for the upper zones, particularly the posterior segments. Disease in the lower lobes is usu ally in the apical segments. The shadowing initially is an in \201 ltrate, which can then become con \202 uent with cavitation and loss of volume developing. In association with HI V-infection the pattern becomes increasing less typi- cal as immunosuppression progresses. Clinical approach Suspicion of respiratory TB is a synthesis of 3 elements: a) the clinical setting (for which a knowledge of the above epidemiology is important), b) symptoms, and c ) CXR appearances (see later). Of the common respiratory symptoms, cough, weight loss, feve r, night sweats, breath- lessness and haemoptysis, only fever and night sweats are statisti cally more associated with TB than other respiratory conditions. Fig. 8.7.1 CXR: in \201 ltration and cavitation left upper lobe 5 \200\2238% of respirator y TB presents as a pleural effusion. This is associated with a strongly positive tuberculin test and the \202 uid is a lymphoc yte rich exudate. It is usually within 3 \200\22312 months of primary infection. Pleural bi opsy gives gran- ulomas in 50 \200\22360% of cases and 50 \200\22360% are culture positive. Examination \200 Unless there is extensive lung involvement, or a signi \201 - cant pleural effusion there are seldom signs in the lung. General examination may show evidence of TB at other sites, p articularly cervical lymphadenopathy. Investigation \200 CXR de \201 nes extent and the clinical pattern raises suspi- cion (see later). Bacteriolo gy is crucial both to con \201 rm the diagnosis and to obtain drug susceptibility testing. Three early morning sputums should be sent for TB microscopy and culture if the patient is expectorating. If no spontaneous sputum is produced consider induced sputum, or preferably bronchoscopy with washings tar- geted to the areas of X-ray abnormality (with appropriate infection control measures). Blood tests may be normal and only give non-speci \201 c abno rmalities. Tuberculin testing is usually unhelpful in pulmonary TB as it does not different iate between disease and infec- tion, and may be falsely negative due to illness or co- mor bidities e.g. HIV co-infection. Fig. 8.7.2 CXR: right pleural effusion. 5 \200\2238% of respiratory TB presents as isolated mediastinal lym- phadenopathy, associat ed with a strongly positive tuberculin test. CT scan may show lymphadenopathy with central CHAPTER 8.7 Respiratory tuberculosis 189 Commencing treatment \200 hypodensity (caseation). Mediastinoscopy is only needed if either the tuberculin test is we ak or negative (to exclude lym- phoma or sarcoidosis) or if there is not some reduction in gland size after 2 months standard treatment. If sputum or respiratory secretions are microscopy posi- tive, or the probablility of TB is high after samples have been sent, TB treatment should be commenced. Treatment should be w ith rifampicin, isoniazid, pyrazina- mide and ethambutol as Rifater plus ethambutol 15mg / kg (to the nearest 100mg), unless there is signi \201 cant renal impairment. Pyridoxine (10mg) is not routinely required unless there are risk factors for peripheral neuropathy \200\223 e.g. diabetes, alcoholism, malnutrition or HIV-positivity. U&Es and LFTs should be checked pre-treatment, to con \201 rm normal renal function and give a base-line for LFTs Visual acuity using Snellen chart should be checked, full ophthalmolgical assessment is no t necessary. Patients starting on TB treatment should be noti \201 ed to the Consultant in Communicable Disease Control. Consideration should be given to named HIV-testing to \201 nd/exclude co-existent HIV infection. Material sent to the lab should be screened by auram ine stain and cultured using rapid liquid culture. An assessment of likely adherence with t reatment should be made before starting treatment and consideration given to Directly Obser ved Treatment (DOT) with a three times weekly regimen. Isoniazid 15mg/kg, rifampicin 600 \200\223900mg, pyrazinamide 2.0 \200\2232.5gm, and ethambutol 30mg/kg should be given thric e weekly, most conveniently Monday, Wednesday and Friday under direct observation if this i s used. A risk assessment for drug resistance should be made, particularly if there is any prior treatment history, and a rifampicin resistance probe requested on any micros- copy or culture-positive material if concern exists. Adherence to medication should be monitored a t least monthly with pill counts and random urine tests for rifampicin. If a large contact tracing exercise is likely e.g. in a school or a hospital or care facility con \201 rm tha t the organisms seen/isolated is M.tuberculosis by appropriate gene probe before embarking on the contact tracing (with attendant publicity). Fig. 8.7.3 CXR: right paratracheal lymphadenopathy. Classical miliary TB occurs in a few % of cases. The full X-ray picture is easy to spot, wi th homogenous micro-nodules of 1 \200\2232mm spread throughout all lung zones. The early st ages are more subtle and are best seen on HRCT scans. The diag- nosis is usually easily con \201 rmed with positive cultures, and often scanty-positive microscopy positive bronchial washings \200 A lumbar puncture and CT scan should be carried out in classical miliary T B even in the absence of symptoms. 30% of such cases will have either LP or CT abnormali- t ies, showing CNS involvement. Such CNS involvement then needs a 12-month regimen and cortic osteroid treatment (see Chapter 8.8). Treatment in special situations \200 \200 Diabetes \200\223 standard treatment plus pyridoxine. Pregnancy \200\223 standard treatme nt, only streptomycin and prothionamide to be avoided. Liver disease \200\223 standard tre atment but regular LFTs \200\223 weekly \201 rst 2 weeks, then 2-weekly. Renal disease \200\223 rifampicin, isoniazid and pyrazinamide in standard dosages. Reduced dosages of eth ambutol or streptomycin. Moxi \202 oxacin 400mg od is an acceptable alternative. HIV-posit ive. TB takes precedence. Standard treat ment, adjust HAART if necessary to avoid rifampici n interac- tions. Fig. 8.7.4 CXR: classical miliary TB. AUTHOR \200\231S TIPS \200 Infection control \200 In ethnic minority groups, pleural effusion or isolated mediastinal glands with a positive tuberculin test, should be treated as TB until proved otherwise. Cavititation is active TB is highly (>0.00001) correlated with sputum microscopy positivity for AFB. If 3 sponta- neo us sputum tests are negative for AFB, the diagnosis of TB should be reconsidered. Suspected respiratory TB if admitted should be to a single side ward until results of 3 spu tums known. Sputum microscopy cases remain infectious until 2 weeks standard treatment. Mas ks are only needed for suspected or proven MDR-TB cases. P ORMEROD 190 resistance is M.bovis. Pyrazinamide should stopped and treatment should be with 2 months ri fampicin, isoniazid and ethmabutol, followed by a continuation phase of rifampicin and ison iazisd for 7 months. Ethambutol: ethambutol mono-resistance is very uncom- mon. It does not affect the ef \201 cacy of standard 6-months short course chemotherapy which should be co ntinued. Rifampicin: Isolated rifampicin resistance is uncommon, accounting for only 5 \200 \22310% of rifampicin resistance. The \201 nding of rifampicin resistance, particularly o n a gene- probe, SHOULD BE TREATED AS MDR-TB, with the patient isolated as for, and treated for MDR-TB until proved otherwise. If rifampicin monoresistance is con \201 rmed on full suscep- tibility tests then a regimen of 18 months isoniazid and ethambutol, supplemented b y an initial 2 months pyrazi- namide should be used. Suspected or proven MDR-TB should be in a negative pressure room if in hospital. NICE Guide lines and JTC 2000 guidance give criteria for cessation of respiratory isolation. During treatment \200 Regular LFT monitoring is not needed unless these are abnormal pre treatment or unless the patient has pre- existing liver disease or is Hep B or Hep C positive. Modest elevations of the transaminases are not uncom- mon in the pre-treatment LFTs of TB patients and usually improve rapidly with treatment. 3% of individuals will develop hepatitis/jaundice due to th e drugs, with a raised bilirubin or a rise in transaminases to >5x normal. If this happens treatment with rifampicin/isoniazid and pyrazinamide should be stopped If the patient is not unwell and the form of TB is non-infectious, no treat- ment needs to be given until liv er function returns to normal. If the patient is unwell, or the sputum microscopy posi- tiv e within 2 weeks of starting treatment, some form of treatment needs to be given until the LFTs improve. Streptomycin and ethambutol with appropriate checks should be used unless cli nically contraindicated or drug resistance is known or suspected. Pyrazinamide is the most likely drug, followed by rifampicin and then least likely isoniazid. Treatment re-introduct ion, if cessation of treatment is needed, follows the reverse order of probability. Multiple resistance \200 The commonest multiple resistance is combined isoni- azid and streptomycin resistance. This should be treated as per isolated isoniazid resistance, but the use of a 3 times weekly DO T regimen (with appropriate dosage adjustments) should be considered. Other combined (non-M DR) resistances are uncommon and need to be discussed on a case by case basis with an exper t in TB management. MDR-TB \200 MDR-TB is de \201 ned as high level resistance to rifampicin (the main sterilizing drug) a nd isoniazid (the main killing drug) 9 other TB drugs. Fortunately this occurs in only 50 \200\22360 new cases/year in the UK. Most of these have a history of prior treatment abroad , with prior treatment increasing the risk 15-fold. Lithuania, Latvia, Estonia, Cote D \200 \231Ivoire and the Dominican Republic all have MDR-TB rates of over 5% of cases. MDR-TB can now be subdivided into: (a) Basic MDR-TB with only rifampicin and isoniazid Schedule for re-introduction of anti-TB drugs A detailed schedule for drug re-introduction is given in the 1998 Joint TB Committee Guidelines (see Further reading). At 2 months \200 If a positive culture is obtained, if the organism is fully sensitive then pyrazinamide and ethambutol can be stopped. If the organism is resistant then treatment should be modi \201 ed as per NICE Guidelines. If cultures are negative, stop pyrazinamide and ethambutol. If a culture is positive but susceptibilities are outstanding, continue all 4 drugs until they are known. Only stop pyrazinamide and ethambutol once full susuceptibility is con \201 rmed, total duration of treatment however does not need extending beyond 6 months. Con tinuation treatment with rifampicin/isoniazid as Ri \201 nah should continue for 4 month s (unless drug resistant). resistance. (b) MDR-TB with rifampicin and isoniazid resistance, plus some other drugs including pyrazi namide and ethambutol. (c) XDR-TB \200\223 extremely resistant TB, with resistance to rifampicin, isoniazid,pyraz inamide, ethambutol, and at least aquinolone and one rejectable amikaar, capreomycin kanamy cin. The \201 nding of rifampicin resistance should lead to appro- priate isolation and treatm ent. Proven or suspected MDR-TB SHOULD NOT BE TREATED without the input of a physician expe rienced in such cases. The principles of treatment are: (a) Use at least 5 drugs to which t he organism is, or is thought likely to be, susceptible, including 1 injecta- ble if availa ble until culture negative. At least 3 drugs to be continued, for at least 9 months after b ecomes culture negative. Management of drug resistance The management of drug resistance depends on the drug resista nce pattern, which must be followed (unlike in opportunist mycobacteria (see later)). Monoresistance \200 Streptomycin: this does not alter the effectiveness of standard treatment and no modi \201 cation is needed. Isoniazid: Isoniazid should be stopped and treatment should be with 2 mo nths initial rifampicin, pyrazinamide and ethambutol. The continuation phase should then be with 7 \200\22310 months of rifampicin and ethambutol. Pyrazinamide: The usual cause of is olated pyrazinamide (b) Transfer the patient to another hospital/physician unless both expertise AND a negative pressure room co-exist at the same location. (c) Close liaison with the Mycobacterium Reference Centers and Unit of the HPA is essential. CHAPTER 8.7 Respiratory tuberculosis 191 During the continuation phase \200 Treatment of latent TB infection (LTBI) \200 Check sputum, if still being produced, or if clinical progress is unsatisfactory at 4 month s. A positive TB cul- ture at 4 months is regarded as treatment failure, and should lead to repeat drug susceptibility tests and a molecular probe for rifampicin resistance. NEVER AD D A SINGLE DRUG TO A FAILING REGIMEN. Such individuals are tuberculin positive, preferably con- \201 rmed by a positive IGRA te st, aged up to 35 years and identi \201 ed through new entrant or contact screening. It is important to con \201 rm that there is no evidence of disease \200\223 lack of symptoms, normal CXR, and examina- tion, as the regimens below are only suitable for treat- ment of LTBI. Treatment with either rifampicin and isoniazid (3RH) or isoniazid for 6 months (6H) i s recommended. At end of treatment \200 End of treatment CXR as baseline for future compari- son. If no drug resistance, adherence good and no residual complications, discharge with advice to patient and GP to refer back i f symptoms recur (unlikely relapse rate 0 \200\2233% for standard TB). Only follow up if co ntinuing clini- cal problem or doubt about adherence. If isoniazid resistance follow up at 6 and 12 months. If MDR-TB long term follow-up. Further reading Citron KM, Thomas GO. Ocular Toxicity and ethambutol. Thorax 1986; 41: 737 \200\223739. Dye C, Scheele S, Dolin P, et al. Global burden of tuberculosis. Estimated incidence, preva lence and mortality by country. JAMA 1999; 282: 677 \200\223686. Health Protection Agency. Focus on TB. Annual Surveillance Report 2006. England, Wales and Northern Ireland. London: HPA Center for Infections. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management o f tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998; 53: 536 \200\22354 8. Contact tracing/new entrant screening NICE guidelines (2006) set out who to screen and how to screen, including the use of interferon-gamma assays (IGRAs). The main aims of such scre ening is to (a) detect those with disease, particularly pulmonary; (b) identify those with latent TB infection who may bene \201 t from treat- ment; and (c) those without immunity w ho may bene \201 t from BCG vaccination. Between 1 \200\22310% of new TB cases, are found through screening of household contacts, with the majority of cases being in the non-BCG \200\231d contacts of sputum smear-positive disease on the \201 rst attendance. Only 1 in 200 of new entrants are found to have active TB on entry to the UK. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tub erculosis in the United Kingdom: recommendations Thorax 2000; 55: 887 \200\223901. National Collaborating Center for Chronic Conditions (for NICE). Tuberculosis: clinical dia gnosis and management of tuberculosis and measures for its prevention and control. London: Royal College of Physicians 2006. ISBN 1 86016 227 0. Ormerod LP, Skinner C, Wales JM. Hepatotoxicity of antituberculo- sis drugs. Thorax 1996; 51: 111 \200\223113. Ormerod LP, Green RM, Hors \201 eld N. Outcome of treatment of culture negative tuberculos is (respiratory and nonrespiratory) Blackburn 1996-2000. J Infection 2002; 45: 88 \200\2238 9. P ORMEROD 192 8.8 Non-respiratory tuberculosis Epidemiology The overall epidemiology follows that of TB in general (see Chapter 8.7). Howe ver non-respiratory TB occurs with increased frequency in all non-white ethnic groups. Non- respiratory sites account for only 20% of cases in the white population, but nearly 50% in minority groups. Lymph node TB, 90% in the cervical glands, accounts for nearly half of all non-respiratory TB. Some patients will have both res- piratory and non-respiratory TB. After treatment \200 5 \200\22310% may develop new glands or enlargement of glands after cessation of treatment. These are almost invariably sterile if aspirated or biopsied. They are immunologically med iated, due to reaction to tuberculo-proteins from disrupted macrophages. Short courses of s teroids may be needed to suppress these phenomena. TB drug treatment should only be restart ed if there is a positive culture for M. tuberculosis. Treatment All forms of non-respiratory TB should be treated with 6 month \200\231s rifampic in and isoniazid, supplemented by 2 months \200\231 initial pyrazinamide and ethambutol, wi th the sole exception of CNS disease (see sub-section), unless there is drug intolerance or drug resistance. Modi \201 cation of treat- ment for drug resistance or intolerance is as for respira- tory TB (see Chapter 8.7). The drug treatment of all cases of TB should be un der the management of either a respira- tory or infectious disease physician, or if a child in conjunc- tion with a pediatrician. Bone and joint TB Clinical \200 \200 50% of all cases are spinal, largely thoraco-lumbar. Back pain may be present for weeks or months before the diagnosis, with some local tenderness. The disease begins as a discitis i nvolving inferior and superior borders of adjacent vertebrae, leading to loss of disc space . Kyphosis and angulation are later features. Paraspinal and extradural abscesses can form, the former sometimes presenting as a para-spinal mass, or a psoas abscess pointing in the groin. 50% of bone and joint TB is non-spinal and can involve virtually any bone or joint. Any subacute mono-arthritis in an ethnic minority patient should have TB high in the differ ential, particu- larly if pus can be aspirated or there is sinus formation. Neurological si gns or symptoms in the legs, or sphincter disturbance suggest spinal cord compression. \200 Lymph node TB Clinical \200 \200 90% of cases involve the cervical nodes. 10% of those with cervical nodes also have mediast inal lymphadenopathy with no visible lung lesion on CXR. Are usually \200\230cold \200\231 without the warmth and erythema of pyogenic infection. Usually painless and of gradual ons et but can be painful if enlargement is more rapid. Central caseation leads to \202 uctua nce, which can then lead to discharge and then sinus formation. Constitutional symptoms, we ight loss, fever, malaise, night sweats, are seen only in a small minority of patients. Per istent lymphadenopathy for over 4 weeks in an ethnic minority patient should be regarded as TB until proved otherwise, and investigated accordingly. Investigation \200 \200 Plain radiology can initially be normal. CT or MRI are the investigations of choice for sus pected spinal TB. Needle or open biopsy may be needed to make the diagnosis. Surgeons need to be reminded not to place all material in formalin but send TB cultures. Investigations \200 Treatment \200 CXR may show other disease. Surgical intervention in spinal disease is only indicated if there are neurological signs o r symptoms. Management should be jointly with an orthopedic sur- geon who manages the mecha nical aspects of disease, but not drug treatment. FNA is useful for cytology but does not give enough mate- rial for TB culture. \200 If there is any hint of \202 uctuance aspirate the node with a wide-bore (white needle) a fter a little local anesthetic in the overlying skin. Obtaining even a small amount of pus from a \200\230cold \200\231 node is suf \201 cient to start treatment. If no pus can be obtained, node biopsy for histology and culture should be performed. The \201 nding of gr anulomatous histology supported by a positive Mantoux allows treatment to start pending cul ture results. Only 60 \200\22370% of cases are culture con \201 rmed. Gastrointestinal TB Clinical \200 Approx 1/3 present as an acute abdomen mimicking appendicitis or with acute intestinal obst ruction. The other 2/3 are more gradual usually with abdominal pain if there is a degree of intraluminal disease, or distension if there is ascites due to peritoneal disease. Only 25 \200\22330% have any CXR evidence of respiratory TB. Systemic symptoms of weight loss, fev er, and malaise are found in over 50%. During treatment \200 \200 Enlargement of current nodes, or the development of new nodes, occur in 20% of cases, and d o not imply treatment failure, but are usually immunologically mediated. 5 \200\22315% of c ases have a degree of persistent lymphaden- opathy at the end of treatment. Investigations \200 \200 Ultrasound may show ascites or bowel masses. Small bowel studies may show strictures, \201 stulae and skip CHAPTER 8.8 Non-respiratory tuberculosis 193 lesions. They cannot distinguish between Crohn \200\231s disease and TB. Caecal and colonic lesions can simulate carcinoma: colonoscopy is useful. Ascitic \202 uid is a lymphocyte- rich exudate. Laparoscopy is the investigation of choice in asctic/peri- toneal presentatio ns. Fever should respond within 2 weeks if a trial of treatment is given. Urological TB \200 \200 Sterile pyuria should lead to EMU x 3 for AFB. Urine microscopy for AFB is unreliable for d iagnosis because of genital mycobacteria (M. smegmatis), and the use of intravesical BCG fo r bladder cancer. IVP shows chronic clubbing of calyces, there may also be intra-renal calc i \201 cation. Steroids for 2 months might be of bene \201 t if there is ureteric stenosi s, but this may need temporary stenting. Chronic TB cystitis leads to severe frequency due to marked bladder capacity reduction. An ileal loop may be needed after TB treatment is com pleted to increase bladder capacity. Chronic prostatitis or epididymitis or testicular mass es in ethnic minority patients have TB in the differential diagnosis. \200 Treatment \200 Bowel resection is only required if there is mechanical obstruction. 10% of female cases wi ll have secondary infertility. In an ethnic minority patient with granulomatous changes in the bowel on biopsy, it is much safer to \201 rst treat for TB than Crohn \200\231s disea se, than vise versa. \200 TB meningitis Although making up only 1 \200\2232% of cases of TB, the diagnosis is very im portant because of the morbidity and mortality, particularly if the diagnosis is delayed or missed. Gynecological TB \200 Clinical \200 Salpingitis or endometritis are usually found during investigation of infertility. Granulom atous histology on D&C or fallopian tubes are very suggestive and bacteriology should be so ught. Onset is insidious usually over a few weeks with headache and malaise. Focal neurological s igns or confusion follow (Stage 2 disease), and later coma (Stage 3). Prognosis crucially d epends on the clinical stage at start of treatment, so suspicion and early diagnosis are im por- tant. Skin TB \200 Half is due to underlying lymph node, bone or renal disease (scrofuloderma). Chronic skin l esions in ethnic minority individuals, particularly if granulomatous, should be considered suspicious (remember leprosy). Investigation \200 CXR is normal in over 70% of cases but may show acute miliary disease. LP shows a lymphocyt osis (rarely above 500/ml), with a raised protein and reduced glucose. Microscopy for AFB i s rarely positive. PCR tests for AFB are misleading and give false negative results in 20-4 0%, do not use. Baseline CT or MRI may show initial increased menin- geal uptake, tuberculo mas, or hydrocephalus. Pericardial TB \200 Apparent cardiomegaly is seen on CXR, echo con \201 rms the degree of pericardial \202 u id. Pericardial \202 uid is a lymphocyte rich exudates. Prednisolone beginning at 60mg/da ily tailing over 3 months is given as well at standard TB treatment. Steroids signi \201 c antly reduce death, the need for pericar- diocentesis and pericardectomy. \200 \200 Treatment \200 Treatment is for a minimum of 12 months with rifampicin and isonaizid, supplemented by 2 mo nths \200\231 initial pyrazi- namide and a fourth drug. Ethambutol, streptomycin (not intra thecal) or prothionamide can be used. Steroids, starting at prednisolone 40 \200\22360mg/da y, tailing over several weeks are now recommended for all cases of TBM. Tuberculomas can de velop during treatment. Repeat CT scanning is needed if there is clinical deterioration. Sh unting may be needed if hydrocephalus develops. Other sites Chronic abscesses or sinuses in ethnic minority patients should have TB activel y considered with histology and cul- tures sent. Further reading British Thoracic Society Research Committee. Six-months versus nine-months chemotherapy for tuberculosis of lymph nodes: \201 nal results. Respir Med 1993; 87: 621 \200\223623. \200 National Collaborating Center for Chronic Conditions (for NICE) Tuberculosis: clinical diag nosis and man agement of tuberculosis and measures for its prevention and control. London: Royal College of Physicians 2006. ISBN 1 86016 227 0. Miliary TB \200 \200 Non-Respiratory TB. In Davies PD et al. Clinical Tuberculosis, 4th Acute classical miliary TB (see respiratory). Cryptic miliary TB presents as a PUO, with we ight loss and high ESR. Biopsies from liver and bone marrow may show granulo- mata. EMU, li ver, and bone marrow are the best sites for culture. edn. London: Hodder Arnold, 2008. P ORMEROD 194 8.9 Opportunist (non-tuberculous) mycobacteria Epidemiology Opportunist mycobacteria, also called non-tuberculous mycobacteria, atypical m ycobacteria and mycobacteria other than tuberculosis (MOTT) can be found throughout the env ironment. They can be isolated from water (includ- ing tap water), soil, milk, dust and fro m various animals and birds. They are very low grade pathogens in humans and person to pers on spread is vanishingly rare. Because of this it is not necessary to isolate patients (hav ing proved it is not TB) or to contact trace. Because of their ubiquitous distribution, whi ch can include hospital water supplies and even bronchoscope cleaning systems, it is very i mportant to determine whether an isolate or isolates is/are signi \201 - cant and differen tiate them from contamination. Because they are acid-fast bacilli they cannot be differenti ated from M. tuberculosis microscopically, but require PCR tests for speciation to differen tiate them from the M. tb complex, which requires either microscopy-positive or culture pos i- tive material. There are some regional variations in the commonest organisms. M. kansasi i is overall the common- est, M. xenopi is the commoner in South East England, and M. malmo ense in Scotland and Northern England. organisms such as M. chelonae or M. gordonae without much clinical or X-ray abnormality are usually environmen- tal contamination. Drug susceptibility results Unlike in true TB where the drug susceptibility results have to be scrupulously adhered to, drug susceptibility results in the opportunist mycobacteria ar e not often helpful and are often misleading and can cause confusion and even panic. All th e opportunist mycobacteria are genetically resistant to pyrazinamide. They are often report ed resistant to many other drugs on single agent testing, which bears no corre- lation to r esponse to clinical combinations. This is because drugs which are reported as resistant as single agents, work synergistically when used together, and are effective. Rifampicin and e thambutol are the key drugs. Drug suscep- tibility results are only of utility in M. kansas ii infection, and possibly to predict macrolide susceptibility. Clinical patterns (HIV negative) Pulmonary disease \200 This accounts for 90 \200\22395% of all the disease with M. kansasii, M. malmoense, M. xeno pi and M. avium intra- cellulare (MAC). One cannot differentiate beween these species or fr om M. tuberculosis radiologically. Cavitation is seen in 50 \200\22370%. More chronic prese ntations and colonization followed by disease are seen in cystic \201 brosis and other fo rms of bronchiectasis. Who may get them? Essentially to get true disease there has to be either reduced immunity a nd/or tissue damage to allow these very low grade pathogens to cause disease. Three scenar- ios are the main settings:- 1. Cervical lymphadenopathy usually in the under 5 \200\231s d ue to their immature immune system, due to M. malmoense or M. avium intracellulare (MAC). H istology shows granu- lomata, and often AFB on microscopy (which is uncom- mon in true lymp h node TB), and the tuberculin test is often weak or negative. (treatment is by excision of the affected node(s) and not by drug treatment. \200 Lymph node disease \200 Largely con \201 ned to ages 1 \200\2235 years. Other sites \200 M. fortuitum or M. chelonae tend to infect skin or soft tissues after surgery or penetratin g trauma, with recur- rent abscess or \201 stula formation. M. marinum occurs following s kin tauma in swimming pools or aquaria so-called \200\230 \201 sh tank granuloma \200\231 . M. ulcerans may cause chronic indolent necrotic skin ulcers \200\230Buruli ulcer \200 \231 which may be seen in immigrants or asylum seekers from Equatorial Africa. Infection of bone, joints and the genitourinary tract are rarely seen. 2. In HIV-positive individuals with CD4 counts of under100/ ml, particularly MAC can cause a disseminated infection with positive blood cultures for AFB from the buffy coat layer of blood. Lung infiltrates, lymphadenopathy and colonic disease can also occur. These problems are now seen much less with the introduction of HAART, and prophylaxis against MAC with ma crolides in such individuals. 3. In persons with lung damage due to COPD, or other lung conditions causing scarring, incl uding previous TB, and cystic \201 brosis, these organisms can cause disease which is ind istinguishable from respiratory TB, with simi- lar symptoms and lung CXR appearances. Pleur al effu- sion and isolated mediastinal lymphadenopathy are rarely X-ray features with these organisms. The great majority of cases are in middle-aged to older smokers with a mild mal e predominance. Clinical patterns (HIV positive) Pulmonary disease \200 Disease only involving the lung accounts for only 5% of opportunist mycobacterial infection in these patients. Symptoms are similar to HIV-negative patients but haemoptysis is less c ommon. As with standard TB in HIV-positive individuals cavitation is not common. Diffuse in terstitial, reticulonodular, or alveolar in \201 ltrates are seen. Is it true infection or contamination? The significance of an isolate can only be derived b y considering the type of specimen from which the Mycobacterium has been isolated, the numb er of isolates, the degree of growth and the identity of the organism. Usually a positive c ulture from a sterile site, particularly if there is granulomatous histology is suf \201 c ient, but for other sites particularly the lung there should be multiple isolates, preferab ly separated by at least 7 days, and a consistent clinical and X-ray picture. Single isolat es of fast growing Lymph node disease \200 Can sometimes seen and can be associated with skin lesions. Safer to treat as standard TB u ntil culture results available. Can be part of the immune reconstitution (IRIS) syn- drome, in severely immunocompromised patients start- ing on HAART. CHAPTER 8.9 Opportunist (non-tuberculous) mycobacteria 195 an alternative if cipro \202 oxacin is not tolerated; for M. mal- moense and M. xenopi, 2 years rifampicin, ethambutol and clarithromycin is best. Other extrapulmonary sites Intrabdominal lymphadenopathy, skin lesions and other sites can also be a manifestation of the IRIS syndrome. Corticosteroids may be needed to reduce the i mmune response in the short term. MAC, M. malmoense, M. xenopii: extrapulmonary disease \200 \200 Lymph node excision in children. As for respiratory disease. Treatment Recommendations for some organisms is based on some controlled clinical trials, b ut the evidence base is not as robust are for the treatment of M. tuberculosis. Fast growing organisms e.g: M. chelonae, M. gordonae, M. fortuitum, M. abscessus. pulmonary disease \200 \200 Surgical excision if possible. Rifampicin, ethambutol and clarithromycin in the \201 rst instance. Cure may not attainable. Consult JTC Guidance for more detail if needed. HIV negative individuals M. kansasii: pulmonary disease \200 \200 A regimen of rifampicin and ethambutol for 9 months gives a >95% cure rate in HIV-negative individuals. If there is obvious immuno compromise including HIV- positivity, then treatmen t for 15 \200\22324 months, or until cul- tures have been negative for at least 12 months w ould be advised. Extra-pulmonary disease Consult JTC Guidance. HIV-positive individuals Improving the immune system with HAART is probably more impor tant than active mycobacterial drug treatment. M. kansasii: extrapulmonary disease \200 Lymph node disease in young children should be treated by excision. In HIV-negative treat f or a minimum of 9 months with rifampicin and ethambutol. Addition of a macrrolide, prothion amide or streptomycin may need consideration, if the response is poor. In HIV positive indi viduals if disseminated disease (bacteraemia) then give rifampicin, ethambutol and clari- t hromycin. Improvement of the immune system on HAART may allow cessation of these drugs afte r some months. M. kansasii: pulmonary or disseminated Rifampicin and ethambutol for 24 months +/ \210\222 clarithro- mycin. MAC or M. xenopii: pulmonary or disseminated disease \200 \200 Rifampicin, ethambutol and clarithromycin for 24 months. HAART may need to be modi \201 ed because ofrifampicin interactions. Fast growing organisms As for HIV negative MAC, M. malmoense, M. xenopi: pulmonary disease \200 Further reading Banks J, Jenkins PA. Combined versus single antituberculosis drugs on the i n vitro sensitivity patterns of non-tuberculous mycobac- teria. Thorax 1987; 42:838 \200 \223842. Trials by the BTS have shown that up to 15% of such individuals do not respond to 24 months \200\231 treatment. Individuals with these infections have a high 5-year mor- tality from cardio-respiratory failure, of between 25-40%, with M. xenopi having the worst prognosis. I n those who are \201 t enough, and the disease is unilateral, surgical excision and conti nuation of drug treatment is an option. Treatment is with rifampicin and ethambutol for 24 months, plus a third drug, either isoniazid, clarithro- mycin or cipro \202 oxacin is best . The results of the most recent study of rifampicin and ethambutol with either clarithromy cin or cipro \202 oxacin show no greater ef \201 cacy but mild species differences. For M . avium 2 years \200\231 treatment with rifampicin ethambutol and cipro \202 oxacin is bes t, with isoniazid being British Thoracic Society. Mycobacterium kansasii pulmonary infec- tion: a prospective study of the results of nine months of treat- ment with rifampicin and ethambutol. Thorax 1994; 49: 442 \200\223445. Joint Tuberculosis Committee of the British Thoracic Society. Manageme nt of oppor tunist mycobacterial infections: Joint Tuberculosis Committee guidelines 1999. Thorax 2000; 55: 210 \200\223218. Research Committee of the British Thoracic Society. First randomized trial of treatments fo r pulmonary disease caused by M. avium intracellulare, M. malmoense, and M. xenopi in HIV n ega- tive patients: rifampicin, isoniazid and ethambutol versus rifampicin and ethambutol. Thorax 2001; 56: 167 \200\223172. A GOODMAN 196 8.10 Fungal and parasitic lung disease Fungal lung disease occurs primarily in those with a back- ground of immune compromise or u nderlying pulmonary disease. Fungal lung infections have increased in incidence over recent decades as the number of patients at risk has increased. This is due to a combination of i atrogenic causes (e.g. increased organ transplantation and prescription of immunosuppressan t medications) and the emergence and increasing prevalence of HIV. Worldwide travel has inc reased, leading to exposure to a greater range of fungal infections. There has fortunately been a corresponding increase in the range of available treatments. However, untreated pulm o- nary fungal infections still result in appreciable morbidity and mortality. It is critic al that physicians have a high index of clinical suspicion, allowing early diagnosis and ap propri- ate treatment of these conditions. Additional essential criterion for ABPA-CB: \200 Central bronchiectasis. Clinical features (not all of these need be present): \200 \200 Wheeze. Long history of asthma which has recently worsened (often requiring recurrent cours es of oral steroids). Fever. Pleuritic chest pain. Cough with expectoration of brown mucus plugs which may contain airway casts. Haemoptysis. Late presentation may be with features o f end-stage lung disease such as dyspnoea, cyanosis, cor pulmonale and clubbing. Investigat ions: \200 \200 \200 \200 Aspergillus This \201 lamentous fungus is capable of causing a variety of patterns of pul monary disease. When spores are inhaled into the healthy lung they rarely cause morbidity. However, they can cause a variety of disease manifestations in those who are immunocompromi sed or those with asthma or chronic lung disease. These syndromes are distinct clinical ent ities and more than one may occur in the same patient. Traditionally three types of pulmona ry disease due to the inhalation of Aspergillus species were described. This cate- gorisati on is still valid but sub-categories have been included as further manifestations of this d isease are recognized: 1 Immune-mediated Aspergillus disease: Cytological examination of sputum may reveal fungal hyphae or eosinophilia. CXR may demonst rate \202 eeting pulmonary in \201 ltrates (tending to involve the upper lobe), bronchie ctasis and mucoid impaction. CT appearances in ABPA-CB are of proximal bron- chiectasis, pr edominantly in the upper lobes. Treatment: \200 Prednisolone, initially at high doses (40mg/day) for 1 \200\2232 weeks but then gradually r educed to maintenance doses (5 \200\22310mg/day). Monitor total IgE as a marker of response . Anti-fungal medication. Oral itraconazole 200mg BD for 4 months is of bene \201 t in cas es of steroid dependant ABPA. LFTs and aspergillus precipitins should be moni- tored regula rly. Voriconazole is emerging as an alterna- tive anti-fungal agent. Symptoms of wheeze sho uld be treated with bronchodi- lators. If mucus plugging is severe, bronchial aspiration ma y be required. (a) Atopy. (b) Allergic bronchopulmonary aspergillosis (ABPA). (c) Hypersensivity pneumonit is (HP). 2 Aspergilloma. 3 Aspergillosis. (a) Chronic pulmonary aspergillosis. (b) Invasive aspergillosis. 1 Immune-mediated Aspergillus disease (a) Atopy (c) HP (Previously known as extrinsic allergic alveolitis (EAA)) See Chapter 7.8, p. 148 Ex amples include Malt worker \200\231s lung (Aspergillus clavatus or fumigatus) and Farmer \200\231s lung (Aspergillus umbrosus).