PRACTICE

GUIDELINES Diagnosis of active and latent : summary of NICE guidance Ibrahim Abubakar,1 Chris Griffiths,2 Peter Ormerod,3 on behalf of the Guideline Development Group

1Research Department of Infections Tuberculosis is a major preventable infectious cause of six weeks and repeat the to reduce the and Population Health, University morbidity and mortality globally, which has re-emerged rate of false negative results for latent infection. College London, London 2 in high risk groups such as migrants, homeless people, Centre for Primary Care and Public 1 Health, Queen Mary University of problem drug users, and prisoners in the UK. This arti- Household contacts younger than 2 years and older than London cle summarises the most recent recommendations (2011) 4 weeks 3Royal Blackburn Hospital, from the National Institute for Health and Clinical Excel- • If contact was with a person whose smear is Blackburn, UK lence (NICE)2 on the diagnosis of positive for acid fast bacilli: Correspondence to: I Abubakar [email protected] (including the use of new tests) and of active tuberculo- ––For children not vaccinated with BCG, perform a Cite this as: BMJ 2012;345:e6828 sis. Although this summary focuses on diagnosis, the full Mantoux test and offer doi: 10.1136/bmj.e6828 guidelines cover the public health and clinical manage- –– If the Mantoux test is positive, assess the child ment of tuberculosis and replaced the guidelines pub- for active tuberculosis. If active tuberculosis is This is one of a series of BMJ 3 summaries of new guidelines lished in 2006. excluded, offer full treatment for latent infection based on the best available –– If the Mantoux test is negative (<6 mm evidence; they highlight important Recommendations induration), continue isoniazid for six weeks, recommendations for clinical practice, especially where NICE recommendations are based on systematic reviews and then repeat the Mantoux test together with uncertainty or controversy exists. of best available evidence and explicit consideration of an IGRA. If the repeat tests are negative, isoniazid Further information about the cost effectiveness. When minimal evidence is available, may be stopped and BCG vaccination performed. guidance, a list of members of the ­recommendations are based on the Guideline Development If either repeat test is positive, assess the child guideline development group, and the supporting evidence Group’s experience and opinion of what constitutes good for active tuberculosis and consider treating for statements are in the full version practice. Evidence levels for the recommendations are given latent tuberculosis on bmj.com. in italic in square brackets. Evidence levels for the recom- ––For vaccinated children, perform a Mantoux test. mendations are in the full version of this article on bmj.com. If the Mantoux reaction is <15 mm, repeat the Mantoux test after six weeks, together with an IGRA. Diagnosing latent tuberculosis (new/updated If both repeat tests are negative, no further action recommendations) is needed. If either test is positive, exclude active All contacts of tuberculosis cases, aged 5 years or older tuberculosis and follow with treatment for latent • Offer Mantoux testing in line with the Department of tuberculosis. Health’s Green Book4 to: ––Household contacts of all people with active Contacts in outbreak tuberculosis • If large numbers of individuals need to be screened, ––Non-household contacts (other close contacts, such consider a single IGRA for people aged ≥5 years. as in workplaces and schools). • A positive Mantoux test is an induration of ≥6 mm New entrants from countries with a high incidence of diameter for those who have not been vaccinated with tuberculosis BCG and ≥15 mm diameter for those who have been • For children under 5 years, offer a Mantoux test. If vaccinated. strongly positive, refer to consider treating latent • Consider -γ release assay (IGRA) for people tuberculosis. whose Mantoux test shows positive results, or in • For children aged 5–15 years, offer a Mantoux test. If people for whom Mantoux testing may be less reliable positive, follow with an IGRA. (such as those who have been vaccinated with BCG). • For people aged 16–35 years, offer either an IGRA • Refer people with a positive IGRA or an inconclusive alone or a dual strategy (Mantoux test followed by Mantoux test to a tuberculosis specialist. IGRA). • For people over 35 years, consider the individual risks Household contacts aged 2–5 years and benefits of likely subsequent treatment before • Offer Mantoux testing. offering testing. • If the initial test is positive (taking into account BCG vaccination history), refer to a tuberculosis specialist People who are immunocompromised to exclude active disease and consider treating latent • If latent tuberculosis is suspected in children who are tuberculosis. immunocompromised, refer to a tuberculosis specialist. • If the initial Mantoux test is negative but the child is • For people with HIV infection and CD4 counts <200 a contact of a person with disease that is positive for cells/mm3 (<200×106/L), offer concurrent IGRA and acid fast bacilli on a sputum smear, offer an IGRA after Mantoux tests. If either test is positive, perform a

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bmj.com clinical assessment to exclude active tuberculosis and Active non-respiratory tuberculosis Previous articles in consider treating latent tuberculosis. • Discuss the advantages and disadvantages of both this series • For people with HIV and CD4 counts of 200–500 and needle aspiration with the patient, with 3 ЖЖAssessment and cells/mm , offer an IGRA alone or concurrent IGRA the aim of obtaining adequate material for diagnosis. management of psoriasis: and Mantoux tests. If either test is positive, perform a • If non-respiratory tuberculosis is a possibility, place summary of NICE guidance clinical assessment to exclude active tuberculosis and part or all of any of the following samples in a dry pot consider treating latent tuberculosis. (do not place in formalin) and send for tuberculosis (BMJ 2012;345:e6712) • For other people who are immunocompromised, culture: lymph node biopsy, pus aspirated from lymph ЖЖPrevention and offer an IGRA test alone or concurrent IGRA and nodes, pleural biopsy, any surgical sample sent for management of Mantoux tests. If either test is positive, perform a routine culture, any radiological sample sent for neutropenic sepsis in clinical assessment to exclude active tuberculosis and routine culture, histology sample, aspiration sample, patients with cancer: consider treating latent tuberculosis. autopsy sample. summary of NICE guidance • Microbiology staff should routinely perform (BMJ 2012;345:e5368) Healthcare workers tuberculosis culture on the above samples (even if it is ЖЖDiagnosis and • Offer a Mantoux test to new NHS employees who will not requested). management of be in contact with patients or clinical materials if the • Take a chest x ray of all patients with non-respiratory headaches in young employees are not new entrants from high incidence tuberculosis to exclude or confirm coexisting people and adults: countries and have not had BCG vaccination (they do respiratory tuberculosis. In addition, consider summary of NICE guidance not have a vaccination scar, other documentation. or imaging, biopsy, and histopathology as well as (BMJ 2012;345:e5765) reliable history). If the Mantoux test is negative, refer bacterial culture depending on the affected organ. ЖЖDiagnosis and to the Green Book for BCG immunisation guidance. If • If clinical signs and other laboratory findings are management of lower the Mantoux test is positive, offer an IGRA. consistent with tuberculosis meningitis, start limb peripheral arterial • For new NHS employees who have recently arrived treatment, even if a rapid diagnostic test is negative, from high incidence countries or who have had because the potential consequences for the patient are disease: summary of NICE contact with patients in settings where tuberculosis is severe. guidance highly prevalent, offer an IGRA. • Carry out rapid diagnostic tests for M tuberculosis (BMJ 2012;345:e4947) • Screen healthcare workers who are complex on biopsy material only if all the sample has ЖЖManagement of lower immunocompromised in the same way as other people been inappropriately placed in formalin and acid-fast urinary tract dysfunction who are immunocompromised. bacilli are visible on microscopy. in neurological disease: summary of NICE guidance Hard to reach groups Large scale contact investigation (BMJ 2012;345:e5074) • Offer people from hard to reach groups a single IGRA • With a positive result by microscopy or tuberculosis (see NICE guidelines on the control of tuberculosis in culture, confirm the species of to be hard to reach groups5). M tuberculosis complex by rapid diagnostic tests on material before starting large scale contact tracing Diagnosis of active tuberculosis (such as in a school or hospital). Use clinical judgment Active respiratory tuberculosis if tests are inconclusive or delayed. • Take a posterior-anterior chest x ray. If the x ray appearance suggests tuberculosis carry out further Multiple drug resistant (MDR) tuberculosis diagnostic investigation. • Undertake a risk assessment for MDR tuberculosis. • Send multiple sputum samples (at least three, Risk factors for MDR tuberculosis include prior with one early morning sample) for tuberculosis tuberculosis drug treatment; prior tuberculosis microscopy and culture for suspected respiratory treatment failure; contact with a known case of drug tuberculosis, before starting treatment if possible or, resistant tuberculosis; birth in a foreign country, failing that, within seven days of starting. particularly one with a high incidence of tuberculosis • If possible obtain spontaneously produced sputum; as defined by the Health Protection Agency; HIV otherwise use induction of sputum or infection; residence in London; age profile (with and lavage. highest rates between the ages of 25 and 44 years); • In children unable to expectorate sputum, consider and male sex. induction of sputum if it can be done safely; consider • If a risk assessment suggests a patient has MDR gastric washings as third line. tuberculosis, carry out rapid diagnostic tests for • Use rapid diagnostic tests for Mycobacterium resistance and start infection control tuberculosis complex (M tuberculosis, M bovis, M measures and treatment for MDR tuberculosis pending africanum) on specimens obtained from patients the result of the tests. only if rapid confirmation of a tuberculosis diagnosis in a person whose sputum smear is positive would Starting treatment alter the patient’s care or before conducting a large • If clinical signs and symptoms are consistent with contact tracing initiative. Do not use such tests for a diagnosis of tuberculosis, start treatment without pleural fluid, , or urine to exclude waiting for culture results. Continue the standard the diagnosis of tuberculosis as they have a high false recommended regimen in patients whose subsequent negative rate. culture results are negative.

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Overcoming barriers Competing interests: All authors have completed the ICMJE uniform disclosure Primary care can and should play a key role in promot- form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the ing early diagnosis of both active and latent tuberculosis submitted work; no financial relationships with any organisations that might through a systematic approach to screening for tubercu- have an interest in the submitted work in the previous three years, no other losis. Studies indicate that screening in primary care can relationships or activities that could appear to have influenced the submitted work. IA is funded through an NIHR senior research fellowship. The views contribute to the detection of latent tuberculosis in high expressed in this publication are those of the authors and not necessarily those risk groups.6 However, the resources available for the of the NHS, National Institute for Health Research, or Department of Health. necessary tests are limited, with consequent variation in Provenance and peer review: Not commissioned; not externally peer reviewed. the extent to which interferon-γ release assays (IGRA) are 1 Abubakar I, Lipman M, Anderson C, Davies P, Zumla A. Tuberculosis in the UK—time to regain control. BMJ 2011;343:d4281. 7 implemented, as too often screening is not prioritised by 2 National Institute for Health and Clinical Excellence. Tuberculosis: commissioners. Demonstration of the potential impact of clinical diagnosis and management of tuberculosis, and measures for its prevention and control. (clinical guideline 117). NICE; 2011. http:// this intervention on local tuberculosis rates and of more guidance.nice.org.uk/CG117. pragmatic thresholds for screening migrants8 are the 3 National Institute for Health and Clinical Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for most effective ways to improve funding. its prevention and control (clinical guideline 33). NICE, 2006. http:// The application of the tests outlined in this arti- guidance.nice.org.uk/CG33. 4 Salisbury D, Ramsey M, Noakes K. Immunisation against infectious cle to achieve prompt diagnosis of active tuberculosis diseases—the green book. Department of Health, 2008. requires early recognition and referral of individuals 5 National Institute for Health and Clinical Excellence. Tuberculosis—hard to with sy­mptoms and signs of tuberculosis by general reach groups (public health guidance 37). NICE, 2012. http://guidance. nice.org.uk/PH37. prac­titioners. Greater awareness of the clinical presen- 6 Griffiths C, Sturdy P, Brewin P, Bothamley G, Eldridge S, Martineau A, et al. tation of tuberculosis and risk factors among healthcare Educational outreach to promote screening for tuberculosis in primary care: a cluster randomised controlled trial. Lancet 2007;369:1528-34. providers remains the primary route to achieve early 7 Pareek M, Abubakar I, White PJ, Garnett GP, Lalvani A. UK immigrant diagnosis and avert transmission and adverse outcomes screening is inversely related to regional tuberculosis burden. Thorax 2011;66:1010. for the patient. 8 Pareek M, Watson JP, Ormerod LP, Kon OM, Woltmann G, White PJ, et al. Contributors: All authors contributed to the conception and writing of Screening of immigrants in the UK for imported latent tuberculosis: a this manuscript and have agreed on the final version of the paper. IA is multicentre cohort study and cost-effectiveness analysis. Lancet Infect Dis guarantor. 2011;11:435-44.

A PATIENT’S JOURNEY Tuberculosis Mel Burden, Hugh Bakere

Royal Devon and Exeter Hospital, Ten months after returning home from ever, I provided a sputum sample for culture and sensitiv- Exeter EX2 5DW, UK ity testing and took the prescribed amoxicillin. Correspondence to: M Burden working in a rural South African hospital, My sputum grew a penicillin resistant Staphylococcus [email protected] an infection prevention and control nurse aureus, so my antibiotic was changed to erythromycin. The Cite this as: BMJ 2012;345:e6713 symptoms persisted. At this point, I could not walk up two doi: 10.1136/bmj.e6713 developed tuberculosis. She describes the flights of stairs without becoming breathless, and I joined This is one of a series of occasional challenges of dealing with her treatment, our local gym in an attempt to improve my fitness. articles by patients about their experiences that offer lessons her isolation, and the reactions of friends After two weeks of antibiotics, continual coughing, and to doctors. The BMJ welcomes and colleagues a negative sputum sample, I voiced the possibility of TB contributions to the series. Please to my GP. However, asthma remained the working diagno- contact Peter Lapsley (plapsley@ I was 28 years old and newly married when I was diag- sis and I left the surgery with a course of prednisolone. A bmj.com) for guidance. nosed with pulmonary tuberculosis (TB). I had recently chest x ray was to be considered if there was no improve- started a new job as an infection control nurse, and the ment. irony of this was not lost on me or those around me. Ten months previously I had returned to Devon having spent Disbelief and guilt six months working with my husband, Tom, in a rural My husband asked me if he could talk to his consultant, South African hospital where drug resistant and sensitive respiratory physician Hugh Bakere, and I agreed. After TB were rife. With minimal hospital resources, we worked an informal chat, Dr Bakere saw me in clinic. My chest everyday without personal protective equipment. Several x ray appeared normal. He mentioned the possibility of nurses there developed TB; some died. bronchiectasis and the need to rule out TB, and said he Having had a persistent cough and mild breathlessness didn’t think it was cancer. Over the following weekend I for about a month, I went to see my GP. I saw a locum coughed up the usual thick green sputum and diligently who diagnosed a chest infection with exacerbation of my dispatched more samples to microbiology. On the Wednes- asthma. I told him this did not feel like asthma: my peak day I received a phone request to see Dr Bakere immedi- flow was normal and I had no expiratory wheeze. How- ately. The sputum samples had tested positive for acid fast

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bmj.com A DOCTOR’S PERSPECTIVE Previous articles in this series Mel presented to me through a slightly unusual route; on standard pulmonary mycobacterium TB therapy. This her husband, a junior doctor, approached me with his is six months of isoniazid and rifampicin supplemented in ЖЖFatigue in primary concerns about her. I met Mel with her husband in my the first two months with and . I biliary cirrhosis office. Mel had had a productive cough for seven weeks, also gave her pyridoxine as prophylaxis against isoniazid (BMJ 2012;345:e7004) had occasional night sweats, and felt generally lethargic. induced neuropathy. We advised her to remain isolated at ЖЖNeuromuscular Her weight was stable. She was worried about tuberculosis home avoiding new contacts for two weeks as a standard degeneration as she had returned from working in a rural hospital with precaution. We were more concerned about this than usual (BMJ 2012;345:e6880) TB patients in South Africa, six months earlier. Mel had as South Africa is an area with an increased incidence of ЖЖNon-small cell a history of asthma, normally well controlled, but her multidrug resistant TB. Her case was notified and contact cancer symptoms were different and more prolonged than those traced in the usual way. She has successfully completed her she had experienced with previous exacerbations of treatment. (BMJ 2012;345:e6443) asthma. The case highlights several points. Firstly, it is important ЖЖHow no one acted I felt on initial assessment that pulmonary tuberculosis to consider the diagnosis; key here was her travel and when they should have was a real possibility, along with perhaps bronchiectasis, occupational history. As a respiratory physician in (BMJ 2012;345:e5366) and ordered a and three sets of sputum south west England, I am working in an area with a low ЖЖIrreversible renal for microscopy culture and sensitivity analysis, examination incidence of TB (5.1 cases/100 000 in 2010) and see only damage from accidental for acid fast bacilli, and TB culture. The chest radiograph a smattering of TB in the local population. Mel, however, mushroom poisoning was clear but two sputum samples were acid fast bacilli was returning from a high incidence area (with significant positive, and Mycobacterium tuberculosis (fully sensitive) exposure in the hospital she worked in) and her risk of (BMJ 2012;345:e5262) was later cultured. I was slightly surprised by the clear contracting TB was therefore much higher. It was this chest radiograph, but given her history and two confirmed history along with her clinical presentation that pushed sputum samples I was fairly happy with the diagnosis. A TB up towards the top of my list of differential diagnoses. positive Quantiferon test result provided further support. Secondly, a normal chest radiograph does not completely Endoscopy of the ear, nose, and throat showed no evidence exclude TB. Thirdly, we should remember the value of good of oropharangeal TB. I considered computed tomography TB nurses, who delivered much of Mel’s ongoing care. of the thorax, which I expect would have shown a focus of Lastly, it is important to formalise care for our colleagues disease, but decided against it as I did not want to expose with an ongoing healthcare problem; Mel was slotted into this young woman to the associated radiation dose. the usual clinic set up quickly. Immediately after the positive sputum result, I started Mel Hugh Bakere

bacilli. All this didn’t really sink in . . . “I can’t have TB, my for ages, maybe I’ve got it.” People tried to hide their con- chest x ray was normal—was this a lab error?” cerns with humour: “Will I give it to my kids?” “Don’t come The following day, having been signed off work, I had too close,” “Can I still get it?” None of these was funny a formal respiratory clinic appointment. We discussed to me. Tom continually provided comfort by rationalis- reasons for Quantiferon and HIV testing, baseline blood ing the stigma and guilt: did I feel annoyed or angry with tests, treatment options, and the importance of compli- the person who “gave me” TB? No, so why should anyone ance and prognosis. else? It was logical, but sadly it didn’t help. So, I had TB. A part of me was excited at having an inter- And then there was the isolation. The first two weeks esting infection. A greater part was embarrassed at being after diagnosis I spent at home without visitors or visits to an infection control nurse with TB. The over-riding feeling public places. I took isolation particularly seriously. I was was guilt. I had a deep concern that I could have poten- determined not to give anyone else TB and thought of the tially infected friends, family, colleagues, and patients. public’s reaction to an infection control nurse spreading Compiling a contact screening list only worsened this TB around our small community. feeling. I was very low, frustrated, and overwhelmingly lonely. Part of me was disbelieving—I felt relatively well; it I had only just started my new job and already missed couldn’t be right. I was apprehensive about treatment, the the companionship and the office banter. These feelings side effects, and prognosis after treatment. There was also were made worse by the complicated treatment and asso- a part of me that felt bitter that I hadn’t been listened to. ciated side effects. I felt extremely nauseous and tired. This passed after I realised how quickly I was diagnosed in My joints ached and a tingling sensation developed in the grand scheme of things, but I sometimes wonder what my hands. The consequences of the medication made me could have happened. feel so much worse than the TB itself did, and I can now understand why treatment compliance is so difficult and Psychological effects the importance of understanding why medication has to Overriding all of this was stigma. I was infectious. I was be taken. I had always struggled to swallow tablets, so the to be confined to my house, unable to socialise. I had to sheer number I had to take proved difficult at the begin- make phone calls and explain to people why I could not ning. As a healthcare professional I now have a great deal see them, or why they had to be screened. more empathy for people taking multiple medications. The psychological and emotional effects of TB affected My isolation worsened my guilt. The contact tracing me. People’s perceptions of TB came across strongly. Peo- programme began for my friends and family, who took it ple I hadn’t seen while coughing said, “I’ve had a cough in their stride, telling me not to worry, but I did. Blood tests

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Tom was a great support, and appointments with the USEFUL RESOURCES FOR PATIENTS AND CLINICIANS respiratory team soon made me more positive. I was also Health Protection Agency—Provides useful and fortunate to be working within the infection control team, comprehensive information on TB (www.hpa.org.uk/Topics/ who provided a huge amount of support. Regular contact InfectiousDiseases/InfectionsAZ/Tuberculosis) from my GP added to the support. On the advice of the TB World Health Organization’s observations on the observance nurses, I researched several organisations (see resources of World TB Day in 2010 are available at box) to gain a deeper understanding of TB. Reading other www.who.int/dg/speeches/2010/world_tb_ peoples’ stories was helpful, and I started to keep a diary, day_20100324/en/index.html which, in part, motivated me to write this article. TB Alert (www.tbalert.org)—The only British charity working Now treatment is complete I am back at work full time— solely on fighting TB in the UK and overseas my manager and colleagues have been instrumental in my British Lung Foundation (www.lunguk.org)—Resources graduated return to work. The medication and side effects are focused on providing support for people affected by are no more, and I can enjoy food again. I have regained lung disease. The foundation funds world class research, weight, have no cough, and my stamina has increased. My campaigns to bring about positive change in lung health, family and friends have all been screened with encourag- and aims to improve treatment, care, and support for those ing results. The huge worry and guilt regarding infecting affected by lung disease others has gone. Did this contribute to my feeling better? The truth about TB (www.thetruthabouttb.org) contains My patient journey has shown me that TB is not just a information on symptoms and risks of TB, treatment, and medical disease—so many emotional and social factors information and stories about people who have had TB in interplay, making it paramount that a TB patient gets the UK appropriate care and support for these issues as well as Heymann DL. Control of communicable diseases manual. medical treatment. 18th ed. American Public Health Association, 2004. Competing interests: Both authors declare no support from any organisation for the submitted work; no financial relationships with any for children seemed cruel, with some of them too young to organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear understand; x ray radiation to adults concerned me. Oth- to have influenced the submitted work. ers were self employed and could have lost earnings while Provenance and peer review: Not commissioned; not externally peer attending appointments, and all because of my desire to reviewed. experience healthcare in a developing country. Accepted: 29 August 2012

ANSWERS TO ENDGAMES, p 50 For long answers go to the Education channel on bmj.com

PICTURE QUIZ Neonatal seizure: what is the cause? STATISTICAL 1 Common causes of neonatal seizures include hypoxic ischaemic encephalopathy, QUESTION intracranial haemorrhage, intracranial infections, congenital cerebral malformations, metabolic disorders, and focal ischaemic stroke. Analysis of 2 Jitteriness and benign neonatal sleep myoclonus are the two most common outcome conditions that mimic seizure in neonates. measures within 3 The MRI of the brain shows extensive venous thrombosis. treatment groups 4 Neonatal cerebral sinovenous thrombosis. Statements a, b, and c 5 Management involves anticoagulation with low molecular weight heparin, are all false. ultrafractionated heparin, or warfarin and management of seizures and any identified acquired causes of cerebral sinovenous thrombosis. ANATOMY QUIZ Anatomy of the pituitary region A: Optic chiasm B: Hypothalamus C: Pituitary stalk D: Posterior lobe of pituitary gland E: Anterior lobe of pituitary gland F: Suprasellar cistern

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