LATENT TB INFECTION 511 HIV-positive patients should receive long-term follow-up as part of their ongoing HIV management. Chemoprophylaxis is given to contacts with strongly positive Heaf r eactions, who have no radiological or clinical evidence of active disease. The risk of deve loping disease after exposure depends on a number of factors, including BCG and HIV/immune status, and whether infection was recent. Younger patients must have had relatively recent infection, and have a longer life expectancy from which to gain the bene \201 ts of chemo- prophylaxis. Chemoprophylaxis is recommended for: \200 \200 \200 Those with recent documented tuberculin conversion HIV-infected contacts of smear-positive cases Children aged <16 with a strongly positive Heaf (grade 2 \200\2234 if no prior BCG, g rade 3 \200\2234 if prior BCG) Individuals with HIV, injecting drugs, with hematological ma lignancy, chronic renal failure or on dialysis, with silicosis, gastrectomy, solid organ tr ansplant or receiving anti-TNFA therapy have a higher risk of developing active TB Drug regimes \200 Rifampicin and isoniazid daily for 3 months (3RH). Best compliance, but slightly higher sid e-effect pro \201 le Isoniazid daily for 6 months (6H). Lowest toxicity regime. Has a 60 \200\22390% effectiveness in reducing progression of latent infection to clinical disease 6 H is recommended for people with HIV 6R is recommended for contacts of patients with isonia zid resistant disease Individuals who decline chemoprophylaxis should be given the \200 \230Inform and advise \200\231 information lea \202 et, and have a CXR at 3 and 12 months. \200 512 CHAPTER 42 Respiratory infection: mycobacterial TB and anti-TNFA treatment Humanized monoclonal anti-TNFA antibody has recently been approv ed for the treatment of rheumatoid arthritis (RA), Crohn \200\231s disease, psori- atic art hropathy, and juvenile idiopathic arthritis. Etanercept (Enbrel) is a fusion protein that b inds free TNFA using a soluble portion of the TNFA receptor, and is licensed for use in rhe umatoid arthritis. Adalimumab (Humira) is a recombinant humanized monoclonal antibody again st TNFA, also licensed for use in RA. In \202 iximab (Remicade) is a human chimera monoclo nal antibody, licensed for the treatment of RA, Crohn \200\231s disease, and ankylosing spo ndylitis. These drugs cause profound immunosuppression, and patients treated with them have an increa sed risk of developing TB. Most TB cases have been seen with in \202 iximab (242 at time o f publication), with most occurring within three treatment cycles (within a mean of 12 week s of starting treat- ment). TB is the most frequently described opportunistic infection in this context. 50% of the reported cases are extrapulmonary disease. The initial high incide nce of cases has now plateaued, presumably due to improved assessment and awareness and the use of isoniazid chemoprophylaxis. The calculated TB prevalence in etanercept/in \202 ixi mab-treated RA patients in America is 41 per 100 000, 9 per 100 000 for Crohn \200\231s dis ease. Overall, there is an average 5-fold increased risk of developing TB with anti-TNFA. A ll patients due to start anti-TNFA antibody treatment should be screened for active and lat ent TB \200 All patients should have a clinical examination, with history of previous TB treatment and exposure carefully documented. All should have a CXR and tuberculin test Those with an abno rmal CXR consistent with previous TB or those who have a history of extrapulmonary TB, who have received adequate treatment (as assessed by an expert), can start anti-TNFA therapy, b ut need monitoring every 3 months with a CXR and symptom assessment. The onset of any new r espiratory symptoms, especially within 3 months of starting anti-TNFA therapy, should be in vestigated promptly Those with an abnormal CXR consistent with previous TB or those who hav e a prior history of extrapulmonary TB, who have NOT had adequate treatment, need to have a ctive tuberculosis excluded by appropriate investigations. They should receive chemoprophyl axis before anti-TNFA therapy commences (assuming active disease is not identi \201 ed). I f there is clinical concern because of the delay in starting anti-TNFA treatment, a shorter course of chemoprophylaxis can be given, but this may be more toxic Any TB diagnosed (pulm onary or extra-pulmonary) should be treated with standard chemotherapy If active TB is pres ent, patients should receive a minimum of 2 months anti-TB chemotherapy before starting ant i-TNFA therapy If the CXR is normal, the tuberculin test may be helpful if the patient is n ot on immunosuppressants, and must be interpreted knowing the BCG history. A tuberculin ski n test is unhelpful if the patient is on immunosuppressants. In this situation, an individu al assessment should be made: if the risk of drug-induced hepatitis is less than the annual risk of developing TB, chemoprophylaxis should be given. However, if the TB AND ANTI-TNFA TREATMENT 513 risk of hepatitis is greater, the patient should be monitored regularly and any suggestive symptoms investigated promptly. See Table 42.6 No chemoprophylaxis regime is 100% effective : the protective ef \201 cacy of 6H is reported at 60 and 50% for 3HR In those without pre vious BCG, Heaf grades 0 \200\2231 (Mantoux 1 in 10 000, 0 \200\2235 mm) are negative, and Heaf grades 2 \200\2234 (Mantoux 1 in 10 000, >6 mm) are positive and should lead to a risk assessment In those with prior BCG, Heaf grades 0 \200\2232 (Mantoux 1 in 10 000, 0 \200 \22314 mm) are negative, and Heaf grades 3 \200\2234 (Mantoux 1 in 10 000, >15 mm) may repr esent either latent infection or BCG effect, and therefore need further investigation In ge neral, all black African patients aged >15 and all South Asians born outside the UK should be considered for chemoprophylaxis with 6 months isoniazid If a patient develops TB, whilst on anti-TNFA therapy, treat with the full standard course of antituberculous chemotherapy. The anti-TNFA can be continued if indicated Close liaison between the prescriber of the TN FA antibody treatment and TB specialists is needed. Table 42.6 Sample calculations for aiding TB risk assessment for patients starting anti-TNF -A treatment. Risk/bene \201 t conclusion TB risk adjusted \2275 for anti- TNFA effect Case type Annual risk of TB disease/ 100 000 Risk of hepatitis following 6H chemoprophy- laxis/100 000 White, UK born, age 55 \200\22374 7 35 278 Observation ISC, in UK >3 years, age >35 593 2965 278 Prophylaxis Black African age 35 \200\22354 168 840 278 Prophylaxis Other ethnic group, in UK >5 years, age >35 39 195 278 Observation ISC = Indian subcontinent. The risk of hepatitis with 3RH chemoprophylaxis is 1766/100, 000 Further information BTS recommendations for assessing risk and for managing Mycobacterium t uberculosis infection and disease in patients due to start anti-TNF-A treatment. Thorax 200 5; 60: 800 \200\2235. 514 CHAPTER 42 Respiratory infection: mycobacterial TB: screening and contact tracing Immigrant screening Immigrants are screened, as ethnic mi nority groups in the UK constitute 50% of TB cases. New entrants are screened at port of ar rival. The incidence of TB is highest in the \201 rst few years after arrival to the UK. Return visits to countries with a high background prevalence are a risk factor for acquirin g disease. Immigrants with symp- toms suggestive of TB, and those who are asymptomatic with a grade 3 or 4 tuberculin skin test, should be referred to the local chest clinic for CXR and assessment. BCG vaccination is recommended for tuberculin-negative immigrants (but not in those who are HIV-positive, because of the risk of generalized BCG infection). Contact t racing identi \201 es those with TB, and those who are infected but without evidence of di sease. It also identi \201 es those suitable for BCG vaccination. Close contacts are usual ly those within the same household, sharing kitchen facilities, and frequent household visi tors. Casual contacts usually include most occupational contacts. Examination is usually on ly needed if the index case was smear-positive, or if the contacts are at high risk. This a lso applies if more than 10% of the close contacts have been infected, i.e. the index case is considered highly infectious. \200 10% of TB is diagnosed by contact tracing, with disease occurring in about 1% of contacts S mear-negative patients are much less infectious, but contact tracing is still recommended i n these patients Contacts should be traced for the period the index case has been infectiou s, or for 3 months prior to the \201 rst positive sputum or culture, if the time period i s uncertain Most disease in contacts is found at the \201 rst screening visit Subjects sh ould be advised to report suspicious symptoms Follow-up is recommended at 3 and 12 months f or those not receiving chemoprophylaxis. School index cases. If a pupil is diagnosed with s mear-positive TB, the rest of the class and year group who share classes should be assessed as part of routine contact tracing. If a school teacher is diagnosed with smear-positive T B, the pupils in their class during the previous 3 months should be assessed as part of rou tine contact tracing. The extension of contact tracing to include non-teaching staff etc. w ill depend on the infectivity and proximity of the index case, and whether the contacts are likely to be especially susceptible to infection. \200 \200 Airplane transmission Transmission rates are low, even on long haul \202 ights. Contract tracing of passengers and crew is only necessary if the index case was smear-positive and c oughing during a \202 ight of at least 8 h. In this situation, screening is only recommen ded in those at high risk \200\224immunocompromised travelers and children, or if the index case was unusually infectious or had MDR-TB. TB: SCREENING AND CONTACT TRACING 515 M. bovis Cattle TB is due to M. bovis. Humans are at low risk, as the majority of milk cons umed is pasteurized. M. bovis is distinguishable from M. tuberculosis in the laboratory, al though initial diagnosis can be dif \201 cult (only distinguishable on culture, not using DNA or RNA testing). Around 40 cases are isolated per year. BCG is live attenuated M. bovis . Extrapulmonary disease Contact screening is not recommended. Contact examination This usu ally involves symptom enquiry, BCG vaccina- tion status, Mantoux test, and CXR. Contacts of smear-positive index case If symptoms are present, and if the contact was not previously v accinated, those with negative Mantoux should be retested after 6 weeks to allow for tuberc ulin conversion. If retesting is not possible, give BCG after the \201 rst negative Manto ux. HIV-infected contacts CXR is indicated, as a negative Mantoux test may be due to anergy , and may therefore be a false negative. Mantoux testing is not contraindicated in HIV (PPD is dead). BCG is contraindicated (it is a live vaccine). BCG vaccination The UK national schools \200\231 vaccination program ceased in 2005 and now aims to target vaccination to selected \200\230at risk \200\231 groups. Vaccination is of fered to: \200 All infants whose parents or grandparents originate from a country with a TB incidence of 4 0/100 000 or higher, or those living in areas with a TB incidence of 40/100 000 or higher A ll Mantoux-negative contacts of patients with respiratory TB, if they are previously unvacc inated and aged <35 years. Laboratory and health care workers who are contacts meeting the same criteria should be vaccinated if they are aged >36. All Mantoux-negative new entrants from high-incidence countries if previously unvaccinated, if aged <16. If originating from sub-Saharan Africa or a country with a TB incidence of 500 per 100 000, those aged 16 to 35 should also be offered vaccination All Mantoux \200\223negative health care workers, irres pective of age, who are previously unvaccinated and who will be exposed to patients and cli nical materials Mantoux-negative, previously unvaccinated individuals aged <35, if potentia lly at risk of TB exposure because of their occupation, including veterinary and abattoir w orkers, prison staff, staff in care homes for the elderly, staff of accommodation for refug ees and the homeless, and those going to work in a high-incidence country for more than one month BCG has an ef \201 cacy of around 70% against TB in children, but dif \201 cul- ti es with vaccine supply and regional policies have meant that not all children in the UK hav e been vaccinated in the past. It is less effective in adults, and is not used in America A dverse events include pain and suppuration at the injection site, and localized lymphadenit is. A course of rifampicin and/or isoniazid for 3 \200\2236 months, depending on response, may be needed 516 CHAPTER 42 Respiratory infection: mycobacterial Disseminated BCG infection (BCGosis) Live attenuated BCG immunotherapy is the most effectiv e intravesical agent for the treatment and prophylaxis of super \201 cial bladder cancer. It prevents tumor recurrence and prolongs disease-free survival, and may be more effective than chemotherapy in this setting. BCG can penetrate deep within the detrusor muscle and ha s been identi \201 ed in pelvic lymph nodes after instillation, so has a potentially much longer duration of action than standard intravesical chemotherapy. BCG leads to a T-cell-me diated immune response, which has anti-tumor activity. After intravesical instill- lation, live mycobacteria attach to the urothelial lining. BCG organisms are internalized by bladde r epithelial cells, leaving bacterial cell surface glycoproteins attached to the epithelial cell membrane. These antigens are thought to mediate the immune response. \200 The standard treatment regime is 6 weekly instillations of 100 million to 1 billion colony- forming units of BCG (cfu). Some advocate a further 3-week course, 6 weeks after cessation of the \201 rst cycle. The dose \200\223 response curve is bell shaped, with excess BCG p robably promoting increased tumor activity Local side-effects are common, with cystitis rep orted in around 90% of patients; low-grade fever and malaise are frequent. Cystitis persist ing >48 h after treatment should be treated with a \202 uoroquinolone or iso- niazid 300 mg od, rifampicin 600 mg od should be added if the symptoms persist at one week Breaks in t he uro-epithelium are a risk factor for systemic infection, and therefore patients with per sistent cystitis or haematuria should have their treatment delayed Signi \201 cant reactio ns are reported in around 5%, with high fever com- monest. A high fever post treatment (>39 C) may represent the onset of systemic BCG infection or hypersensitivity, and hospital ad mission is recommended BCG sepsis is reported in around 0.4 \200\2230.7%, with 10 deaths at tributed to intravesical BCG to date. The major differential diagnosis is Gram- negative se psis; thus patients should be treated with broad-spectrum antibiotics Later onset symptoms (at up to 8 \200\22312 weeks, though may occur much earlier) including fever, malaise, arth ralgia, and breathlessness may represent systemic BCG infection, though there is debate as to whether these sorts of systemic symptoms are due to systemic BCG infection or hypersensi tivity to BCG. Non-caseating granulomas can be identi \201 ed on lung and liver biopsy. Cu lture of organisms is rarely reported, but tissue M. bovis can be identi \201 ed by PCR Di sseminated infection \200\224treat with rifampicin 600 mg od and isoniazid 300 mg od for 6 months. Some advocate the addition of ethambutol. Prednisolone 40 mg od may be added, and r esponse to cortico steroids is said to support the diagnosis of hypersensitivity. There are no trial data to support these treatment regimes or length of treatment, but M. bovis is s usceptible to most anti-TB drugs, except pyrazinamide and cycloserine. There is no evidence that isoniazid reduces the anti- tumor effects of BCG DISSEMINATED BCG INFECTION (BCGOSIS) 517 BCG hypersensitivity pneumonits is suggested by pulmonary in \201 ltrates; micronodular an d miliary appearances are reported with or without eosinophilia Granulomatous hepatitis is reported. Standard TB treatment (6 months) is suggested, with prednisolone if symptoms of h ypersensitivity predominate Systemic BCG infection is reported in HIV-positive infants and infants with severe immune de \201 ciency, undiagnosed at the time of BCG vaccination. Sys temic BCG infection is reported after BCG injection into melanoma. Future developments in TB \200 New TB vaccine (MVA85A) \200\224heterogolous prime boost immunization regimes have been sho wn to induce higher levels of cellular immunity than homologous boosting with the same vacc ine. Initial data on a BCG prime-recombinant modi \201 ed vaccinia virus Ankara, expressin g Ag 85A, are promising. This is now in clinical trials in the UK and Africa. The TB Vaccin e Cluster Project (EU funded) aims to provide novel vaccines for human use, and boost BCG e ffect using modi \201 ed BCG. Compound R207910 is a new antibiotic which has shown in vitr o anti- TB activity in mice models Nebulized gamma interferon used in the USA as additional treatment in MDR-TB in those failing multiple agent chemotherapy. Further information Chemotherapy and management of tuberculosis in the UK: recommendations 1998. Drug doses and regimes as recommended in this document. Thorax 1998; 53: 536 \200\223 48. Control and prevention of tuberculosis in the UK: Code of practice 2000. Thorax 2000; 55: 8 87 \200\223901 NICE Guideline: Clinical diagnosis and management of tuberculosis, and measures for its pre vention and control 2006. See www.nice.org.uk/CG033. BTS recommendations for assessing risk and managing Mycobacterium tuberculosis infection an d disease in patients due to start anti-TNFA treatment. Thorax 2005; 60: 800 \200\2235. UK s national tuberculosis charity. www.tbalert.org 518 CHAPTER 42 Respiratory infection: mycobacterial Non-tuberculous mycobacteria (NTM) NTM is also called atypical mycobacteria, opportunistic mycobacteria, envi- ronmental mycobacteria, mycobacteria other than tuberculosis (MOTT). Etiology \200 Found in the environment: in soil, water (including tap water), dust, milk, animals, and bi rds Many different species. The four most important are Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium mal- moense, and Mycobacterium xenopi They are low-gr ade pathogens in humans Most commonly cause pulmonary infections in middle-aged and older a dults, and in those with pre-existing lung disease, such as bronchiec- tasis, CF, emphysema , or old healed TB, or in immunode \201 ciency Disseminated infection may occur, especiall y in the immunocompromised Lymphadenitis typically occurs in children aged 1 \200\2235 year s. This presents with enlarged non-tender cervical lymph nodes and a normal CXR. The node s hould be surgically resected. Antibiotic treatment is only required if there is recurrence. Large nodes may need antituberculous chemotherapy to shrink the node prior to resection Lo cal invasion may occur from skin lesion (e.g. M. marinum, M. ulcerans, M. fortuitum, M. abs cessus, M. chelonae, M. avium complex). \200 \200 Clinical features The symptoms are generally non-speci \201 c, hence the dif \201 culty i n diagnosis. \200 Sub-acute illness with weight loss, productive cough, dyspnoea, fever, and occasionally hae moptysis May present in a patient with known underlying lung disease, such as COPD, in whom disease progression is atypical Colonization of abnormal lung may not cause symptoms, but can progress to cause disease later May be similar to symptoms caused by Mycobacterium tube rculosis \200\230Lady Windermere syndrome \200\231 is habitual voluntary cough suppres- si on, which may lead to failure to clear airway secretions, predisposing to lingula or RML co nsolidation, bronchiectasis, and MAC infection. Found in otherwise healthy middle-aged wome n (Reich JM, Chest 1992;101:1605 \200\2239). \200 Investigations \200 CXR can be indistinguishable from that of MTB, with upper zone in \201 l- trate with cavit ation. Airway nodularity and associated bronchiectasis are recognized. The CXR may be dif \201 cult to interpret in the presence of pre-existing lung disease. HRCT may help. It is i mpossible to iden- tify which atypical mycobacterium is causing infection from the CXR appe arance NON-TUBERCULOUS MYCOBACTERIA 519 Sputum samples Microbiology for ZN stain, culture, and further testing. If there is growth of an atypical acid-fast bacillus: \200 Where was the isolate from? Culture from lung biopsy, BAL, pleural \202 uid, or blood cul ture is more signi \201 cant than culture from sputum What is the isolate and what is the degree of growth? How many samples have been positive? \200 A single isolate from a non-sterile site may not be signi \201 cant. Contamination can occur, especially from bronchoscopes when BAL is performed. Multiple isolates (>2) from non-sterile sites are needed to establish disease, or >1 from a sterile site, especially i f there is sup- portive histopathology. Liaise with microbiologists to help to determine th e signi \201 cance of a positive result May need lung biopsy to help differentiate No skin test is available. \200 Diagnosis Pulmonary disease is likely if: \200 CXR is suggestive and 3 or more positive sputum cultures are obtained 1 week apart, with or without symptoms Or 1 positive culture from a sterile site, such as pleural \202 uid or biopsy Or 2 positive cultures from bronchoalveolar lavage on separate occa- sions. \200 In the UK, pulmonary infection is most commonly caused by Mycobacterium kansasii, Mycobacte rium avium complex, Mycobacterium malmoense, and Mycobacterium xenopi. 520 CHAPTER 42 Respiratory infection: mycobacterial NTM: management \200 \200 \200 The decision to treat is based on the likelihood of active infection No need to notify or c ontact trace as there is low risk of cross-infection De-notify if the MTB grown turns out t o be an atypical mycobacterium, and change treatment accordingly Treatment considerations a ccording to BTS guidelines: \200 M. kansasii \200\224progresses without treatment. Treat with rifampicin and ethambutol for a minimum of 9 months. A longer treatment period is required if immunocompromised (2 years or until sputum is clear of infection for 12 months). Good response to treatment. Inde \201 nite treatment if non-compliant. 100% response rate, >90% 5-year cure, with <10% relap se with full compliance M. avium complex (MAC) \200\224may be asymptomatic. Can be antibiot ic resistant. Treat with triple therapy: rifampicin with ethambutol with or without isoniaz id for 2 years. 50% response rate and 20% relapse rate. Clarithromycin or azithromycin may be effective M. malmoense \200\224treat with ethambutol and rifampicin for 18 \200\22324 mo nths M. xenopi \200\224often resistant. Disease may progress despite treatment. Treat with ethambutol, isoniazid, and rifampicin for at least 2 years M. malmoense, and M. xenopi \200 \22490% response rate, and 10% relapse rate at 2 years. \200 It is recognized that laboratory antibiotic sensitivities and resistance may not correlate with the clinical therapeutic response. Antibiotic choice is best judged on clinical respon se. HIV-positive patients \200 \200 \200 \200 HIV is a risk factor for NTM Mycobacterium avium complex is the cause of infection in 90% o f cases Infections may occur late in the disease, when CD4 count <50 Infections may develop during the \201 rst 2 months of highly active anti- retroviral treatment (HAART) Disease is rarely con \201 ned to the lungs. Lymphadenitis and disseminated infection are recogni zed Lung disease causes similar symptoms to those seen in the non-immuno- compromised CXR s hows diffuse interstitial, reticulonodular, or alveolar in \201 ltrates A single isolate m ay represent colonization If an organism is repeatedly isolated in the presence of symptoms and/ or an abnormal CXR, start treatment Lifelong antibiotic treatment is recommended for pulmonary or dis- seminated disease, with a 3 \200\2234 drug regimen Disseminated MAC incid ence is decreased by antibiotic prophylaxis (with azithromycin weekly) and HAART restoring immunocompetence There are potential drug interactions between rifampicin, macrolides, and protease inhibitors and NNRTIs. \200 \200 NTM: MANAGEMENT 521 Further Information Management of opportunistic mycobacterial infections. Thorax 2000; 55: 210 \200\22318. Grif \201 th DE et al. ATS/IDSA Statement: diagnosis, treatment and prevention of NTM. Am J Respir Crit Care Med 2007; 175: 367 \200\223416. This page intentionally left blank 523 Chapter 43 Respiratory infection: parasitic Pulmonary hydatid disease 524 Amoebic pulmonary disease 525 Pulmonary ascariasis 525 Strong yloidiasis 525 Toxocariasis 526 Diro \201 lariasis 526 Schistosomiasis 526 Paragonimiasis 527 Tropical pulmonary eosinophilia 527 524 CHAPTER 43 Respiratory infection: parasitic A wide variety of parasitic organisms may infect the lungs, although clinical disease is ra re in the UK. In general, parasites may cause lung disease by two different mechanisms: \200 Hypersensitivity reactions, e.g. L f \202 er \200\231s syndrome and eosinophilic lung dis ease, most commonly from helminths such as Ascaris, Toxocara, and liver \202 ukes Direct infection and invasion, e.g. amoebic disease, pulmonary hydatid disease. Some of the more important examples are noted below. Pulmonary hydatid disease \200 \200 Hydatidosis is the commonest parasitic lung disease worldwide Human infection follows inges tion of parasite eggs, with the adult worm found in dogs, sheep, goats, horses, camels, and moose; infection is common in sheep-raising regions, particularly Central Europe and the M editerranean, as well as Alaska and Arctic Canada Two main forms: \200 Echinococcus granulosus, which causes cystic hydatid disease as the larvae grow in the lung s. Common. Symptoms include cough (some- times productive of cyst contents, \200\230hydati doptysis \200\231), haemoptysis, and chest pain. CXR shows rounded cysts, sometimes with ca lci \201 ed walls, most commonly in lower lobes; CT may show \200\230daughter cysts \200 \231. Cyst rupture may occur, with wheeze, eosinophilia, and bronchial or pleural spread Ec hinococcus multilocularis, which leads to alveolar hydatid disease following tissue invasio n. Rare. Lung masses are less clearly delin- eated on CT than in cystic disease Diagnose from serology or sputum analysis. Serology is insensitive for the diagnosis of pul monary disease (around 50%). Demonstration of liver cysts supports the diagnosis. Avoid nee dle aspiration of cysts, which may result in hypersensitivity or dissemination Treatment is with surgical excision in most cases. Medical treatment with albendazole if the patient is un \201 t for surgery or following cyst rupture and dissemination. STRONGYLOIDIASIS 525 Amoebic pulmonary disease \200 Intestinal and liver infection is common, with lung involvement in a minority Lung disease can develop either directly from the liver or via the blood- stream or lymphatics Pulmonary manifestations include right lower lobe consolidation, empyema, lung abscess, or hepatobro nchial \201 stulae (resulting in large volumes of brown or \200\230anchovy \200\231 sput um). May be associated pericardial disease Diagnose using serology or following identi \201 cation of trophozoites in stool, sputum, or pleural \202 uid Treatment is with metro nidazole plus iodoquinol or diloxanide. Pulmonary ascariasis \200 \200 Distributed worldwide Lung involvement occurs during maturation of Ascaris lumbricoides, an d is typically manifest as a hypersensitivity reaction with cough, wheeze, fever, CXR in \201 ltrates, and peripheral eosinophilia Examination of stool for eggs may con \201 rm th e diagnosis Usually resolves spontaneously after 1 \200\2232 weeks. Consider treatment with mebendazole for gastrointestinal infection. \200 Strongyloidiasis \200 Caused by Strongyloides stercoralis, found in Central and South America and Africa Pulmonar y involvement may lead to a L f \202 er-type syndrome with wheeze, skin rash, eosinophili a, and CXR in \201 ltrate. In the setting of immunocompromise, disseminated infection may occur leading to the \200\230hyperinfection syndrome \200\231. ARDS may develop, and secon dary bacterial sepsis is common Diagnose using serology or following microbiological analys is of stool or duodenal \202 uid Treatment is with thiabendazole. 526 CHAPTER 43 Respiratory infection: parasitic Toxocariasis \200 Caused by Toxocara canis, distributed worldwide. Dogs are the primary host Ingestion of egg s from contaminated soil may result in visceral larva migrans. Migration of larvae through the lungs results in an immune response, with wheeze, cough, and eosinophilia Diagnosis may be made from serology Treatment often not required; steroids may be bene \201 cial in sev ere cases. \200 Diro \201 lariasis \200 \200 Found in USA, Japan, South America Infection is caused by Diro \201 laria immitis followin g mosquito transfer from animals, especially dogs. Worms lodge in the pulmonary arteries an d elicit an in \202 ammatory response, leading to a necrotic nodule Presentation is classi cally asymptomatic with a single peripheral nodule on CXR, mimicking cancer. Patients may p resent with cough, chest pain, and haemoptysis, presumably due to pulmonary infarction De \201 nitive diagnosis requires lung biopsy. Serology lacks sensitivity and speci \201 city Treatment is not usually needed. Schistosomiasis \200 Found in the Middle East, South America, South-east Asia, Africa, and the Caribbean Schisto soma species are carried by snails, and infection follows skin penetration, often during sw imming Pulmonary involvement may re \202 ect acute tissue migration, causing cough, wheeze , and CXR in \201 ltrates, or chronic infection, leading to interstitial in \201 ltrates, pulmonary hypertension, or AV \201 stulae Diagnosis from observation of ova in sputum, B AL, urine, or stool, or from lung biopsy Treatment is with praziquantel. TROPICAL PULMONARY EOSINOPHILIA 527 Paragonimiasis \200 Caused by Paragonimus westermani, distributed in West Africa, the Far East, India, and Cent ral and South America Following ingestion, \202 ukes migrate to the lung or pleura. Clini cal fea- tures may be acute or chronic, and include chest pain, pneumothorax, pleural effus ion, L f \202 er \200\231s syndrome, and recurrent haemoptysis. Serum eosinophilia is com mon Diagnose with serology or observation of eggs in sputum, TBB, BAL, or pleural \202 ui d Treatment is with praziquantel. Tropical pulmonary eosinophilia \200 Follows infection with Wuchereria bancrofti or Brugia malayi in the tropics Pulmonary invol vement is common and represents a hypersensitivity reaction to the organism, with cough, wh eeze, CXR in \201 ltrates, and raised serum IgE Treatment is with diethylcarbamazine. This page intentionally left blank 529 Chapter 44 Respiratory infection: viral Viral pneumonia: overview 530 In \202 uenza: diagnosis 532 In \202 uenza: management 534 Cytomegalovirus pneumonia 536 Varicella pneumonia 538 Respiratory syncytial virus 539 Measl es 539 Hantavirus pulmonary syndrome 540 Severe acute respiratory syndrome (SARS): epidemio logy and pathophysiology 542 SARS: clinical features and management 544 530 CHAPTER 44 Respiratory infection: viral Viral pneumonia: overview \200 Viral upper respiratory tract infections are common, but typically self- limiting, and are usually managed in the community. Viral pneumonia is much less common but is more serious a nd usually requires hospitalization. Viral pneumonia in the immunocompetent is rare and typ ically affects children or the elderly; in \202 uenza strains are the commonest cause in a dults Viruses may cause serious respiratory infection in the immunocompro- mised (particula rly patients with depressed T-cell function, e.g. following organ transplantation). CMV is the commonest serious viral pathogen that affects immunocompromised patients. In \202 uenz a, parain \202 uenza, RSV, measles, and adenovirus may also cause pneumonia in the immuno- compromised, although diagnosis of these viruses is dif \201 cult and infection is common ly undetected The clinical and radiological features of viral pneumonia are non- speci \201 c. Worsening cough and breathlessness following an upper respi- ratory tract infection suggest the development of pneumonia; wheeze may accompany bronchiolitis. CXR typically sh ows non-speci \201 c diffuse interstitial in \201 ltrates, and hypoxia may occur. Seconda ry bacterial infec- tion may complicate viral pneumonia A variety of diagnostic techniques are available, including viral culture and immuno \202 uorescence staining (e.g. of BAL \202 uid) and serology Treatment consists of supportive care and in some cases antivirals. Infection with certain viruses may require isolation. Treat secondary bacterial infection w ith antibiotics Speci \201 c features of the common and/or important viruses are noted in the remainder of the chapter. This page intentionally left blank 532 CHAPTER 44 Respiratory infection: viral In \202 uenza: diagnosis \200 Commonest cause of viral pneumonia in immunocompetent adults. It is transmitted via respira tory secretions and is extremely contagious. Seasonal in \202 uenza is very well recognize d in the UK, particularly during the winter months, and recently outbreaks of H5N1 avian in \202 uenza have occurred in many countries, raising fears of the development of sustained human-to-human transmission and a new global pandemic Three pathogenic serotypes: A, B, an d C. Type A causes more severe disease and occurs in annual epidemics and intermittent pand emics. Types B and C cause epidemics The surface antigens haemagglutinin and neuraminidase determine in \202 uenza serotype. Genetic mutations may result in antigenic shifts (major genetic rearrangements between strains, associated with pan- demics) and antigenic drifts ( more minor genetic variations associated with epidemics). Genetic rearrangement of virus oc curs in animal and bird reservoirs, and the virus may then be transferred to humans Seasona l in \202 uenza may affect previously well individuals, although it occurs more commonly i n the elderly, particularly in the setting of chronic heart or lung disease or immunocompro mise. Pandemic in \202 uenza differs in that it is also associated with signi \201 cant m ortality in younger adults. Regularly updated information on seasonal, avian, and pandemic in \202 uenza is available from the Health Protection Agency website: http://www.hpa.org.uk/infections/topics_az/in \202 uenza Additional guidelines are available for the management of suspected in \202 uen za in the setting of a pandemic with UK Pandemic Alert Level 2 (cases of pandemic in \202 uenza identi \201 ed in UK): http://www.brit-thoracic.org.uk/PandemicFlu.html http://www.d h.gov.uk/en/PandemicFlu/index.htm Clinical and laboratory features Incubation period typica lly 1 \200\2234 days; adults contagious for 7 days and children for 21 days from illness on set. The clinical picture following infection is variable and may be in \202 uenced in par t by the in \202 uenza subtype. Features include: \200 \200 Asymptomatic infection \200\230Flu \200\231 (acute onset of fever, cough, headache, coryza l symptoms, myalgia, sore throat) Complications include: \200 \200 Bronchitis/bronchiolitis Primary in \202 uenza viral pneumonia (onset typically within 48 h of initial fever; cough dry or productive, haemoptysis may occur, bilateral crackles and/ or wheeze; may progress very rapidly to respi- ratory failure and death; described in major ity of patients infected with avian in \202 uenza H5N1, often associated with lymphopenia, thrombocytopenia, abnormal liver function, and multi-organ failure) INFLUENZA: DIAGNOSIS 533 Secondary bacterial pneumonia (signi \201 cantly more common than viral pneumonia; onset t ypically 4 \200\2235 days after initial fever, during early convalescence, although may occ ur earlier; pathogens include S. pneumoniae, S. aureus \200\224particularly associated with lung abscess \200\224and H. in \202 uenzae; mixed bacterial/viral pneumonia may occur) Ga strointestinal symptoms (e.g. watery diarrhea; more frequently described during avian in \202 uenza A H5N1 than seasonal infection) Otitis media (particularly in children), conjunc tivitis; rarely parotitis Myositis (creatine kinase may be elevated; rarely myoglobinuria w ith renal failure) Neurological (encephalitis, acute necrotizing encephalopathy, trans- ver se myelitis, Guillain \200\223Barr syndrome all rare; Reye \200\231s syndrome with enceph alopathy and fatty liver following aspirin use is well described in children and adolescent s) Cardiovascular (ECG abnormalities common, myocarditis or peri- carditis rare). \200 Imaging \200 CXR typically shows bilateral mid-zone interstitial in \201 ltrates in primary viral pneum onia, although focal consolidation is also well described. Lobar consolidation occurs in se condary bacterial pneumonia. Differential diagnosis of \200\230 \202 u-like \200\231 illness includes adenovirus, RSV, rhinovirus, parain \202 uenza, Chlamydia pneumoniae, Legionella, Mycoplasma, and S. pneum oniae. A very high fever is said to favor a diagnosis of in \202 uenza. Consider SARS (p 5 42) in patients with an appropriate travel history. Diagnosis is often suggested by knowled ge of a local outbreak. Diagnostic investigations include: \200 Virology (not routinely required if pandemic established with wide- spread infection across the UK \200\224Alert Level 4 \200\224when diagnosis will be clinical) \200 Presentation <7 days after illness onset: nose and throat swabs in virus transportation med ium (for direct immuno \202 uorescence, ELISA, virus culture, and/or PCR) Presentation >7 days after illness onset: \200\230acute \200\231 serum and subse- quently \200\230convale scent \200\231 serum after 7 days (for in \202 uenza serological testing) Bacteriology (in patients with in \202 uenza-related pneumonia) \200 \200 \200 Blood culture Pneumococcal and Legionella urinary antigen Sputum M,C&S (if purulent sputum and either no prior antibiotics or failure to respond to empirical antibiotics) \200\230Ac ute \200\231 serum and subsequently \200\230convalescent \200\231 serum after 7 days for i n \202 uenza/other agents serological testing 534 CHAPTER 44 Respiratory infection: viral In \202 uenza: management Severity assessment \200 \200 Patients with uncomplicated in \202 uenza do not require admission For in \202 uenza-rela ted pneumonia, a CURB-65 score (p 424) of \211 3 indi- cates severe pneumonia and a high r isk of death; patients with a score of 0 or 1 may be considered for home treatment Bilatera l CXR in \201 ltrates consistent with primary viral pneumonia should be considered as seve re pneumonia, irrespective of CURB- 65 score. Infection control \200 Outside the setting of a UK pandemic, most suspected cases of in \202 uenza are likely to be seasonal, although H5N1 avian in \202 uenza should be seriously considered in patients with: \200 \200 