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Respiratory infection—mycobacterial 

Respiratory infection—mycobacterial
Chapter:
Respiratory infection—mycobacterial
Author(s):

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

DOI:
10.1093/med/9780198703860.003.0042
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date: 26 October 2021

Tuberculosis: epidemiology and pathophysiology

Tuberculosis (TB) is the second leading infectious cause of death worldwide (after AIDS), despite being a potentially curable disease. It kills around 1.4 million people per year, of whom 0.43 million are HIV +ve and 64, 000 are children. Rising rates of HIV and immigration mean TB remains a large proportion of the workload for respiratory physicians in some parts of the UK. The disease is a great ‘mimicker’ and should often be considered as part of the differential diagnosis in patients with respiratory disease.

Epidemiology

Globally, the WHO estimates there are 125 cases of TB per 100, 000 population (2011). The highest incidence is in sub-Saharan Africa (262 cases per 100, 000 population). High population density countries in Asia (India, China, Pakistan, and Indonesia) account for half the global burden. The countries comprising the former Soviet Union have rapidly increasing rates because of economic decline and failing health services, with around 25% multidrug resistance in this area. Globally, a significant proportion of people are co-infected with HIV; this number is particularly high in sub-Saharan Africa.

In the UK, there were 8, 800 cases of TB in 2011, 14 per 100, 000. This number has been relatively stable for the past 5–10y. UK death rates from TB are decreasing. The majority of cases in the UK are in people born abroad, but a significant amount of TB is in UK-born Caucasians. Around 8% of cases are co-infected with HIV. TB is concentrated in the major cities, with 40% of cases in London.

Pathophysiology

The disease is spread by airborne droplets containing Mycobacterium tuberculosis (MTB). Droplets remain airborne for hours after expectoration because of their small size. Infectious droplets are inhaled and become lodged in the distal airways. MTB is taken up by alveolar macrophages, triggering the innate immune system, and spreads via the lymphatics to hilar lymph nodes. Later, a cell-mediated immune process leads to granuloma formation by activated T-lymphocytes and macrophages, which limits further bacterial replication and disease spread. Most (over 90%) immunocompetent individuals successfully contain the infection (either eliminated or contained in a latent state); 10% progress to active 1° disease (1° progressive TB).

Many factors influence whether or not infection leads to active disease, including age, host immunity, and time since infection (risk highest in first few years after infection). The estimated lifetime risk of clinical disease in a child newly infected with MTB is about 10%.

Active disease occurs when the host’s immune response is unable to contain MTB replication, with absent or poorly formed granulomas. Active disease occurs most often in the lung parenchyma (due to high O2 content, in which the bacillus grows well) and hilar lymph nodes. It can occur in any organ from haematogenous spread. This is most common in young children and immunosuppressed adults. Most disease in adults is due to reactivation of childhood disease, so-called ‘post-primary disease’, from activation of latent TB (the Ghon focus) lying dormant in the lung.

The term smear-positive TB refers to the identification of AFB on sputum smear (ZN stain). Infectious. Patient will require isolation if admitted to hospital.

Culture-positive TB

refers to AFB not seen on smear (smear-negative). TB grown on culture (may take up to 9 weeks). Much less infectious than smear-positive disease, although transmission can still occur.

Main risk factors for active TB in the UK

  • Place and date of birth:

    • Caucasian population; increasing prevalence with age (♂ > ♀)

    • Afro-Caribbean immigrants; highest prevalence in the young (♂ = ♀)

    • Indian subcontinent; highest prevalence in middle age (♂ = ♀)

  • HIV/AIDS

  • Poverty, undernutrition, and overcrowding

  • Heavy alcohol consumption and smoking

  • Medical factors—diabetes, end-stage renal failure, malignant disease, systemic chemotherapy, steroids and TNF-α‎ antagonists, e.g. infliximab, vitamin D deficiency (vitamin D has pleiotropic effects on the immune system, including macrophage activation).

TB: pulmonary disease

Symptoms

Most cases present with pulmonary disease, classically:

  • Productive cough

  • Haemoptysis

  • Breathlessness

  • Systemic symptoms—weight loss, night sweats, and malaise

  • Chest pain.

Haemoptysis

is more common with cavitatory disease, and up to two-thirds will be smear-positive. Most haemoptysis is small volume. Massive haemoptysis is rare and is most common as a consequence of destruction of a lobe, with consequent bronchiectasis formation (possibly with 2° Aspergillus infection or mycetoma in a healed TB cavity). This is seen in those untreated in the pre-chemotherapy era. Most haemoptysis will resolve with antituberculous chemotherapy.

Signs

are often non-specific.

  • Examination may be normal

  • Lymphadenopathy (particularly cervical)

  • Crackles

  • Signs of a pleural effusion

  • Signs of consolidation (with extensive disease)

  • Signs of weight loss/underlying immunocompromise

  • Look for evidence of extrapulmonary disease, e.g. skin, joints, CNS, retina, and spinal disease.

Complications

Long-term sequelae of inadequately treated infection include:

  • Bronchiectasis, bronchial obstruction, and airway stenosis (uncommon) may result from endobronchial disease, though this is much less common in the post-chemotherapy era. It is more common in the presence of extensive parenchymal disease and is associated with lymph node enlargement, with compromise of airway size

  • Pleural disease (see Respiratory infection—mycobacterial p. [link]) is due to either 1° progressive disease or reactivation of latent infection. It probably represents an increased immune response—a delayed-type hypersensitivity reaction to mycobacterial antigens, rather than a diminished one, which is the case in other forms of TB infection. Culture is more likely from pleural tissue than fluid (where the organism burden is lower)

  • Pneumothorax is rare (<1% in the developed world) and results from the rupture of a peripheral cavity. Can lead to the formation of a bronchopleural fistula

  • Draining abscess

  • Right middle lobe syndrome—compression of the right middle lobe bronchus by hilar lymph nodes leads to lobar collapse

  • The previous treatment with thoracoplasty can lead to respiratory failure in later life due to compromised VC.

TB: extrapulmonary disease

Extrapulmonary disease is seen in about 20% of patients with TB. This proportion is higher in HIV-positive patients.

The tuberculin skin test (see Respiratory infection—mycobacterial pp. [link][link]) is more frequently positive in extrapulmonary disease, as this most commonly represents reactivated disease and less commonly 1° disease. Anergy is more likely in those with poor nutritional status, underlying disease (including HIV), and the elderly.

CNS disease

is the most serious manifestation and includes meningeal involvement and space-occupying lesions (tuberculoma) that may lead to cranial nerve lesions. The clinical manifestations are due to the presence of MTB and the host’s inflammatory immune response.

TB meningitis

presents with headache, fever, altered conscious level, and focal neurological signs, including cranial nerve palsies. Fits are common.

CSF

contains lymphocytes, high protein, and low glucose. PCR of CSF may be useful but is not 100% sensitive.

Pericardial TB

The yield is low from pericardial fluid and biopsy. 85% have a positive tuberculin test. A large effusion may lead to cardiac tamponade and may need to be drained.

Spinal disease

can affect any bone or joint; spine involvement (Pott’s disease) is most common in the thoracic spine. Surgery may be needed if there is evidence of cord compression or instability.

Genitourinary disease

from seeding during haematogenous spread. Involvement of the renal and genital tracts is uncommon.

In men—may cause prostatitis and epididymitis.

In women—genitourinary TB is a cause of infertility. Sterile pyuria (white and red blood cells in the urine, in the absence of bacterial infection) may indicate TB infection.

Peripheral cold abscess

can occur at almost any body site.

Disseminated disease

is more common in immunosuppressed individuals. Pulmonary disease is typically a miliary (millet seed) pattern, but pulmonary disease is not universal in disseminated disease. This has a higher mortality than localized disease.

TB: investigations

The diagnosis is usually made in one of three ways: smear or culture of sputum (or other sample, e.g. pus, CSF, urine, biopsy tissue), or histology with the identification of caseating granulomas on biopsy.

  • CXR classically shows upper lobe infiltrates with cavitation

    • May be associated with hilar or paratracheal lymphadenopathy

    • May show changes consistent with prior TB infection, with fibrous scar tissue and calcification

    • HIV-infected patients typically have less florid CXR changes and are less likely to have cavitatory disease. Miliary pattern is more common in later stages of AIDS

    • All patients with non-pulmonary TB should have a CXR to exclude or confirm pulmonary disease

  • Sputum ZN stain and culture is required for definitive diagnosis and is vital for drug resistance testing. ZN is only 50–80% sensitive

    • New sputum processing techniques, along with fluorescence microscopy, have improved smear sensitivity and efficient reading of slides

    • Smear-negative disease accounts for about 20% of disease transmission; smear-positive cases are more infectious

    • Induced sputum is as effective as BAL, especially if the CXR shows changes consistent with active disease (but should not be used for potential MDR-TB, due to the danger to health workers)

    • Conventional culture takes 6 weeks or longer, although use of the mycobacterial growth indicator tube (MGIT) culture system can lead to positive cultures within days

    • Nucleic acid amplification techniques are increasingly used to confirm mycobacteria serotype and drug susceptibility. The Xpert MTB/RIF assay can simultaneously detect MTB and identify rifampicin resistance (which is strongly associated with MDR-TB) within 2h and has been recommended by the WHO for use in regions with high rates of HIV/TB co-infection or MDR-TB

  • Tuberculin skin test (Mantoux) are only useful if strongly positive (suggesting active disease) or if negative (see Box 42.1). The skin test must be interpreted with the clinical picture and with knowledge of the patient’s ethnic origin, exposure, and BCG vaccination history

  • IGRAs (see Respiratory infection—mycobacterial p. [link]) High sensitivity, but low specificity, of IGRAs mean a negative/low result rules out active or latent TB, but a positive result cannot differentiate between the two

  • Bronchoscopy/EBUS may be needed to obtain BAL or lymph node samples if there is a high index of clinical suspicion but a non-productive cough or unhelpful sputum culture. In extensive disease, macroscopic bronchoscopic abnormality may be present, with erythematous or ulcerated airways. Granulation tissue or enlarged lymph nodes may be visible. Nodes can perforate or protrude into the bronchial lumen, extruding caseous material into the airway

  • Biopsy from extrapulmonary sites, e.g. neck lymph nodes, or mediastinoscopy may be warranted. Lymph node biopsy samples, pleural biopsies, and pus aspirated from lymph nodes should be transported to the laboratory in a dry pot (not formalin). Bone marrow or liver biopsy may aid diagnosis in miliary TB. The bone marrow culture yield is higher in pancytopenia

  • Gastric washings reflect TB swallowed overnight. Rarely performed if bronchoscopy is readily available. Used more commonly in children

  • Urine Early morning urine (EMU) only if renal disease suspected

  • Blood tests Baseline FBC, renal and liver function tests. Useful to document normal baseline levels before starting antituberculous chemotherapy

  • HIV test should be offered to all patients

  • CT scan is more sensitive than CXR, especially for smaller areas of disease. It may show cavitatory disease and signs of airway disease—the ‘tree-in-bud’ appearance, useful for differentiating between active disease and non-active old disease and guiding area for BAL. May also be needed to assess mediastinal or hilar lympadenopathy.

A tuberculoma is an encapsulated focus of reactivated TB. These lesions rarely cavitate, and the differential diagnosis is wide, including malignancy (pulmonary nodule, see Respiratory infection—mycobacterial p. [link]) and vasculitis. Diagnosis may only be possible by percutaneous biopsy, as, in the absence of a main airway component, cultures may be negative.

TB: management 1

Treatment aims to cure disease without relapse, prevent transmission, and prevent emergence of drug resistance. Long-term treatment with a number of drugs is required, as TB can remain dormant for long periods prior to treatment, making the emergence of naturally resistant mutants possible.

  • Send material for bacteriological diagnosis prior to initiating treatment, if possible, to allow for subsequent drug susceptibility testing

  • In practice, if there is a high clinical suspicion of TB, treatment should be started before culture and full sensitivities are available.

  • Never treat with a single drug

  • Never add a single drug to a failing regime

  • The majority of patients can be treated as outpatients

  • Every TB patient should have an easily contactable key worker

  • Smear-positive HIV-negative patients should become smear-negative within 2 weeks of starting treatment (this does not apply to MDR-TB). These patients should be isolated either in hospital (if they are admitted) or at home for this time period

  • All patients should be discussed and managed within a TB MDT

  • From 2007, there are no prescription costs for TB drugs in the UK

  • All new cases must be notified (including those diagnosed after death), as this initiates contact tracing. In some districts, notification triggers specialist nursing input. The doctor making the diagnosis has a legal responsibility to notify. It also provides epidemiological and surveillance data, enabling treatment and screening services to be planned. A patient can be denotified if the mycobacterium cultured turns out to be an NTM.

Drug treatment

is usually in two phases:

  • Phase 1—initial intensive phase Designed to kill actively growing bacteria

    • This phase lasts 2 months and shortens the duration of infectivity

    • At least three drugs are needed, e.g. isoniazid, rifampicin, and pyrazinamide, and guidelines recommend four drugs, with ethambutol added because of risks of drug resistance

  • Phase 2—continuation phase is usually with two drugs, typically isoniazid and rifampicin for 4 months

    • Fewer bacteria are present in this phase, and there is therefore a lower chance that drug-resistant mutants will emerge, so drug resistance is less of a problem.

Compliance is of major importance,

and all patients should have a risk assessment for treatment adherence. If the clinical response is not satisfactory, check sputum 2 months before the end of the planned treatment period. Compliance can be monitored with urine colour testing (turns red with rifampicin) and tablet counts. If concerns about compliance, consider directly observed treatment (DOT).

DOT

aims to increase compliance by nurse-supervised and observed daily or weekly tablet swallowing. This has been shown to increase treatment completion, reduce relapses, and reduce development of drug resistance, as the ingestion of each dose is witnessed. This is recommended for patients unlikely to comply, including alcoholics, drug abusers, the homeless, those with serious mental illness (the so-called ‘hard to reach’), and those with MDR-TB. Some areas consider other incentives to improve adherence such as providing food and transport costs.

Compulsory detention under Sections 37 and 38 of the Public Health Act (England) is allowed for infectious pulmonary TB, but compulsory treatment is not allowed. This is only used in extreme circumstances to protect public health.

TB: management 2

Standard treatment regimes for drug-sensitive TB

(see Respiratory infection—mycobacterial p. [link])

  • The standard first-line regime is for 6 months—four drugs in the initial 2-month phase (rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) (or streptomycin)) and two drugs in the last 4 months (rifampicin and isoniazid) in patients with fully sensitive organisms

  • Rifampicin should always be given throughout the 6-month course in first-line therapy

  • If drug sensitivity is unavailable at 2 months, continue the four-drug regime until it is available

  • The fourth drug (usually ethambutol) can be omitted in those at low risk of isoniazid resistance (not previously treated, HIV-negative, UK-born Caucasians, with no drug-resistant contacts). There is a higher risk of isoniazid resistance in ethnic minority groups, immigrants, refugees, those who have had previous treatment, and those who are HIV-positive. This depends on local policy and the ethnic make-up of the local area. If in doubt, treat with four drugs

  • Other treatment regimes are also effective (e.g. daily for 2 months, then two or three times weekly for 4 months with DOT, or three times weekly for the whole 6 months with DOT), though are used less commonly

  • Check baseline renal and liver function in all patients. If normal and not at high risk of adverse drug reaction, they do not need to be re-checked. Treatment in the setting of liver and renal disease is described on Respiratory infection—mycobacterial p. [link] and p. [link]

  • Dosages are weight-dependent and may need to be changed for weight loss or gain during the treatment course

  • A 6-month treatment course is effective for all other forms of non-CNS extrapulmonary TB (including lymph node and spinal disease), with the same drugs as for respiratory disease. Surgery may be needed, in addition, for spinal disease

  • CNS disease needs a 12-month treatment course

  • Steroids may be indicated for large pleural effusions, pericardial effusions (60mg/day for constrictive pericarditis), and CNS disease, especially if associated with neurological impairment (see further text). Steroids may also be indicated in ureteric disease and to suppress hypersensitivity reactions to the antituberculous drugs

  • Peripheral lymph nodes may enlarge and abscesses may form during treatment; this does not imply failure of treatment but should prompt a compliance check

  • Pyridoxine is not required, unless subjects are at higher risk of pyrazinamide-related peripheral neuropathy—in diabetes, renal failure, HIV, and alcoholics.

Table 42.1 Recommended doses of standard anti-TB drugs

Drug

Daily dose

Intermittent dose

Isoniazid (H)

300mg

15mg/kg three times weekly

Rifampicin (R)

<50kg

450mg

600–900mg three times weekly

≥50kg

600mg

Pyrazinamide (Z)

<50kg

1.5g

<50kg—2.0g

≥50kg

2.0g

≥50kg—2.5g three times weekly or 3.5g twice weekly

Ethambutol (E)

15mg/kg

30mg/kg three times weekly or 45mg/kg twice weekly

Meningitis

A 12-month course of rifampicin and isoniazid, with pyrazinamide and a fourth drug (e.g. ethambutol) for at least the first 2 months, is effective. If pyrazinamide not used, extend treatment period to 18 months. Steroids may be needed for severe disease, equivalent to prednisolone 20–40mg od if on rifampicin, otherwise 10–20mg od. Steroids can usually be tapered after the initial 2–3 weeks of treatment. Ethambutol should be used with caution in unconscious patients, as visual acuity cannot be tested and there is a small risk of ocular toxicity.

Cerebral tuberculoma without meningitis

12-month regime.

Disseminated TB/miliary TB

6-month regime unless CNS involvement. Exclude CNS disease in miliary TB with CSF examination, whether or not symptoms are present. Start treatment, even if LFTs are abnormal (this may be due to intrahepatic granulomas). Seek advice if LFTs deteriorate significantly on treatment (see Respiratory infection—mycobacterial p. [link]. See Box 42.2).

Bone and spinal TB

6-month standard regime. A CT or MRI should be performed in patients with active spinal disease who have neurological symptoms and signs. If there is direct spinal cord involvement (e.g. a spinal cord tuberculoma), treatment should be as for meningeal TB. There is no place for routine spinal surgery (e.g. anterior spinal fusion) in the absence of spinal instability.

Pericardial TB

Standard 6-month regime. Steroids, e.g. prednisolone 60mg od if on rifampicin, tapered after 2–3 weeks of treatment, may be required. Repeat echo may be needed.

Peripheral lymph node TB

Standard 6-month regime, which should be used, even if the infected node has been surgically removed. Stop treatment at the end of the 6-month course, regardless of the appearance of new nodes, residual nodes, or draining sinuses.

Patient advice to document on starting TB chemotherapy

  • Possibility of nausea and abdominal pain

  • Persistent vomiting and/or jaundice—stop drugs immediately, and contact doctor

  • Red urine with rifampicin

  • Red contact lenses with rifampicin

  • Contraception advice, if on the OCP as efficacy reduced

  • Visual acuity (Snellen chart) (ethambutol)

  • Visual disturbance (ethambutol)—stop drugs immediately, and contact doctor

  • Potential drug interactions (see Table 42.2).

Table 42.2 Interactions of TB drugs

Drug

Increases level of

Decreases level of

rifampicin

(Level decreased by ketoconazole and PAS)

  • warfarin

  • OCP

  • phenytoin

  • glucocorticoids

  • theophyllines

  • digoxin

  • Methadone

  • sulfonylureas

  • ciclosporin

isoniazid

  • phenytoin

  • carbamazepine

  • warfarin

  • diazepam

azoles, e.g. ketoconazole

pyrazinamide

probenecid

First-line anti-TB drugs

  • Isoniazid (H) Bactericidal. Single daily dose, well tolerated. Major side effect is age-dependent hepatitis. Increased toxicity with alcohol. Peripheral neuropathy is uncommon, although increased risk with diabetes and pregnancy; reduce incidence with 10mg pyridoxine daily

  • Rifampicin (R) Bactericidal. Single daily dose, well tolerated. Increases hepatic microsomal enzymes; therefore, increases clearance of hepatic metabolized drugs, including prednisolone and the OCP, thus the risks of pregnancy must be highlighted. Red discoloration of urine and contact lenses occurs, and GI upset

  • Pyrazinamide (Z) Bactericidal. Single daily dose. GI upset common. Major side effect is hepatic toxicity. Renal excretion leads to hyperuricaemia

  • Ethambutol (E) has some bactericidal effect, mostly bacteriostatic at usual doses. Single daily dose, well tolerated. Side effect—optic neuritis, uncommon. Document visual acuity (Snellen chart) before starting, and warn patient to stop drugs immediately and contact doctor if any visual disturbance

  • Streptomycin Bactericidal. Given parenterally. Increased risk of ototoxicity in the foetus and the elderly.

Combined preparations

  • Rifinah® 150 (contains rifampicin 150mg and isoniazid 100mg), Rifinah® 300 (contains rifampicin 300mg and isoniazid 150mg)

  • Rifater® (contains 120mg rifampicin, 50mg isoniazid, and 300mg pyrazinamide).

Table 42.1 shows the recommended doses of the main four drugs.

For example, a 75kg adult commencing quadruple therapy would be given:

  • Isoniazid 300mg od

  • Rifampicin 600mg od

  • Pyrazinamide 2.0g od

  • Ethambutol 1.2g od ± pyridoxine 10mg od.

If using a combined preparation, e.g. Rifater®, with ethambutol:

  • 45kg adult: Rifater® four tablets and ethambutol 700mg od

  • 60kg adult: Rifater® five tablets and ethambutol 900mg od

  • 80kg adult: Rifater® six tablets and ethambutol 1.2 g od.

Drug regimes are often abbreviated to the number of months each phase of treatment lasts, followed by the letters for the drugs being administered during that treatment phase, e.g. 2HRZE/4HR is the standard 6-month recommended regime; 2HRE/7HR is 2 months of isoniazid, rifampicin, and ethambutol, followed by 7 months of isoniazid and rifampicin.

Potential TB drug interactions are listed in Table 42.2.

TB: adverse drug reactions

These occur in around 10% of patients, often requiring a change of therapy. Reactions are more common in those on non-standard therapy and in HIV-positive individuals.

Isoniazid peripheral neuropathy

can be prevented by pyridoxine 10mg daily (recommended in those at highest risk—diabetes, renal failure, alcoholics, HIV-positive).

Rifampicin

may cause shock, acute renal failure, thrombocytopenia. Withdraw, and do not reintroduce the drug. Double maintenance steroid doses at the start of treatment (because of enzyme induction).

Ethambutol

causes rare optic toxicity; recommend baseline visual acuity assessment with a Snellen chart. Use only in those with adequate visual acuity and those able to report changes in visual acuity or new visual symptoms. Document that the patient has been told to cease the drug immediately at the onset of new visual symptoms. Check baseline renal function before starting ethambutol, and avoid in renal failure.

HIV-positive patients

Rifampicin and isoniazid lead to reduced serum concentrations of antifungals. Ketoconazole can inhibit rifampicin absorption. Rifampicin may reduce drug levels of protease inhibitors (as they are metabolized via the cytochrome P450 pathway, which is induced by rifampicin). Rifabutin can cause a severe iritis. Liaise closely with HIV specialist.

Drug resistance

occurs in <2% of Caucasian cases in the UK, with higher levels in ethnic minority groups.

  • Isoniazid resistance is seen in up to 6% in patients of African and Indian subcontinent origin

  • Increased drug resistance is seen in HIV-positive patients (fourfold increased risk)

  • Second-line drugs are generally more toxic and less effective than first-line drugs, and the treatment of drug resistance can therefore often be complex and difficult—seek specialist advice

  • The regime must include at least three drugs to which the organism is known to be susceptible. An injectable drug is often added, as this has shown improved outcomes

  • The initial regime will depend on the incidence of drug resistance in the community and should be altered, depending on local drug susceptibility patterns

  • In general, always add at least two drugs to which the MTB is susceptible

  • Parenteral treatment is usually recommended when there is resistance to two or more drugs.

See Table 42.3.

Table 42.3 Recommended drug regimes for non-MDR drug-resistant TB

Drug resistance

Initial phase

Continuation phase

S

2RHZE

4RH

H known before treatment

2RZSE

7RE

H known after treatment

2RZE

10RE

Z

2RHE

7HR

E

2RHZ

4RH

R (only if confirmed as isolated resistance)

2HZE

16HE

S and H

2RZE

10RE

Isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E)

Rifampicin monoresistance

is uncommon but does require regime modification. In most cases, rifampicin resistance is a marker of MDR-TB (see Respiratory infection—mycobacterial pp. [link][link]) and should be treated as such, until full sensitivities are known.

TB: inpatient admission

  • This is rarely needed, but, if necessary, patients with suspected pulmonary TB should initially be admitted to a side room vented to the outside air (until proven non-infectious)

  • Patients with smear-positive non-MDR-TB should be managed as infectious (in a side room, with face mask). This especially applies if they are on a ward with immunosuppressed patients (who may be at higher risk)

  • A risk assessment (including an assessment of the immune status of other ward patients) can be made once the infectiousness and likelihood of drug resistance of the patient are known

  • Patients with non-pulmonary TB can be nursed on a general ward (but aerosol-generating procedures, e.g. abscess irrigation, may need patient isolation)

  • Staff should wear face masks if the patient is potentially infectious

  • Inpatients with smear-positive pulmonary TB should be asked to wear a face mask whenever they leave their room, unless they have received 2 weeks’ drug treatment

  • Barrier nursing is unnecessary for smear-negative non-MDR-TB

  • Liaise closely with infection control/microbiology/public health specialists

  • If a patient on an open ward is found to have infectious TB, the risk to the other patients is small. Patients whose exposure is considered comparable to that of a household contact should be screened. Only those in the same bay as a coughing infectious case, for at least 8h, are considered at risk. Exposure should be documented and the patient and the GP contacted

  • Non-MDR-TB HIV-negative patients usually become non-infectious after 2 weeks’ chemotherapy. Any bacilli seen in smears after that time are likely to be dead

  • Patients with HIV and those with TB should not be nursed in close proximity

  • All patients with known or suspected MDR-TB should be admitted to negative pressure ventilated side room. Staff should wear protective face masks (FFP3)

  • At discharge, a clear plan must be in place for the administration and supervision of all chemotherapy; this is particularly important for patients with MDR-TB where close liaison with the infection control team and consultant in communicable disease control is paramount.

Treatment failure/disease relapse

  • This is usually due to poor compliance

  • Drug resistance may have developed

  • Never add a single drug to a failing regime. Add only two or three, ideally those to which the patient has not been previously exposed

  • Assume drug resistance to all, or some, of the drugs in the failed regime

  • Repeat cultures and sensitivity testing in this situation. Consider specific molecular tests for rifampicin/isoniazid resistance. If found, then treat as for MDR-TB (see Respiratory infection—mycobacterial pp. [link][link])

  • UK TB death rates have decreased since 2001, but death is still the most common cause for not completing treatment course. Higher proportions of deaths were found in older patients of white ethnicity who were born in the UK. A higher proportion of deaths were in patients with pulmonary TB than with extrapulmonary. One-quarter of patients who died were diagnosed with TB post-mortem where it was thought to cause or contribute to death in 33%.

TB: treatment follow-up

  • CXR is advised at the end of therapy for pulmonary disease

  • Relapse is uncommon in those compliant with standard treatment regimes in the UK (0–3%); therefore, long-term follow-up is not recommended

  • Follow-up at 12 months after treatment completion is recommended for patients treated for drug-resistant TB

  • Relapse after good compliance is usually due to fully sensitive organism; therefore, treatment can be with the same regime again

  • Relapse due to poor compliance needs a fully supervised regime.

MDR-TB follow-up

Prolonged follow-up is recommended; lifelong for HIV-positive patients.

TB in pregnancy

There is no increased risk of developing clinical disease in pregnancy. Presentation is the same as in non-pregnant individuals, but the diagnosis may be delayed by the non-specific nature of the symptoms in the early stages of disease, with malaise and fatigue being common in the early stages of pregnancy. A CXR is more likely to be delayed.

The tuberculin skin test result is not affected by pregnancy; this applies to HIV-positive and negative subjects. A negative skin test should not lead to BCG vaccination, as live vaccines are contraindicated in pregnancy. In this situation, the skin test should be repeated after delivery and BCG given then after a second negative test.

TB outcome in pregnancy

  • If diagnosed in the first trimester, the disease has the same outcome as for non-pregnant women

  • If diagnosed in the second or third trimester, studies give more variable outcomes (some studies show a good foetal outcome; some show higher rates of small-for-date babies, pre-eclampsia, and spontaneous abortion), but these effects tend to be related to late diagnosis and incomplete drug treatment. Some studies also show a poorer foetal outcome in extrapulmonary disease

  • Late diagnosis of pulmonary TB can lead to a 4-fold increased obstetric mortality and 9-fold increased pre-term labour in some developing countries.

Treatment in pregnancy

  • Isoniazid, rifampicin, and ethambutol are not teratogenic and can be used safely in pregnancy. The ‘standard’ short-course therapy is recommended (i.e. 6-month treatment)

  • Limited pyrazinamide data on the risk of teratogenicity

  • Streptomycin may be ototoxic to the foetus

  • Active TB must be treated in pregnancy because of the risk of untreated disease to the mother and foetus

  • Reserve drugs may be toxic, and the risk/benefit ratio of each case must be assessed individually if second-line drugs are needed

  • Babies of sputum-positive mothers, who have had <2 weeks’ treatment by delivery, should be treated with isoniazid and have a skin test at 6 weeks. If the skin test is negative, the chemoprophylaxis should be stopped and BCG given 1 week later (as BCG is sensitive to isoniazid)

  • Congenital infection is very rare (<300 reported cases). The child can be infected at delivery (this is rare).

Breastfeeding

  • Most anti-TB drugs are safe. Isoniazid—monitor infant for possible toxicity, as there is a theoretical risk of convulsions and neuropathy. Give prophylactic pyridoxine to the mother and infant

  • Concentrations of drugs reaching breast milk are too low to prevent or treat infection in the infant.

TB chemotherapy with comorbid disease

Liver disease

  • Drug-induced hepatitis can be fatal. A raised ALT (see Box 42.2) is more common in those who regularly consume alcohol, have viral hepatitis or other chronic liver disease, take concomitant hepatotoxic drugs, are pregnant, or are within 3 months post-partum

  • About 20% of those treated with isoniazid alone will have an asymptomatic transient rise in ALT. In the majority, this represents hepatic adaptation. Acetylator status (fast or slow) may influence this

  • Isoniazid-induced hepatitis can be symptomatic or asymptomatic and usually occurs within weeks or months of treatment and is age-related

  • Isoniazid inhibits several cytochrome P450 enzymes, potentially increasing the plasma concentrations of other hepatotoxic drugs

  • Rifampicin can cause subclinical hyperbilirubinaemia without hepatocellular damage. It can also cause direct hepatocellular damage and potentiate the hepatotoxicity of other TB drugs

  • Decompensated liver disease—use a drug regime without rifampicin

  • Avoid pyrazinamide in patients with known chronic liver disease

  • Baseline and regular monitoring of liver function is necessary (weekly LFTs for the first 2 weeks, then at 2-weekly intervals) in patients with chronic liver disease.

Renal failure

  • Isoniazid and rifampicin have biliary excretion so can be given in normal doses in renal disease

  • Pyrazinamide metabolites are renally cleared; the dose may need to be less frequent in those with renal insufficiency

  • Give pyridoxine, in addition to isoniazid, in those with severe renal disease to prevent isoniazid-induced peripheral neuropathy

  • Ethambutol can accumulate, causing optic neuropathy; use only with caution and at a lower dose

  • Dialysis patients should receive drugs after dialysis

  • Post-renal transplant immunosuppressive drug doses also need alteration.

HIV infection

  • Regimes are the same for HIV-positive as HIV-negative patients: standard four-drug regime. Liaise closely with HIV specialists

  • Identification of HIV allows additional package of care to be added, including co-trimoxazole prophylaxis and early antiretroviral therapy (ART), which improves mortality—hence the importance of HIV testing in all patients with TB

  • In newly diagnosed HIV-positive individuals, the usual practice is to start TB chemotherapy before HIV chemotherapy. ART should be started within the first 8 weeks of TB treatment, and patients with CD4 counts <50 × 106/L should start ART within the first 2 weeks; an exception is treatment of tuberculous meningitis when early ART should be avoided

  • Protease inhibitors should not be used with rifampicin (they interfere with each other’s metabolism)

  • Paradoxical worsening of disease (worsening fever, CXR infiltrates, increased lymphadenopathy, or new manifestations of the disease) at the initiation of HIV treatment is common (in ~15%)—so-called TB IRIS. This reflects the restoration of pathogen-specific immune responses. Steroids reduce the morbidity associated with IRIS

  • Death during TB chemotherapy is more common in HIV-infected patients, who also have higher relapse rates than non-HIV-infected subjects

  • Atypical presentations of TB are common in patients with CD4 counts <200 × 106/L and disseminated TB with multi-organ involvement and mycobacteraemia, but sparing the lung may occur with CD4 counts <75 × 106/L. Active TB may be asymptomatic in the setting of HIV

  • Patients co-infected with TB and HIV should be considered potentially infectious to others at each admission, until proved otherwise, and should be segregated. Review the immune status of other patients and their likely drug resistances and their potential infectivity.

Diabetes

  • Increased risk of TB and the disease may be more extensive. Note that rifampicin reduces the efficacy of sulfonylureas.

Multidrug-resistant TB (MDR-TB)

Defined as MTB resistant to two or more first-line agents, usually isoniazid and rifampicin.

  • Treatment is complex and time-consuming

  • MDR-TB is not more infectious than other forms of TB, but the consequences of acquiring it are more serious

  • 3.6% of new TB cases in the world have MDR-TB. The frequency varies between countries. Of 450, 000 new MDR-TB cases in 2012, half were in China, India and the Russian Federation

  • Specialist advice essential; patients should be managed by experts with experience of managing resistant cases, in a hospital with isolation facilities. The MDRTBservice@lhch.nhs.uk email address, based in Liverpool, can be used to seek advice from a panel of experts in the management of MDR disease. An MDR-TB UK database is run from the Cardiothoracic Centre in Liverpool

  • Rapid molecular tests for rifampicin resistance should be carried out in all patients suspected of having MDR-TB. Liaise closely with the reference laboratory

  • Close monitoring (because of increased drug toxicity) is needed

  • Compliance is paramount, and all patients should receive DOT (see Respiratory infection—mycobacterial p. [link])

  • Start treatment with at least four drugs with certain or almost certain effectiveness. Often >4 drugs are started if the susceptibility pattern is unknown (see Table 42.4). Smears and cultures should be performed monthly, even after they become negative. Treatment should be given for a minimum of 18 months after culture conversion, but 24 months may be indicated in chronic disease with extensive pulmonary damage

  • If the drug choice is limited by drug resistance and intolerance, consider desensitization and reintroduction of the offending drug. Desensitization must be carried out with concurrent treatment with two other drugs (to minimize emergence of resistant strains)

  • Surgery may be indicated

  • Successful outcomes reported in 48% of patients worldwide.

Table 42.4 second-line TB chemotherapy

Drug

Dose

Potential side effects

Amikacin

15mg/kg

Tinnitus, ataxia, renal impairment, vertigo

Azithromycin

500mg od

GI upset

Capreomycin

15mg/kg

As for amikacin

Ciprofloxacin

750mg bd

Abdominal upset, headache, drug interactions

Clarithromycin

500mg bd

GI upset

Ethionamide (or protionamide)

<50kg: 375mg bd ≥50kg: 500mg bd

GI upset, hepatitis. Avoid in pregnancy

Kanamycin

15mg/kg

As for amikacin

Ofloxacin

400mg bd

Abdominal upset, headache

PAS

10g od or 5g bd

GI upset, fever, rash, hepatitis

Rifabutin

300–450mg od

As for rifampicin. Uveitis (particulary with HIV infection) with drug interactions, e.g. with macrolides

Streptomycin

15mg/kg (max dose 1g od)

As for amikacin

Thiocetazone

150mg

GI upset, rash, conjunctivitis, vertigo. Avoid if HIV-positive (risk of Stevens– Johnson syndrome)

Contacts of MDR-TB

Chemoprophylaxis for contacts should include at least two drugs. Base the drug choice on the sensitivities of the index case for a minimum of 6 months (although there are no data to support this treatment period). If there is extensive resistance, no regime may be suitable, and regular follow-up needed instead.

Risk factors for resistant disease

  • Previous anti-TB treatment, prior treatment failure

  • Lack of response to intensive phase of standard short-course therapy/treatment failure

  • HIV infection

  • Contact with patients with drug-resistant disease

  • History of poor adherence, aggravated by social deprivation or substance abuse

  • Residence in regions with high prevalence of drug-resistant disease.

Extensively drug-resistant TB’ (XDR-TB)

is MDR-TB with added resistance to all fluoroquinolones and one of three injectable anti-TB drugs (capreomycin, kanamycin, and amikacin) represents 10% of MDR-TB cases. In September 2013, 92 countries had reported at least one case to WHO. Genotyping data suggest the emergence of XDR-TB is due to the transmission of XDR strains between individuals and is not a consequence of previous unsuccessful treatment. 85% of South African XDR isolates are from the KZN family of TB strains, which were mostly fully susceptible when first described in 1996. Outcomes are variable, but association with advanced HIV infection in a localized outbreak in South Africa was universally fatal. Some TB strains have also been reported which are resistant to all anti-TB drugs.

Latent TB infection

Defined

as a positive skin test or IGRA, showing MTB infection but with a normal CXR and no symptoms. This represents the presence of a small total number of mycobacteria, with the host immune system retaining control over mycobacterial replication. It should be distinguished from active disease, which is usually accompanied by symptoms and an abnormal CXR and for which the mainstay of diagnosis is sputum microscopy and culture; IGRA and skin tests have no role in the diagnosis of active disease.

An estimated 2 billion people worldwide have latent TB. Treatment of latent TB with chemoprophylaxis (see further text) reduces the risk of subsequent development of active disease by about 90%, but a proportion of people will be treated who would never have developed active disease.

Tuberculin skin test

A positive skin test (Mantoux) results from the development of cell-mediated immunity against TB. Potential problems with skin testing are:

  • Low sensitivity in the immunocompromised and cross-reactivity with BCG

  • The patient has to return to have the test read after 48–72h

  • Criteria for a positive test depend on the population in which it is being used.

IGRA

Two blood tests (T-SPOT.TB, Oxford Immunotec Ltd., and QuantiFERON-TB Gold, QIAGEN) are available and are based on the detection of IFN-γ‎ released by T-cells in response to MTB-specific antigens. The T-SPOT.TB test is an ELISpot test, counting individual T-cells producing IFN-γ‎; the QuantiFERON test is based on a whole blood ELISA and measures the IFN-γ‎ level in the supernatant of the stimulated whole blood sample. Both assays use two proteins (ESAT-6 and CFP10) encoded by a unique genomic sequence of MTB, which is absent from M. bovis BCG and the majority of opportunistic mycobacteria. These proteins are the main targets for IFN-γ‎-secreting T-lymphocytes in individuals infected with MTB. These tests have several advantages over the tuberculin skin test: no return visit for test reading is required, the result is available the next day, and repeated testing does not cause boosting. With both tests, blood must be collected in a heparinized tube and processed within 6–8h of venepuncture. The blood should be transferred to the laboratory at room temperature. Both tests are more sensitive for the diagnosis of latent TB than the tuberculin skin test, particularly in children and HIV-positive individuals, and, on current available evidence, there is little difference between the two, although the T-SPOT.TB test may be more sensitive in HIV-positive individuals.

HIV infection

The tuberculin skin test may be falsely negative, and radiological changes may be atypical. Current WHO guidelines recommend isoniazid chemoprophylaxis for HIV-infected patients in low-income, high-burden countries, with positive or unknown skin tests in the absence of active disease. Uptake of this recommendation is slow, partly because of the difficulties in distinguishing active from latent disease in the setting of HIV co-infection and concern regarding emergence of resistant strains. Exposure to smear-positive disease should lead to chemoprophylaxis in the absence of active disease. Recommended follow-up is at 3 and 12 months for those not receiving chemoprophylaxis (but who were eligible for it). HIV-positive patients should receive long-term follow-up as part of their ongoing HIV management.

Chemoprophylaxis

is given to contacts or screened immigrants with a strongly positive skin test or positive IGRA, who have no radiological or clinical evidence of active disease. The risk of developing disease after exposure depends on a number of factors, including BCG and HIV/immune status, and whether infection was recent. Younger patients must have had relatively recent infection and have a longer life expectancy from which to gain the benefits of chemoprophylaxis.

Chemoprophylaxis is recommended for:

  • Those aged <35 (because of the increased risk of drug hepatotoxicity with age)

  • Those with recent documented tuberculin conversion

  • HIV-infected contacts of smear-positive cases (any age)

  • Any age health care worker

  • Children aged <16 with a strongly positive Mantoux (>15mm if prior BCG)

  • Individuals with HIV, injecting drugs, with haematological malignancy, chronic renal failure or on dialysis, with silicosis, gastrectomy, solid organ transplant, or receiving anti-TNF-α‎ therapy have a higher risk of developing active TB.

Drug regimes

  • Rifampicin and isoniazid daily for 3 months (3RH). Improved compliance but slightly higher side effect profile

  • Isoniazid daily for 6 months (6H). Lowest toxicity regime. Has a 60–90% effectiveness in reducing progression of latent infection to clinical disease

  • 6H is recommended for people with HIV

  • 6R is recommended for contacts of patients with isoniazid-resistant disease

  • Individuals who decline chemoprophylaxis should be given ‘inform and advise’ information, regarding TB risks and symptoms and have a CXR at 3 and 12 months.

TB and anti-TNF-α‎ treatment

Humanized monoclonal anti-TNF-α‎ antibody is approved for the treatment of rheumatoid arthritis, Crohn’s disease, psoriatic arthropathy, and juvenile idiopathic arthritis. Etanercept is a fusion protein that binds free TNF-α‎, using a soluble portion of the TNF-α‎ receptor, and is licensed for use in RA. Adalimumab is a recombinant humanized monoclonal antibody against TNF-α‎, also licensed for use in RA. Infliximab is a human chimera monoclonal antibody, licensed for the treatment of RA, Crohn’s disease, and ankylosing spondylitis.

These drugs cause profound immunosuppression, and patients treated with them have an increased risk of developing TB. Most TB cases have been seen with infliximab (242 at time of publication), with most occurring within three treatment cycles (within a mean of 12 weeks of starting treatment). TB is the most frequently described opportunistic infection in this context. 50% of the reported cases are extrapulmonary disease. The initial high incidence of cases has now plateaued, presumably due to improved assessment and awareness and the use of isoniazid chemoprophylaxis. The calculated TB prevalence in etanercept/infliximab-treated RA patients in America is 41 per 100, 000, 9 per 100, 000 for Crohn’s disease. Overall, there is an average 5-fold increased risk of developing TB with anti-TNF-α‎ therapy. All patients due to start anti-TNF-α‎ antibody treatment should be screened for active and latent TB.

  • All patients should have a clinical examination, with history of previous TB treatment and exposure carefully documented. All should have a CXR and tuberculin test or IGRA. The IGRA is less sensitive in those taking concomitant prednisolone and/or disease-modifying drugs, e.g. azathioprine

  • Both those with an abnormal CXR consistent with previous TB, or those who have a history of extrapulmonary TB, who have received adequate treatment (as assessed by an expert), can start anti-TNF-α‎ therapy but need monitoring every 3 months with a CXR and symptom assessment. The onset of any new respiratory symptoms, especially within 3 months of starting anti-TNF-α‎ therapy, should be investigated promptly

  • Both those with an abnormal CXR consistent with previous TB, or those who have a prior history of extrapulmonary TB, who have NOT had adequate treatment, need to have active TB excluded by appropriate investigations. They should receive chemoprophylaxis before anti-TNF-α‎ therapy commences (assuming active disease is not identified). If there is clinical concern because of the delay in starting anti-TNF-α‎ treatment, a shorter course of chemoprophylaxis can be given, but this may be more toxic

  • Any TB diagnosed (pulmonary or extrapulmonary) should be treated with standard chemotherapy

  • If active TB is present, patients should receive a minimum of 2 months’ anti-TB chemotherapy before starting anti-TNF-α‎ therapy

  • If the CXR is normal, the tuberculin test or IGRA may be helpful if the patient is not on immunosuppressants. The skin test must be interpreted knowing the BCG history. A tuberculin skin test is unhelpful if the patient is on immunosuppressants. In this situation, an individual assessment should be made (see Table 42.5); if the risk of drug-induced hepatitis is less than the annual risk of developing TB, chemoprophylaxis should be given. However, if the risk of hepatitis is greater, the patient should be monitored regularly and any suggestive symptoms investigated promptly

  • No chemoprophylaxis regime is 100% effective; the protective efficacy of 6H is reported at 60 and 50% for 3HR

  • In those without previous BCG, Mantoux 1 in 10, 000, 0–5mm is negative, and Mantoux 1 in 10, 000, >6mm is positive and should lead to a risk assessment

  • In those with prior BCG, Mantoux 1 in 10, 000, 0–14mm is negative, and Mantoux 1 in 10, 000, >15mm may represent either latent infection or BCG effect and therefore needs further investigation

  • In general, all black African patients aged >15 and all South Asians born outside the UK should be considered for chemoprophylaxis with 6 months’ isoniazid

  • If a patient develops TB whilst on anti-TNF-α‎ therapy, treat with the full standard course of anti-TB chemotherapy. The anti-TNF-α‎ can be continued, if indicated

  • Close liaison between the prescriber of the TNF-α‎ antibody treatment and TB specialists is needed.

Table 42.5 Sample calculations for aiding TB risk assessment for patients starting anti-TNF-α‎ treatment

Case type

Annual risk of TB disease/ 100, 000

TB risk adjusted × 5 for anti-TNF-α‎ effect

Risk of hepatitis following 6H chemoprophylaxis/100, 000

Risk/benefit conclusion

White, UK born, age 55–74

7

35

278

Observation

ISC, in UK >3y, age >35

593

2965

278

Prophylaxis

Black African age 35–54

168

840

278

Prophylaxis

Other ethnic group, in UK >5y, age >35

39

195

278

Observation

ISC = Indian subcontinent. The risk of hepatitis with 3RH chemoprophylaxis is 1, 766/100, 000.

Further information

BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-α‎ treatment. Thorax 2005;60:800–5.Find this resource:

TB: screening and contact tracing

Immigrant screening

Immigrants are screened, as ethnic minority groups in the UK constitute 50% of TB cases. New entrants are screened at port of arrival. The incidence of TB is highest in the first few years after arrival to the UK. Return visits to countries with a high background prevalence are a risk factor for acquiring disease. Immigrants with symptoms suggestive of TB and those who are asymptomatic with a grade 3 or 4 tuberculin skin test should be referred to the local chest clinic for CXR and assessment. BCG vaccination is recommended for tuberculin-negative immigrants (but not in those who are HIV-positive because of the risk of generalized BCG infection).

Contact tracing

identifies those with TB and those who are infected but without evidence of disease. It also identifies those suitable for BCG vaccination.

Close contacts

are usually those within the same household, sharing kitchen facilities, and frequent household visitors.

Casual contacts

usually include most occupational contacts. Examination is usually only needed if the index case was smear-positive or if the contacts are at high risk. This also applies if >10% of the close contacts have been infected, i.e. the index case is considered highly infectious.

  • 10% of TB is diagnosed by contact tracing, with disease occurring in about 1% of contacts

  • Smear-negative patients are much less infectious, but contact tracing is still recommended in these patients

  • Contacts should be traced for the period the index case has been infectious or for 3 months prior to the first positive sputum or culture, if the time period is uncertain

  • Most disease in contacts is found at the first screening visit

  • Subjects should be advised to report suspicious symptoms

  • Follow-up is recommended at 3 and 12 months for those not receiving chemoprophylaxis

  • School index cases—if a pupil is diagnosed with smear-positive TB, the rest of the class and year group who share classes should be assessed as part of routine contact tracing. If a school teacher is diagnosed with smear-positive TB, the pupils in their class during the previous 3 months should be assessed as part of routine contact tracing. The extension of contact tracing to include non-teaching staff will depend on the infectivity and proximity of the index case and whether the contacts are likely to be especially susceptible to infection.

Airplane transmission

rates are low, even on long-haul flights. Contact tracing of passengers and crew is only necessary if the index case was smear-positive and coughing during a flight of at least 8h. In this situation, screening is only recommended in those at high risk—immunocompromised travellers and children or if the index case was unusually infectious or had MDR-TB.

Extrapulmonary disease

Contact screening is not recommended.

Contact examination

This usually involves symptom enquiry, BCG vaccination status, Mantoux test and/or IGRA, and CXR.

HIV-infected contacts

CXR is indicated, as a negative Mantoux test may be due to anergy and may therefore be a false negative. Mantoux testing is not contraindicated in HIV (PPD is dead). BCG is contraindicated (it is a live vaccine). IGRA usually useful.

BCG vaccination

remains the only licensed vaccine for TB. The UK national schools’ vaccination programme ceased in 2005 and now aims to target vaccination to selected ‘at-risk’ groups. Vaccination is offered to:

  • All infants whose parents or grandparents originate from a country with a TB incidence of 40/100, 000 or higher or those living in areas with a TB incidence of 40/100, 000 or higher

  • All Mantoux-negative contacts of patients with respiratory TB if they are previously unvaccinated and aged <35y. Laboratory and health care workers who are contacts meeting the same criteria should be vaccinated if they are aged >36

  • Previously unvaccinated entrants from high incidence areas aged <16. If originating from sub-Saharan Africa or a country with a TB incidence of 500 per 100, 000, those aged 16–35 should also be offered vaccination

  • All Mantoux-negative health care workers, irrespective of age, who are previously unvaccinated and who will be exposed to patients and clinical materials

  • Mantoux-negative, previously unvaccinated individuals aged <35, if potentially at risk of TB exposure because of their occupation, including veterinary and abattoir workers, prison staff, staff in care homes for the elderly, staff of accommodation for refugees and the homeless, and those going to work in a high-incidence country for >1 month

  • BCG has an efficacy of around 70% against TB in children, but difficulties with vaccine supply and regional policies have meant that not all children in the UK have been vaccinated in the past. It is less effective in adults and is not used in America

  • Adverse events include pain and suppuration at the injection site and localized lymphadenitis. A course of rifampicin and/or isoniazid for 3–6 months, depending on response, may be needed.

M. bovis

Cattle TB is due to M. bovis. Humans are at low risk, as the majority of milk consumed is pasteurized. M. bovis is distinguishable from MTB in the laboratory, although initial diagnosis can be difficult (only distinguishable on culture). Around 40 cases are isolated per year. BCG is live attenuated M. bovis.

Disseminated BCG infection (BCGosis)

Live attenuated BCG immunotherapy is the most effective intravesical agent for the treatment and prophylaxis of superficial bladder cancer. BCG leads to a T-cell-mediated immune response, which has anti-tumour activity. After intravesical instillation, live mycobacteria attach to the urothelial lining. BCG organisms are internalized by bladder epithelial cells, leaving bacterial cell surface glycoproteins attached to the epithelial cell membrane. These antigens are thought to mediate the immune response.

  • The standard treatment regime is 6-weekly instillations of 100 million to 1 billion cfu of BCG. Some advocate a further 3-week course, 6 weeks after cessation of the first cycle. The dose-response curve is bell-shaped, with excess BCG probably promoting increased tumour activity

  • Local side effects are common, with cystitis reported in around 90% of patients; low-grade fever and malaise are frequent. Cystitis persisting >48h after treatment should be treated with a fluoroquinolone or isoniazid 300mg od; rifampicin 600mg od should be added if the symptoms persist at 1 week

  • Breaks in the uroepithelium are a risk factor for systemic infection, and, therefore, patients with persistent cystitis or haematuria should have their treatment delayed

  • Significant reactions are reported in around 5%, with high fever commonest. A high fever post-treatment (>39°C) may represent the onset of systemic BCG infection or hypersensitivity, and hospital admission is recommended

  • BCG sepsis is reported in around 0.4–0.7%, with ten deaths attributed to intravesical BCG to date. The major differential diagnosis is Gram-negative sepsis; thus, patients should be treated with broad-spectrum antibiotics

  • Later-onset symptoms (at up to 8–12 weeks, though may occur much earlier), including fever, malaise, arthralgia, and breathlessness, may represent systemic BCG infection, though there is debate as to whether these sorts of systemic symptoms are due to systemic BCG infection or hypersensitivity to BCG. Non-caseating granulomas can be identified on lung and liver biopsy. Culture of organisms is rarely reported, but tissue M. bovis can be identified by PCR

  • Disseminated infection—treat with rifampicin 600mg od and isoniazid 300mg od for 6 months. Some advocate the addition of ethambutol. Prednisolone 40mg od may be added, and response to corticosteroids is said to support the diagnosis of hypersensitivity. There are no trial data to support these treatment regimes or length of treatment, but M. bovis is susceptible to most anti-TB drugs, except pyrazinamide and cycloserine. There is no evidence that isoniazid reduces the anti-tumour effects of BCG

  • BCG HP is suggested by pulmonary infiltrates; micronodular and miliary appearances are reported with or without eosinophilia

  • Granulomatous hepatitis is reported. Standard TB treatment (6 months) is suggested, with prednisolone if symptoms of hypersensitivity predominate

  • Systemic BCG infection is reported in HIV-positive infants and infants with severe immune deficiency, undiagnosed at the time of BCG vaccination. Systemic BCG infection is reported after BCG injection into melanoma.

Future developments in TB

  • Molecular techniques are increasingly employed in TB diagnostics and for the detection of drug resistance, and recently the use of whole genome sequencing for rapid MTB antibiotic susceptibility testing was reported. Whole genome sequencing of mycobacteria also allows delineation of TB outbreaks

  • Current clinical trials are investigating the use of fluoroquinolones and higher doses of rifamycins as part of shorter treatment regimens. A number of antibiotics are under investigation for the treatment of drug-resistant disease, including bedaquiline, the nitroimidazoles delamanid and PA-824, and linezolid

  • 12 vaccines are currently in clinical trials. Most recently, a large placebo-controlled trial showed a lack of efficacy of the vaccine MVA85A against TB in infants

  • The role of vitamin D supplementation in the treatment and prevention of TB needs further assessment

  • Additional treatments aimed at immunomodulation may facilitate bacillary clearance and increase cure rates, particularly in MDR disease. Small studies suggest that IL2 and nebulized interferon gamma-1b may have some benefit in this setting and in patients with HIV co-infection. A larger study in HIV-negative patients with pulmonary TB has not shown improved bacillary clearance. In MDR-TB, however, there may be greater benefits of treatment

  • A change is planned to roll out the UK CXR-based pre-entry screening programme to 82 countries, as entry screening at UK airports has not been found to be cost-effective. For those people who apply for a ≥6 month UK visa from countries with TB incidence of 40/100, 000 or above, they will only be eligible for a visa if they have proven clearance of active TB disease.

Further information

NICE Guideline CG117: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control 2011. Respiratory infection—mycobacterial http://www.nice.org.uk/CG117.

Zumla A et al. Tuberculosis. N Engl J Med 2013;368:745–55.Find this resource:

Chemotherapy and management of tuberculosis in the UK: recommendations 1998. Thorax 1998;53:536–48.Find this resource:

Control and prevention of tuberculosis in the UK: Code of practice 2000. Thorax 2000;55:887–901.Find this resource:

UK’s national tuberculosis charity. Respiratory infection—mycobacterial http://www.tbalert.org and Respiratory infection—mycobacterial http://www.thetruthabouttb.org.

TB National Knowledge Service. Respiratory infection—mycobacterial http://www.hpa.org.uk/tbknowledge.

Non-tuberculous mycobacteria (NTM)

NTM (also called atypical mycobacteria, opportunistic mycobacteria, environmental mycobacteria) are found in the environment, including in soil and water, and may cause disease in susceptible individuals. They are divided into rapid and slowly growing species (for clinically relevant examples, see Respiratory infection—mycobacterial pp. [link][link]). NTM are less virulent than MTB and—unlike MTB—are unable to adhere to intact, undamaged airway mucosa.

Risk factors for NTM disease

  • Chronic lung disease such as CF, bronchiectasis, COPD, cavitary lung disease 2° to prior TB

  • Immunodeficiency, e.g. HIV, organ transplantation, anti-TNF-α‎ therapy, rare genetic mutations in IL12/IL23/IFN-γ‎ signalling, autoantibodies against IFN-γ‎

  • GORD, pectus excavatum, and kyphoscoliosis may be risk factors

  • NTM disease is well described in otherwise healthy, thin, tall, middle-aged women; the pathogenesis is obscure, although one hypothesis is habitual voluntary cough suppression, leading to failure to clear airway secretions (so-called ‘Lady Windermere syndrome’)

  • Monotherapy with macrolides (e.g. in the setting of CF) may increase the risk of NTM infection through inhibition of autophagy, a key process in anti-mycobacterial host defence; stop macrolide if NTM is suspected.

Clinical features

  • Symptoms are non-specific: typically chronic productive cough, fatigue, sometimes with weight loss, dyspnoea, fever

  • Often complicates known underlying lung disease, such as COPD, leading to atypical disease progression

  • Colonization of abnormal lung may not cause symptoms but can progress to cause disease later

  • Disseminated infection may occur, especially in immunocompromised

  • HP 2° to NTM may occur following use of hot tubs, indoor swimming pools, or contaminated metalworking fluids; breathlessness tends to be a prominent symptom.

Investigations

  • CXR can be indistinguishable from that of MTB, with upper zone infiltrate with cavitation. Airway nodularity and associated bronchiectasis are recognized. CXR may be difficult to interpret in the presence of pre-existing lung disease

  • Sputum samples Microbiology for AFB stain, culture, and further identification. If there is growth of an atypical AFB, send at least two further sputum samples at intervals of 7 days for AFB smear and culture

  • Bronchoscopy with lavage may be required

  • HRCT chest typically shows thin-walled upper lobe cavities, with marked pleural involvement, or small nodules with tree-in-bud pattern and cylindrical bronchiectasis; bilateral diffuse ground-glass infiltrates, nodules, or mosaic pattern may be seen with NTM-associated HP.

Diagnosis

Distinguishing contamination or colonization with NTM from clinical disease may be challenging. A single positive NTM sputum culture is unlikely to be of significance, although such patients should be followed up with periodic sputum cultures. Treat patients who are deteriorating clinically and who have repeatedly positive cultures or smears for NTM. At least two separate positive sputum cultures or a single positive bronchial wash/lavage or biopsy culture are usually considered sufficient to justify treatment in the appropriate clinical context. Compatible histopathology (granulomatous inflammation), when available, further supports a decision to commence treatment. HRCT may be useful in facilitating treatment decisions, as an abnormal baseline HRCT consistent with NTM infection appears to be predictive of disease progression.

Management

  • The decision to treat is complex and is based on the likelihood of clinical disease, weighed against the side effects and potential toxicity of treatment

  • No need to notify or contact-trace, as there is low risk of cross-infection

  • Typical drug regimens for specific NTM species are described on Respiratory infection—mycobacterial pp. [link][link]. Prolonged courses of treatment are required, and drug side effects frequently limit therapy

  • Avoid macrolide monotherapy, which encourages macrolide resistance

  • Be alert to the possibility of drug interactions. In the setting of HIV, there are potential drug interactions between rifampicin, macrolides, and protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rifampicin induces liver enzymes, and, therefore, the elimination of other drugs (e.g. oral contraceptives, warfarin, phenytoin, prednisolone, ciclosporin, etc.) may be increased. Macrolides may cause QT interval prolongation, particularly when taken alongside other QT-prolonging drugs

  • Curative therapy is not always possible, reflecting antibiotic resistance in the NTM species, drug intolerance due to side effects, and/or significant comorbid disease

  • Although rarely employed in the UK, surgical resection of focal disease, in combination with drug therapy, may be curative in patients who are able to tolerate resection—consider in patients with highly resistant isolates who have failed to respond to standard therapy.

Further information

Griffith DE et al. ATS/IDSA Statement: diagnosis, treatment and prevention of NTM. Am J Respir Crit Care Med 2007;175:367–416.Find this resource:

NTM species and lung disease

Slowly growing species

Mycobacterium avium complex (MAC)

  • MAC includes the different M. avium subspecies as well as M. intracellulare; it is also referred to as M. avium intracellulare (MAI)

  • Classical presentations include upper lobe fibrocavitary disease in elderly ♂ smokers and nodular/bronchiectatic disease in non-smoking ♀

  • Initial treatment should be triple therapy with a macrolide (clarithromycin or azithromycin), rifampicin, and ethambutol. A three times weekly regimen may be used in less severe disease. Consider adding nebulized/IV amikacin or IV streptomycin in severe (usually cavitary) disease

  • Antibiotic susceptibility testing is not predictive of clinical response in MAC, with the exception of macrolide susceptibility, and so routine susceptibility testing of MAC isolates is performed for clarithromycin only. Macrolide resistance is associated with a poor prognosis, and its management is complex—seek microbiology advice. The major risk factor for macrolide resistance is macrolide monotherapy, and macrolides should never be used as monotherapy for treatment of MAC

  • Antibiotic treatment should be continued for 12–18 months of negative sputum cultures whilst on therapy

  • MAC is the leading cause of NTM infection in the setting of HIV and may occur late in the disease when CD4 count <50 or during the first 2 months of ART. Disease is rarely confined to the lungs in this setting, and lymphadenitis and disseminated infection are common.

Mycobacterium kansasii

  • M. kansasii classically presents with progressive upper lobe fibrocavitary disease similar to TB, and isolation of M. kansasii is usually associated with disease (rather than reflecting contamination)

  • Treatment is usually with rifampicin, ethambutol, and isoniazid for a minimum of 12 months of negative sputum cultures. Clarithromycin and moxifloxacin may be useful agents, e.g. for rifampicin-resistant isolates. Usually good response to treatment: >90% 5y cure and <10% relapse with full compliance.

Mycobacterium malmoense

  • M. malmoense typically causes cavitary disease, often in patients with underlying COPD, and isolation of M. malmoense is usually associated with disease (rather than contamination)

  • Treatment is usually with 2–4 drugs, including ethambutol and rifampicin, and often a macrolide, for 12–24 months.

Mycobacterium xenopi

  • M. xenopi typically causes upper lobe cavitary disease resembling TB

  • Treatment regimens include ethambutol, isoniazid, and rifampicin for at least 24 months; macrolides may be useful. Disease may progress, despite treatment, and mortality appears to be relatively high.

Mycobacterium gordonae

  • M. gordonae is frequently isolated from sputum but is usually a contaminant and only rarely causes progressive lung disease.

Rapidly growing species

Mycobacterium abscessus

  • M. abscessus comprises three species M. abscessus (sensu stricto), M. massiliense, and M. boletii, which may differ in treatment response (with a better prognosis in M. massiliense, compared to M. abscessus)

  • M. abscessus has emerged as a major pathogen in CF where it is the leading mycobacterial cause of progressive lung disease. Recent reports suggest the existence of person-to-person spread of M. abscessus between CF patients, and segregation in CF centres is increasingly recommended

  • M. abscessus also causes nodular/bronchiectatic disease in patients without CF, classically non-smoking ♀

  • M. abscessus is uniformly resistant to standard antituberculous agents, and there is currently no proven curative antibiotic regimen for M. abscessus lung disease. Regimens based on in vitro drug susceptibilities are recommended; a typical treatment protocol in CF might comprise induction therapy for at least 3–4 weeks with IV amikacin, IV cefoxitin or imipenem, and PO azithromycin, followed by long-term maintenance therapy with nebulized amikacin, PO azithromycin, and another PO agent to which the isolate is sensitive (e.g. a quinolone). Azithromycin appears to induce less macrolide resistance and is probably more effective than clarithromycin against M. abscessus. Tigecycline may be a useful second-line agent for induction, although nausea often limits its use

  • Although guidelines recommend continuing antibiotic treatment for 12–18 months once cultures are negative, in practice, achieving this level of suppression of M. abscessus is often unrealistic. This is a chronic incurable infection for many CF patients, and intermittent courses of IV agents (e.g. amikacin, cefoxitin, or imipenem) are typically required to treat exacerbations and control symptoms/minimize progression of lung disease.

Mycobacterium chelonae

  • Rarely causes lung disease. Treat with at least two drugs to which the isolate displays in vitro susceptibility; often susceptible to macrolides, tobramycin, amikacin, imipenem; resistant to cefoxitin.

Mycobacterium fortuitum

  • Often does not cause progressive lung disease in the absence of treatment; when therapy is needed, usually susceptible to macrolides, quinolones, imipenem, cefoxitin.