOT be offered to assess for evidence of hepatitis or other adverse as initial therapy to persons with LTBI for either HIV. mended for children. Intermittent (twice weekly) INH for nine months Recent TB infection (≤2 years) 15 42. not the duration of therapy alone. 89 children and adolescents (up to age 18 years).0-25. 39. relative to persons Risk factor References ii. Four basic regimens are currently recommended Estimated risk for TB (Table 5).[Downloaded free from http://www. 46.net 43 . 73 who cannot tolerate INH or for persons exposed to cases with resistance to INH. such as in HIV-infected persons taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. and adherence to negative or HIV-infected persons. symptoms of TB disease. 2010] GUIDELINES FOR LTBI guidelines 2. for 2-3 53 recommended for adults. fibronodular changes typical of healed TB provided all doses of therapy are directly observed. Isoniazid alone—preferred regimen Human immunodeficiency virus infection 20-74 37. 71. Completion of therapy is based on the total number of with no known risk factor doses administered. 53. careful questioning and a brief physical examination toxicity.saudiannals. Recommended regimens for treatment Table 4. (AIDS) a.net on Saturday. • Daily INH for a nine-month regimen for HIV. 41 (HIV) Daily INH for 9 months is the preferred regimen for the treatment of LTBI. 38. Treatment interruptions of more than two months High risk require another evaluation to exclude active TB be- Acquired immunodeficiency syndrome 110-170 33.5-4 45.4 treatment of LTBI. Jejunoileal bypass 27-63 90. 93 competent adults. Relative risk for developing active tuberculosis by selected clinical conditions i. Therefore.57-59 Silicosis 30 40. January 23.2-5 52. • All persons receiving treatment for LTBI should 3. 43 has not been compared directly with daily administra- Abnormal chest x-ray with apical 6-19 44. 95 concerns about side effects or adherence. 96 in the above regimens in situations where rifampin cannot be given. most individuals. Transplantation (related immunosuppressant 20-74 76-79 therapy) infected persons or persons suspected of having HIV infection. 91 • Daily INH for a nine-month regimen for immuno- Carcinoma of head or neck 16 92. Rifampin and pyrazinamide for two months—NOT verse effects occur. the regimen. mass index (BMI) ≤20. recommended • Follow-up evaluation at least monthly.4 (not granuloma) Moderate risk b. Rifampin for 4 to 6—acceptable alternative Diabetes mellitus (all types) 2-3. 36 fore restarting therapy.4. iii. Six months INH alone—acceptable alternative: • INH may be given for six months if there are any Tumor necrosis factor (TNF)-α inhibitors 1.3 35.saudiannals. Low risk • Rifampin (RIF) alone for four months is generally Underweight (<85% of ideal body weight). Treatment with glucocorticoids 4-9 47 c. 88 • Daily isoniazid INH for a 9 month regimen for Chronic renal failure on hemodialysis 10. beginning at the first initial Ann Saudi Med 30(1)  January-February 2010  www.

Current use of hepatotoxic drugs baseline abnormalities in LFTs or other risk factors • We recommend withholding INH if serum trans- for drug-induced hepatitis.4 The treatment of LTBI during pregnancy remains 5. Regular alcohol use controversial. aminase concentrations exceed three times the up- dicated if symptoms or signs indicative of hepatitis per limit of the normal range when accompanied develop.net . Interval and Oral dosage Criteria for Drug Comments duration (maximum) completion Isoniazid Daily×9 mo Adult: 5 mg/kg 270 doses INH daily for 9 months is the preferred regimen for (300 mg) within 12 mo all persons and the only regimen for persons with fibrotic lesions on CXR Child: 10-20 mg/kg (300 mg) Twice. Adult: 15 mg/kg 52 doses <18 years.net on Saturday. RIF + PZA: Generally should not be offered for treatment of LTBI. under ordinary circumstances. visit and at least monthly thereafter. Abnormal baseline LFT active disease and to prevent its consequences on the 44 Ann Saudi Med 30(1)  January-February 2010  www. months after delivery. [Downloaded free from http://www. Consult web-based updates for the latest specific recommendations. or five times the upper limit of the • Indications for baseline LFTs. Chronic liver disease • Routine laboratory monitoring of liver function iii. Pregnancy has minimal influence on the pathogenesis of tum TB and there is no evidence to suggest a greater risk of 4. Adult: 15 mg/kg 76 doses Use twice-weekly regimen only if daily regimen weekly by (900 mg) within 12 mo not feasible. weekly by (900 mg) within 9 mo DOT must be used with twice-weekly dosing. For HIV-infected persons. (300 mg) within 9 mos Not recommended for HIV-infected persons† those with fibrotic changes on CXR. progression of LTBI to active disease during pregnan- titis or cirrhosis cy. History or initial evaluation indicative of hepa. Recommended drug regimens for the treatment of LTBI. including serum bili. rubin and either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are as follows: Treatment of latent tuberculosis in special 1. 6. are as follows: who are HIV-positive or at high risk of progression to i. January 23. including serum bili. DOT must be used with twice-weekly DOT×9 mo Child: 20-40 mg/kg dosing (900 mg) Isoniazid Daily×6 mo Adult: 5 mg/kg 180 doses Use ONLY if preferred regimen not feasible. or children aged Twice. DOT×6 mo Rifampin Daily×4 mo Adult: 10 mg/kg 120 doses Use ONLY if preferred regimen not feasible. ii. unless exposed to INH-resistant. most protease inhibitors or non-nucleoside reverse transcriptase inhibitors should not be administered concurrently with RIF.saudiannals. Regular alcohol use tests (LFTs) is recommended for persons with iv. (600 mg) see comments] Not recommended for persons aged <18 years. Use of potential hepatotoxic medication physicians should delay treatment until two to three • Indications for monthly LFTs. Pregnancy or less than three months postpar. Additional testing is in.4 However. RIF-susceptible TB. normal range in asymptomatic patients.saudiannals. for pregnant women rubin and either AST or ALT. by symptoms. However. Person with viral hepatitis or for whom com. 2010] guidelines GUIDELINES FOR LTBI Table 5. HIV infection Pregnancy/lactation 3. (600 mg) within 6 mo Not recommended for persons with fibrotic [Child: 10-20 mg/kg changes on CXR. situations plete hepatitis serology results are unknown 2.

67-70 If isoniazid is chosen for treatment of ally tolerate INH better than adults. frequent clinical and labora- tory monitoring for drug side effects is prudent. Patients should be treated during Infants and young children (i. initiation of therapy should not years of age) with LTBI are at high risk of progression to be delayed on the basis of pregnancy alone. anergic reaction is common among patients dence of infection among such patients is estimated to requiring hemodialysis. The risk of progression decreases for LTBI. Four months of RIF may be safer TB and need for treatment of LTBI should be deter.net on Saturday.7. especially menin- Recommendations for HIV-infected adults are in gen.7 by DOT twice weekly. Infants and young chil- dren are more likely than older children and adults to Treatment of HIV-infected persons develop life-threatening forms of TB. they have up to 40% likelihood the first trimester.4 Routine administration of However.3) and all patients Solid organ transplantation is associated with a very with positive reaction are recommended for therapy. but should be given to (1) breastfeeding infants. of LTBI in HIV-negative children is a nine-month dition.4 pretreatment liver transaminase levels are normal.73 In particular. so that TST may not be very sensitive to should be treated for LTBI if their TSTs are positive.net 45 . young chil- en and is not toxic to the unborn child....4.e.72. detect LTBI. Persons with fibrotic lesions/suspected disease and adolescents when INH could not be tolerated. although the more effective for children than adults.saudiannals. and adolescents gener- tions vary.4.4 INH can be given to pregnant wom. January 23. Common strategies include INH for nine months or Children and adolescents RIF for four months.61-66 Pregnant women hold contacts) are at high risk for developing TB disease taking INH should receive vitamin B6.38. or Patients who have a chest radiograph demonstrating when the child has had contact with a patient infected upper lobe fibronodular changes or scarring compatible with an INH-resistant but RIF-susceptible organism. calcified solitary Liver disease pulmonary nodules. RIF alone has been used for the treatment of LTBI in infants.72.52. house- first four months of gestation. those younger than five the pretransplant period.4. and (3) children who experience treatment of TB and HIV. mendation is that management should be attempted (2) children and adolescents with diets likely to be de- in consultation with physicians who are experts in the ficient in pyridoxine. especially in liver are specific for this population. calcified hilar lymph nodes. rifampin should generally be avoided in persons course of INH as self-administered daily therapy or who are taking protease inhibitors (PIs) or NNRTIs.4. if possible. then a six-month treatment regi- evidence of active disease and no history of treatment for TB. nine months of isonizid transplant recipients. tion of 70-90%. but is generally safe as long as (INH) is recommended.76-79 They demic areas. even during active TB. even during the dren in contact with adults with active TB (i. The inci- However.4 established. Ann Saudi Med 30(1)  January-February 2010  www. children. the management of persons co-infected with pyridoxine is not recommended for children taking HIV and LTBI can be highly complex.73 should receive treatment. 10. Renal failure Patients with chronic renal failure are at a high risk of Solid organ transplantation reactivation (relative risk.e.44. nine months of The only recommended regimen for the treatment therapy is recommended rather than six months. and Patients with chronic liver disease with LTBI pose a apical pleural capping) have only slightly increased risk special problem.7. are considered at high risk of reactivation and men is recommended. be 20-74 times that for the general population.4.4 gradually through childhood. 2010] GUIDELINES FOR LTBI guidelines mother and the fetus. primary TB (i.71 Persons with evidence suggestive of healed. as all available regimens are poten- for TB (about double that of the healthy).39 high risk of LTBI reactivation to active TB. even in patients resident in en. paresthesias while taking INH. Breastfeeding and should therefore be targeted for LTBI therapy (after is not contraindicated when the mother is being treated ruling out active TB). Infants. of developing active TB.0-25.4. Our recom. although the efficacy of such a regimen has not been mined by considering other risk factors. INH. Their risk for tially hepatotoxic. with risk reduc- quality of evidence and strengths of the recommenda.e.74.saudiannals. In ad. INH therapy for LTBI is eral similar those for HIV-negative adults. with previous TB and a positive TST (>5 mm) without If RIF alone is used. geal and disseminated disease.72.4. In the absence of randomized trials that Safety of INH remains a concern.[Downloaded free from http://www. If untreated.75 However. children.73 LTBI in persons with HIV infection.

the treat.80. who are tein derivative (PPD).net on Saturday.31 in Europe: the QuantiFERON-TB Gold® In-Tube (QFT) assay (Cellestis Ltd. a requirement to draw peripheral blood. cal practice. cause they cannot distinguish between LTBI and active treatment should be with at least two active agents. Evidence is still men is very poorly tolerated. They are standardized and quality-controlled lab- TB. viduals. preventive therapy with two is compromised by BCG vaccination after infancy or by drugs to which the organism is expected to be suscep. Pyrazinamide (PZA) and ethambutol (EMB) or IGRAs have some disadvantages. particularly in countries where TST specificity gression to active TB.84. even if repeat skin testing remains Administration (FDA)-approved. this appeared to be effective for tuber- There are many potential advantages of these new culin converters in two outbreaks of INH-resistant tests. including those with HIV infection. likely to be susceptible. Carnegie. tible is recommended. January 23.. and marked for use negative. Use of interferon release assays ommended regimens listed above. some A major advance in recent times has been the develop- tuberculin-negative close contacts who are at high ment of T-cell-based interferon-gamma release assays risk to develop severe active disease (e. the selection of drugs Sensitivity of IGRAs and TST is not consistent should be guided by in vitro susceptibility test results across tests and populations.82 However. the interpretation of IGRA conver- ommended for 9 to 12 months for children because sions and reversions is unclear. They do not have a ‘booster’ effect.4.TB® assay (Oxford Immunotec. 6 [ESAT-6] and culture filtrate protein 10 [CFP-10]) ment should be discontinued. including higher PZA and fluoroquinolones (FQN) have been recom.4 In addition.86 46 Ann Saudi Med 30(1)  January-February 2010  www. and evidence is rather FQN use is contraindicated in pediatric patients. For those who are at high risk of pro.81 In situations in which RIF cannot be used.saudiannals. They have excel- Contacts of patients with a multidrug-resistant lent specificity and are unaffected by BCG and NTM tuberculosis index case (estimated specificity >98%). Ideally. we recommend treatment with four less expensive.net . and mended for 6 to 12 months. Two IGRAs are currently avail- close contacts of persons with active TB. If the repeat skin test is negative. and their added value in TB diagnosis and con- preferred regimen for adults.85 However.85 The high specificity of Treatment of LTBI after possible exposure to mul- IGRAs is likely to be useful in BCG-vaccinated indi- tidrug-resistant TB has not been evaluated in a ran- domized trial. months of RIF. the latter regi.g. disease. we recommend limited on the prognostic (predictive) value of these an FQN (levaquin or moxifloxacin) and EMB as the tests.saudiannals. Furthermore.83 hence. regardless to properly define the role of IGRA in day-to-day clini- of the treatment regimen.84. and INH-resistant TB. should also able as commercial kits that are US Food and Drug receive treatment. 2010] guidelines GUIDELINES FOR LTBI Contacts of patients with drug-susceptible not be used. When FQN and EMB can. material cost.85 IGRAs are in vitro tests that are based younger than five years of age) should be treated and on interferon-gamma (IFN-γ) release after stimula- another skin test performed a few weeks after contact tion by antigens (such as early secreted antigenic target has ended. trol. children (IGRAs). Many studies on IGRA are ongoing in this area should be followed for at least two years. ceptible TB and who have positive tuberculin skin- test reactions should be treated with one of the rec.31 limited in children and immunocompromised popula- All persons with suspected latent MDR-TB infection tions. the need for an equipped laboratory.31 Immunosuppressed which are more specific to MTB than the purified pro- persons. multiple BCG vaccinations. [Downloaded free from http://www.84.. the QFT assay is For TST-positive contacts of index or source cases with simple and easy to use because of its ELISA format. but IGRAs appear to be from the isolate to which the patient was exposed and at least as sensitive as the TST (estimated with active is presumed to be infected. experts recommend using a combination tuberculosis index case of two other drugs to which the infecting organism is Persons who are contacts of patients with drug-sus. TB as the surrogate reference standard). PZA and EMB are rec. Australia) and Contacts of index cases with isoniazid-resistant the T-SPOT. Of the two commercial tests. and can be repeated without the need for two-step testing. ri- oratory tests that provide results in a single patient visit. tuberculosis UK). For persons who are likely to be infected with IGRAs should not be used to diagnose active TB be- MDR-TB and are at high risk of developing TB.4. fabutin can be substituted. Abingdon.

King Fahd University Hospital 2. In contrast.. Diseases University of Modena and Reggio Emilia ly recommend and use IGRAs. Pulmonary Consultant.e. the CDC Policlinico Hospital (Italy) guidelines for the USA recommend using either TST Dr. Canada. Hani Lababidi. King Faisal Conclusions Specialist Hospital Saudi Arabia is a country of medium prevalence for TB Dr. There is Dr. Pulmonary consultant. MOH Ann Saudi Med 30(1)  January-February 2010  www.net 47 . IGRAs may be used to Dr. infection The use of IGRAs is steadily increasing in low or in. Infectious Disease Consultant adolescents and adults. More than a dozen We wish to acknowledge the following contributors for countries (e.87 it may be best to collect blood Critical Care Medicine King Fahad Medical City -Riyadh for IGRA at the time the TST is read (i. Hatem Quteb. Head Pulmonary Division.[Downloaded free from http://www. Omer Alamoudi. within three Dr. Italy) recommend a two-step Dr. Faisal Kassimi. Abdulaah Adlaan.Abha Dr. Head of Pulmonary and Intensive rule out LTBI. in combination with TST.e. or IGRA for LTBI testing. Consultant Head Occupational mens advocated in this statement after due care is taken Medicine Dept. Soror Al-Aithan. Tawfik Khoja. College of popular and possibly a very cost-effective strategy. their outstanding effort in reviewing this manuscript and Switzerland. to check if the TST result is a false Abdulaziz University Jeddah positive). College of Medicine. Director General. because of the potential boosting effect of Dr. Acknowledgments termediate incidence countries. they may be used as an ad- Faisal Specialist Hospital junct test. Dr. King TST result (i. A negative division King Abdulaziz Medical City-Jeddah IGRA alone should not be used to rule out ac- Dr. Kheder Alzahrani. King Saud University 1. Adeba AlNashmi. January 23. Japan. Pulmonary Consultant.. Sameeh Almail. Dr. Germany. If a positive TST result is confirmed by Dr. UK. Pulmonary Consultant. IGRAs may be used to confirm a positive Dr. Pulmonary Consultant King Abdulaziz a positive IGRA result. Dr. For example. Respiratory Medicine Recommendations Section. IGRAs should not be used to diagnose active TB Dr. Director Center for Rare Lung considerable diversity in how various countries current. the two-step approach seems to be the most Dr. President of Saudi Society of Family approach where TST is done first. Spain. Pulmonary Consultant. and TST on IGRA results. Intensive Care Unit. Dammam Medical Tower Dr.Riyadh However. Head Pulmonary Division. King Saud Hospital –Riyadh ing active TB should be treated with the standard regi. Ahmad Bahmmam.. In immunocompromised patients. USA. NTM infec. Luca Richeldi. Medicine. King tion and BCG vaccination (routinely given in infancy) Fahd Medical City Riyadh do not interfere with the interpretation of the test in Dr. Abdullah Mobereik. Abugad.saudiannals. Head of Infectious disease and microbiological investigations. In children. followed by IGRA. and days of placing PPD). Netherlands) now have at least one their valuable comments and suggestions: guideline or statement on the use of IGRAs. Hassan A. Consultant Internal Medicine Kind 3. Faisal Specialist Hospital cation of subjects with latent TB infection. LTBI treatment should be University Jeddah initiated after ruling out active TB.g. King infection. if a false-negative Abdulaziz Medical City -Riyadh TST result is suspected. Dr. Head. Bader Algamdi.saudiannals. France. UK. King Saud University. Mohmad Zetoni. 2010] GUIDELINES FOR LTBI guidelines Use of IGRA for the diagnosis of latent TB in excluding active TB disease. Care. The TST remains a useful tool in the identifi. Imad Haassan. Abdulhakeem Althaqafi. Canada. Head Pulmonary Division and tive TB. Patients at high risk of develop. In BCG-vaccinated individuals (adults and chil- dren)..g. Seraj Wali. Critical Care Medicine King Saud University. chest x-ray. Executive board. King in adults. and Community Medicine Globally. many countries Health Ministers Council for GCC States States-KSA (e.net on Saturday. Head Pulmonary Division.

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