Outcome \200 Mortality <10% in the setting of AIDS, but >30% in patients with other forms of immunocompr omise, probably re \202 ecting the adverse consequences of the greater pulmonary in \202 ammatory response to pneumocystis which is observed in non-HIV immunocompromise. Mortality from PCP requiring mechanical ventilation in HIV-infected patients is about 60%, although m ay be signi \201 cantly higher in patients with low CD4-counts. PCP: TREATMENT 479 Relapse rate in AIDS is high (60% in one year), so secondary prophylaxis with co-trimoxazol e is recommended. Primary prophylaxis is offered to HIV-positive patients with CD4 count <2 00 x 106/L. The indications for prophylaxis in non-HIV patients are less well de \201 ned; consider prophylaxis for patients who are likely to receive high doses of prednisolone for prolonged periods Future developments \200 The effect of co-infection with CMV on the outcome of PCP in HIV- infected patients is uncl ear. In patients with severe PCP treated with steroids, the presence of CMV in BAL \202 u id is associated with a worse outcome; the role of anti-CMV therapy such as ganciclovir in such cases is unknown The use of PCR to detect pneumocystis may further increase diagnostic sensitivity, although in a proportion of cases detection using PCR is not accompanied by e vidence of clinical infection and appears to represent colonization. It is unclear if asymp tomatic carriage precedes infection in such patients, and the consequences of carriage in i mmunocompetent individuals are also unknown Pneumocystis is one of only a handful of cells known to be unable to synthesize the metabolic intermediate molecule S-adenosylmethionine ( AdoMet), and as a result must scavenge this molecule from its host. In a small study, lower plasma levels of AdoMet were demonstrated in PCP when compared with healthy controls and i ndividuals with other pulmonary infections, suggesting a possible role for AdoMet in diagno sis. This \201 nding has not yet been replicated in a larger study, however. Further information Kovacs JA et al. New insights into transmission, diagnosis, and drug tr eatment of Pneumocystis carinii pneumonia. JAMA 2001; 286: 2450 \200\22360 Thomas CF, Limpe r AH. Pneumocystis pneumonia. NEJM 2004; 350: 2487 \200\22398 480 CHAPTER 41 Respiratory infection: fungal Endemic mycoses Several types of dimorphic fungi are known to commonly cause pulmonary dise ase in endemic regions, particularly in North America: histoplasmosis, blastomycosis, cocci dioidomycosis, and paracoccidioidomycosis. Endemic fungi can rarely present in non-endemic areas, and diagnosis is often delayed because of their non-speci \201 c and varied clinica l features and the failure to obtain a detailed travel history. Fungal infection may mimic other diseases such as tuberculosis and lung cancer, often leading to inappro- priate inves tigations and treatment. Fungal infections can also cause granu- lomata on lung biopsy, whi ch sometimes results in diagnostic confusion (e.g. with sarcoidosis). Infection in immunocompetent individuals is usually either asymptomatic or mild and self-li miting, although severe infection may rarely occur in apparently immunocompetent individual s. Outbreaks of disease may occur, as well as sporadic cases. Unlike invasive candidosis an d aspergillosis, where neutrophils are the key host defense mechanism, T-cell-mediated immu nity is essential for defense against the endemic mycoses. Patients with impaired T-cell-me diated immunity (e.g. AIDS, lymphoma, steroid use) are therefore at particular risk of deve loping severe or disseminated infection. Histoplasmosis Epidemiology Histoplasma capsulatum is found in bird and bat dropping contam inated soil in the mid-west and south-east USA, particularly the Ohio and Mississippi valle ys, as well as in Mexico and parts of South America. The mycelial form is inhaled and subse quently develops into the yeast form ( \200\230dimorphism \200\231) within the lung, before spread via the lymphatics and the acti- vation of T-cell-mediated immunity with granuloma development. Clinical features Manifestations of infection are highly variable. \200 Asymptomatic infection occurs in the majority of cases. CXR may be normal or demonstrate si ngle or multiple nodules, which may calcify in a characteristic \200\230target lesion \200 \231 pattern. Lymphadenopathy may occur with eggshell calci \201 cation Acute symptoms may follow heavy or recurrent exposure (e.g. pigeon fanciers, cavers). Range from a self-limit ing \202 u-like illness of fever, cough, and malaise to fulminant disease with respirator y failure. CXR may be normal or show consolidation, bilateral alveolar shadowing, multiple small nodules, and sometimes lymphadenopathy Chronics progressive lung disease occurs parti cularly in patients with underlying COPD; lung cavitation is common, sometimes leading to a n incorrect diagnosis of tuberculosis or cancer Disseminated disease may affect the immunoc ompromised (particularly AIDS) and the elderly. Presentation may be acute or chronic, and m anifestations include fever, weight loss, and diffuse lung involvement, although almost any organ system may be affected; other features may include hepatosplenomegaly, gastrointesti nal symptoms, headache and meningism, cytopenias, endocarditis, and adrenal failure HISTOPLASMOSIS 481 Other unusual manifestations include broncholithiasis, mediastinal \201 brosis (with comp ression of large airways, esophagus, or superior vena cava), or isolated extrapulmonary dis ease (e.g. arthritis, pericar- ditis, erythema nodosum, erythema multiforme) Diagnosis \200 Smears or culture of infected material, e.g. sputum or BAL \202 uid (for chronic pulmonar y disease, insensitive for acute disease), blood, urine, or bone marrow (for disseminated d isease). May take several weeks Serology in acute disease \200\224typically negative at pre sentation, and becomes positive after several weeks. A variety of serological tests are in use, including: \200 Complement \201 xation, designed to detect antibodies to Histoplasma mycelial antigen or Histoplasma yeast antigen. A positive result (serum titre \211 1: 16 for mycelial antigen , \211 1: 32 for yeast antigen) for either antigen, in a compatible clinical setting, is considered diagnostic of active disease Immunodiffusion may distinguish active disease from previous exposure, but is less sensitive than complement \201 xation, and a negative res ult does not exclude the diagnosis Serum or urine Histoplasma polysaccharide antigen test \200\224useful for diagnosis of diss eminated disease and also pulmonary disease. Positive in 85 \200\22395% cases in AIDS patie nts. Antigenuria is seen in 90%, and antigenaemia in <50% of non-AIDS patients Treatment \200 Infection in immunocompetent individuals is typically self-limiting, and symptoms usually r esolve within 2 \200\2234 weeks without treatment Indications for antifungal treatment are: \200 \200 \200 \200 Oral itraconazole is appropriate for persistent symptoms in mi ld \200\223 moderate disease and for disseminated disease, including patients with AIDS who have mild disease. Treat for 6 \200\22312 weeks in acute histoplasmosis, and for 1 \200 \2232 years in chronic disease. In the setting of AIDS, treatment should be lifelong or unt il CD4 count >200 for at least 6 months after starting HAART. Check itraconazole drug inter actions and monitor liver function (ideally monthly) if taking for >1 month. Hypokalaemia m ay be associated with long-term use Intravenous amphotericin B should be used to treat seve re infection in the setting of ARDS or immunocompromise. Persistent symptoms (usually lasting > 1 month) Progressive disseminated disease Heavy expo sure leading to ARDS Infection in the setting of immunocompromise 482 CHAPTER 41 Respiratory infection: fungal Blastomycosis Epidemiology Infection with Blastomyces dermatitidis follows the inhala- tion of spores from contaminated soil, and clinical infection may follow outdoor activities. Bl astomycosis is endemic in a distribution similar to that of histoplasmosis in the USA, alth ough extending further north: it is endemic in the south-east USA, and the Mississippi, Ohi o, and St Lawrence river valleys. Blastomycosis also occurs in Africa, India, and the Middl e East. It is signi \201 cantly less common than histoplasmosis. Clinical features Clinica l presentation is variable, and may mimic other diseases such as bacterial pneumonia, tuber culosis, and lung cancer. Clinical manifestations include: \200 \200 Asymptomatic in at least 50% of those infected Acute presentation is typically with fever, cough, productive of muco- purulent sputum, and sometimes pleuritic chest pain; misdiagnosi s as bacterial pneumonia is common. Acute presentation of fulminant respi- ratory disease w ith ARDS may occur. Other acute presentations include a \202 u-like illness with fever, m yalgia, arthralgia, and erythema nodosum Chronic presentation may occur with fever, product ive cough, and weight loss Disseminated disease occurs in a minority of patients (especiall y in the immunocompromised), and most commonly involves the lungs, skin, bone, joints, and CNS. CXR Airspace in \201 ltrates are the most common \201 nding, but a very wide range of ap pearances are seen, including nodular pattern, lobar consolida- tion, diffuse in \201 ltra tes, or large peripheral masses (often with air broncho- grams). Lymphadenopathy and pleura l effusions may rarely occur. Diagnosis \200 Diagnosis is by the staining or culture of infected material. A pyogenic in \202 ammatory response to the fungus is common (unlike in histoplasmosis) and facilitates diagnosis Cultu re of sputum has a high yield and is diagnostic in most cases of acute pulmonary disease. M ultiple specimens may be required, however. A drawback of sputum culture is that several we eks may be required before the fungus is identi \201 ed. Cytological examination of sputum may provide a rapid diagnosis if the examiner is trained appropriately and alerted to the possible diagnosis Bronchoscopy has a similar diagnostic yield to sputum culture (92% in on e study), and is recommended for patients with negative sputum results; note that lidocaine may inhibit the fungal growth and minimal concentrations should be used More invasive proc edures such as surgical lung biopsy or thoracoscopy are only rarely needed. Histological sp ecimens require particular stains (e.g. silver stain) to facilitate identi \201 cation of the fungus Currently available serological tests lack sensitivity and are rarely helpful. T reatment is usually with itraconazole for at least 6 months. Observation without treatment is not generally recommended, although this is contro- versial and symptoms are usually sel f-limiting in immunocompetent indi- viduals. Amphotericin B should be used to treat very il l patients. PARACOCCIDIOIDOMYCOSIS 483 Coccidioidomycosis Coccidioidomycosis is endemic in parts of south-west USA (Arizona, Calif ornia, Texas, New Mexico, Utah, Nevada), northern Mexico, and Central and South America. In fection follows inhalation of Coccidioides immitis spores from soil. Manifestations of infe ction are variable, including: \200 Asymptomatic infection, which appears to be common in endemic regions Acute pulmonary disease. Presents in a similar manner to bacterial pneumon ia, with fever, cough, pleuritic chest pain, and often skin rash (e.g. erythema nodosum or erythema multiforme). Eosinophilia may be present. CXR appearance is variable, and may show areas of consolida- tion, lymphadenopathy, and pleural effusion, or be normal. The disease is self-limiting in most cases; a minority progress to ARDS or chronic disease Chronic pul monary disease. Uncommon, may be asymptomatic. CXR typically shows single or multiple nodul es that may cavitate; upper lobe in \201 ltrates similar to those seen in tuberculosis may develop Disseminated disease. Rare, occurs particularly in the immunocompro- mised. Presen tation may be acute or chronic. Pulmonary disease occurs in association with involvement of the skin, bones, joints, genitourinary system, or CNS. Diagnosis is with stains or culture of infected tissues. Sputum cultures are often positive in cavitating disease. BAL \202 uid culture and lung biopsies may also be diagnostic. Se rological tests are also available. Treatment is not required in the majority of patients, who have mild self-limiting disease. Fluconazole is the antifungal of choice, when required . Paracoccidioidomycosis \200 Paracoccidioidomycosis is endemic in parts of Central and South America and Mexico Typicall y presents as chronic pulmonary disease, although acute disseminated disease may occur in t he immunocompromised Diagnosis is made on culture of sputum or BAL \202 uid, or following staining of lung biopsy samples Treatment is with itraconazole, and long courses of up to 6 months may be needed. 484 CHAPTER 41 Respiratory infection: fungal Other fungi: cryptococcosis Epidemiology \200 Cryptococcus neoformans is found worldwide in bird droppings. Following inhalation, yeasts propagate within the alveoli without usually causing symptoms. Migration to the central ner vous system may then occur, and meningoencephalitis is the most common clinical manifesta- tion of infection Patients with impaired cell-mediated immunity (e.g. AIDS, sterioid use, l ymphoma) are particularly vulnerable to cryptococcal infection Clinical features \200 Clinically evident cryptococcal lung disease is rare but well described, even in HIV-negati ve patients. Symptoms are non-speci \201 c, including fever and cough, and presentations m ay be acute or chronic. The CXR nods to interstitial or pleural involvement Pulmonary invol vement is often associated with meningitis, and clinical signs of meningism are characteris tically absent. CT head (to exclude a space-occupying lesion) followed by lumbar puncture s hould therefore be considered in all patients with pulmonary cryptococcal disease. Diagnosis Diagnostic techniques include: \200 India ink stain on CSF, or latex agglutination test for capsular antigen in BAL or pleural \202 uid, blood, or CSF Stains and culture of sputum, blood, urine, or BAL \202 uid. Po sitive culture from sputum may indicate colonization rather than active disease, and should be interpreted in the clinical context Serum cryptococcal antigen test is extremely sensit ive and speci \201 c for the diagnosis Treatment of cryptococcal infection in the immunocompromised is with amphotericin B IV and \202 ucytosine IV for 2 \200\2233 weeks, followed by \202 u- conazole. The natural hist ory of disease in immunocompetent patients is poorly understood, and observation alone is o ften recommended; dissem- inated disease may occur, however, and some experts advise treatm ent with \202 uconazole. CANDIDAL PNEUMONIA 485 Candidal pneumonia \200 Candida occurs as part of the normal human \202 ora, and is found in the gastrointestinal tract and on the skin. Invasive disease may occur in the immunocompromised, particularly i n neuropenic patients. Prophylaxis with \202 uconazole is used following bone marrow tran splantation Candida is often isolated from respiratory secretions, but very rarely causes r espiratory disease. Seeding of the lungs leading to in \201 ltrates or enlarging nodules m ay occur with disseminated candidal infection Risk factors for candidaemia include immunoco mpromise, central venous lines, parenteral nutrition, and gastrointestinal surgery. In lung transplant recipients a positive donor tracheal culture for Candida is a marker for post-t ransplant candidal infection The clinical and radiological features of pulmonary involvemen t are non-speci \201 c. Extrapulmonary manifestations of infection are common, e.g. skin, eye, hepatic, or CNS involvement. Candidaemia is typically associated with a high fever De \201 nitive diagnosis of pulmonary disease requires identi \201 cation of tissue invasion by Candida on TBB or surgical lung biopsy Treat with amphotericin B 0.7 mg/kg/day IV or \202 uconazole 400 mg/day PO, and remove any central lines Candidaemia carries a mortality of 30 \200\22340%. This page intentionally left blank 487 Chapter 42 Respiratory infection: mycobacterial Tuberculosis: epidemiology and pathophysiology 488 TB: pulmonary disease 490 TB: extrapulmo nary disease 491 TB: investigations 492 TB: management 1 494 TB: management 2 496 First-lin e antituberculosis drugs 498 TB: in-patient admission 500 TB in pregnancy 502 TB chemothera py with comorbid disease 504 TB: adverse drug reactions 506 Multiple drug resistant TB (MDR -TB) 508 Latent TB infection 510 TB and anti-TNFA treatment 512 TB: screening and contact t racing 514 Disseminated BCG infection (BCGosis) 516 Non-tuberculous mycobacteria (NTM) 518 NTM: management 520 488 CHAPTER 42 Respiratory infection: mycobacterial Tuberculosis: epidemiology and pathophysiology Tuberculosis (TB) is the second leading infe ctious cause of death world- wide (after AIDS), killing around 2 million people per year, d espite being a potentially curable disease. Rising rates of HIV and immigration mean that T B remains a large proportion of the workload for respiratory physicians in some parts of th e UK. The disease is a great mimicker and should often be considered as a differential diag nosis. Epidemiology The highest incidence is in sub-Saharan Africa (290 cases per 100 000 p opulation). High population density countries in Asia (India, China, Pakistan, and Indonesi a) account for half the global burden. The countries comprising the former Soviet Union hav e rapidly increasing rates because of economic decline and failing health services, with ar ound 10% multi-drug resistance in this area. Globaly, around 11% of TB cases are co-infecte d with HIV, with this number increasing to 38% in sub-Saharan Africa, and less than 1% in I ndia and China. In the UK, 37% of TB cases are in Caucasians (usually over the age of 50), with 60% in peop le born abroad (median age of 30). At least 3% of cases are co-infected with HIV. TB is con centrated in the major cities, with 40% of cases in London. Pathophysiology The disease is spread by airborne droplets containing Mycobacterium tuberculosis (MTB). Droplets can remai n airborne for hours after expectoration, because of their small size. Infectious droplets are inhaled and become lodged in the distal airways. MTB is taken up by alveolar macrophages, with either successful containment of the infectio n, or progression to primary disease (primary progressive TB). MTB replicates following ingestion by alveolar macrophages, with spread via the lymphatics to hilar lymph nodes. Cell-mediated immunity leads to granuloma formation by activated T ly mphocytes and macrophages, which limits further bacterial replication and disease spread. U nless there is a de \201 ciency in cell-mediated immunity, active disease may never occur. Active disease occurs when the host \200\231s immune response is unable to contain MTB repl ication, occurring most often in the lung parenchyma and hilar lymph nodes. It can occur in any organ, from haematogenous spread. This is most common in young children and in immunos uppressed adults. Many factors in \202 uence whether or not infection leads to active disease, including age , host immunity, and time since infection. The estimated lifetime risk of clinical disease of a child newly infected with MTB is about 10%. Most disease in adults is due to reactivation of childhood disease, so-called \200\230post primary disease \200\231, from activation of latent TB lying dormant in the lung Gohn \200 \231s focus. TUBERCULOSIS: EPIDEMIOLOGY AND PATHOPHYSIOLOGY 489 Main risk factors for active TB in the UK 1. Place and date of birth: \200 \200 Caucasian population, increasing prevalence with age (M >F) Black immigrants, highest preva lence in the young (M = F) Indian subcontinent, highest prevalence in middle age (M = F) 2. HIV/AIDS 3. Poverty \200\2241 in 50 homeless people in London have TB 4. Medical factors \200\224diabetes, renal disease, malignant disease, systemic chemotherapy, steroids and ne w TNFA antagonists e.g. in \202 iximab. Also smoking and vitamin D de \201 ciency (a rela tionship between the vitamin D receptor and interleukin-1 levels is postulated) Smear positive TB Acid-fast bacilli (AFB) seen on sputum smear (Ziehl \200\223Neelsen stain ), potentially infectious. Patient may need to be isolated. Culture positive TB AFB not seen on smear. TB grown on culture (may take up to 9 weeks). Mu ch less infectious. 490 CHAPTER 42 Respiratory infection: mycobacterial TB: pulmonary disease Symptoms Most cases present with pulmonary disease, classically: \200 \200 \200 \200 \200 Haemoptysis is more common with cavitatory disease, and u p to two-thirds will be smear positive. Most haemoptysis is small volume. Massive haemoptys is is rare, and is most common as a consequence of destruction of a lobe, with consequent b ronchiectasis formation (possibly with secondary aspergillus infection or mycetoma in a hea led TB cavity). This is seen in those untreated in the pre-chemotherapy era. Most haemo- pt ysis will resolve with antituberculous chemotherapy. Signs are often non-speci \201 c. \200 Examination may be normal \200 Lymphadenopathy (particularly cervical) \200 Crack les \200 Signs of a pleural effusion \200 Signs of consolidation (with extensive diseas e) \200 Signs of weight loss/underlying immunocompromise \200 Look for evidence of extr apulmonary disease, e.g. skin, joints, CNS, retina, and spinal disease Productive cough Haemoptysis Breathlessness Systemic symptoms \200\224weight loss, night sw eats, and malaise Chest pain Complications Long-term sequelae of inadequately treated infection include: \200 Bronchiectasis, bronchial obstruction, and airway stenosis (uncommon) may result from endob ronchial disease, though this is much less common in the post-chemotherapy era. It is more common in the pres- ence of extensive parenchymal disease, and is associated with lymph nod e enlargement with compromise of airway size Pleural disease is due to either primary progr essive disease or reactiva- tion of latent infection. It probably represents an increased i mmune response \200\224a delayed type hypersensitivity reaction to mycobacterial antigens, rather than a diminished one, which is the case in other forms of TB infection. Culture is more likely from pleural tissue than \202 uid (where the organism burden is lower). See p 294 Pneumothorax is rare (<1% in the developed world) and results from the rupture of a pe ripheral cavity. Can lead to the formation of a bronchopleural \201 stula Draining absces s Right middle lobe syndrome \200\224compression of the right middle lobe bronchus by hilar lymph nodes leads to lobar collapse The previous treatment with thoracoplasty can lead to respiratory failure in later life due to compromised vital capacity \200 TB: EXTRAPULMONARY DISEASE 491 TB: extrapulmonary disease Extrapulmonary disease is seen in about 20% of HIV seronegative patients. This proportion is higher in HIV positive patients. The tuberculin skin test (see p 492) is more frequently positive in extra- pulmonary diseas e, as this most commonly represents reactivation disease, and less commonly primary disease . Anergy is more likely in those with poor nutritional status, underlying disease (includin g HIV), and the elderly. CNS disease This is the most serious manifestation, and includes m enin- geal involvement and space-occupying lesions (tuberculoma) that lead to cranial nerve lesions. The clinical manifestations are due to the presence of MTB, and the host \200\231 s immune response to it. TB meningitis presents with headache, fever, altered conscious level, and focal neurological signs, including cranial nerve palsies. Fits are common. CSF contains lymphocytes, high protein, and low glucose. PCR of CSF may be useful, but is not 100% sensitive. Pericardial TB The yield is low from pericardial \202 uid and biopsy. 85% have a positive tuberculin test. A large effusion may lead to ca rdiac tamponade, and may need to be drained. Spinal disease can affect any bone or joint; s pine involvement (Pott \200\231s disease) is most common in the thoracic spine. Surgery may be needed if there is evidence of cord compression or instability. GU disease from seeding during haematogenous spread. Involvement of the renal and genital tracts is uncommon. In men \200\224may cause prostatitis and epididymitis. In women \200\224genitourinary TB is a cause of infertility. Sterile pyuria (white and red blood cells in the urine, in the abs ence of bacterial infec- tion) may indicate TB infection. Peripheral cold abscess can occur at almost any body site. Disseminated disease is more common in immunosuppressed individua ls. Pulmonary disease is typically a miliary (millet seed) pattern, but pulmo- nary disease is not universal in disseminated disease. This has a higher mortality than localized disea se. 492 CHAPTER 42 Respiratory infection: mycobacterial TB: investigations The diagnosis is usually made in one of three ways: sputum (or other sam ple, e.g. pus, CSF, urine, a minimum of three samples) smear or culture, or the identi \201 cation of tissue caseating granulomas. \200 CXR classically shows upper lobe in \201 ltrates with cavitation. \200 \200 May be associated with hilar or paratracheal lymphadenopathy May show changes consistent wi th prior TB infection, with \201 brous scar tissue and calci \201 cation HIV infected pa tients typically have less \202 orid CXR changes, and are less likely to have cavitatory disease. Miliary pattern is more common in later stages of AIDS All patients with non-pulmo nary TB should have a CXR, to exclude or con \201 rm pulmonary disease Sputum Ziehl \200\223Neelsen (ZN) stain and culture is required for de \201 nitive diagnos is, and is vital for drug resistance testing. ZN is only 50 \200\22380% sensitive \200 Smear negative disease accounts for about 20% of disease transmission; smear positive cases are more infectious Induced sputum is as effective as BAL, especially if the CXR shows cha nges consistent with active disease (but should not be used for potential MDR-TB, due to th e danger to health workers) Conventional culture takes 6 weeks or longer Nucleic acid ampli \201 cation techniques and DNA \201 nger printing may be used to con \201 rm mycobacte ria serotype and drug susceptibility. May also be useful in elucidating the epidemiology of TB outbreaks Non-mycobacterial TB (opportunistic mycobacteria) tend to be present in much lower concentrations than MTB, and are therefore seen on a smear much less commonly, but ma ny grow much faster, and are therefore seen on culture much earlier \200 Tuberculin skin test is only useful if strongly positive (suggesting active disease) or if negative. The skin test must be interpreted with the clinical picture, and with knowledge o f the patient \200\231s ethnic origin, exposure, and BCG vaccination history. Novel immune- based rapid blood tests for the diagnosis of latent TB are probably more sensitive and spec i \201 c and some now favor their use (p 510) Bronchoscopy may be needed to obtain BAL sam ples if there is a high index of clinical suspicion, but a non-productive cough or unhelpfu l sputum culture. In extensive disease, macroscopic bronchoscopic abnormality may be presen t, with erythematous or ulcerated airways. Granulation tissue or enlarged lymph nodes may b e visible. Nodes can perforate or protrude into the bronchial lumen, extruding caseous mate rial into the airway. This is rare in the developed world Biopsy from extrapulmonary sites, e.g. neck lymph nodes, or medi- astinoscopy may be warranted. Lymph node biopsy samples, p leural biopsies, and pus aspirated from lymph nodes should be transported to the laboratory in a dry pot (not formalin). Bone marrow or liver biopsy may aid diagnosis in miliary TB. The bone marrow culture yield is higher in pancytopenia TB: INVESTIGATIONS 493 Gastric washings re \202 ect TB swallowed overnight. Rarely performed if bronchoscopy is r eadily available. Used more commonly in children Blood tests Baseline FBC, renal, and liver function tests. Useful to docu- ment normal baseline levels before starting antituberculou s chemo- therapy. HIV test is mandatory in all Urine Early morning urine (EMU) if renal dis ease suspected CT scan is more sensitive than CXR, especially for smaller areas of disease. It may show cavitatory disease, and signs of airway disease \200\224 the \200\230tree in bud \200\231 appearance, useful for differentiating between active disease and non-active o ld disease. Less commonly needed. \200 A tuberculoma is an encapsulated focus of reactivated TB. These lesions rarely cavitate, an d the differential diagnosis is wide, including malignancy and vasculitis. Diagnosis may on ly be possible by percutaneous biopsy as, in the absence of a main airway component, cultur es may be negative. Skin tests \200 Mantoux \200 \200 Read at 48 h Intradermal. Use 0.1 mL of 1 in 1000 (= 0.1 mL of 100 TU/mL = 10 tuberculin un its) Graded: <5 mm 5 \200\22314 mm >15mm negative positive strongly positive Heaf test. This has been phased out in the UK. Mantoux testing is the method of choice \200 Read at 1 week \200 100 000 TU/mL (multipuncture) Graded: \200 \200 \200 \200 \200 \200 Grade 0 no reaction Grade 1 4 \200\2236 small dots Grade 2 coalesces, normal skin in center Grade 3 coalesces, central skin \201 lled (5 \200\22310 mm wide) Grade 4 solid induratio n >10 mm 9 vesiculation or ulceration An excessive response can be treated with topical bet novate (PPD is dead material) 494 CHAPTER 42 Respiratory infection: mycobacterial TB: management 1 Treatment aims to cure disease without relapse, prevent transmission, and prevent emergence of drug resistance. Long-term treatment with a number of drugs is required as, before treatment is started, TB can remain dormant for long periods, making the emergence of naturally resistant mutants po ssible. \200 \200 \200 Never treat with a single drug Never add a single drug to a failing regime Send material fo r bacteriological diagnosis prior to initiating treatment. The majority of patients can be treated as out-patients. Smear-positive HIV-negative patients should become smear-negative within 2 weeks of startin g treatment (this does not apply to MDR-TB). These patients should be isolated either at ho spital (if they are admitted) or at home for this time period. Noti \201 cation All new ca ses must be noti \201 ed (including those diagnosed after death), as this initiates contac t tracing. In some districts noti \201 ca- tion triggers specialist nursing input. The doc tor making the diagnosis has a legal responsibility to notify. It also provides epidemiolog ical and sur- veillance data, enabling treatment and screening services to be planned. A pa tient can be denoti \201 ed if the mycobacterium cultured turns out to be an opportunistic mycobacterium, for example. Drug treatment It is vital to send material for laboratory dia gnosis if possible (to allow for subsequent drug susceptibility testing) prior to the initi ation of treatment. In practice, if there is a high clinical suspicion of TB, treatment sho uld be started before culture and full sensitivities are available. Drug treatment is usually in 2 phases: Initial intensive phase (designed to kill actively g rowing bacteria), followed by a continuation phase (designed to eliminate residual bacteria ). \200 The intensive phase (8 weeks) shortens the duration of infectiousness At least three drugs are needed, e.g. isoniazid (bactericidal), rifampicin (bacteriostatic), and pyrazinamide (b acteriostatic/partially bacteriocidal). Three drugs reduces the treatment time from 9 to 6 months Ethambutol added if there is a likelihood of drug resistance (in practice this is st andard therapy for non-Caucasian patients, who are more likely to have come from an area wi th a high prevalence of resistance) The continuation phase is usually with two drugs. Fewer bacteria are present at the start of this phase, and there is therefore a lower chance tha t drug-resistant mutants will emerge, making drug resistance less of a problem. Compliance is of major importance and all patients should have a risk assess- ment for trea tment adherence. If the clinical response is not satisfactory, check sputum 2 months before the end of the planned treatment period. TB: MANAGEMENT 1 495 Compliance can be monitored with urine color testing (turns red with rifampicin) and tablet counts. If concerns about compliance, consider directly observed treatment (DOT). Every TB patient should have a key worker, who should be easily contactable. From September 2007 there are no prescription costs for TB drugs in the UK. Table 42.1 Annual risk of TB/100 000 in England and Wales based on age and place of birth Age Place of birth Years after All patient rate Indian subcontinent rate \201 rst entry 0 \200\22314 UK 3 21 Abroad 31 88 >15 UK 4 59 15 \200\22334 Abroad 0 \200\2234 180 540 >5 53 87 >35 Abroad 0 \200\2234 146 593 >5 39 108 496 CHAPTER 42 Respiratory infection: mycobacterial TB: management 2 Directly observed therapy (DOT) aims to increase compliance, by nurse-supe rvised and observed daily or weekly tablet swallowing. This has been shown to increase trea tment completion, reduce relapses, and reduce development of drug resistance, as the ingest ion of each dose is witnessed. This is recommended for patients unlikely to comply, includi ng alcoholics, drug abusers, the homeless, those with serious mental illness, and those wit h MDR-TB. Consider other incentives to improve adherence such as providing food and transpo rtation costs. Compulsory detention under Sections 37 and 38 of the Public Health Act (England) is allowed for infectious pulmonary TB, but compulsory treatment is not allowed. This is only used in extreme circumstances to protect public health. Standard treatment regimes (see p 498) \200 The standard regime is for 6 months \200\224four drugs in the initial 2-month phase (rifamp icin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) (or streptomycin) and 2 drugs in the last 4 months (rifampicin and iso- niazid) in patients with fully sensitive organis ms If drug sensitivity is unavailable at 2 months, continue the 4-drug regime until it is a vailable (even if this is for more than 2 months) The fourth drug (usually ethambutol) can be omitted in those at low risk of isoniazid resistance (non-previously treated, HIV-negati ve, UK-born Caucasians, with no drug-resistant contacts). There is a higher risk of isoniaz id resistance in ethnic minority groups, immigrants, refugees, those who have had previous treatment, and those who are HIV positive. This depends on local policy and the ethnic make -up of the local area. If in doubt, start treatment with 4 drugs Other treatment regimes ar e also effective (e.g. daily for 2 months, then 2 or 3 times weekly for 4 months, or 3 time s weekly for the whole 6 months), though are used less commonly Check baseline renal and li ver function in all patients. If normal, and not at high risk of adverse drug reaction, the y do not need to be re-checked Dosages are weight dependent, and may need to be changed for weight loss or gain during the treatment course A 6-month treatment course is effective fo r all other forms of non-CNS extrapulmonary TB (including lymph node and spinal disease), w ith the same drugs as for respiratory disease. Surgery may be needed in addition, for spina l disease CNS disease needs a 12-month treatment course Steroids may be useful for large pl eural effusions, pericardial effusions (60 mg/day for constrictive pericarditis), and CNS d isease, especially if associated with neurological impairment. Steroids may also be indicat ed in ureteric disease, and to suppress hypersensitivity reactions to the TB drugs. \200 TB: MANAGEMENT 2 497 Peripheral lymph nodes may enlarge and abscesses may form during treatment; this does not i mply failure of treatment, but should prompt a compliance check Pyridoxine is not required, unless subjects are at higher risk of pyrazinamide-related peripheral neuropathy \200\224i n diabetes, renal failure, HIV, and alcoholics. Meningitis A 12-month course of rifampicin and isoniazid, with pyrazina- mide and a fourth drug (e.g. ethambutol) for at least the \201 rst 2 months, is effective. If pyrazinamide not used, extend treatment period to 18 months. Steroids may be needed for severe disease, equivalent to prednisolone 20 \200\223 40 mg OD if on rifampicin, otherwise 10 \200\22320 m g OD. Steroids can usually be tapered after the initial 2 \200\2233 weeks of treatment. Eth ambutol should be used with caution in unconscious patients, as visual acuity cannot be tes ted and there is a small risk of ocular toxicity. Cerebral tuberculoma without meningitis 12-month regime. Disseminated TB/miliary TB 6-month regime unless CNS involvement. Exclude CNS disease in miliary TB with CSF examination, whe ther or not symptoms are present. Start treatment even if LFTs are abnormal (this may be du e to intrahepatic granulomas). Seek advice if LTFs deterio- rate signi \201 cantly on trea tment. See p 505. Bone and spinal TB 6-month standard regime. A CT or MRI should be perform ed in patients with active spinal disease who have neurological symptoms and signs. If ther e is direct spinal cord involvement (e.g. a spinal cord tuberculoma), treatment should be a s for meningeal TB. There is no place for routine spinal surgery (e.g. anterior spinal fusi on) in the absence of spinal instability. Pericardial TB standard 6-month regime. Steroids, e.g. prednisolone 60 mg OD, tapered after 2 \200\2233 weeks of treatment may be required. Peripheral lymph node TB standard 6-month regime, which should be used even if the infected node has been surgically removed. Stop treat- ment at the end of the 6-month course, regar dless of the appearance of new nodes, residual nodes, or draining sinuses. Patient advice to document on starting standard anti-TB chemotherapy \200 \200 Possibility of nausea and abdominal pain Persistent vomiting and/or jaundice \200\224stop d rugs immediately and contact doctor Red urine with rifampicin Red contact lenses with rifam picin Contraception advice, if on the oral contraceptive pill as ef \201 cacy reduced Visu al acuity (Snellen chart) (ethambutol) Visual disturbance (ethambutol) \200\224stop drugs i mmediately and contact doctor Potential drug interactions. \200 \200 \200 498 CHAPTER 42 Respiratory infection: mycobacterial