Medical Consensus Development Panel
Kementerian Kesihatan Malaysia
Academy of Medicine Malaysia

1. List of participants
2. Introduction
3. Diagnosis
       Pulmonary tuberculosis
       Extrapulmonary tuberculosis
4. Treatment of tuberculosis
       Choice of regimen
       Recommended doses
       Flow chart of recommended treatment 
5. Monitoring of patient
6. Indications for hospitalisation
7. Management of drug toxicity
8. Management of tuberculosis in specific situations
9. Chemoprophylaxis
10. Notification
11. Defaulter tracing
12. Home visits
13. Contact investigations
14. Conclusion
15. Audit indicators
16. References

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Participants :

DR.I.KUPPUSAMY CONSULTANT CHEST PHYSICIAN
INST.OF RESPIRATORY MEDICINE HOSPITAL KUALA LUMPUR and CONSULTANT, NATIONAL TUBERCULOSIS CONTROL PROGRAMME.

DATO DR.TAN MONG HING CONSULTANT PHYSICIAN
HOSPITAL KUALA TERENGGANU

PROF.DR.AZIZI OMAR CONSULTANT PAEDIATRICIAN
UNIVERSITI KEBANGSAAN MALAYSIA

ASSO.PROF.ZAINUDDIN MD.ZIN CONSULTANT CHEST PHYSICIAN
UNIVERSITI KEBANGSAAN MALAYSIA

PROF.DR.LIAM CHONG KIN CONSULTANT CHEST PHYSICIAN
HOSPITAL UNIVERSITI,UM

DR.WONG WING KEEN CONSULTANT CHEST PHYSICIAN
HOSPITAL TUNG SHIN

DR.(MRS.)BALAKRISHNAN CONSULTANT CHEST PHYSICIAN
HOSPITAL SUTANAH AMINAH, JOHORE BAHRU

DR.GEORGE SIMON CONSULTANT CHEST PHYSICIAN
HOSPITAL ALOR SETAR

DR.HOOI LAI NGOH CONSULTANT CHEST PHYSICIAN
HOSPITAL PENANG

DR.AZIAH A.MAHAYIDDIN CONSULTANT CHEST PHYSICIAN
INST.RESPIRATORY MEDICINE

HOSPITAL KUALA LUMPUR
(COORDINATOR)

MANAGEMENT OF TUBERCULOSIS

INTRODUCTION

By now it is clear that tuberculosis is once again a major public health problem. It remains the leading cause of death by infectious disease. Recent statistics have reawakened the awareness as to the magnitude of the problem caused by the disease. According to the World Health Organisation, there are approximately 20 million active cases in the world today, and they infect 50-100 million people largely children annually. The mortality due to disease is approximately 3 million annually and at least 80 per cent of them are in the developing countries. Tuberculosis accounts for 26 per cent of all avoidable deaths in Third World countries. These statistics are surely alarming as tuberculosis is a curable disease if properly managed.

With regards to Malaysia, the number of cases detected per year has not declined substantially either. Since 1989, we detected on the average 11,500 to 12,000 cases per year. In 1995, we detected 11,778 cases of which 6,500 cases are sputum positive and therefore are infectious.

The aim of this consensus statement is to provide guidelines to doctors who need to start a patient on anti-tuberculosis chemotherapy and follow him up. At the present time anti-tuberculous drugs that are available can render almost 100 per cent of the patients cured if the drugs are given in the doses recommended for an adequate period of time with proper education and supervision to ensure patient adherent.

DIAGNOSIS

Diagnosis of tuberculosis involves clinical, radiological and/ or bacteriological evidence.

The commonest form of tuberculosis in adults is post-primary pulmonary tuberculosis. It is the only form of tuberculosis which is infectious and thus has great epidemiological significance.

Symptoms which suggest pulmonary tuberculosis include :

- cough , usually more than two weeks

- cough with sputum which is occasionally blood stained

- loss of appetite and weight

- fever

- dypsnoea, night sweats,chest pain and hoarseness of voice, all of which are not common.

Signs can be subtle as in minimal cases or obvious such as consolidation, fibrosis or stony dullness due to pleural effusion.

The laboratory investigations include sputum direct smears for acid fast bacilli which are usually positive in cavitary disease. Three specimens are collected for diagnosis. Cultures using Lowenstein-Jensen medium take up to 8 weeks for a final result. There are radiometric methods such as the BACTEC test which give results within a week; subsequently sensitivity tests can be done within the following week.

Chest X-rays often reveal lesions in the apical and posterior segments of the upper lobes. Lesions are often soft in active pulmonary tuberculosis and there is usually no or little fibrosis or calcification. These latter findings would suggest healed tuberculosis. Cavities in the apex further enhance the diagnosis of active disease unless the patient has been previously treated.

Apart from the typical sites at the apex, other sites such as the apical segment of the lower lobe can be involved.

The tuberculin or Mantoux test has some role in the diagnosis of tuberculosis especially in paediatric cases and cases of extra-pulmonary tuberculosis.

The Mantoux test is used in Malaysia using the strength of 10 IU PPD. The result is read after 72 hours.

*INTERPRETING A TUBERCULIN TEST

A diameter of induration of less than 10mm is graded as negative but this does not exclude a diagnosis of tuberculosis. A positive Mantoux is merely indicates TB infection and not necessarily active disease.

A reading of 10mm or more in a child or adult who has not had BCG vaccination is positive. A diameter of 15mm in a child who has had BCG vaccination is considered significant and may indicate recent infection.

The erythrocyte sedimentation rate (ESR) has little role except perhaps in a case of miliary tuberculosis. This investigation cannot be recommended routinely in the follow up of cases of tuberculosis.
 
EXTRAPULMONARY TUBERCULOSIS

This is due to lymphohaematogenous dissemination during primary tuberculosis infection.

Symptoms are often nonspecific such as lassitude, anorexia, fever and weight loss.

The specific features relate to the organ of involvement.

Tuberculous lymphadenitis can be diagnosed by fine needle aspiration of glands which are accessible especially in the neck The specimen should be sent for direct smear, culture for the tubercle bacilli and cytological examination. Biopsy is done in cases when the fine needle aspiration is negative.

Tuberculous pleural effusion is diagnosed from pleural aspirates and pleural biopsy. The pleural aspirate often reveals straw coloured fluid with protein >30 g/l, cells (mainly lymphocytes) and low glucose (<30mg/dl). Direct smears and cultures of the pleural fluid should always be requested for.

Other organs which can be involved include the genito-urinary system and diagnosis is made from radiological investigations (IVU) and culture of the urine for Mycobacterium tuberculosis. Genital TB requires tissue biopsy for confirmation.

Tuberculosis of bones and joints is often diagnosed from X-rays and tissue biopsy. The diagnosis of tuberculous infection of the intestines and the peritoneum would require tissue biopsy and barium studies. Diagnosis of cutaneous tuberculosis may be made by skin biopsy.

Miliary TB is often diagnosed on the plain chest X-ray although liver biopsy is sometimes done and may reveal granulomas in up to 88% of cases. TB meningitis requires CSF fluid for microscopic, biochemical and bacteriological examination; however the patient is often ill and there is a role for a therapeutic trial of anti-tuberculosis treatment in these cases. CT scans can help by showing up features of basal meningitis, tuberculoma or obstructive hydrocephalus.

TREATMENT OF TUBERCULOSIS

THE AIMS OF TREATMENT ARE:

1. To cure patients and render them non-infectious
2. To reduce morbidity and mortality
3. To prevent relapse and emergence of resistant tubercle bacilli.
 
FIRST LINE DRUGS

Five drugs are considered essential to the treatment of tuberculosis. They are:

1. isoniazid (H)
2. rifampicin (R)
3. pyrazinamide(Z)
4. streptomycin(S)
5. ethambutol (E)

CHOICE OF REGIMENS

In general, newly diagnosed cases and those with sputum positive pulmonary tuberculosis and other clinically serious forms of disease should receive the highest priority.

Treatment regimens are divided into the initial or intensive phase and the continuation phase. During the intensive phase, the effects of these drugs lead to rapid sputum conversion and amelioration of clinical symptoms. During the continuation phase, two or three drugs are given intermittently or daily, the sterilising effect of the therapy eliminates remaining bacilli (persisters) and reduces drastically the chances of a subsequent relapse.

The following are the recommended regimens:

STANDARD ANTI TUBERCULOSIS DRUGS AND THE RECOMMENDED DOSAGES
 

Dly: daily BW: biweekly

FLOW CHART FOR RECOMMENDED 24WEEKS/6MONTHS TREATMENT REGIMEN(ADULT)

¯

¯

¯

¯

¯

¯

¯

(TOTAL FOLLOW UP PERIOD OF 18 MONTHS AFTER
COMPLETING TREATMENT)
S=STREPTOMYCIN, H=ISONIAZID , R=RIFAMPICIN , P=PYRAZINAMIDE,
E=ETHAMBUTOL

BASELINE INVESTIGATIONS:

Sputum D/S x 3, sputum culture AFB if D/S negative, renal profile, liver functions, visual test *, blood sugar, HIV test when indicated.

* If ethambutol is used

** Recommended to be done where facilities are available

*** Routine follow up is optional.

PATIENT MONITORING

To monitor treatment outcome, it is recommended that all patients with pulmonary tuberculosis have repeat sputum smears performed at the end of the second month of treatment. To verify treatment success, additional sputum examinations should be done at the end of the 6-month treatment period.

Where culture facilities are available, sputum cultures should be obtained at the start of treatment. Sensitivity tests for all available drugs if possible should be performed for new patients whose sputum is still positive at the end of the intensive phase of treatment, and for any patients suspected to be at risk of being drug resistant eg. relapsed cases, defaulters, immigrants from high prevalence countries.

PATIENT SUPERVISION

As far as possible, all patients must be on Directly Observed Treatment, Short course (DOTS).Local arrangements for supervision must be arranged either at the nearby health facilities, family practitioner or by a responsible person / relative. Patients not on directly observed therapy should be followed up more regularly.

The patient must be made aware of his follow up appointments to ensure compliance with treatment. To strengthen patient adherence, the following factors should be considered:

1. Patient education on his illness and treatment.
2. Education of immediate members of the patients family.
3. Regular motivation during the course of treatment to the patient.
4. Ensuring direct supervision by health service staff.
5. Prompt defaulter tracing.
6. Socio-economic assistance and advice.

    In certain situations today, hospitalisation has been one of the critical elements in achieving nearly 100% patient compliance during the intensive phase of short course chemotherapy, how ever, it must be emphasised that routine hospitalisation of tuberculosis patients is not required.

INDICATIONS FOR HOSPITALISATION

1. Gravely ill patients with far advanced disease or respiratory distress.

2. Cases of acute disseminated TB such as miliary TB or tuberculous meningitis.

3. Tuberculosis involving central nervous system, pericardium, adrenals and spine.

4.Multidrug-resistant tuberculosis.

5. Patients who default treatment frequently or whose compliance is suspect.

6. Patients with complications such as haemoptysis, pneumothorax and empyema.

7. Patients who have associated diseases such as uncontrolled diabetes mellitus and renal failure.

8. Patients who develop severe side-effects such as severe skin reactions or jaundice.

9. Patients who need to be desensitised to anti-tuberculous drugs.

10. Initial intensive chemotherapy- if daily ambulatory treatment proves difficult eg. homeless patients, drug addicts and alcoholic.

DRUG TOXICITY MONITORING AND MANAGEMENT

(A) MONITORING

Where facilities are available,adult patients should have baseline measurements of :

1. liver function tests.
2. renal function including blood urea nitrogen and/or serum creatinine
3. full blood count
4. visual acuity if ethambutol is used

All patients should be monitored clinically for adverse reactions during the period of chemotherapy. They should be informed about symptoms of common adverse reactions to the medications they are receiving.

(B) MANAGEMENT

MINOR SIDE EFFECTS:

Minor side effects, such as gastrointestinal intolerance, mild skin rash, pruritus or flushing are best managed by reassurance and symptomatic treatment and the patient should be encouraged to continue anti tuberculosis treatment. Treatment with non steroidal anti inflammatory drugs (NSAID)provide symptomatic relief of pyrazinamide related arthralgia. Skin rashes can usually be managed by withholding the causative drug and if it is really necessary to reintroduce the drug, the patient should undergo desensitization.

MAJOR SIDE EFFECTS:

Severe skin reaction and Steven-Johnson syndrome must be managed by physicians. Other common serious drug toxicity is hepatitis. Patients who develop jaundice or other signs of liver dysfunction during therapy should have treatment stopped immediately. Although many patients with drug-induced hepatotoxicity can be successfully rechallenged, this is best done in a where liver function can be carefully monitored. Thus, patients with this problem should be sent to a referral centre for management.

The development of the following conditons contraindicates further use of the drug:

-thrombocytopenia , shock and/or renal failure due to rifampicin.

-visual impairment due to ethambutol

-eighth nerve damage from streptomycin.

-Steven-Johnson syndrome.

If the period without drugs is likely to be prolonged, and the patient requires treatment, at least two other drugs should be given until it is determined whether the offending drug can be resumed. Drugs causing severe intolerance are best avoided and substituted with other drugs. All patients who require alteration from the standard regimen should be referred to experienced physicians.

MANAGEMENT OF TUBERCULOSIS IN SPECIFIC SITUATIONS

(A) PULMONARY TUBERCULOSIS IN CHILDREN

Diagnosis in children is usually difficult to make. Features that may be indicative of tuberculosis include

1) recent contact with a person (usually an adult) with active pulmonary tuberculosis.

2) positive Mantoux test

A Mantoux test reaction of > 10mm induration at 72 hours constitutes a positive test. The test may be weak or negative if the child is very ill, wasted, malnourished, immunocompromised or having HIV infection even when he is having active tuberculosis. A weakly positive reaction may occur after BCG vaccination.

3) chest radiography which shows

4) Signs and symptoms:

Infants are more likely to have non specific symptoms such as

5) Laboratory tests, the following investigations may be helpful:

1. Sputum AFB direct smear and culture in older children.
2. gastric aspiration for AFB direct smear and culture.
3. an elevated ESR may be suggestive of tuberculosis.

ANTI-TUBERCULOUS CHEMOTHERAPY IN CHILDREN

Children often present with primary tuberculosis. Chidren who require drug treatment fall into several clinical groups.

1. Children without evidence of disease but with a strongly positive tuberculin test.

2.Children with pulmonary disease.

i) INTENSIVE PHASE (2 Months)

Daily HRZ(56 doses). Syrup preparations should generally be dispensed on a fortnightly basis.

ii) MAINTENANCE PHASE (4 Months)

There are 2 regimens :

a. Daily RH regimen

This is preferred for younger children because biweekly regimen may result in omission of doses by the mother and the larger doses that need to be given with biweekly regimen may not be acceptable to the child.

b. Biweekly RH fully supervised regimen.

May occasionally be used for older children especially those who live relatively near to the health facility.

Ethambutol is best avoided because of the difficulty in detecting visual impairments.

3. Children with symptomatic extra pulmonary disease.

3.1)TUBERCULOUS MENINGITIS,MILIARY TB, BONE AND JOINT TB

Daily HRZ for 2 months followed by either daily or biweekly RH for 10 months. Streptomycin may be considered as an additional drug in the initial intensive phase. The total duration of treatment should be a minimum of 12 months. Steroids should be given in tuberculous meningitis and may also be considered in miliary tuberculosis.

3.2) OTHER FORMS OF EXTRAPULMONARY TUBERCULOSIS

The regimen and duration of treatment is the same as for pulmonary tuberculosis but may be extended depending on the clinical and/or radiological response.

(B) TUBERCULOSIS DURING PREGNANCY AND LACTATION

Untreated tuberculosis presents a much greater risk to a pregnant woman and her foetus than does the treatment of the disease. Standard treatment using ethambutol, rifampicin, isoniazid and pyrazinamide is used. Doses of anti-tuberculous drugs given in pregnancy is similiar to that in a non pregnant patient . Streptomycin is best avoided because of the risk of ototoxicity to the foetus. Normal recommended dosages of rifampicin are safe in pregnant patients. Tuberculosis treatment in lactating mothers is safe as the amount of drug ingested by the nursing infant is minimal. If the mother at the time of delivery is smear positive, the newborn should be separated from the mother at least for a period of two weeks. Breast-feeding is best avoided during this two weeks and expressed milk should be given to the child. BCG should be given as scheduled and isoniazid prophylaxis should be given for 6 months followed by Mantoux test at the end of 6 months. In the event of absence of scar, BCG vaccination should be repeated. When there is doubt about the presence of active tuberculosis, the child should be treated.

Congenital tuberculosis, although rare should be suspected if infant born to tuberculous mother fails to thrive, or has non specific symptoms such as fever, respiratory distress, poor feeding and vomiting.

(C) TUBERCULOSIS IN PATIENTS WITH LIVER IMPAIRMENT

Since isoniazid, rifampicin and pyrazinamide are hepatotoxic, liver function should be closely monitored. In patients with liver disease, therapy should be modified using drugs which are relatively non-hepatotoxic. During treatment drugs should be stopped if the liver enzymes rise more than three times normal or if the patient becomes jaundiced clinically. These cases are best referred to specialists for management.

(D) TUBERCULOSIS IN PATIENTS WITH RENAL IMPAIRMENT

Streptomycin should be avoided because of its nephrotoxicity. Ethambutol should be avoided or dosage reduced in renal failure as normal dosages may cause optic nerve damage. Tuberculosis patient with severe renal impairment should be managed by specialists.

(E) TUBERCULOSIS IN PATIENTS WITH HIV INFECTION
 

(F) DRUG RESISTANT TUBERCULOSIS

These cases should be referred to experienced physicians for management. Drugs available in Malaysia for treatment of tuberculosis resistant to first line drugs are enviomycin, kanamycin, capreomycin, clarithromycin, ciprofloxacin, ofloxacin, clofazamine, cycloserine and rifabutin.

CHEMOPROPHYLAXIS

Preventive chemotherapy is indicated in all HIV positive patients who have reaction of 5mm or more regardless of age or prior skin testing results. Preventive chemotherapy with isoniazid should also be considered for anergic HIV infected patients who are known contacts of persons with infectious tuberculosis. They should be evaluated carefully for active tuberculosis before preventive therapy is started The recommended duration of preventive chemotherapy with isoniazid in HIV infected patients is 12 months. Compliance to chemotherapy with isoniazid should be considered as a very important factor whenever preventive chemotherapy is to be instituted. In the event of suspected isoniazid resistance combination of two drugs e.g isoniazid and rifampicin may be required for 6 months.

- Asymptomatic children under 5 years old who are contacts of infectious TB cases, with Mantoux test readings of 10mm or more should receive Isoniazid 5 mg/kg once daily for a minimum of 6 months.

RELAPSE CASES

Relapse cases and treatment failures should be referred for physician management. Relapsed cases are defined as patients who have completed treatment successfully and developed active disease after a period of time.

NOTIFICATION OF TUBERCULOSIS

Tuberculosis of any form appears in the list of notifiable infectious diseases in Malaysia under the Prevention of Disease Enactment (Cap.186) Section 6.The prescribed form for notification is Health 1(Rev. 7/93) Notification of Infectious Disease (Borang Notis).

Mandatory notification to the nearest Medical Officer of Health is the responsibility of the doctor who made the diagnosis.

DEFAULTER TRACING

Defaulters must be identified immediately and every effort must be made to retrieve them promptly by the managing health facility.

There are 3 types of defaulters:

1. Treatment defaulters: the most important being sputum positive patients who are on treatment who:

a) fail to attend for supervised daily or biweekly chemotherapy.

b) fail to collect their supply of drugs for self administered oral chemotherapy.

2. Review defaulters who fail to attend follow up appointment for:

a) review of sputum or other examinations

b) progress review and further management after the examination have been completed.

3. Patients who default review while undergoing investigations to rule out active tuberculosis.

Where possible, an immediate home visit should be made. Where this is not possible, a letter should be despatched immediately or a phone call made. If the patient is on treatment home visit must be made if the patient fails to turn up within three days after the letter or the telephone call.

HOME VISITS

Home visits are made for the following purposes:

1. Defaulter retrieval.

2. Health education of newly diagnosed patients and their families.

3. Contact investigation.

The home visitor can be the nurse, medical assistant, medical social worker, public health inspector, public health overseer or mid wife of the health facility. When facilities are not available for home visiting, doctors must notify the nearest government medical officer of health.

CONTACT TRACING

1.On registration,the index case must inform the contact clinic personnel regarding his/her contacts. The contacts should be called to the clinic to be investigated (see chart).

2.Household contacts who admit to having cough of more than two weeks duration and children without BCG scar noted during home visits, should be advised to attend the nearest health facility for further investigations.

3. If a child is diagnosed to have tuberculosis, all family contacts must be investigated.

CONCLUSION

Multidrug-resistant tuberculosis is not yet becoming a problem in Malaysia.Learning from the experience of other countries, if steps are not taken to prevent this problem, it may emerge as a major setback to the tuberculosis control programme here in the near future. This can happen if haphazard and inadequate attention is given to factors like using effective treatment regimen, proper supervision of treatment, prompt retrieval of treatment defaulters and contact investigation .

AUDIT INDICATORS

The effectiveness of the guideline is determined by two major factors: the cure rate and the level of acquired drug resistance.

The cure rate is defined, for all registered smear positive or culture -positive patients, as the proportion of patients that completed treatment and had sputum negative at 4 months and at the end of the treatment period. It is evaluated from the result of the cohort analysis done yearly by the National Tuberculosis Control Programme. The cure rate is the most important factor and is inversely related to the rate of acquired drug resistance and directly related to the rate of noncompliance to treatment.

REFERENCES

1. American Academy of Peadiatrics : Chemotherapy for tuberculosis in infants and children. Bronchus Vol.8 No.1 1992.

2. American Thoracic Society: Treatment of Tuberculosis and tuberculosis infection in adult and children. Rev.Respir.Dis.1986:134:355-363.

3. Clinical Tuberculosis, TALC and IUATLD 1992. Crofton J, Norman H,Hiller F.

4. Treatment of Tuberculosis: Case holding until cure. WHO/TB/1983.141.Chaulet P.

5. Antituberculosis regimens of chemotherapy.Recommendations from the committee on treatment of the IUATLD 1990.Girling D.J,Chaulet P.

6. Guidelines for chemotherapy of tuberculosis :National Tuberculosis Centre ,Kuala Lumpur 1992.

7. Surveillance of Tuberculosis including the evaluation of chemotherapy programmes. Proceedings of the Royal Society 0f Medicine 70,4-15.Fox W.

8. The global tuberculosis situation and the new control strategy of the world Health Organisation.Kochi A.Tubercle 1991, 72:1-6.

9. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 1994.Thorax 1994;49;1193-1200.

10. National Tuberculosis Control Programme, Annual Report 1995, Ministry of Health, Malaysia. 

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