Prognosis Mortality is 1 \200\2232% from type A; type B is benign in humans. Further information Tarnvik A, Berglund L. Tularaemia. Eur Resp J 2003; 21: 361 \200\22373 This page intentionally left blank CHAPTER 40 Respiratory infection: bacterial 460 Melioidosis De \201 nition and epidemiology Melioidosis is caused by Burkholderia pseudoma llei, a Gram-negative bacillus that is found in soil and water in Southeast Asia, northern Australia, China, and India; clinical disease is par- ticularly common in Thailand, where i t may account for up to a third of all pneumonia deaths. Infection is thought to follow ent ry via skin abrasions or inhalation, and pneumonia is the most common clinical presentation . Most cases represent recent infection; reactivation of infection is rare but can occur ma ny years after exposure. Risk factors for melioidosis include diabetes, alcohol excess, ren al disease, and chronic lung disease (including cystic \201 brosis). Consider melioidosis in returning travelers from Asia or Australia with community-acquired pneumonia or a subacute/chronic \200\230tuberculosis- like \200\231 respiratory illness. Clinical features include: \200 Acute septicaemic melioidosis Patients present acutely unwell with a severe pneumonia and w idespread nodular consolidation on CXR, may progress rapidly to death Localized subacute me lioidosis Subacute cavitating lobar (often upper) pneumonia, mimicking tuberculosis Chronic suppurative melioidosis Chronic lung abscess empyema; suppurative infection may involve other organs, including skin, brain, joints, bones, liver, spleen, kidney, adrenal, prosta te, lymph nodes Diagnosis Identi \201 cation by culture is the principal method of diagnosis. Blood cul- t ures may be diagnostic; alert the laboratory to the possibility of this infec- tion. ELISAs are relatively insensitive. Management \200 B. pseudomallei is resistant to multiple antibiotics. Treat with high-dose IV ceftazidime o r meropenem for at least 10 \200\22314 days (longer if severe pulmonary disease or organ ab scesses), then oral antibiotic (e.g. co-trimoxazole alone or in combination with doxycyclin e) for at least 12 weeks to ensure eradication. Supportive care, with ITU admission for sep tic shock or severe pneumonia. Prognosis Documented mortality rates range 19 \200\22346%. Further information Currie BJ. Melioidosis: an important cause of pneumonia in residents of and travelers returned from endemic regions. Eur Resp J 2003; 22: 542 \200\22350 This page intentionally left blank CHAPTER 40 Respiratory infection: bacterial 462 Leptospirosis De \201 nition and epidemiology Leptospirosis is a zoonosis trans- mitted fr om water or soil contaminated with urine of infected animals (e.g. rats, dogs, cats, pigs, cattle, hamsters, bats) through skin abrasions or mucosa. Present worldwide, more common in tropical countries, but well described in UK. Individuals most at risk in the UK include f armers, vets, sewage workers, returning travelers from the topics, military personnel, and canoeists. Incidence peaks in spring/summer. In the tropics, epidemics may occur following storms or \202 oods. Consider leptospirosis in all patients with diffuse alveolar hemorrhage, and in at-risk ind ividuals with pneumonia or ARDS. Clinical features Disease manifestations are highly variable, ranging from asymptomatic inf ection to multi-organ failure, pulmonary haemor- rhage, and death. Patients may present sol ely with pulmonary haemor- rhage, without other features of Weil \200\231s disease. Manifes tations include: \200 Acute (anicteric) leptospirosis Self-limiting \202 u-like illness; myalgia, rash and asep tic meningitis may occur Weil \200\231s disease (icterohaemorrhagic fever) Classic form of leptospirosis. Features include fever, myalgia, conjunctival hemorrhage, rash, jaundice/ he patic failure, renal failure, coagulopathy and thrombocytopaenia, shock, myocarditis/cardia c arrthymias Pulmonary disease Occurs in at least a third of hospitalized patients with acu te leptospirosis or Weil \200\231s disease. Manifestations include mild symptoms/signs (cou gh, wheeze, and crackles), pneumonia, pulmonary oedema secondary to myocarditis, and ARDS o r fulminant alveolar hemorrhage syndrome. Investigations \200 Serology con \201 rms the diagnosis and is performed in a single Leptospira Reference Unit in the UK. Both ELISA and microscopic agglutination tests may be performed CXR and CT typi cally demonstrate patchy consolidation and ground- glass shadowing, commonly bilateral with lower lobe predominance. Management \200 Discuss treatment with infectious diseases and renal specialists. Antibiotic choices includ e penicillin, ceftriaxone, or doxycycline Ventilatory support required for alveolar hemorrh age and ARDS Ensure adequate hydration; blood products may be required High-dose glucocorti coids are occasionally used, although there is no convincing evidence of bene \201 t. Plas ma exchange and desmopressin infusions have been tried. \200 \200 LEPTOSPIROSIS 463 Prognosis Acute leptospirosis typically resolves spontaneously after about 14 days. Severe pulmonary disease can progress very rapidly (over hours), with reported mortality rates app roaching 50%. Differential diagnosis of zoonotic microbial causes of community-acquired pneumonia (with e xposures) \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Avian in \202 uenza virus (birds, animals) Bacillus anthracis (anthrax; animals) Brucellos is (animals) Chlamydia psittaci (psittacosis; poultry, birds) Coxiella burnetii (Q fever; p arturient cats, cattle, sheep, goats, rabbits) Cryptococcus neoformans (birds) Francisella tularensis (tularaemia; rabbits, cats, rodents) Hantavirus (rodents, the Americas) Histopla sma capsulatum (histoplasmosis; birds or bats, the Americas) Leptospirosis (water contamina ted with infected animal urine) Pasteurella multocida (pasteurellosis; animals, birds) Rick etsia rickettsii (Rocky mountain spotted fever; tick bite or exposure to tick-infested habi tats, USA) Yersinia pestis (pneumonic plague; rodents, cats) This page intentionally left blank 465 Chapter 41 Respiratory infection: fungal Aspergillus lung disease: classi \201 cation 466 Atopic allergy to fungal spores 467 Asthm a and positive IgG precipitins to Aspergillus 467 Bronchopulmonary aspergillosis 468 Invasi ve aspergillosis 470 Semi-invasive aspergillosis 472 Aspergilloma/mycetoma 474 Pneumocystis pneumonia (PCP): diagnosis 476 PCP: treatment 478 Endemic mycoses 480 Histoplasmosis 480 B lastomycosis 482 Coccidioidomycosis 483 Paracoccidioidomycosis 483 Other fungi: cryptococco sis 484 Candidal pneumonia 485 466 CHAPTER 41 Respiratory infection: fungal Aspergillus lung disease: classi \201 cation Types of disease Aspergillus fumigatus and ot her Aspergillus molds are ubiquitous fungi that can be isolated from the air in most houses , and this increases with increasing indoor humidity. Inhalation of spores (conidia) can pr oduce a range of diseases, some of which are related to each other, and some of which are n ot. The \201 nding of fungal hyphae (rather than just spores) in the sputum should provok e an assessment. Classi \201 cation 1. IgE-mediated allergic asthma inhaled Aspergillus spores. One of many common antigens provoking airway in \202 ammation and bronchospasm from 2. Exuberant IgE and IgG reaction to Aspergillus in the airways of (usually) asthmatics pro voking mucous plugging with distal consolidation that may \202 it from area to area. This is one of the causes of pulmonary eosi- nophilia 3. Allergic bronchopulmonary aspergillosis (APBA) A probable evolu- tion and progression of (2) in (usually) asthmatics with in \202 ammatory damage to the airways and resultant bro nchiectasis (but no actual invasion of Aspergillus into the airway walls) 4. Invasive Aspergillus pneumonia due to invasion of Aspergillus into lung tissue secondary to immunosuppression. This can be a multisystem dis- order with Aspergillus invading almos t any part of the body 5. Semi-invasive aspergillosis, a much lower grade process than invasive aspergillus pneumonia, usually seen in older individuals with no apparent immunosuppression, but usually some underlying chronic lung disease 6. Aspergilloma, where Aspergillus lives and grows as a separate ball of fungus in a pre-ex isting lung cavity. There is usually an in \202 ammatory response to limited hyphae invasi on into the tissue walls of the cavity 7. Hypersensitivity pneumonitis (or extrinsic allerg ic alveolitis) due to an immune in \202 ammatory reaction to inhalation of large numbers o f spores (see p 249). The presentation and clinical setting of these various Aspergillus-related disorders are cl early different and thus are detailed separately. ASTHMA AND POSITIVE IgG PRECIPITINS TO ASPERGILLUS 467 Atopic allergy to fungal spores Approximately 10% of asthmatics are skin prick positive to Aspergillus species, compared with about 70% to house dust mite. It is assumed that this al lergy contributes to allergic in \202 ammation in the airways but, in the few relevant stu dies, symptoms have not always correlated with exposure. However, in some studies asthma ad missions to hospital correlated better with fungal spore counts than with pollen counts. Fu ngal spore release may explain an association between thunderstorms and asthma attacks. Par ticularly high exposure results from working with moldy vegetable matter, e.g. in compost h eaps during late summer/early autumn. Asthma and positive IgG precipitins to Aspergillus De \201 nition Asthmatics with IgE resp onses to Aspergillus can also develop IgG antibodies (precipitins). Why this happens is not clear. Aspergillus hyphae can sometimes be isolated from the sputum and it has been sug- g ested that Aspergillus spores are able to germinate and grow in the mucous within the airwa ys. This may explain the mucous plugging and \202 it- ting areas of pulmonary consolidati on. Clinical features and investigations Associated features may include: \200 \200 \200 \200 \200 Serum IgE >1000 ng/mL Blood eosinophilia >500/mm3 Skin prick +ve to Aspergillus IgG precipi tins to Aspergillus (many different allergenic proteins) Long history of asthma, perhaps re cently deteriorated. Therefore suspect this development in: A patient with long-term asthma whose control deteri orates, with CXR changes, lgE & lgG to Aspergillus, eosinophilia, and perhaps hyphae in the sputum. Management may only require an increase in inhaled steroids. However, there is a suggestion that courses of oral steroids are particularly effec- tive and may prevent progression to bronchiectasis (see next section). Steroids limit the host \200\231s immunological response but do not seem to lead to Aspergillus invasion of the tissues. Poorly documented evidence of improvement with antifungal agents such as itraconazole. 468 CHAPTER 41 Respiratory infection: fungal Bronchopulmonary aspergillosis De \201 nition This condition is probably an extension of ( 2), where the in \202 ammatory response to the Aspergillus in the airways provokes a more exuberant response, with damage to the bronchial walls and bron- chiectasis. Some authors r eserve the use of the term ABPA for when bronchiectasis is present; others may include (2), and subdivide into ABPA-S (seropositive only), and ABPA-CB (central bronchiectasis). The prevalence of ABPA in asthmatic populations has varied considerably between studies, an d clearly will depend on whether the de \201 nition includes bronchiectasis or not. It pro bably occurs in about 1 \200\2232% of asthmatics. A related condition occurs in patients wi th cystic \201 brosis where it appears about 7% have evidence of colonization and potenti al ongoing damage. Pathophysiology The factors promoting the evolution from atopic asthmati c to ABPA are not known. A particular HLA association has been shown, with the suggestion t hat a CD4/Th2 response to a particular Aspergillus antigen (Asp f1 antigen) with release of IL-4 and IL-5 may be critical. Proteolytic enzymes are released by Aspergillus as part of its exo- phytic feeding strategy and these enzymes may damage airway mucosa. However, most believe that the damage results from host defense mecha- nisms. Hyphae (rather than just sp ores) may be visible in the mucus and grown from sputum, but there does not appear to be ac tual invasion of the bronchial mucosa. This immune in \202 ammatory activity produces muco id impaction in the airways, eosinophilic pneumonitis, and broncho- centric granuloma forma tion. Main criteria for diagnosis (the \201 rst four are the most important) \200 \200 \200 \200 \200 \200 \200 Long history of asthma Skin prick/IgE +ve to Aspergillus fumigatus IgG precipitins to Asper gillus fumigatus Central (proximal) bronchiectasis Blood/sputum eosinophilia Total serum Ig E >1000 mg/mL Lung in \201 ltrates \200\224 \202 itting. Other clinical features \200 \200 \200 \200 \200 \200 Long-standing asthma, recent deterioration Recurrent episodes of mucous plugging Fever/mala ise Expectoration of dark mucous plugs, sometimes as casts of the airways Eosinophilia (spu tum and blood) Occasional haemoptysis. The major complication is poorly controlled asthma that requires repeated courses of oral s teroids. BRONCHOPULMONARY ASPERGILLOSIS 469 Investigations \200 \200 \200 \200 Spirometry \200\224degree of airways obstruction Skin prick sensitivity to Aspergillus (IgE ) Sputum \200\224Aspergillus hyphae and eosinophils Blood \200 \200 \200 \200 CXR \200 \200 CT Central (proximal) bronchiectasis with upper lobe predominance Management T he management is essentially that of severe chronic asthma, but with generous use of course s of oral steroids. Several rand- omized controlled trials have shown courses of itraconazo le (200 mg bd for 4 months) are well tolerated, reduce steroid requirements, and improve ex ercise tolerance. There appears to be a sustained effect after the itracona- zole is stoppe d, suggesting at least temporary eradication of the Aspergillus. Response and relapse can b e monitored with IgG precipitins to Aspergillus. Itraconazole can cause liver dysfunction, so LFTs need monitoring. Differential diagnosis This list revolves mainly around the pulmon ary in \201 ltrates and eosinophilia. \200 \200 \200 \200 IgG precipitins IgE RAST to Aspergillus Total serum IgE Eosinophil count (suppressed if on steroids) Flitting in \201 ltrates Bronchiectasis, mucous impaction (gloved \201 nger shadows) Acute/chronic eosinophilic pneumonia Churg \200\223Strauss syndrome Various parasites (e.g. \201 lariasis, ascaris; L f \202 er \200\231s syndrome) Drug-induced eosinophilic pneu monia. Further information Denning DW et al. The link between fungi and severe asthma: a summary o f the evidence. Eur Resp J 2006; 27: 615 \200\22326 Wark PA et al. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. C ochrane database Syst Rev 2004; 3: CD001108 470 CHAPTER 41 Respiratory infection: fungal Invasive aspergillosis De \201 nition The term \200\230invasive aspergillosis \200\231 is reserved for the situation where Aspergillus hyphae actually invade tissue (hyalohyphomyco sis). This usually occurs with severe immune suppression, particularly neutropenia and ster oid use. The port of entry is probably the lungs, but spread can be to almost any area of t he body. The species most commonly seen are Aspergillus fumigatus, \202 avus, terreus, an d niger. Mortality is very high. The source of Aspergillus is unclear, but has been found i n hospital water supplies. Pathogenesis Alveolar macrophages probably normally destroy Aspe rgillus spores. Macrophage failure may allow more spores to germi- nate and any subsequent invasion with hyphae seems to be prevented by neutrophils. Inadequate neutrophil function a llows invasion across tissue planes and into vessels, with infarction and further spread th roughout the body. There is some evidence that CMV may inactivate macrophages, allowing spo res to germinate. The fungal digestive proteases do the damage rather than the host \200 \231s limited immunological responses. Clinical features Typical setting Fever, chest pain, cough, haemoptysis, dyspnoea, and pulmonary in \201 ltrate in a neutrop enic patient failing to respond to broad-spectrum antibiotics. Risk factors \200 Following chemotherapy, particularly provoking severe neutropenia (<100 cells/ l) Bone mar row suppression for allogeneic stem cell transplants Advanced HIV infection and AIDS Immune suppression following transplant In \202 iximab (or other anti-TNF ) therapy \200 \200 \200 Spread can occur anywhere with the following well recognized: \200 \200 \200 \200 Sinuses (paranasal) and spread into the brain Endocarditis Eyes Skin (papular, ranging to u lcerative, lesions). Careful examination and particular investigations may be needed to detect spread to these a reas. INVASIVE ASPERGILLOSIS 471 Investigations \200 Isolate Aspergillus hyphae from respiratory tract by: \200 \200 \200 \200 Sputum Expressed sputum (3% saline via nebulizer) Bronchoalveolar lavage Transbronchial bio psy (Hyphae may be present when not the primary cause of the in \201 ltrate) \200 Biopsies from other sites (most convincing when acute-angle branching, septated non-pigment ed hyphae are seen) Circulating levels of galactomannan, an exo-antigen of Aspergillus (com mercial EIA kit not universally available, and not found so useful by all groups on account of low sensitivity and false positivity due to presence of certain antibiotics, piperacill in and tazobactam). Serial sam- pling is recommended CXR/CT CXR changes are usually non-spe ci \201 c. CT may show a halo of low attenuation surrounding a nodular lesion early on. An \200\230air crescent \200\231 sign may develop on CXR with air appearing at the edge of a n area of consolidation. Usually occurs when neutrophil count rising, and prob- ably repres ents gradual containment of the infection into a cavity, not unlike an aspergilloma Ultimately, it is the clinical picture that dominates the diagnosis. Management Prompt use of antifungals is essential. \200 \200 Intravenous amphotericin B (only about 35% response rate) Intravenous lipid-based amphoteri cin (less nephrotoxic, but very expensive) Itraconazole IV: 200 mg bd for 2 days, then 200 mg od for 12 days Voriconazole (recently available, less experience, but probably better th an itraconazole, and safer than amphotericin, very expensive) Caspofungin (recently availab le, less experience, very expensive) \200 Some centers use oral itraconazole as prophylaxis when commencing substantial immune suppre ssion. Differential diagnosis The differential will be the large number of other opportunistic inf ections seen in immunosuppressed patients. Another invasive mycosis, Candida albicans, is n ow less common due to its susceptibility to \202 uconazole. Further information Upton A et al. Invasive aspergillosis following hematopoietic cell tran splantation. Clin Infect Dis 2007; 44: 531 \200\22340 Patterson TF. Advances and challenges in the management of invasive mycoses. Lancet 2005; 3 66: 1013 \200\22325 472 CHAPTER 41 Respiratory infection: fungal Semi-invasive aspergillosis (also known as chronic necrotizing aspergillosis, or chronic pu lmonary aspergillosis) De \201 nition This entity is poorly de \201 ned but it is clear that a low-grade chronic invasion of Aspergillus into airway walls and surrounding lung can occur. In the original descriptions, some cause of mild immuno-incompe- tence was present, such as diabetes, stero id therapy, chronic lung disease, poor nutrition, etc. Previous asthma is not usually prese nt, unlike ABPA. Pathogenesis It is assumed that this form of aspergillosis results from lo wered immunity in those without a tendency to make Th2, eosinophilic, responses to antigens . There is in \201 ltration of hyphae into lung tissue, ranging from minor patchy consolid ation to multiple cavities. There is little, if any, angio-invasion. It is assumed that the fungal digestive proteases gradually do the damage, rather than the host \200\231s immunol ogical response. Clinical features Suspect semi-invasive aspergillosis when \200 \200 \200 \200 \200 \200 Middle-aged Reason for mild immunosuppression A pre-existing chronic lung disease Fever Pro ductive cough Patchy indolent CXR changes. Investigations \200 \200 Sputum samples may allow isolation of hyphae CT will show an airway-centered type of pictur e with \200\230tree in bud \200\231 appearance. With increasing severity this gives way to denser areas and small cavities that occasionally may contain a fungus ball Likely to have IgG precipitins to Aspergillus, but not always. Management On the assumption that mild immune suppression is the dominant cause, steroids a re not usually recommended for fear of further immune suppression. This is in contrast to A BPA where the damage is due to the host \200\231s immune defense mechanisms. Oral antifunga ls, such as itra- conazole, are recommended. Fluconazole has been used with apparent succes s in case series only. This page intentionally left blank 474 CHAPTER 41 Respiratory infection: fungal Aspergilloma/mycetoma De \201 nition The term aspergilloma is used to describe a ball of f ungal hyphae within a cavity in the lung. It is assumed that this is colonization of a prio r cavity, rather than arrested invasion. Aspergillomas can occur in other organs, including the pleural space. Pathogenesis Cavities can occur in the lung following a variety of insu lts such as tuberculosis, sarcoid, ordinary pneumonia/lung abscess, treated tumors, and cys tic \201 brosis. Fungal spores entering the cavity germi- nate and survive in a relativel y protected environment. The ball consists of hyphae, in \202 ammatory cells, \201 brin, and debris. Around the cavity is an intense in \202 ammatory response, often with conside rable extra vasculariza- tion from bronchial arteries and occasional fungal hyphae. Clinica l features Aspergillomas are often asymptomatic. Up to 75% will present with haemoptysis, a ssumed to come from damaged vessels on the inner surface of the cavity wall, via a communic ation with a bronchus. Sometimes there are systemic symptoms, malaise, and fever, as well a s chest pain. Superadded infection may provoke exacerbations. Investigations \200 CXR apical cavity with ball within that changes position if CXR is performed decubitus CT o bvious cavity with fungus ball, and possible invasion into surrounding lung (uncommon) Sput um culture Aspergillus IgG precipitins. Often higher levels than seen in other Aspergillus diseases. \200 Management \200 \200 May not require treatment Systemic symptoms of fever and malaise may be hard to ascribe to a mycetoma and require a therapeutic trial of itraconazole The most signi \201 cant compli cation is life-threatening haemoptysis. The emergency management of haemoptysis is describe d on p 43 Itraconazole will not eradicate the fungus, but seems to reduce cavity size and l essen the tendency to haemoptysis. It is assumed that it kills any fungus in the walls and inhibits growth in the cavity. The place of newer agents such as voriconazole is not known. ASPERGILLOMA/MYCETOMA 475 General approach to chronic haemoptysis \200 Tranexamic acid (must be taken during clot formation as binds to \201 brin to prevent act ion of endogenous \201 brinolytics) Treat associated bacterial infections. Speci \201 c to aspergilloma \200 \200 \200 Itraconazole Arterial embolization Surgical resection. Bronchial arteriograms should reveal a leash of vessels supplying part of the cavity wall t hat can be embolized, even if not actively bleeding. Short-term success rate is good; long- term, less good Surgery can be dif \201 cult, as mycetomas may be stuck to the chest wall. Problems of seeding the pleural space are seen less often than in the past, probably due t o better antifungal agents A few case reports exist of successful reduction of haemoptysis with radiotherapy Older approaches involving intracavity injections of amphotericin are rar ely used now, although a recent case series of 40 patients seemed promising. Overview of Aspergillus lung disease The essential differences between the Aspergillus lung diseases depends on whether the damage to the lung is mediated by host defense mechanisms (atopic asthma, \202 itting consolidation, ABPA, possibly aspergilloma) or by the fungus \200\231s own digestive proteolytic enzymes (invasive aspergillosis, semi-invasive, aspergi lloma). These two disease states are clearly different, but there probably exists a continu um between each of the subdivisions within each group, and the dominant mechanism in asperg illoma is not entirely clear. Therefore it is likely that patients with mixed and transitio nal features will be encountered. Future developments \200 New antifungals \200\224voriconazole, posaconazole, ravuconazole (the tri- azoles), caspofu ngin, micafungin, anidulafungin (the echinocandins) Combination therapy Antifungal action o f older drugs \200\224 \202 ucytosine, rifampicin, \202 uconazole Place of early surgery Place of prophylaxis Value of galactomannan and -D-glycan blood levels in diagnosis. \200 \200 \200 \200 Further information Aspergillus Trust (for patients), www.aspergillustrust.org Soubani A et al. The clinical spectrum of pulmonary aspergillosis. Chest 2002; 121: 1988 \200\22399 476 CHAPTER 41 Respiratory infection: fungal Pneumocystis pneumonia (PCP): diagnosis De \201 nition Pneumocystis pneumonia (PCP) is the clinical syndrome of pneumonia resulting from infection with the fungus Pneumocystis jirov eci (previously termed Pneumocystis carinii). Pneumocystis jiroveci is wide- spread in the environment and most people are infected by the age of 2 years; PCP is thought, however, to follow new infection rather than reactivation of latent infection. Most cases of infection are likely to be person-to-person airborne transmission rather than environmental. Causes Risk factors for PCP include HIV infection (particularly with CD4 count <200 x 106/L), trea tment with chemotherapy (especially \202 udara- bine), corticosteroids, or other immunosu ppressive agents, and malnutri- tion in children. Neutropenia does not appear to be a parti cular risk factor. PCP occurring in the setting of AIDS is associated with both a greater n umber of organisms and fewer in \202 ammatory cells in the lungs when com- pared with infe ction associated with other causes of immunocompromise. PCP is much less common following t he routine use of co-trimoxazole prophylaxis in HIV and post-transplantation, although case s still occur, e.g. in patients presenting with advanced HIV or in those non-compliant with prophylaxis. The threshold steroid dose for predisposition to PCP is unclear, although a d ose equivalent to 16 mg prednisolone or greater for 8 weeks appears to signi \201 cantly i ncrease risk; the risk is likely also to re \202 ect the underlying condition, e.g. PCP ma y develop in patients with hematological malignancy taking as little as 5 mg prednisolone d aily. PCP often appears to present as immunosuppressant drug doses are tapered or increased . Clinical features Gradual onset of dry cough and exertional breathless- ness, sometimes w ith retrosternal tightness. Fever and tachypnoea may occur; chest examination is typically normal. May present with pneumo- thorax. Extrapulmonary disease is very rare. Investigations \200 CXR pattern is classically of bilateral perihilar in \201 ltrates that progress to alveola r shadowing. Less common patterns include small nodular in \201 ltrates or focal consolida tion. CXR is normal in about 10%. Pleural effusions are very rare. CT is not routinely requ ired except in cases of a normal CXR, when it may demonstrate a bilateral ground-glass patt ern or cystic lesions Hypoxia is common. Desaturation on exercise may suggest the diag- nos is in at-risk individuals with normal saturations at rest White blood count is usually norm al. Serum lactate dehydrogenase is typically raised (sensitive, but non-speci \201 c) Indu ced sputum (see p 769) has a diagnostic yield of about 60% in HIV infection, but is much le ss sensitive when performed in the setting of non-HIV immunocompromise, where the organism burden is lower. It should not be performed on the open ward or out-patient department DIAGNOSIS PCP 477 Bronchoscopy with BAL is the diagnostic investigation of choice in non-HIV-infected patient s and in patients with HIV in whom induced sputum analysis is non-diagnostic. BAL with silv er or immuno \202 uorescent staining has a speci \201 city of nearly 100% and sensitivity of 80 \200\22390%. This sensitivity is lower in non-HIV-infected immunocompromised patient s, re \202 ecting their lower pathogen loads Transbronchial lung biopsy has a slightly hig her sensitivity (around 95%), but is associated with an increased risk of complications, so is reserved for cases where BAL is non-diagnostic. Surgical lung biopsy may be required fo r diagnosis in a minority of HIV-negative patients. 478 CHAPTER 41 Respiratory infection: fungal PCP: treatment Antimicrobial \200 \200 Liaise with infectious diseases or HIV specialist High-dose co-trimoxazole (trimethoprim an d sulphamethoxazole) remains the drug of choice. Administer 120 mg/kg daily in 4 divided do ses PO or IV (dilute 480 mg ampoules in at least 75 mL 5% dextrose; infuse over 60 min). Us e IV route initially and then PO during clinical improvement; PO may be used initially in m ild cases. Side-effects (e.g. rash, nausea, vomiting, blood disorders) are common, particul arly in HIV-infected patients. Consider routine use of anti-emetics Second-line choices if intolerant or unresponsive to co-trimoxazole include intravenous pentamidine, clindamycin a nd primaquine, dapsone and trimethoprim, atovaquone, trimetrexate All treatments should be for 2 \200\2233 weeks If PCP is strongly suspected and the patient is unwell, treatment can be started immediately, as BAL pneumocystis stains remain positive for up to 2 weeks. Empi rical treatment is also required in the occasional situation where the diagnosis is suspect ed but bronchoscopy is non- diagnostic or not tolerated In cases of HIV presenting with PCP , subsequent early introduction of HAART may rarely be associated with acute respiratory fa ilure, perhaps due to an aggressive in \202 ammatory response to residual pneumocystis; co nsider steroid trial or temporarily withholding further HAART. \200 Steroids \200 High-dose steroids (prednisolone 40 mg twice daily PO, or IV hydro- cortisone) are recommen ded for all patients in respiratory failure. Treat at high dose for 5 days; taper dose over 1 \200\2233 weeks (e.g. prednisolone 40 mg daily for days 6 \200\22311, then 20 mg daily f or days 12 \200\22321). Supportive therapy \200 Hypoxia is common: administer supplementary high- \202 ow oxygen, and consider use of CPAP . Mechanical ventilation, if considered appropriate, may be required; make this decision pr ior to initiating CPAP Respiratory isolation is not recommended at present. 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