Epidemiology of TB and risk factors

The incidence of TB, the disease caused by infection with Mycobacterium tuberculosis, fell dramatically during the 20th century in the UK and other industrialized countries, reaching a nadir of approximately 11 cases per 100,000 in 1987.Reference Hayward and Watson¹ Since then the UK rate has increased by about 25%² and TB is again a matter of public health concern. Initially the rise in incidence was associated with the HIV epidemic but, more recently, movement to and from high incidence countries has been largely responsible. Currently 72% of TB in the UK occurs in those born abroad.² Tuberculosis rates remain very high in many countries, particularly in Asia and Africa, and worldwide it is the commonest fatal infectious disease, with almost 2 million deaths per annum.Reference Dye, Scheele, Dolin, Pathania and Raviglione³

Infection with Mycobacterium tuberculosis gives rise to clinically obvious disease in only about 5–10% of cases.⁴ Most individuals mount a strong cellular immune response that suppresses the growth of the mycobacteria and contains them within granulomas, but does not eradicate them. Latent infection may then persist indefinitely, with a risk of reactivation if the immune response fails because of age, immunosuppression or co-morbidity. Occasionally, untreated but inactive infection can be recognized from incidental chest radiograph abnormalities such as upper zone fibrosis or calcified primary foci. More often, it is detectable only from the persisting immune response, either by a positive skin reaction to injected tuberculin protein (e.g. the Mantoux test) or more recently by IGRAs, in vitro tests for latent TB.

Latent TB is very common in countries with a high incidence of active disease with, overall, one-third of the world's population believed to be infected.Reference Dye, Scheele, Dolin, Pathania and Raviglione³ In industrialized countries where current TB incidence is low, latent infection is likely to be most common in older individuals. It is estimated that more than 90% of the population born before the 1950s had contact with TB and many, if not most of these, were infected.Reference Rieder, Gibson, Geddes, Costabel, Sterk and Corrin^5, Reference Mori, Harada, Higuchi, Sekiya, Uchimara and Shimao⁶ Epidemiological studies of latent TB using skin tests do not properly reflect that and show peak prevalences at around age 40.Reference Bennett, Courval, Onorato, Agerton, Gibson and Lambert⁷ However, the Mantoux test becomes less sensitive with age. For example, only 25% of those above 80 years with active disease have a positive response, compared with 70% of younger individuals.Reference Kobashi, Mouri, Yugi, Obase, Miyashita and Okimoto⁸ The pattern of skin responses in the population thus probably reflects a balance between increasing latent TB rates with age and diminishing immunological responses. There have been no population studies using other methods of diagnosing latent TB and so its precise prevalence in older age, and the associated risk of reactivation, is unknown. It might be that, in some individuals, the mycobacteria eventually die and the latent infection clears. More probably, a diminishing systemic immune response with age contributes to the risk of reactivation.

In the past it was thought that more than 90% of TB in adults arose because of reactivation of latent disease.Reference Stead⁹ More recent studies, using molecular typing techniques, have shown that 30–50% of cases occur in clusters with identical strains, suggesting recent transmission from an infected source.Reference Geng, Krieswirth, Driver, Li, Burzynski and Dellalatta^10, Reference Yang, de Haas, Wachmann, van Soolingen, van Embden and Andersen¹¹ Clustering is much less common in older people, in whom about 75% of cases do appear to be due to reactivation of latent disease.Reference Geng, Krieswirth, Driver, Li, Burzynski and Dellalatta^10–Reference France, Cave, Bates, Foxman, Chu and Yang¹² Reactivation of latent disease thus explains the increased risk of active TB with age. This is shown clearly in statistics from the USA¹³ and until recently was apparent in national statistics from England and Wales.Reference Rose, Watson, Graham, Nunn, Drobniewski and Ormerod¹⁴ Currently the British figures are overwhelmed by the high incidence in younger individuals born abroad.² Although only around 12% of TB occurs in those over the age of 65 years,² they are an important group as they often have disease that is more difficult to diagnose and treat, and they have substantially higher mortality than younger cohorts.

Active TB is approximately twice as common in men compared with women,Reference France, Cave, Bates, Foxman, Chu and Yang¹² in smokers,Reference Bates and Khalakdina^15, Reference Aissa, Madhi, Ronsin, Delerocque, Lecuyer and Decludt¹⁶ in diabeticsReference Ponce-de-Leon, Garcia-Garcia, Garcia-Sancho, Gomez-Perez, Valdespino-Gomez and Oliaz-Fernandez^17, Reference Leung, Lam, Chan, Yew, Ho and Leung¹⁸ and in those who are malnourished.Reference Khan, Sterling, Reves, Vernon and Horsburgh¹⁹ HIV infection increases the risk 20- to 40-fold and is now responsible for 10–20% of all TB worldwide.²⁰ At present 8% of those with TB in England and Wales are co-infected with HIV,Reference Ahmed, Abubakar, Delpech, Lipman, Boccia and Forde²¹ but the rate varies considerably in relation to known risk factors, and is less than 1% of those over 65 years.Reference Ahmed, Abubakar, Delpech, Lipman, Boccia and Forde²¹ The rate of co-infection in older people is higher in the USA, at approximately 3.6%.Reference Albalak, O'Brien, Kammerer, O'Brien, Marks and Castro²² The survival of those with HIV continues to increase and approximately 25% of those infected are now aged 50 or more.²³ Continued vigilance for TB in this group will be necessary. It is recommended that HIV testing is carried out on everyone diagnosed with TB.Reference Pozniak, Miller, Lipman, Freedman, Ormerod and Johnson²⁴

Tumour necrosis factor α (TNFα) is a lymphokine which, in animal models, plays an important role in the formation of granulomas and the containment of TB infection. Anti-TNFα medications are now widely used in the treatment of inflammatory joint, bowel and skin disease. The mean age of those on treatment in Britain is 55 yearsReference Dixon, Hyrich, Warson, Silman and Symmons²⁵ and the medications are often used in older individuals. They are associated with an increased risk of TB that appears to be largely due to reactivation of latent disease.Reference Keane, Gershon, Wise, Mirabile-Levens, Kasznica and Schweiterman²⁶ The monoclonal antibodies infliximab and adalimumab are associated with at least a 10-fold increased risk.Reference Tubach, Salmon, Ravaud, Allanore, Goupille and Breban²⁷ The fusion protein etanercept that binds free TNFα has a lower risk, possibly because it has less effect on membrane-bound TNFα in granulomas.Reference Tubach, Salmon, Ravaud, Allanore, Goupille and Breban²⁷ Current recommendations are that all patients are screened for latent TB and treated appropriately before commencing anti-TNFα therapy.²⁸

TB spreads by the inhalation of airborne droplets from infected individuals: infection rates are approximately doubled in confined communities such as prisons and nursing homes. Hutton reported TB rates in US nursing home residents that were 1.8 to 5.7 times those of age-matched community residents with almost twice as many cases identified only at death.Reference Hutton, Cauthen and Bloch²⁹ Similar findings have not been generally reported from the UK,Reference Nisar, Williams, Ashby and Davies³⁰ though outbreaks affecting up to 20% of nursing home residents have been described.Reference Stead³¹ About 4.5% of those over 65 years and 20% of those over 85 years live in nursing homes³² and they represent a vulnerable group in whom TB infection can spread rapidly. The risks extend to employees who are at approximately 3-fold increased risk of TB.³³

Tuberculosis is caused by mycobacteria belonging to the M. tuberculosis complex: principally M. tuberculosis, occasionally M. bovis, and rarely M. africanum. There are many other non-tuberculous mycobacteria (NTMs) that are common in soil and water and are of low human pathogenicity. They can occasionally cause infection, particularly in those who are immunocompromised because of HIV infection. Mycobacterium avium complex (MAC) is the commonest and appears to be an increasingly common cause of disease in previously healthy older people, particularly females.Reference Khan, Wang and Marras³⁴ There is otherwise no association between NTM infection and age. The clinical and radiological features are similar to those of TB, and antituberculosis medication is often started following a positive smear before the correct diagnosis is established from mycobacterial culture. Diagnosis is sometimes uncertain as NTMs can contaminate sputum samples and even laboratory water supplies. Treatment can be difficult as the organisms are generally resistant to several antituberculosis drugs, but person-to-person infection does not occur and so there is no need for isolation or for contact screening procedures.

Clinical features, investigations and diagnosis

The presentation of TB in older people is similar to that in younger adults except that the typical symptoms of fevers, night sweats or haemoptysis are more likely to be absent. Non-specific symptoms, such as malaise, dyspnoea or altered mental state may predominate.Reference Perez-Guzman, Vargas, Torres-Cruz and Villareal-Velarde^35, Reference Rocha, Pereira, Barros and Seabra³⁶ The radiological appearances may also be less specific: cavitation is less common and miliary disease is more common.Reference Perez-Guzman, Torres-Cruz, Villareal-Velarde and Vargas³⁷ These features probably reflect relative lymphopaenia in older individuals, as similar atypical presentations are common in those with HIV infection.Reference Geng, Kreiswirth, Burzynski and Schluger³⁸ They make the diagnosis more difficult and probably contribute to diagnostic delays. Greenaway, in a study of 17 North American hospitals, found that the diagnosis of TB was initially missed in 45% of 430 hospitalized patients. Age was the strongest predictor, with diagnostic delay being eight times more common in those aged 80 years or above. This led to an average delay to isolation of 12.5 days, increased mortality and a suggestion of an associated increase in infection rates in staff.Reference Greenaway, Menzies, Fanning, Grewal, Yuan and Fitzgerald³⁹ Wallace recently highlighted the increasing frequency with which TB patients are presenting with advanced disease and demonstrated that this was more common in areas where TB incidence was low.Reference Wallace, Kammerer, Iademarco, Althomsons, Winston and Navin⁴⁰ These studies emphasize the need for continued vigilance.

Culture of M. tuberculosis is the definitive method of diagnosing active infection and should be attempted whenever possible. In practice, a positive culture is only achieved in about two-thirds of cases of pulmonary TB and in fewer than half of non-pulmonary disease.² Often treatment has to proceed on the basis of clinical, radiological or histological findings. Occasionally the diagnosis is based on the unexpected finding of caseating granulomas on a biopsy, and surgeons should be prompted to send specimens for culture whenever TB is a possibility

When the number of organisms in a specimen exceeds 5000 per millilitre they can usually be seen on direct microscopic examination and the specimen is said to be smear positive.Reference Brewis, Gibson and Geddes⁴¹ The traditional Ziehl-Neelsen stain is now rarely used, having been superseded by auramine or immunofluorescent techniques. Lower mycobacterial counts cannot be detected from the smear, but they can usually be grown on appropriate culture media. Traditional solid media are now generally supplemented by liquid media labelled with ¹⁴C. Actively metabolizing organisms convert the ¹⁴C to radiolabelled CO₂, allowing growth to be detected with greater sensitivity, and in 10–14 days rather than the 2–6 weeks required with conventional media.⁴ It is usually appropriate to start medication if a smear is positive for acid-fast bacilli, but treatment may need to be modified if the organism is non-tuberculous or if drug resistance is identified.

The sputum smear is positive in more than half of pulmonary TB cases, though not always on an initial specimen. Three sputum samples should be obtained routinely if TB is suspected.⁴ Additional techniques such as sputum induction with hypertonic salineReference Brown, Varia, Bassett, Davidson, Wall and Pasvel⁴² or bronchoscopy with bronchial washingsReference Saglam, Akgun and Aktas⁴³ can be used. They are likely to identify additional cases,Reference Saglam, Akgun and Aktas⁴³ but they carry a greater risk of transmission of infection to hospital staff and other patients. In non-pulmonary disease, appropriate samples such as lymph node aspirates or early morning urine specimens may be required.

Amplification of mycobacterial DNA using polymerase chain reaction (PCR) techniques can be used to speed identification. The usefulness of the technique is limited by the presence of inhibitors in body fluids and the sensitivity is only 50–70% in smear-negative specimensReference Al Zahrani, Al Jahdali, Poirier, Rene, Gennaro and Menzies⁴⁴ and in some studies has poor specificity.Reference Noordhoek, Kolk, Bjune, Catty, Dale and Fine⁴⁵ Sensitivity is greater at about 95% in smear-positive samplesReference Al Zahrani, Al Jahdali, Poirier, Rene, Gennaro and Menzies⁴⁴ and in mycobacterial cultures. This allows early differentiation of M. tuberculosis from NTM and can be useful in guiding initial treatment, particularly in the immunocompromised, or in determining the need to embark on a contact-tracing programme. Further probes can identify the genes that code for rifampicin and isoniazid resistance.Reference Barnard, Albert, Coetzee, O'Brien and Bosman⁴⁶ The former, in particular, has high sensitivity and specificityReference Ling, Zwerling and Pai⁴⁷ and is useful in guiding initial treatment if drug resistance is suspected.

The tuberculin skin test has been used for many years to identify TB infection, particularly in its early or latent stages. Purified tuberculin protein is injected intradermally and the degree of delayed hypersensitivity is quantified from the subsequent skin swelling.⁴⁸ In the past the Heaf test was widely used in the UK but now only the Mantoux test is available. It has a number of significant limitations. Intradermal injection is not always carried out properly and there is variability between readers in measuring the skin swelling.Reference Mancusco, Tobler and Keep⁴⁹ The result is read at 48–72 hours and that does not lend itself to weekly clinic organization. False positive reactions can arise from exposure to NTMs and this has led to the investigation of a number of TB pseudoepidemics.Reference Mancusco, Tobler and Keep⁴⁹ Prior BCG immunization also results in a positive response. False negative reactions occur with immunosuppression, active TB and advanced age.Reference Chan-Yeung, Cheung and Dai⁵⁰ An immune response can be stimulated by the test itself and, particularly in older patients, an initially negative response can become positive when repeated, giving the false impression of recent infection.Reference Van Den Brande and Demedts⁵¹

The recent development of in vitro diagnostic tests has been a major advance in identifying latent TB.Reference Mori, Sakatani, Yamagishi, Takashima, Kawabe and Nagao⁵² These tests identify interferon gamma release from lymphocytes stimulated with the M. tuberculosis-specific peptides early secretory antigen (ESAT-6) and culture filtrate protein (CFP-10). There are currently two commercially available tests: QuantiFERON-TB-2 Gold (Cellestis Ltd; Carnegie, VIC, Australia) uses an enzyme-linked immunosorbent assay on the supernatant from stimulated lymphocytes, and T-SPOT.TB (Oxford Immunotec; Oxon, UK) uses an immunospot assay to detect and count individual stimulated T lymphocytes.

IGRAs have the practical advantages over skin tests that they are not observer-dependent and a result can be obtained following a single clinic visit. They do require careful handling of the samples to ensure that viable lymphocytes are transferred to the laboratory. Indeterminate results can be obtained in up to 20% of samples particularly in the presence of lymphopaeniaReference Mori, Harada, Higuchi, Sekiya, Uchimara and Shimao^6, Reference Kobashi, Sugin, Shimuza, Ohue, Mouri and Obase⁵³ and can limit their usefulness in older people.Reference Menzies, Madhukar and Comstock⁵⁴ Overall, they do appear to be less affected by age than the tuberculin skin test.Reference Kobashi, Mouri, Yugi, Obase, Miyashita and Okimoto⁸

The major advantage of IGRAs over the Mantoux test is that ESAT-6 and CFP-10 are not expressed by BCG or by most NTMs and so a positive response is much more specific for M. tuberculosis.Reference Kobashi, Obase, Fukuda, Yoshida, Miyashita and Oka⁵⁵ Because of the anergy produced by active TB, IGRAs are negative or indeterminate in up to 15% of cases of active disease and are of little diagnostic value in that setting.Reference Kobashi, Mouri, Yugi, Obase, Miyashita and Okimoto^8, Reference Kobashi, Obase, Fukuda, Yoshida, Miyashita and Oka^55, Reference Dosanjh, Hinks, Innes, Deeks, Pasvol and Hackforth⁵⁶ They should not be used to diagnose or exclude active TB.

The main use of IGRAs is in identifying latent TB that has a risk of progressing to active disease. The prevalence of positive tests is closely related to the risk of infection in situations such as TB outbreaks.Reference Arend, Thijsen, Leyten, Bouwman, Franken and Koster⁵⁷ IGRAs have a low false positive rate (3–8%) in individuals unlikely to have TB,Reference Mazurek, LaBue and Daley⁵⁸ suggesting that the tests are valid, but their precise sensitivity and specificity in identifying those at risk of active TB has yet to be determined. Diel recently demonstrated that 11% of 601 contacts who had 40 or more hours exposure to TB patients were IGRA positive. Six went on to develop active TB over the course of the next 2 years, all from the group who were IGRA positive and declined chemoprophylaxis.Reference Diel, Loddenkemper, Meywald-Walter, Niemann and Nienhaus⁵⁹ IGRAs are designed to identify effector T cells that are being actively stimulated by exposure to M. tuberculosis rather than memory T cells and so they should become negative after treatment. However, up to two-thirds of tests remain positive after treatment, at least over the course of 6–12 months.Reference Aiken, Hill, Fox, McAdam, Jackson-Sillah and Lugos^60, Reference Chee, KhinMar, Gan, Barkham, Pushparani and Wang⁶¹ Thus while initial experience with IGRAs is encouraging, their precise role and usefulness remains to be determined.

Management of TB

TB treatment is prolonged and complex. The duration of therapy must be sufficient to eradicate slowly dividing intracellular organisms, and several drugs are needed to avoid the development of resistance. The current optimum regimen comprises 2 months quadruple therapy with pyrazinamide, ethambutol, rifampicin and isoniazid, followed by 4 months with rifampicin and isoniazid.⁴ It is highly effective with cure rates exceeding 95% and a subsequent relapse rate of less than 3% if taken properly.⁴ Longer regimens may be needed if there is extensive diseaseReference Nahid, Pai and Hopewell⁶² and are recommended for meningeal TB. Corticosteroids are added for meningeal disease and sometimes in other forms of TB.⁴

TB treatment requires oversight by someone with appropriate experience, preferably in a dedicated clinic with a multidisciplinary team approach. Combination products are used with similar names that can be easily confused; doses vary with weight; and there is a risk of serious adverse effects. One study reported treatment errors in 15% of cases, but these were seven times more common in non-specialist centres.Reference Rao, Mookerjee, Obasanjo and Chaisson⁶³ Considerable efforts are often needed to ensure compliance, particularly with groups such as recent entrants to the country who do not speak the local language, or drug addicts and the mentally ill who are poorly integrated with medical services. Directly observed therapy (DOT) is an important strategy that is widely used in resource-poor countries and is generally recommended for those with drug-resistant disease or in whom there is a risk of non-compliance.⁴ It may be useful for older people with memory problems or who use multiple additional medications. In this setting it may be most useful for a family member to supervise the therapy, with appropriate health worker support. TB medication is exempt from prescription charges in the NHS, when prescribed in a specialist TB centre.

M. tuberculosis is subject to a spontaneous mutation that confers rifampicin resistance at a rate of approximately one per 5 billion organisms per generation.Reference David⁶⁴ Resistant organisms are at a metabolic disadvantage and generally do not thrive,Reference Billington, McHugh and Gillespie⁶⁵ but monotherapy is likely to induce resistance because of the very large numbers of organisms in those with active disease. Resistances to other antituberculosis agents occur at a slightly higher rate, but they are genetically independent and the probability of spontaneous resistance to more than one agent is very low. Drug resistance develops because of inadequate treatment and that is often a consequence of physician error: either the initial regimen is inadequate or a single agent is added to a failing regimen.Reference Mahmoudi and Iseman⁶⁶

Primary resistance occurs when someone is infected by an already resistant organism. It is less common with age, affecting 2% of cases over 65 compared with 7% of younger patients.² That is in part because TB in older individuals is often caused by reactivation of disease that was acquired before the introduction of antibiotic chemotherapy. Multiple drug-resistant tuberculosis (MDR-TB) is resistant to at least isoniazid and rifampicin. It occurs in 1.1% of cases but is rare in those over 65 years. Extensively drug-resistant tuberculosis (XDR-TB) with resistance to second-line agents is increasingly reported.² Treatment of MDR-TB generally involves five drugs for two years and adds hugely to the costs of managing the disease and the morbidity. Considerable resource should be employed to prevent it occurring.

Antituberculous chemotherapy causes serious side-effects sufficient to require interruption of treatment in 9% or more of patients.Reference Yee, Valiquette, Pelletier, Parisien, Rocher and Menzies^67–Reference Fernandez-Villar, Sopena, Fernandez-Villar, Vazquez-Gallardo, Ulloa and Leiro⁶⁹ Older people are at greater riskReference Yee, Valiquette, Pelletier, Parisien, Rocher and Menzies⁶⁷ on account of co-morbidities, age-related changes in drug metabolism, and increased use of other medications with the potential for interactions. Hepatitis is the commonest problem and occurs with isoniazid, rifampicin and pyrazinamide.Reference Schaberg, Rebhan and Lode⁶⁸ The risk increases with age, at least with isoniazid, and is 2–8 times more common in those over 60 years.Reference Chang, Leung, Yew and Tam⁷⁰ Generally, hepatitis is reversible if detected early but it can be severe or fatal if treatment is continuedReference Chang, Leung, Yew and Tam⁷⁰ and so surveillance is mandatory throughout treatment. The reason for the increased risk of hepatitis with age is not entirely clear: isoniazid pharmacokinetics are markedly affected by acetylation status,Reference Saukkonen, Cohn, Jasmer, Schenker, Jereb and Nolan⁷¹ but do not change with age.Reference Farah, Taylor, Rawlins and James⁷² Reduced activity of excretory pathways is probably responsible and there is probably less binding to albumin with higher free drug concentrations.Reference McIlleron, Hackforth, Wash, Burger, Norman and Folb⁷³ Other independent risk factors for hepatotoxicity include a history of hepatitis, low body mass index (BMI) and the presence of diabetes mellitus.Reference Saukkonen, Cohn, Jasmer, Schenker, Jereb and Nolan⁷¹

Rifampicin is a potent inducer of liver cytochrome P450 and so interacts with a number of other drugs. The commonest clinically significant problems are decreased effectiveness of oral contraceptives, oral corticosteroids, warfarin, digoxin, phenytoin, calcium channel blockers, beta-blockers and sulfonylureas. Doses of oral corticosteroids generally need to be doubled to maintain effectiveness.

Isoniazid binds to pyridoxine (vitamin B6) to form a hydrazone that is excreted in the urine. This can cause deficiency which manifests as a peripheral neuropathy, particularly in diabetics, alcoholics, the malnourished or those with renal failure. The neuropathy can be prevented by pyridoxine supplementation during treatment. There is no clear evidence that older people are more prone to isoniazid neuropathy than others. Ethambutol can cause optic neuropathy but that is rare at current doses. There is a range of other uncommon potential side-effects.

The overall mortality rate from TB amongst those undergoing treatment in the UK is low, at approximately 2 per 1000,² but there is additional mortality from co-morbid conditions. Both death from TB and death from co-morbid conditions are strongly associated with age. TB mortality is 20 times higher, at approximately 5%, in those aged 65 years or more.^2, Reference Low, Ang, Cutter, James, Chee and Wang⁷⁴ Older patients with TB have higher prevalences of cardiovascular disease, diabetes, malignancy and previous gastrectomy, and five times as many die from co-morbid conditions.Reference Perez-Guzman, Vargas, Torres-Cruz and Villareal-Velarde³⁵ The overall fatality rate before the completion of treatment is 26%.² It increases progressively with age, exceeding 50% in those over 80 years. The diagnosis of TB in an older person thus carries a very poor prognosis. Other recognized poor prognostic factors include the presence of end-stage renal failure, malnutrition, immunosuppression, respiratory failure,Reference Rao, Iademarco, Fraser and Kollef⁷⁵ HIVReference Pablos Mendez, Sterling and Frieden⁷⁶ and diabetes.Reference Dooley, Tang, Golub, Dorman and Cronin⁷⁷

Treatment of latent TB

The treatment of latent TB is often referred to as chemoprophylaxis, but that nomenclature is potentially misleading. The drugs used are the same as with active disease, but because the number of viable organisms is several orders of magnitude lower, fewer drugs and shorter regimens can be used. Most evidence of efficacy comes from studies of isoniazid that reduces the risk of infection by about two-thirds after six months of treatment.Reference Falk and Fuchs^78, Reference Egsmose, Ang'awa and Pott⁷⁹ Three months of treatment with rifampicin and isoniazid probably has similar efficacy.Reference Girling and Chan⁸⁰

The pharmacological side-effects of treating latent TB are no less than those associated with the treatment of active disease and may even be slightly greater,Reference Lee, Mennone, Jones and Paul⁸¹ possibly because the immunosuppression of active TB reduces drug toxicity. Because the incidence of isoniazid-induced hepatitis increases with age and reaches 3% in those aged 50 years or more,Reference Yee, Valiquette, Pelletier, Parisien, Rocher and Menzies^67, Reference Aziz, Shubair, DeBari, Ismail and Khan⁸² treatment is often not offered to those over 35 years.⁴ In one US study, only 50% of patients considered eligible were treated for latent TB, with age as the commonest stated reason for not offering therapy.Reference Sorresso, Mehta, Harvill and Bentley⁸³ However, most isoniazid-induced hepatitis is mild, and with appropriate surveillance and early detection should be reversible, and so the justification for limiting treatment to younger patients has been questioned.Reference Stead⁹

Compliance is often a problem in treating latent TB as those who are clinically well are required to take regular medication for prolonged periods to prevent a disease that is, in any case, unlikely to develop. Less than one-third of patients have completed a full course of treatment in some studies.Reference Shieh, Snyder, Horsburgh, Bernardo, Murphy and Saukkonen⁸⁴ A perception of a low risk from TB and dislike of venepuncture were cited as the main reasons for discontinuing. With poor compliance there is at least a theoretical risk of inducing drug resistance that might make treatment of subsequent active disease more difficult.Reference Balcells, Thomas, Godfrey-Faussett and Grant⁸⁵

In the US, the incidence of TB has more than halved, from a rate of 10.5 per 100,000 in 1992 to 4.2 in 2008.¹³ This has been attributed, in large part, to an active policy of diagnosing and treating latent TB. Groups considered to be at risk include those with recent contact with active TB, immigrants, and patients with HIV and other conditions that increase their susceptibility. The advent of improved immunological methods of detecting latent TB using IGRAs should allow better targeting of these groups. It may also allow extension of the populations considered for treatment, nursing home residents being a potential target. This group is at increased risk of TB, but currently there are no standard recommendations for managing latent infection when it is detected. The American Thoracic Society includes them amongst those in whom targeted treatment is appropriate⁸⁶ and there are strong advocates of aggressive management of latent TB in this group.Reference Zevallos and Justman⁸⁷ However, the Advisory Committee for the Elimination of Tuberculosis and the American Geriatric Society stop short of recommending routine treatment of latent TB, preferring screening of nursing home residents for TB at entry, repeat annual clinical evaluations, and further TB testing and treatment if clinically appropriate.Reference Thrupp, Bradley, Smith, Simor, Gantz and Crossley⁸⁸

Prevention, isolation and control of TB

Most immunizations work by inducing antibodies, but these are of little or no importance in protection against TB, which is dependent on lymphocyte function. It is therefore not surprising that no fully effective vaccine has yet been developed. Bacille Calmette-Guerin (BCG), a live attenuated form of M. bovis, confers some protection but its efficacy has varied considerably in a number of large studies and in some it has shown no effect.⁸⁹ Overall, it probably confers around 70% protection in childhood, with particular effectiveness against tuberculous meningitis.⁴ Its protection wanes with time and is no longer evident after about 10 years.Reference Sterne, Rodrigues and Guedes⁹⁰ There is no good evidence that reimmunization, or immunization of adults, has any effect.Reference Leung, Tam, Chan, Chan-Yeung, Chan and Chang⁹¹ The UK school BCG programme was disbanded because of lack of cost-effectiveness and immunization is currently restricted to high-risk groups including health care workers and some neonates.⁴ The limited efficacy of BCG has driven a search for novel vaccines with greater efficacy and several are currently under investigation.

Preventing active disease by immunization and the treatment of latent infection are important strategies in the control of TB. Prompt diagnosis, the early institution of correct treatment and the prevention of onward spread of infection are also vital. Because of the efficacy of modern chemotherapy, prolonged isolation is no longer necessary but contact screening procedures are generally employed to identify the source of infection and any additional cases. The risk of infection is determined by the infectivity of the index case and by the frequency and duration of contact, particularly in poorly ventilated indoor settings. Smear-positive patients are about five times more infectious than smear-negative patients,Reference Aissa, Madhi, Ronsin, Delerocque, Lecuyer and Decludt^16, Reference Diel, Loddenkemper, Meywald-Walter, Niemann and Nienhaus⁵⁹ and coughing is an important risk factor, particularly if there is cavitatory disease. Those with TB in organs other than the lungs are rarely infectious, nor are those with latent tuberculosis. The numbers of viable bacilli in sputum fall rapidly with the initiation of treatmentReference Jindani, Dore and Mitchison⁹² and patients are unlikely to be infectious after 2 weeks of chemotherapy.

Patients with TB are likely to have been unwell and potentially infectious for several weeks before the diagnosis is established. The average contact of those selected for screening was in the region of 250 hours in the 3 months preceding the diagnosis in one study,Reference Aissa, Madhi, Ronsin, Delerocque, Lecuyer and Decludt¹⁶ and that was associated with an approximately 20% risk of infection as detected by a positive tuberculin skin testReference Aissa, Madhi, Ronsin, Delerocque, Lecuyer and Decludt^16, Reference Bailey, Gerald, Kimerling, Redden, Brook and Bruce⁹³ and a 1% risk of active disease.Reference Aissa, Madhi, Ronsin, Delerocque, Lecuyer and Decludt^16, Reference Reichler, Reves, Bur, Thompson, Mangura and Ford⁹⁴ Thus each hour of exposure is associated with something in the region of a 1:1000 risk of infection and a 1:10,000 risk of active disease in the short term. In the UK it is generally held that 8 hours of exposure poses sufficient risk to justify screening.⁴ Hospital staff are at increased risk of TB,^4, Reference Meredith, Watson, Citron, Cockcroft and Darbyshire⁹⁵ though the absolute risks are low. The arrival of a patient with TB on a hospital ward often engenders high levels of anxiety, but in most circumstances nursing a patient in a side-ward, with masks used when any sputum-inducing procedures are carried out, provides sufficient protection.⁴ Individuals with MDR-TB need to be treated with greater caution and nursed in appropriate isolation facilities in a negative pressure room. Some individuals are particularly infectious and occasionally extensive screening programmes have to be undertaken.Reference Kline, Hedemark and Davies⁹⁶

As most cases of tuberculosis in England and Wales now occur in those born abroad,² screening of new entrants to the country is an important part of a TB control strategy. There is no systematic targeting of other high-risk groups such as rough dwellers or intravenous drug users, though some ad hoc programmes have reported successes.

Controlling TB remains a challenge, but in an economically developed country it should be possible to reduce rates considerably from their current levels to less than one per million.⁹⁷ Improved diagnostic tools and targeting of treatment will help but clinical vigilance, prompt diagnosis and carefully supervised treatment will remain important. Older patients are an important group because of their high prevalence of latent infection, their increased risk of developing active disease, their often atypical and delayed presentation, their increased risk of treatment side-effects, and ultimately their greater mortality from the disease.

Conflicts of interest

The authors had no conflicts of interest to declare.