The present global situation
Tuberculosis (TB) has been curable for more than 50 years, yet it continues to cause an immense burden of morbidity and mortality. Approximately one-third of the world’s population is infected with Mycobacterium tuberculosis, with 8 to 10 million developing active TB and ~3 million dying of TB each year (almost half of whom are co-infected with HIV). About 95% of cases occur in low-income countries and 75% are in the 15-50 age group. Both globally and within countries, there is a striking link between poverty and TB.
Two important developments have occurred in the past two decades:
- TB incidence has increased dramatically in communities highly endemic for HIV.
- The emergence of drug resistance jeopardizes both individual treatment and control of the disease in communities. In 1993, WHO declared TB a global emergency?
Aerosolized droplets containing M. tuberculosis enter alveoli and initiate a non-specific response. The bacilli are ingested by macrophages and transported to regional lymph nodes. They may either be contained there or spread via the lymphatics or bloodstream to other organs.
With the development of cell-mediated immunity, cytokines secreted by lymphocytes recruit and activate macrophages, which organize into the granulomas characteristic of TB, surrounded by lymphocytes, effectively walling in the organisms.
In an immunocompetent host, most granulomas heal. They can sometimes be seen on CXR; more commonly the lesion is not detectable radiographically and a positive tuberculin skin test (TST) is the only evidence of infection.
Although the lesions become fibrotic, bacilli can persist intracellular in macrophages in a quiescent state capable of reactivation at a later time. This is known as latent tuberculous infection.
Active TB disease
On average ~10% of adults infected with M. tuberculosis ultimately develop active TB, with about half of this risk occurring in the first 1-2 years after infection and the other half distributed over the remainder of the individual’s lifetime. A number of factors can substantially increase the risk of disease reactivation
In a minority of cases, particularly infants or those with depressed cell-mediated immunity, 1Â° infection is not contained and symptomatic or disseminated disease (progressive 1Â° TB) develops directly from 1Â° infection.
Occurs as a reactivation of latent infection, often years or even decades after the 1Â° infection. The genus Mycobacterium includes
- M. tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG, M. africanum): very closely related organisms of which M. tuberculosis is the most important human pathogen.
- M. leprae, the cause of leprosy, is an important mycobacterial pathogen of humans.
- Mycobacteria other than TB: mainly environmental organisms which cause a spectrum of relatively uncommon human diseases (e.g. M. avium complex, M. kansasii, M. fortuitum, M. marinum.) M. ulcerans is the cause of Buruli ulcer, a destructive cutaneous mycobacteriosis seen with increasing frequency inWest Africa. Person to person transmission has not been observed with these organisms. This group will not be considered further in this chapter.
Most commonly affects infants and the immunosuppressed. There is a history of gradual onset fever, malaise, and weight loss in the absence of other apparent causes. Clinical suspicion is raised in a child with known or likely recent contact with an infectious TB patient. Physical findings are commonly non-specific, but include hepatomegaly, slight splenomegaly, tachypnoea, and neck stiffness (meningitis may complicate military TB). Progression to death occurs in the absence of therapy.
Chest X-ray characteristically shows diffuse, tiny, nodular opacities. Sputum smear examination and TST are often negative; where available, biopsy of liver, bone marrow, lymph nodes, or lung parenchyma may yield acid-fast bacilli or granulomas.
Most commonly seen in children and the immunosuppressed. Clinical presentation includes headache, irritability, vomiting, decreased consciousness, or any unexplained progressive central neurologic syndrome. The history is usually less acute than in bacterial meningitis. Neck stiffness may be mild at first, later opisthotonus; coma may occur. Cranial nerve palsies (III, IV, VI, and VIII particularly) occur, reflecting basilar distribution of the disease. Seizures and focal neurologic deficits may also occur.
Diagnosis rests on CSF examination.
There is typically a lymphocytosis with raised protein and decreased glucose in early disease, mild changes may be present. CSF should also be examined for cryptococcus if there is a possibility of HIV infection. Unless concentrated the CSF is rarely positive for acid-fast bacilli; cultures may become positive in most cases.
Once a diagnosis has been made on the basis of clinical features, suggestive CSF abnormalities, and the absence of a likely alternative diagnosis, TB treatment should be started immediately.
The available evidence and most expert opinion support adjunctive therapy with corticosteroids.
Gastrointestinal TB may present as partial bowel obstruction with a history of fever. It can occur at any site in the GI tract, most commonly the terminal ileum. The diagnosis is likely to be made at surgery or endoscopy. Granulomatous hepatitis is characterized by a systemic illness with laboratory evidence of cholestasis and diagnosed on liver biopsy. Peritoneal TB may be suspected on the basis of ascites without another obvious cause such as liver disease and portal hypertension the ascites has the same characteristics as TB pleural fluid (see above). The peritoneum has a characteristic appearance on direct inspection; peritoneal biopsy, ideally taken at laparoscopy, with culture and histology provides a definitive diagnosis.
Often first suspected on the basis of globular enlargement of the cardiac silhouette on CXR in patients being investigated for a variety of systemic and cardio respiratory symptoms. It is seen more frequently in HIV-infected patients. A pericardial rub or clinical features of tamponade (elevated jugular venous pressure, pulsus paradoxus, hypotension) may be present. Ultrasound readily confirms the presence of an effusion. Pericardial fluid has the same characteristics as pleural fluid (see above). The risk of tamponade acutely, and constriction later on, may be reduced by adding corticosteroids for the first 6-12weeks of TB treatment.
Can involve any part of the male or female genitourinary tract. Presentation is sub acute and diagnosis usually requires TB culture or histology of biopsies. Renal TB presents with dysuria, hematuria, flank pain, or mass. The urine contains pus cells on microscopy, but is negative on culture for common bacteria. Genital tract TB in women presents as infertility, pelvic pain, mass, or abnormal bleeding. Epididymal swelling is the most common presentation of genital TB in males.
TB in children
The risk of progression to disease following M. tuberculosis exposure is greater in infants and young children and the death rate may be very high among those infants who develop TB. By contrast, children between around 7 and 12 years of age have the lowest risk of any age group of developing active TB. Even where culture and other facilities are available, diagnosis of childhood TB is difficult. Sputum smears are usually negative in children with PTB.
A history of close contact with a smear-positive pulmonary TB case is essential information.
A positive TST is also strongly suggestive of TB in a child with unexplained illness, particularly in younger children in whom the background rate of TST positivity is low.
Scoring systems have been developed to rationalize the diagnosis of childhood TB none has been well validated, but they may provide useful guidance.
An aid to diagnosis of TB in children
- Score chart for child with suspected TB
Score 0 1 3 Length of illness <2 weeks 2â€“4 weeks >4 weeks Weight for age >80% 60â€“80% <60% Family TB (past or present) None Reported by family Proved sputum +ve
- Score for other features if present:
Positive tuberculin skin test (TST) 3 Large painless lymph nodes: firm, soft, and/or sinus in neck, axilla, and groin 3 Unexplained fever, night sweats, no response to malaria treatment 2 Malnutrition, not improving after 4 weeks 3 Angle deformity of the spine 4 Joint swelling, bone swelling, or sinuses 3 Unexplained abdominal mass or ascites 3 CNS: change in temperament, convulsions, or coma 3
- If the TOTAL score is 7 or more treat for TB
Treat children with a score less than 7 if:
- CXR is characteristic of TB infection, or
- The child does not respond to two 7-day courses of two different antibiotics
2 Dr Keith Edwards, University of Papua New Guinea, published in Crofton et al. (1997) Clinical tuberculosis, MacMillan
Three sputa should be examined whenever a cough has been present for >2â€“3 weeks. In patients who travel some distance to the clinic, the 1st specimen is collected at first presentation, the 2nd is an early morning sputum collected at home on the day the patient returns for follow up, and the 3rd is collected in clinic that day.
In patients who cannot produce sputum, or in suspected PTB with repeated negative sputum smears, induction with 3% hypertonic saline significantly improves the sensitivity of smear and culture. Gastric lavage is useful in children, where culture facilities are available.
CXR is not routinely necessary for the diagnosis and management of TB. A normal CXR makes PTB unlikely, but CXRs cannot distinguish reliably between TB and other diseases or between changes of current and past TB. The interpretation of CXR varies according to the skill of the reader and between readers. They do not predict infectiousness (as the sputum smear does), nor supply the definitive identification provided by culture. CXR is useful in patients with undiagnosed chest symptoms who are repeatedly smear negative.
Tuberculin skin testing (TST)
Relies on the fact that cell-mediated hypersensitivity typically develops within 8 weeks of infection with M. tuberculosis. The test involves intradermal injection of PPD (purified protein derivative). The diameter of skin induration (swelling; not redness) is measured at 48â€“72 hours. Training and experience in interpreting skin test responses is critical to achieving accurate results. In most situations, 10 mm of induration to a standard tuberculin dose is the cut-off point between positive and negative; 5 mm is considered to be positive in an HIV-infected individual. Both false negative and false positive TST results occur commonly. The stronger the TST response, the less likely it is to be a false positive.
Uses of the TST
- Epidemiologic determining prevalence or incidence in populations or specific groups such as health care workers.
- Diagnostic to aid in assessing the likelihood of TB as the cause of a clinical illness. In high-prevalence countries, this use is largely limited to children because of the high background prevalence of TST positivity in the adult population.
- Determination of candidates for ˜chemoprophylaxis (e.g. paediatric contacts of pulmonary TB patients, HIV-infected individuals).
Diagnosis of sputum-negative PTB
Reassessment and repeat sputum examination after 2â€“3 weeks, following a therapeutic trial of a broad-spectrum antibiotic, may clarify the diagnosis. CXR, interpreted with the cautions mentioned below, may help to estimate the likelihood of TB in suspects who remain smear-negative.
Before diagnosing smear-negative PTB, consider alternative
diagnoses such as:
Pneumonia Bronchiectasis Asthma Lung abscess Chronic bronchitis Lung cancer Non-TB respiratory complications of HiV infection
In some TB programmes, a decision to start treatment for smear-negative PTB can only be made by a doctor or individual with particular expertise in TB.
A therapeutic trial of treatment
A therapeutic trial is widely used by some practitioners to diagnose TB. Therapeutic trials have not been validated, and this approach risks creating confusion among health care workers. If therapeutic trials are to be used, then:
- All efforts to make a diagnosis should have been exhausted.
- The endpoint used to determine success or failure should be established before starting treatment and should be objective (eg. fever, weight gain).
- The duration of the trial should be established at the beginning: fever can be expected to settle within 14 days of starting treatment in most cases, and weight gain should be evident by 4 weeks.
- The drugs used for the trial should have antimycobacterial activity (isoniazid, ethambutol, and pyrazinamide) but not be effective against other infections (rifampicin and streptomycin)
- The patient’s status as a trial patient should be clearly established in the local TB programme.
A false positive TST can be caused by:
- BCG: TST response following BCG is variable; BCG in infancy is unlikely to account for a strongly positive TST in adulthood
- Exposure to environmental mycobacteria
- Incorrect interpretation
A false negative TST can be caused by:
- Normal variation
- Long interval since infection
- Reduced cell-mediated immune response (HIV, old age, corticosteroid therapy, measles, malnutrition)
- Severe illness, including overwhelming TB
- Incorrect TST technique or interpretation
Aims of treatment
- To cure the patient.
- To prevent transmission in the patient’s family and community.
- To prevent development of resistant bacilli.
Principles of anti-TB therapy
- Use at least 2 drugs to which the organism is presumed to be sensitive.
- Administer treatment for an adequate duration (6â€“8 months with the regimens used in most national TB programmes).
- Ensure that each patient completes the full course of therapy with a high level of adherence.
First- and second-line anti-TB drugs (see box )
Treatment is the same regardless of disease site, although some advise a prolonged consolidation phase for TB meningitis and bone disease (12 months total). Anti-TB drugs should be provided in the form of fixed-dose combination (FDC) tablets which make monotherapy impossible and provide a further defence against the development of drug resistance.
Anti-TB drug dosage and standard regimens
Most national TB programmes have a standard regimen and a re-treatment regimen â€” the latter for patients who have defaulted, failed treatment, or relapsed.
Anti-TB drug (abbreviation) Recommended dose (mg/kg) od 3 Ã— week Isoniazid (H) 5 10 Rifampicin (R) 10 10 Pyrazinamide (Z) 25 35 Streptomycin (S) 15 15 Ethambutol (E) 15 30 Thiacetazone (T) 2.5 N/A
First-line regimen (WHO) 2HRZE 4HR or 2HRZE 4H3R3
- Isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months
- Followed by isoniazid and rifampicin either or 3Ã—/week for4 months
First-line regimen (International Union against Tuberculosis and Lung Disease)
- Isoniazid, rifampicin, pyrazinamide, and ethambutol od for 2 months
- Followed by isoniazid and ethambutol od for 6 months
Re-treatment regimen (defaulters, treatment failure, relapse).
2HRZES 1eHRZE 5H3R3E3
- Isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin od for 2 months
- Followed by isoniazid, rifampicin, pyrazinamide, ethambutol od for 1 month
- Followed by isoniazid, rifampicin, ethambutol 3Ã—/week for 5 months
- Isoniazid(INH): potent anti-TB activity. Main serious adverse effect is liver toxicity.
- Rifampicin(rifampicin): essential to the success of modern short course TB therapy (<12 months). Rifampicin is characterized by a high rate of drug interactions (induces liver enzymes and lowers serum levels of warfarin, anticonvulsants, oral contraceptives, some antiretrovirals, etc). It can cause hepatitis.
- Pyrazinamide: sterilizing activity allows treatment courses of 6 months. May cause vomiting, arthralgias, less commonly hepatitis. Contribution to first-line regimens limited largely to the first 2 months of therapy
- Ethambutol: main role is prevention of resistance to other drugs, particularly when 1Â° resistance to one or more first-line agents is possible. Main serious adverse effect is ocular toxicity, which is uncommon at recommended doses.
- Thiacetazone: formerly used in conjunction with isoniazid in the continuation phase. Largely abandoned in high HIV-prevalence countries because of high rates of Stevens Johnson syndrome in HIV-co-infected patients.
- Streptomycin: now limited to second-line or re-treatment regimens because of the cost of needles and syringes and the desire to avoid unnecessary injections in the HIV era. Ototoxicity (vertigo >hearing loss) and renal toxicity are the main adverse effects. The drug should be avoided or dosage adjusted carefully in renal dysfunction. Contraindicated in pregnancy.
- Isoniazid causes peripheral neuropathy more commonly in diabetic, malnourished, alcoholic, and pregnant patients; and in those with pre-existing neuropathy. Give pyridoxine 10â€“15 mg/d to prevent peripheral neuropathy.
- Women on oral contraceptives must use another form of contraception (e.g. an IUD) during rifampicin therapy and for 4â€“8 weeks after stopping rifampicin.
- Pregnancy: TB drugs, except for streptomycin, may be used in pregnancy. Any theoretical risks to the fetus are much less than the risks from untreated TB.
Third-line anti-TB drugs
Recently, some programmes have acquired anti-TB drugs for the treatment of multidrug-resistant (MDR) TB. Treatment of MDR TB is much longer (>18 months), much more toxic, much more costly, and considerably less effective than treatment of drug-sensitive TB. Therefore it must only be introduced in settings where a DOTS (directly observed therapy, short course) programme is established and demonstrating good outcomes. MDR TB treatment requires supervision of every treatment dose, a well-structured programme with guidelines, appropriate laboratory resources, assured drug supply, and access to expert advice, as recommended by the WHO ˜Green Light Committee
Sputum-positive patients should be monitored by sputum smear examination after 2 months of treatment and prior to treatment completion. All other patients should be monitored clinically. Monitoring for adverse drug reactions is essential.
Concordance: patients usually feel better soon after starting treatment, so may lose the motivation to continue therapy for many months. Treatment completion is essential for cure and prevents the development of drug resistance. The treating health care worker and the TB programme must ensure that patients complete TB therapy. This is most likely to succeed if the patient and community are active and informed participants and aware of the risks of drug resistance. The relationship between the patient and program or clinic staff is a major factor promoting concordance.
Resistance: small numbers of M. tuberculosis are mutants naturally resistant to single TB drugs. Combination chemotherapy ensures that these resistant organisms will be killed by other drugs. Poor choice of treatment or poor concordance with therapy results in selection for these resistant organisms.
Treatment failure: follow guidelines in the national TB manual or the re-treatment regimen.
Smear-positive PTB patients transmit infection. Curing smear-positive cases is the 1Â° means of reducing TB transmission in the community.
Once availability and quality of treatment have been established, the next priority is case finding. This activity must be integrated with the primary health care service since it depends upon recognition and appropriate investigation (most importantly by sputum smear examination) of TB suspects by primary health care workers.
Bacille Calmette Guerin (BCG):
is a live attenuated vaccine derived from M bovis. Protective efficacy ranges from 0 to 80% for reasons which remain controversial. BCG provides some protection against miliary TB and TB meningitis, and should be given at birth to all children in high TB-prevalence countries (except those with symptomatic HIV disease). BCG has little or no impact on the rate of infectious TB in a community.
Household and close contacts of TB cases: Symptomatic contacts should be investigated for active TB. Chemoprophylaxis should be offered to asymptomatic household contacts aged <5 years, of smear-positive PTB patients. In high-prevalence countries, HIV prevention is an important form of TB control.
Health care workers are exposed to a significant occupational risk of TB, and HIV-infected subjects are at very high risk. The important infection control principles are:
- Early diagnosis and treatment of patients to minimize the period of infectiousness.
- Encourage patients to cover their mouths when coughing or sneezing.
- Early identification and respiratory isolation of TB suspects pending diagnosis.
- Increased natural ventilation and sunlight in TB wards and clinics.
- Encourage health care workers to be tested for HIV and employ those with HIV where there is lower risk of TB exposure (e.g. non-clinical jobs, paediatrics).
Wearing of common surgical masks by staff provides very limited protection against TB. The infectious droplets are too small to be blocked by these masks and the masks do not seal around the mouth.
In the laboratory, most TB risk occurs in handling of TB cultures. The risk in handling specimens and preparing sputum smears is much lower.
Patients should cough sputum specimens in a separate, well-ventilated area. Wearing of masks by lab staff is not needed.
TB and HIV
TB incidence has increased up to 6-fold in some communities affected by the HIV pandemic. HIV prevalence is up to 80% among TB patients in these places. TB is the most common cause of death in patients with HIV. The main mechanism involved is suppression of cell-mediated immunity (CD4 helper T-cells and macrophages) by HIV which impairs the immune response to TB.
Differences in management of TB in HIV +ve patients
Presentation: most patients with HIV-related TB do not know their HIV status. Some have clinical features of HIV infection: oral candidiasis, chronic diarrhoea, skin and hair changes, peripheral neuropathy, herpes zoster scars, etc. However, since TB can occur early during the course of immune suppression, other clinical features of HIV are often absent.
Extrapulmonary TB is common in HIV +ve patients, particularly lymphadenopathy, pleural and pericardial effusions, miliary TB, and meningitis. However, PTB continues to be the most common form of TB.
The radiographic appearance of PTB in HIV +ve patients sometimes differs from the classical appearances, roughly according to the individual’s degree of immune suppression. HIV +ve patients less commonly have upper lobe disease and cavities and more commonly have hilar adenopathy, effusions, and miliary and nodular shadowing.
Diagnosis: sputum smear microscopy is slightly less sensitive in HIV +ve patients. Differential diagnosis of lung disease in the HIV +ve includes:
- Bacterial (most often pneumococcal) pneumonia: a short history and a response to antibiotic therapy is suggestive.
- Pneumocystis jiroveci pneumonia: it is less common in some tropical settings but characteristic features are a history of cough and fever for weeks, severe dyspnoea and hypoxia, diffuse changes on X-ray, and a response to high-dose co-trimoxazole therapy.
- Pulmonary Kaposi’s Sarcoma: most patients have cutaneous or mucosal lesions (e.g. on the hard palate).
The same drug regimens are used in HIV +ve and uninfected patients, so knowledge of HIV status is not required to provide anti-TB treatment. Sputum conversion rates and initial cure rates are similar in HIV +ve patients and those without HIV provided modern rifampicin-containing regimens are used.
Recurrence rates and re-infection rates are higher. Mortality during and after treatment is markedly increased among patients with HIV, with most deaths being due to HIV-related causes other than TB.
Increasing numbers of patients have access to ART. Treatment with anti-TB and antiretroviral drugs can lead to complex and clinically important drug interactions:
- Rifampicin reduces serum levels of most protease inhibitors and some non-nucleoside reverse transcriptase inhibitors such as nevirapine.
- Immune reconstitution reactions can result in temporary clinical deterioration when ART is started early in the course of TB treatment.
One strategy is to delay ART until completion of the intensive phase of TB treatment and use of a non-rifampicin-containing continuation phase such as 6 months of isoniazid and ethambutol. Seek expert advice if ART and TB therapy are to be given together.
There are potential benefits to patients with HIV and TB from giving prophylaxis with co-trimoxazole. Consult national guidelines on this issue. Compared to HIV uninfected people, persons with HIV have:
- A much higher risk of progressive primary disease following infection.
- A much higher risk of reactivation of latent TB infection â€” about 10% per year (compared to 10% in a lifetime in HIV uninfected people).
- After successful treatment of TB, an increased risk of re-infection with a new strain of M. tuberculosis.
TB increases HIV replication and may enhance progression to AIDS.
Treatment of latent TB infection in HIV-infected patients:
HIV +ve individuals, who are also TST-positive and who have no evidence of active TB disease, have significantly less risk of developing active TB if given chemoprophylaxis though the benefit declines with time, especially if the patient continues to live in a community where the risk of is high. TB transmission Isoniazid for 6-9 months is standard, and seems not to cause increased isoniazid resistance.
Large-scale chemoprophylaxis programmes for people with HIV are uncommon in practice. Care must be taken that anti-TB drugs, especially rifampicin, are not used or distributed in ways that could promote development of resistance.
HIV testing of TB patients:
TB patients are a sentinel group, often selected for epidemiologic surveillance of the HIV epidemic. When treating individual patients, there is an ethical obligation to inform patients when strong clinical evidence of HIV infection is found and to provide them with the option of serologic testing to confirm or exclude HIV.
Whether all TB patients should be offered HIV testing should be determined at local or national level based on availability of testing and counseling resources and care for HIV infection, policies regarding voluntary testing and counseling, anticipated local reaction in relation to stigmatization of TB patients, and other local factors.
Oxford Handbook of Tropical Medicine, 2nd Edition