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). IgE-mediated atopy (type I hypersensitivity) to fungal spores. Atopy to Aspergillus species leads to a positive skin-prick test in 10 \200\22325% of patients with asthma when exposed to Aspergillus spores. Other features of ABPA are not detected in this condition. (b) ABPA A type I plus type III hypersensitivity reaction to the inhala- tion of Aspergillus fumiga tus spores. This can be divided into ABPA with seropositivity (ABPA-S) alone or ABPA with c entral bronchiectasis (ABPA-CB). Essential criteria for diagnosis of ABPA: \200 \200 \200 \200 2 Aspergilloma (Mycetoma) \200 Growth of a fungal ball of Aspergillus fumigatus/ \202 avus/ niger in a pre-existing cavit y in the lung. Commonly follows tuberculosis but may occur in the setting of any cavitary l ung disease. Often asymptomatic and detected on CXR. May present with haemoptysis. Rarely p resents with systemic symptoms or cough. Diagnosis is usually radiological. Sputum may cont ain fungal hyphae. Aspergillus precipitins may be present. Treatment only indicated if symp toms are present. Treat haemoptysis with drugs (tranexamic acid), surgery (resection) or ar terial embolisation. Itraconazole may reduce size of fungal cavity but does not act rapidly enough to be of use in life threatening haemoptysis. \200 \200 \200 \200 \200 \200 Asthma (long history). Immediate skin-prick positivity. Total IgE >1000ng/ml (unless taking steroids). Eosinophilia (blood) >1000mm3. Additional diagnostic criteria for ABPA-S: \200 \200 Current or previous pulmonary in \201 ltrates. Increased serum IgG (precipitins) and IgE ( RAST) to A. fumigatus. CHAPTER 8.10 Fungal and parasitic lung disease 197 during growth. The galactomannan test is an ELISA which tests for the presence of this anti gen and is highly spe- ci \201 c (89%) but less sensitive (71%) for invasive disease. Test ing of sera should be performed twice a week in a high risk patient who is unwell to enable early diagnosis of invasive aspergillosis. False positive results may occur within 5 days of taking beta-lactam antibiotics. PCR for Aspergillus antigen may become a useful diag- no stic test in the future 3 Aspergillosis (a) Chronic pulmonary aspergillosis This rare disease usually occurs in tho se with mildly impaired host defenses and older patients with chronic lung disease. It is a slowly progressive disease with local invasion (but not dissemination) occurring over week s or months. There may be an aspergilloma present prior to disease onset. Patients complain of a prolonged (>3 month) history of chronic productive cough and systemic symp- toms such as malaise, fever and weight loss. Haemoptysis is common. CXR changes include new or expan ding cavita- tion, pleural thickening and consolidation, primarily in the upper lobes. Bloo d tests reveal high in \202 ammatory markers. Serum aspergillus precipitins (IgG) may be p ositive. The organism may be isolated from sputum, BAL or pleural fluid or biopsy samples. Treatment is with anti-fungal therapy such as voriconazole 200mg BD for 1 \200\2236 months. Alternative anti-fungal agents include itraconazole or amphotericin B. Interferon gamma is emerging as a possi- ble future adjunctive therapy. Surgery is occasionally required. Treatment: Prompt treatment is essential and reduces mortality in this condition. \200 Anti-fungal medications: the treatment of choice is oral voriconazole (e.g. 6mg/kg BD on da y 1 then 4mg/kg BD until day 7 then oral 200mg BD). Limited studies of com- bination therap y suggest a possible role for combining the use of capsofungin with voriconazole or amphote r- icin. Adjuvant therapies directed at treating the underlying immunocompromise include GM -CSF, granulocyte transfusions and IFN Reduce immunosupressants where possible. (b) Invasive pulmonary aspergillosis Invasive pulmonary aspergillosis is a severe disease, respon- sible for signi \201 cant mortality amongst those with immune system compromise. A spergillus fumigatus is the common- est cause of this condition but the contribution of oth er Aspergillus species is increasing. Major risk factors include: \200 Further information & patient support: http://www.aspergillus.org.uk Endemic mycoses These dimorphic fungi cause disease in endemic areas. They are easily misse d if the patient presents in a non- endemic area and the travel history is not taken carefu lly. The disease is usually self-limiting if host immunity is intact. However, when T-cell mediated immunity is impaired or exposure is great, severe or disseminated disease may occu r. Neutropenia (especially <500cells/mm3 for >10 days or persistent dysfunction). Transplantat ion. Prolonged high dose corticosteroids (>3 weeks). Hematological malignancy. Cytotoxic th erapy. Advanced AIDS (usual CD4 <100cells/mm3). Admission to ICU. \200 \200 \200 \200 \200 PCP Pneumocytis jeroveci causes a fungal pneumonia in those with impaired T-cell immunity s uch as malignancy or HIV. This condition is described further in the Chapter 9.2 (p. 210). Clinical features: \200 Yeast infections Candida Although Candida spp. often colonize the respiratory tract, primar y Candida infection of the lungs is rare. Fungal pneumonia due to Candida occurs when heavy colonisa- tion of the oral cavity occurs or in the setting of dissemi- nated disease (cand idaemia). This is most often seen in the ITU or in those with neutropenia. Diagnosis relies on the culture of Candida spp. from a normally sterile site. This condition is described f urther in Chapter 9.1 (p. 202). Symptoms of a pneumonia that fails to respond to stand- ard antibiotic therapy. Pleuritic p ain, haemoptysis or unexplained fever in a patient with major risk factors. Rarely, present s as a tracheobronchitis with airway in \202 ammation and ulceration. Dissemination may oc cur, leading to involvement of other organs such as the CNS. Investigations: \200 CXR may demonstrate cavitation, wedge opacities and/ or nodules(s). CT may show small nodul es surrounding haemor- rhage (halo sign) or central necrosis (air-crescent), con- solida tion or ground-glass opaci \201 cation. CT should be performed early in order to look for this disease in patients who are immunocompromised and have unex- plained fever. Histologic al examination of thoracic biopsy specimens may reveal fungal hyphae. Culture (e.g. of sput um or BAL \202 uid) may demonstrate growth of Aspergillus spp. This is diagnostic alone i f the patient has major risk factors and the organism is cul- tured from a normally sterile site. Galactomannan is a polysaccharide component of the fungal cell wall that is released by Aspergillus spp. Cryptococcus neoformans Inhalation of Cryptococcus spp. in those with impaired immunity (e. g. due to HIV) can lead to pulmonary infec- tion. There may be no pulmonary symptoms or sym ptoms may be those of cough, dyspnoea and chest pain. Rarely acute respiratory failure may occur. In HIV the organism commonly disseminates or spreads to the CNS, leading to severe d isease with a high mortality. This disease has fallen in incidence as a result of the wides pread use of anti-fungal prophylaxis in high risk patients. Molds Rare fungal mold infections affecting the lungs include mucormycoses, zygomycoses and fusariosis. Mucormycosis is an opportunistic fungal infection with a very high mortality a nd should be treated by early surgical A GOODMAN 198 Endemic regions Clinical features Diagnosis Treatment Endemic mycosis (causative organism) nodules or calci \201 ed lymph nodes on CXR in a healthy individual \200 systemic \202 u-like illness multilobar in \201 ltrate on CXR following high level exposure to histo plasma \200 Chronic: Progressive lung disease and cavitation on CXR in those with prior u nderlying lung disease \200 Multi-organ disease and organ failure with reticulonodular CX R in \201 ltrates in immunocompromised individuals \200 Rarities: Broncholithiasis, gran ulomatous mediastinitis, \201 brosing mediastinitis \200 \200 \200 Treat if: \200 Antigen detection test on blood or urine (up to 95% sensitive) Smear or culture of sputum/ BAL \202 uid/ blood/ urine/ bone marrow aspirate (may take 4 days or more to become posit ive) Serology (takes weeks to become positive) Asymptomatic: Mid-west (along river valleys) and southeast USA Parts of Central America and the Caribbean (especially Puerto Rico and the Dominican Republic) Africa (especially Nigeria+ Niger) Asi a Histoplasmosis (Histoplasma capsulatum) Immunocompromised host Symptoms > 1 month Disseminated disease Respiratory failure \200 \200 Acute: Treat with: \200 Oral itraconazole 200mg BD for 2 \200\2234 months If chronic disease fails to respond after 12 weeks or the patient requires parenteral therapy then commence amphotericin B Corticote roids may be used to reduce the in \202 ammatory response Disseminated: Treat severe disease with amphotericin B Once stable this can be switched to oral itracona- zole 200mg BD for at least 6 months 10%KOH digest test of respiratory secretions Rapid staining of BAL \202 uid Open lung bio psy may be required Serological tests have poor sensitivity Progressive pneumonia Respiratory failure Rarely disseminated disease involving the meninge s Mid-west and southeast USA Canadian great lakes Blastomycosis (Blastomyces dermatitides) Usually self-limiting but if severe disease or meningitis treat with: \200 The organism is dif \201 cult to culture and diagnosis usually relies on an accurate trave l history in combination with a characteristic lymphocytic CSF (or neutrophilic or eosinoph ilic) or positive serology. \200 \200 Parts of southwest USA Pneumonia (sometimes with effusions) Erythema nodosum or multi- forme Life-threatening meni ngitis Severe pulmonary disease and ventilatory failure may occur in immunocompromised pati ents Cavitating nodules may occur Coccidioido- mycosis (Coccidioides immitis) Fluconazole (or itracona- zole or posaconazole) for life Or amphotericin B if the onset is acute and severe Mexico and areas of South America \200 Culture sputum/BAL Stain lung biopsy sam- ples Parts of Central & South America (especially Brazil) Typically presents as a chronic pulmonary disease May be acute and disseminated in an immun ocompromised host Paracoccidioido- mycosis (Paracoccidioides basiliensis) Treat with oral itracona- zole for 6 months Fig. 8.10.1 Table of endemic mycoses resection combined with amphotericin B. Zygomycosis and fusariosis have clinical presentati ons that are similar to aspergillosis. Zygomycosis fails to respond to voriconazole. These organisms especially cause fungal infection in those with hematological malignancy. with eggs from dog or sheep feces leads to infection of the liver. Spread to the lungs may then occur across the diaphragm or via blood or lymph. Intact cysts cause symptoms due to c ompression of surrounding tissues and presentation may be with cough, chest pain or dyspnoe a. Cyst rupture leads to pneumonia, hypersensitivity reactions or haemoptysis. Diagnosis is by serology and radiology. Surgery should be performed to excise an intact cyst if possibl e, even if no symptoms are present. Anti-helminth medications (albendazole or mebendazole) can be used to prevent recurrence or secondary bacterial infection. Echinococcus multilocul aris is a rare infection occuring in the Arctic, Northern Europe and Asia. It presents with a lung mass on CXR. Anti-fungal therapy Antifungal prophylaxis is recommended for those at high risk of fungal infection (e.g. cotrimoxazole in those with HIV and low CD4 counts to prevent PCP). Treatme nt of fungal infections is often empirical with oral azoles or intravenous amphotericin B. If the speci \201 c organ- ism is identi \201 ed targeted antifungal therapy, taking drug sen- sitivities into account, should be prescribed. Echinocandins are of use in treating a zole-resistant Candida infections. Flatworms Lung \202 ukes (Paragonamiasis) Paragonimus spp. (esp. westermani) cause a pulm onary syn- drome in SE Asia, S America or Africa. Parasitic larvae are ingested in undercoo ked crabs or cray \201 sh. These penetrate the intestinal wall and migrate through the per itoneum, Parasitic lung disease Tapeworms Hydatid disease Echinococcus granulosus causes cystic pulm onary disease in sheep rearing areas. Oral ingestion of food contaminated CHAPTER 8.10 Fungal and parasitic lung disease 199 Clinical features of L f \202 er \200\231s syndrome include: \200 diaphragm and pleura to the lung, where they mature into adult \202 ukes. Presentation ma y be with fever, cough, haemo- ptysis, chest pain, lung abscess or pleural effusion. CXR ma y reveal pleural or parenchymal lesions or both. Diagnosis is on the basis of detection of eggs (in bronchial tissue or secretions) or serology. Eosinophilia is usual. Treatment is w ith praziquantel (75mg/kg/day for 3 days) or bithionol. Symptoms of paroxysmal cough, wheeze, dyspnoea and haemoptysis (pneumonitis). Blood (and sp utum) eosinophilia. Raised total IgE. Hepatosplenomegaly. Transient migratory patchy in \201 ltrates on CXR. \200 \200 \200 Diagnosis is by recognition of these clinical features. The exact organism can be determine d by serology or detec- tion of larval stages in bronchial secretions or of larval stages o r eggs in stool or duodenal aspirates. Trichinella spiralis may be diagnosed on muscle biop sy. Treatment is with thiobendazole, albendazole or mebenda- zole. In some cases (e.g. visc eral larva migrans) adjunctive steroids may be indicated. Tropical pulmonary eosinophilia This is an asthma-like syndrome occurring due to infection with Wucheria bancrofti or Brugia malayi. Following a mosquito bite, larvae enter the body, producing micro- \201 laria that become trapped in the lungs. Patients complain of cough , dyspnoea and nocturnal wheeze, and systemic symptoms such as fever, weight loss and malai se. Symptoms fail to respond to asthma medications. Blood tests reveal eosinophilia (>3000 cells/mm3), raised total IgE, leucocyto- sis and raised in \202 ammatory markers. Firm dia gnosis relies on detection of anti- \201 larial antibodies (IgG and/or IgE) in the blood o r, rarely, on detection of micro \201 laria on a noc- turnal blood smear. Radiographic cha nges are of diffuse reticulonodular shadowing, miliary mottling or prominent hila. Treatmen t is with diethylcarbamazine (6mg/kg/day for 3 weeks). Untreated, pulmonary \201 brosis m ay result. Fig. 8.10.2 Paragoniamasis (See Plate 6). Blood \202 ukes (Schistosomiasis) Schistostoma japonicum causes disease in the Far East. Schistostoma mansoni and haematobium cause disease in sub-Saharan Africa and South America. Larvae from water snails penetrate human skin (when washing or swimming) and pass through the blood to the lungs and/or liver and into the circulation. Patients may present with \200\230Katayama fever \200\231 (dry cough, fever, SOB, wheeze, malaise) or more chronic sy mptoms due to pulmonary hypertension. CT may reveal small nodules, reticulonodular shadowin g or areas of ground-glass. Diagnosis is made by detection of eggs in stool or urine, or by serology. Eosinophilia may be present. Treatment is with praziquantel. Steroids can be use d in addition to reduce the immune response in Katayama fever. Artemether may be used as ad junctive therapy in acute disease as this has been found to be active against immature form s of the parasite. Dog heartworm Diro \201 laria immitis (or repens) is transmitted from dogs to man via a mo squito bite. A solitary nodule on CXR, which is positive on PET scan, may result. This diag nosis therefore needs to be considered in tropical or subtropical areas in the differential diagnosis of lung cancer. It is usually a benign condition not requiring treatment. Protozoa Malaria Plasmodium falciparum or Plasmodium vivax can cause pul- monary complicati ons by sequestration of parasitised red blood cells in the lungs. This may result in cough, dypnoea and pulmonary oedema. Occasionally respiratory failure may result due to ARDS. The diagnosis of malaria is made on the basis of a blood smear. Treatment varies from region t o region and is constantly changing due to patterns of drug resistance. Up to date advice c an be found at: http:// www.elsevier.com/framework_products/promis_ misc/malaria_guidelines .pdf Roundworms Roundworm infection follows the oral ingestion of eggs or skin penetration by la rval stages. These eggs or larvae may then cause an eosinophilic pneumonia (L f \202 er \200\231s syn- drome) as they pass through the lungs. Alternatively, adult worms may cause obstruction in the bronchial tree (e.g. tracheal obstruction secondary to Ascaris lumbri- c oides) or, in an immunocompromised host, dissemination may occur (e.g. hyperinfection syndr ome due to Strongyloides stercoralis in patients with HIV or HTLV-1). Amoebiasis Entamoeba histolytica usually infects the liver but may spread to the lung by di rect invasion or via blood or lym- phatic drainage. Pulmonary involvement may result in amo ebic lung abscesses, pleural effusions, empyema or RLL consolidation. Pus resulting from th is infection is character- istically similar in appearance to anchovy sauce. Diagnosis is m ade on the basis of active trophozoites in sputum or pleural pus, serology or sometimes by culture. Cysts or trophozoites may be detected on stool microscopy but these may be due to other Entamoeba spp. so micros- copy should be combined with a PCR assay. Treatment is with metronidazole but resistance may occur. Diloxanide Parasitic causes of L f \202 er \200\231s syndrome include: \200 \200 \200 \200 \200 \200 Ascaris lumbricoides. Strongyloides stercoralis. Ancylostoma duodenale. Necator americanus. Trichinella spiralis. Toxocara canis/catis (visceral larva migrans). A GOODMAN 200 furoate should be co-administered in order to eliminate the cysts. Li YS, Chen G, He HB, et al. A double-blind \201 eld trial on the effects of artemether o n Schistosoma japonicum infection in a highly endemic focus in southern China. Acta Trop 20 05; 96: 184 \200\223190. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosi s using a galactomannan assay: a meta-analysis. CID 2006; 42:1417 \200\22327. Pound MW, Dre w RH, Perfect JR. Recent advances in the epidemi- ology, prevention, diagnosis and treatmen t of fungal pneumonia. Curr Opin Inf Dis 2002 15:183 \200\223194. Pulmonary leishmaniasis Leishmania donovani infection is transmitted by the sand \202 y an d causes leishmaniasis. Pulmonary involvement may occur in the presence of immunocompromise for example due to HIV or lung transplantation. A pneumonitis, pleural effusion or mediast inal lymphadenopathy may result. Diagnosis is by detection of leishmania amastigotes in bro nchial secretions or tissues. Treatment is with ampho- tericin B (liposomal) and pentamidin e. Oral miltefosine is bene \201 cial in visceral leishmaniasis but its exact role on infe ctions with pulmonary involvement is yet to be established. Ross AG, Vickers D, Olds ER, et al. Katayama syndrome. Lancet Infect Dis. 2007; 7(3): 218 \200\22324. Sambatakou H, Dupont B, Lode H, et al. Voriconazole treatment for subacute invasive and chr onic pulmonary aspergillosis. Am J Med. 2006; 119 (6): 527. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraco- nazole in allergic br onchopulmonary aspergillosis. N Engl J Med 2000; 16; 342(11): 756 \200\22362. Further reading Bateman ED. A new look at the natural history of aspergillus hypersensitivi ty in asthmatics. Resp Med 1994; 88(5): 325 \200\223327. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotencin B for primary therapy of invasive aspergillosis N Engl J Med 2002; 347: 408 \200\223415. Soubani AO and Chandrasekar PH. The clinical spectrum of pulmo- nary aspergillosis. Chest 2002; 121: 1988 \200\2231999. Vijayan VK. How to diagnose and manage common parasitic pneu- monias Curr Op Pulm Med 13: 218 \200\223224. Yao Z and Liao W. Fungal respiratory disease. Curr Opin Pulm Med 2006; 12: 222 \200\223227. Zmeili OS and Soubani AO. Pulmonary aspergillosis: a clinical Hinson KF, Moon AJ, Plummer NS. Bronchopulmonary aspergillosis. A review and a report of ei ght new cases. Thorax 1952; 7: 317. Kuzucu A. Parasitic diseases of the respiratory tract. Curr Opin Pulm update. Q J Med 2007; 100: 317 \200\223334. Med 2006; 12(3): 212 \200\223221. 201 Chapter 9 The immunocompromised host Chapter contents 9.1 Pneumonia in the non-HIV immunocompromised patient 202 9.2 Infection in the HIV comprom ised host 210 9.3 Non-infectious HIV-related lung disease 218 N BELL & A WHITTLE 202 9.1 Pneumonia in the non-HIV immunocompromised patient This chapter addresses the complex problem of \200\230pneumonia \200\231 (abnormal pulmona ry in \201 ltrates) in immunocompromised patients without HIV infection. It is structured as follows: \200 bronchiolitis. Systemic examination may reveal extrapul- monary infection (e.g. meningitis with cryptococcal pneu- monia, or endocarditis with staphylococcal lung abscess). The approach to the immune compromised patient with pulmonary in \201 ltrates. The pattern s of lung disease seen in some common clinical scenarios of immunosuppression. The major or ganisms causing opportunistic infection. Investigations Radiology: a \200\230clear \200\231 CXR does not exclude pulmonary patholog y in this population, and CXR appearances are nonspecific. HRCT is more sensitive than CXR (detected abnormality in 50% of febrile neutropenic patients with normal CXR), and may beco me abnormal several days before CXR. Some CT appearances are diag- nostic, (e.g. thromboemb olism, obliterative bronchiolitis) and CT can localize a target for bronchoscopic lavage or biopsy, but infections and non-infectious processes can have similar appearances. Serology is generally unhelpful in this group due to inability to raise antibodies acutely in respo nse to infection. It may demonstrate past infection and hence risk of reactivation. Any spu tum should be analyzed for fungi, mycobacteria, PCP and viruses as well as routine microbio logy. It is rela- tively insensitive, and organisms may represent upper air- way colonizati on rather than lung infection. Sputum induction with hypertonic nebulised saline has a lowe r diagnostic success rate in this population compared to HIV-positive patients, but should be considered if bron- choscopy is not feasible. Nasopharyngeal washing and tra- cheal suct ion aspiration are alternative routes for obtaining respiratory secretions, with a similar risk of contamination. Bronchoscopy with BAL is diagnostic of infection in approxi- mately two-thirds of cases, and should be considered early if in \201 ltrates are detected. Sensi tivity is higher for diffuse alveolar infection (e.g. PCP) than for localized invasive dis- ease (e.g. fungal nodules). Lavage site should be guided by CT \201 ndings. Send lavage \202 uid (BALF) for bacteria, fungi, mycobacteria, PCP and viruses, plus differential cel l count and cytology. Other tests (cryptococcal antigen testing, CMV PCR) may be available. Negative \201 ndings on BAL are regarded as suf \201 cient to exclude infection in cont exts such as suspected idiopathic pneumonia syndrome, but if CT suggests focal infection su ch as fungal disease, negative BAL does not exclude this. Some authorities recommend addi- tional sampling techniques such as protected specimen brushing, but this has not been prove n to add sensitivity to BAL and (where feasible) transbronchial biopsy. Approach to the immune compromised patient with pulmonary in \201 ltrates The lung is the organ most commonly affected by compli- cations of immunosuppression. The term \200\230pul monary in \201 l- trates \200\231 can refer to many different disease processes (Table 9.1 .1): although infections are the commonest cause, not all in \201 ltrates are infections, and infection may co-exist with non-infectious processes in this population. When managing an immune compromised patient with lung in \201 ltrates, consider the whole picture, inclu ding risk factors and routes of infection. Many factors contribute to the \200\230net stat e of immune suppression \200\231: \200 The immune defect (due to underlying malignancy, drugs, radiotherapy, autoimmune disease, f unctional defects). Different defects are associated with different complica- tions and inf ections (see Table 9.1.2). Functional defects may not be apparent on simple blood tests. Re cent antimicrobial prophylaxis or treatment. Prophylaxis may defer rather than prevent the development of infection. The patient \200\231s past history: pre-existing lung disease inc reases the risk of infection, and previous complica- tions of immunosuppression may recur. Damage to other host defenses: disruption of skin or mucosal barriers by tumor, mucositis, surgery, intravas- cular devices, catheters, drains. The risk of aspiration, increased by s edation, mucositis, debility and myopathy. Co-infection with immunomodulating viruses (CMV, EBV, HHV 6 \200\2237, HBV, HCV). Comorbidity (e.g. renal failure, malnutrition, ischaemic heart disease, alcoholism, cirrhosis, diabetes). Environmental exposure: consider the geogr aphical prevalence of mycobacteria and endemic fungi (e.g. his- toplasma), other occupation al exposures such as aspergillus, zygomycetes and nocardia in gardeners and farmers, crypto coccus in pigeon breeders. Reactivation of existing infection (CMV, herpes viruses, tubercu losis, aspergillus). Infection from donated transplant organs or blood. Table 9.1.1 Some causes of pulmonary in \201 ltrates in the immune compromised patient Infection (opportunistic or non-opportunistic) \200 Drug-induced lung disease \200 Radi ation pneumonitis \200 Pulmonary oedema \200 Pulmonary embolism \200 Pulmonary hemorr hage \200 ARDS \200 Bronchiolitis obliterans organizing pneumonia \200 Transfusion-as sociated lung injury \200 Diffuse alveolar damage \200 Alveolar proteinosis \200 Post -transplant lymphoproliferative disorder \200 Recurrence of underlying disease in lungs ( e.g. metastatic Clinical features Pneumonia in the immune compromised patient often presents with non-speci \201 c symptoms of fever and malaise. Absence of fever does not exclude infection, and fe ver may be due to malignancy or drugs. Sputum is often not puru- lent, and may be absent. R ate of onset of symptoms may help diagnosis, e.g. acute onset (<24 hours) raises suspicion of oedema, haemor- rhage or embolism. Thorough physical examination is essential. There may be few speci \201 c respiratory \201 ndings, but look for clues such as the absence of crackles despite marked in \201 ltrates and hypoxia in PCP, or squeaks and wheezes in obli terative carcinoma, leukemia, lymphoma) CHAPTER 9.1 Pneumonia in the non-HIV immune compromised patient 203 Transbronchial biopsy (guided by recent CT) may detect malignancy, organizing pneumonia or drug-induced lung disease, and is more sensitive than BAL for invasive infec- tions (e.g. m ycobacteria, aspergillus). It should be consid- ered in all cases when BAL is performed, we ighing the potential bene \201 t against the risk of pneumothorax and bleeding. Percutaneo us lung biopsy under radiological guidance is use- ful in diagnosis of peripheral nodules, and surgical lung biopsy remains the de \201 nitive method to sample the lungs for diffuse or focal processes when the patient \200\231s condition permits. Specimens should be sent for microbiological analysis as well as histopathology. remainder being due to transfusions, drugs or tumor. Sputum production and pulmonary infilt rates may be absent in neutropenic patients with pneumonia. Pathogens The most common infectious complications of neutrope- nia due to chemotherapy are bacterial infections, including gram-positive bacteria (S. aureus, S. epidermidis, strepto - cocci) and Gram-negative bacteria (enterobacter spp., E. coli, Klebsiella, Pseudomonas). Invasive fungal infection with aspergillus, candida or mucor becomes more likely in profoun d, prolonged neutropenia (ANC <0.1). Solid organ transplantation (SOT) Pulmonary complications of lung transplantation are con- sidered elsewhere. Overall approach In all patients the aim should be to obtain a de \201 nitive diag- nosis of infective/non-infective disease as soon as possible, with low thresholds for CT scanning , bronchoscopy and biopsy. Exclusion of infection with BAL allows treatment with corticoste roids for many non-infective pathologies. Delay in diagnosis is associated with markedly wo rse out- come. However, if the patient is unwell or profoundly immunosuppressed, broad-spec trum empirical therapy should be started without waiting for the results of special investi gations. Timing of pulmonary infections after transplantation First month: the risk of infection is due more to surgery and intensive care than to immunosuppressive therapy. Prolonged ventila tion increases the risk of nosocomial pneumonia. Surgery, sedation and pain impair cough an d increase risk of aspiration pneumonia. Nosocomial bacterial infections predominate, e.g. gram negative pathogens (inc. Legionella, Pseudomonas), S. aureus and MRSA. 2nd to 6th mont hs: sustained immunosuppression favors the emergence of opportunistic pathogens (aspergillu s, nocardia, MTB, PCP, listeria), and viruses (most commonly CMV, also EBV and respiratory viruses). After 6 months, if graft function is stable enough to allow reduced immunosuppres sion, community acquired organ- isms cause the majority of respiratory infections (pneumo- coccus, Haemophilus, Legionella, respiratory viruses). Patients who require augmented immun osuppression for graft rejection remain vulnerable to opportunistic patho- gens, particular ly Aspergillus, PCP, Cryptococcus and Listeria. Critical care and non-invasive ventilation The mortality rate in immunosuppressed patients who require invasive ventilation for respiratory failure is very high, approaching 100% in many series. The management of these patients requires honest and careful assessment of the ceiling of treatment, involving discussion with the patient, their family, and intensivist s. Non-invasive face- mask ventilation has been shown to reduce the rate of intubation and hence mortality when applied early, before the onset of hypercapnic respiratory failure. Clinical scenarios Neutropenia Neutropenia is the most important risk factor for pulmo- nar y infection in immune compromised patients. It is a major dose-limiting side effect of cyto toxic chemotherapy, which both decreases neutrophil numbers and causes chemotactic and phag ocytic defects, but it is seen in many other conditions that decrease production or increas e consumption of neutrophils. It is de \201 ned as an absolute neutrophil count (ANC) <1.5 x109/l. The risk of infection increases with: \200 