April 2008 - Volume 2, Issue 2

REVIEW ON TUBERCULOSIS

ABSTRACT There is clear evidence that worldwide tuberculosis is increasing. It is estimated that between 2002 and 2020, nearly one billion will be newly infected with tuberculosis, 200 million will develop the disease, and 35 million will die from tuberculosis. The most profound influence on the incidence of tuberculosis is HIV infection, particularly in Sub-Saharan Africa, where HIV and tuberculosis form a lethal combination, each speeding the other's progress. HIV infection has been estimated to account for an excess of 34% of new cases. In countries with high burdens of both tuberculosis and HIV, the continued increase in tuberculosis will depend upon the level and trend of both HIV and tuberculosis infection in the community. Other factors contributing to the global resurgence of tuberculosis include poverty, overcrowding  ,increased travel/immigration, breakdown of tuberculosis control programs, multi-drug resistant tuberculosis (MDR), and incomplete treatment. Recently, specifically in March 2006 a paper published by Morbidity and Mortality Weekly Report (Were the authors trying to "sex up" their report) they had chosen the abbreviation XDR tuberculosis  However huge global interest was sparked by a report at the international AIDS conference in August, of a cluster of cases in South Africa of XDR tuberculosis with high mortality among HIV co-infected patients, with a Google search finding 130 000 hits.

INTRODUCTION

What is XDR tuberculosis, and how concerned should we be about it? (XDR refers to Extreme Drug Resistance). As defined in Morbidity and Mortality Weekly Report an XDR isolate is resistant to Isoniazide and rifampicin  (i.e. the definition of multi-drug resistance), two of the first line anti-tuberculosis drugs and resistant to at least two to three of the six classes of the second line antimicrobials  (amino glycosides, polypeptides, fluroquinolones, thiomides, cycloserine and para-aminosalicylic acid). However, at a WHO meeting in Geneva on October 9-10 2006 ,the definition of XDr tuberculosis was revised to resistance to isoniazise plus rifampicin, to floroquinolones, and to either amino glycosides or capreomycin (a polypeptide).

WHAT IS THE CURRENT EVIDENCE OF XDR-TB?

The MMWR paper reported a survey of 17,690 tuberculosis isolates collected worldwide (almost 12,000 of them were from South Korea) between 2000-2004. 3,520 (19.9%)isolates were multiple drug resistant, of which 347 (2%) were XDR. Among patients with XDR tuberculosis, those in the USA were 64% more likely to die during treatment than patients with the multi drug - resistant form, and those in Latvia were 54% more likely to die or have treatment failure. Although the MMWR study identified XDR tuberculosis from all parts of the world, only one isolate from Africa was XDR. However, the subsequent report from the rural Msinga district of kwazulu Natal, South Africa, described 536 patients with tuberculosis, of whom 221 had a multi drug resistant form and 53 of these were XDR. 52 of the 53 patients died, with a median survival time of just 16 days after giving a sputum sample.

Genotyping of the studies of isolates from 46 of the 53 patients showed 39 to be genetically similar, belonging to the Kwazulu Natal family of tuberculosis strains. A cluster of cases of multi drug resistant tuberculosis in Guateng, South Africa, is not at present believed to involve the strain from Kwazulu Natal. However, South Africa is not alone in experiencing outbreaks of XDR tuberculosis: a recent paper in Clinical Infectious Diseases describes two epidemiologically related  clusters of cases in Iran, and a letter in BMJ reports an outbreak in Norway that has been going on for at least a decade. 

Although the reports of clusters of XDR tuberculosis are as yet limited, they suggest that strains have emerged (or will emerge) in many locations and on many occasions, a worrisome development. A further concern is that with the ease of international travel. XDR strains might move rapidly from their place of origin. Ever since it has been possible to treat tuberculosis with antimicrobials, it has been clear that drug resistance emerges as a result of poor prescribing practices and suboptimal control programs. Organisms exposed to just antibacterial drug, or sub-standard doses of several drugs, – will acquire resistance by genetic mutation, and further suboptimal exposure to additional agents will encourage accumulation of multiple levels of resistance.

For all that the International Standards for Tuberculosis Care (ISTC) were developed through a year long inclusive process, guided by a 28 member steering committee. The purpose of ISTC is to describe a widely endorsed (an up-to-date list of endorsers can be found at http://www.stoptb.org) level of care that all practitioners, public and private, should seek to achieve in managing patients who have, or are suspected of having tuberculosis. The ISTC differ from existing guidelines in that they describe what should be done, whereas guidelines describe how the action is to be accomplished. The ISTC are not intended to replace neither WHO nor local  guidelines and were written to accommodate local differences in practice.

The main target audience for ISTC is the broad group of health care professionals who provide diagnostic and treatment services for tuberculosis outside of government tuberculosis programs. It is anticipated the ISTC will be used as a tool to unify approaches to tuberculosis care between public (at least government tuberculosis control programs) and private providers.

Another anticipated use of the ISTC is to serve as a focus of curricula for medical, nursing, and allied health students a well as for in-service education. The ISTC is to apply to patients of all ages, including those with smear-positive, smear-negative and extra pulmonary tuberculosis caused by drug resistant Mycobacterium tuberculosis complex organisms, and tuberculosis combined with HIV infection.

The basic principles of care for people with, or suspected of having, tuberculosis are the same worldwide: a diagnosis should be established promptly and accurately; standardized treatment regimen of proven efficacy should be used, together with appropriate treatment support and supervision; the response to treatment should be monitored; and the essential public health responsibilities must be carried out. Prompt and accurate diagnosis and effective treatment are not only essential for good patient care; they are also the key elements in the public health response to tuberculosis.

Thus, all providers who undertake evaluation and treatment of patients with tuberculosis must recognize that as well as delivering care to an individual, they are also assuming an important public health function that entails a high level of responsibility to the community, as well as to the individual patients. 

STANDARDS FOR DIAGNOSIS

Standard 1
All persons with otherwise unexplained cough lasting 2-3 weeks or more should be evaluated for tuberculosis.

Standard 2
All patients (adults, adolescents, and children who are capable of producing sputum) suspected of having pulmonary tuberculosis should have at least two, and preferably three, sputum specimens obtained for microscopic examination. When possible at least one early specimen should be obtained.

Standard 3
For all patients (adults, adolescents, and children) suspected for having extra pulmonary tuberculosis, appropriate specimens from the suspected sites of involvement should be obtained for microscopic, and where facilities and resources are available, for culture and histopathological examination.

Standard 4
All people with chest radiographic findings suggestive of tuberculosis should have sputum specimens submitted for microbiological examination.

Standard 5
The diagnosis of sputum smear-negative pulmonary tuberculosis should be based on the following criteria: at least three negative sputum smears (including at least one early morning specimen); chest radiograph findings consistent with tuberculosis; and lack of response to a trial of broad spectrum antimicrobial agents .(Note: because the fluroquinolones are active against M tuberculosis complex, and thus may cause transient improvement in people with tuberculosis, they should be avoided). For such patients, if facilities for culture are available, sputum cultures should be obtained. In people with known or suspected HIV infection the diagnostic evaluation should be expedited.

Standard 6
The diagnosis of intra-thoracic (i.e. pulmonary, pleural, and mediastinal or hilar lymph node) tuberculosis in symptomatic children with negative sputum smears should be based on the finding of chest radiographic abnormalities consistent with tuberculosis and either a history of exposure to an infectious case or evidence of tuberculosis infection (positive tuberculin skin test or interferon gamma release assay). For such patients, if facilities for culture are available, sputum specimens should be obtained (by expectoration, gastric washing, or induced sputum) for culture.

The following are clinical features suggestive of tuberculosis in children based on theWHO guidelines published in 2000:

The risk of tuberculosis is increased when there is an active case (infectious, smear positive tuberculosis) in the same house, or when the child is malnourished, is HIV infected, or has had measles in the past few months.

Consider tuberculosis in any child with a history of:

• unexplained weight loss or failure to grow normally
• unexplained fever, especially when it continues for more than 2 weeks*chronic cough*exposure to an adult with probable or definite pulmonary infectious tuberculosis

On examination:

• fluid on the side of the chest (reduced air entry, stony dullness to percussion)
• enlarged non-tender lymph nodes or a lymph node abscess, especially in the neck
• signs of meningitis, especially when these develop over several days and the spinal fluid contains mostly lymphocytes and elevated protein
• abdominal swelling, with or without palpable lumps<
• progressive swelling or deformity in the bone or a joint, including the spine

STANDARDS FOR TREATMENT

Standard 7
Any practitioner treating a patient for tuberculosis is assuming an important public-health responsibility. To fulfill this responsibility the practitioner must not only prescribe an appropriate regimen, but also be capable of assessing the adherence of the patient to the regimen and addressing poor adherence when it occurs. By so doing the provider will be able to ensure adherence to the regimen until treatment is completed.

Standard 8
All patients (including those with HIV infection) who have not been treated previously should receive an internationally accepted first line treatment regimen using drugs for known bioavailability. The initial phase should consist of 2 months of isoniazide, rifampicin, pyrazinzmide and ethambutol. (Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, do not have extensive pulmonary tuberculosis or severe forms of extra-pulmonary disease and who are known to be HIV negative).

The dose of anti-tuberculosis drugs used should conform to international recommendations .Fixed dose combinations of two (isoniazide and rifampicin), three (isoniazide, rifampicin, and pyrazinamide), and four (isoniazide, rifampicin, pyrazinamide and ethambutol) drugs are highly recommended, especially when medication ingestion is not observed.

* Streptomycin may be substituted for ethambutol  +Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, do not have extensive pulmonary tuberculosis or sever forms of extra pulmonary diseases ,and who are known to be HIV negative

**Associated with higher rate of treatment failure and relapse, should generally not be used in patients with HIV infection

* The recommended daily dose of ethambutol is higher in children (20mg/kg)than in adults (15mg/kg),because the pharmacokinetics are different (peak serum ethambutol concentrations are lower in children than  in adults receiving the same mg/kg dose)

Standard 9
To foster and assess adherence, a patient-centered approach to administration of drug treatment, based on the patient's need and mutual respect  between the patient and the provider, should be developed for all patients. Supervision and support should be gender sensitive and age-specific and should draw on the full range of recommended interventions and available support services, including patient counseling and education.

A central element of the patient-centered strategy is the use of measures to assess and promote adherence to treatment regimen and to address poor adherence when it occurs. These measures should be tailored to the individual patient's circumstances and be mutually acceptable to the patient and the provider.

Such measures may include direct observation of medication ingestion (directly observed therapy [DOT]) by a treatment supporter who is acceptable and accountable to the patient and to the health system.

Standard 10
All patients should be monitored for response to therapy, best judged in patients with pulmonary tuberculosis by follow-up sputum microscopy (two specimens), at least at the time of completion of the initial phase of treatment (2 months), at 5 months, and at the end of treatment. Patients who have positive smears during the 5^th month of treatment should be considered as treatment failures and have therapy modified appropriately (see standards 14 and 15). In patients with extra-pulmonary tuberculosis and in children, the response to treatment is best assessed clinically. Follow-up radiographic examinations are usually unnecessary and might be misleading.

Standard 11
A written record of all medications given, bacteriologic response, and adverse reactions should be maintained for all patients.

Standard 12
In areas with a high prevalence of HIV infection in the general population where tuberculosis and HIV infection are likely to co-exist, HIV counseling and testing is indicated for all tuberculosis patients a part of their routine management. In areas with lower prevalence rates of HIV, HIV counseling and testing is indicated for tuberculosis patients having a history suggestive of high risk of HIV exposure.

Standard 13
All patients with tuberculosis and HIV infection should be evaluated to determine if antiretroviral therapy is indicated during the course of treatment for tuberculosis. Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment.

Given the complexity of co-administration of anti-tuberculosis treatment and retroviral therapy, consultation with a physician who is an expert in this area is recommended before initiation of concurrent treatment for tuberculosis and HIV infection, regardless of which disease appeared first. However, initiation of treatment for tuberculosis should not be delayed. Patients with tuberculosis and HIV infection should also receive cotrimoxazole as prophylaxis for the infections.

Standard 14
An assessment of the likelihood of drug resistance, based on history of previous treatment, exposure to a possible source case having drug-resistant organisms, and the community prevalence of drug resistance, should be obtained for all patients. Patients who fail treatment, and chronic cases, should always be assessed for possible drug resistance. For patients in whom drug resistance is considered to be likely, culture and drug susceptibility testing (DST) for isoniazide, rifampicin and ethambutol should be done promptly.

Standard 15
Patients with tuberculosis caused by drug –resistant (especially) organisms should be treated with specialized regimens containing second line anti-tuberculosis drugs. At least four drugs to which the organisms are known or presumed to be susceptible should be used and treatment should be given for at least 18 months. Patient-centered measures are required to ensure adherence. Consultation with a provider experienced in treatment of patients with MDR tuberculosis should be obtained.

STANDARDS FOR PUBLIC- HEALTH RESPONSIBILITIES

Standard 16
All providers of care for patients with tuberculosis should ensure that people (especially children under 5years of age and those with HIV infection) who are in close contact with patients who have infectious tuberculosis are evaluated and managed in line with international recommendations. Children under 5years of age and people with HIV infection who have been in contact with an infectious case should be evaluated for both latent infection with M tuberculosis and for active tuberculosis.

Standard 17
All providers must report both new and re-treatment tuberculosis cases and their treatment outcomes to local public-health authorities, in conformance with applicable legal requirements and policies.

REFERENCES

Philip C Hopewell, Madhukar Pai, Dermot Maher, Mukund Uplekar, Mario C Ravigilione. International standards for tuberculosis Care. The Lancet Inf Dis 2006; 6:710-725.