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Home , Blastomycosis, Coccidioides immitis, Coccidioides posadasii, Coccidioidomycosis, Cryptococcus neoformans, Dimorphic fungus

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Fungal 3 Pulmonary and sinus fungal diseases in non-immunocompromised patients

David W Denning, Arunaloke Chakrabarti

The is exposed daily to airborne fungi, fungal enzymes, and secondary metabolites. The Lancet Infect Dis 2017 endemic fungi capsulatum, spp, , and Paracoccidioides brasiliensis, and Published Online occasionally fumigatus, are primary pulmonary of otherwise healthy people. Such infections July 31, 2017 resolve in most people, and only a few infections lead to disease. However, many fungi are directly allergenic by http://dx.doi.org/10.1016/ S1473-3099(17)30309-2 colonising the respiratory tract or indirectly through contact with constituents and proteases, causing or See Online/Series exacerbating allergic disease. Increasing evidence implicates high indoor fungal exposures as a precipitant of http://dx.doi.org/10.1016/ in children and in worsening asthma symptoms. or airways by endemic fungi or aspergillus can be S1473-3099(17)30303-1, diagnosed with respiratory sample culture or serum IgG testing. , induced sputum, or bronchial specimens http://dx.doi.org/10.1016/ are all suitable specimens for detecting fungi; microscopy, fungal culture, galactomannan , and aspergillus S1473-3099(17)30304-3, http://dx.doi.org/10.1016/ PCR are useful tests. treatment is indicated in almost all patients with chronic cavitary pulmonary S1473-3099(17)30306-7, infections, chronic invasive and granulomatous rhinosinusitis, and aspergillus . Most patients with fungal http://dx.doi.org/10.1016/ asthma benefit from antifungal . Adverse reactions to oral , drug interactions, and resistance in S1473-3099(17)30316-X, Aspergillus spp limit therapy. Environmental exposures, genetic factors, and structural pulmonary risk factors probably http://dx.doi.org/10.1016/ S1473-3099(17)30442-5, underlie disease but are poorly understood. http://dx.doi.org/10.1016/ S1473-3099(17)30443-7, and Introduction Fungal rhinosinusitis can be classified into four broad http://dx.doi.org/10.1016 Different species of fungi are inhaled; some are capable of clinical presentations:4 immunocompromised, an S1473-3099(17)30308-0 surviving at body temperature and evading the invasive phenotype with fulminant course; mild or no See Online/Comment http://dx.doi.org/10.1016/ defences of healthy individuals. A very small number of discernible impairment of , a chronic invasive S1473-3099(17)30319-5 the fungi that cause pulmonary infection are true or granulomatous phenotype with a chronic course; This is the third in a Series of pathogens—the most notable are those pathogens that colonisation of nasal passage and sinus, a fungal ball eight papers about fungal cause endemic mycoses: Coccidioides spp, Histoplasma spp, phenotype with a chronic course; and atopic or genetic infections Blastomyces dermatitidis, and Paracoccidioides brasiliensis.1 susceptible host, eosinophil-related fungal rhinosinusitis Global Action Fund for Fungal Other pathogens, such as Aspergillus spp and including allergic fungal rhinosinusitis with chronic or Infections, Geneva, Switzerland (Prof D W Denning FRCP); and spp, can overwhelm innate defences when inhaled in occasionally acute course. The National substantial quantities or when patients have defects in the Fungi can be present on nasal mucosa of any healthy Centre, University Hospital innate immunity. Most of these defects are subtle and person and invade the mucous membrane in of South Manchester, poorly understood. immunocompromised patients and patients with chronic The University of Manchester, 5 Manchester Academic Health In this Series paper, we introduce the common fungal invasive disease. Science Centre, Manchester, UK diseases of the upper and lower airways in non- (Prof D W Denning); and immunocompromised patients, their prevalence, the Chronic invasive or granulomatous fungal rhinosinusitis Department of Medical clinical and radiological presentation, the mode of Whether chronic invasive rhinosinusitis and granu­ , Postgraduate Institute of diagnosis, and therapy options (figure 1). Rare lomatous fungal rhinosinusitis are separate diseases or & Research, Chandigarh, India manifestations of these infections are not addressed in different presentations of the same phenotype is unclear. (A Chakrabarti MD) depth. We also explore some less well understood issues Chronic invasive fungal rhinosinusitis is seen worldwide Correspondence to: about the presentation of fungal exposure in buildings or in patients with or who are on steroid therapy, Prof David Denning, through occupation. whereas the granulomatous type is seen in apparently The National Aspergillosis Centre, University Hospital of healthy people in a geographically confined region South Manchester, the University Fungal rhinosinusitis between Sudan and India. Abundant hyphae with mixed of Manchester, Manchester Fungal rhinosinusitis is now more commonly recognised and isolation of Aspergillus fumigatus are Academic Health Science Centre, and is somewhat controversially separated into different hallmarks of chronic invasive fungal rhinosinusitis.4,6 Manchester M23 9LT, UK [email protected] phenotypes, each with a separate treatment strategy. Dematiaceous fungi, including Alternaria spp and About 10% of the adult population has chronic Curvularia spp, are occasionally isolated. In granu-​ rhinosinusitis,2 a proportion of which are various types of lomatous fungal rhinosinusitis, Aspergillus flavusis the fungal rhinosinusitis, which means that many millions most common species indicated, and hyphae are sparse of people are affected.3 A dysfunctional interplay between in tissue and usually present inside giant cells. Both the human host and fungi at the nasal and sinus mucosa diseases have a chronic course with marked orbital results in a wide range of clinical presentations.3 involvement. Diagnosis is established by histopathology www.thelancet.com/infection Published online July 31, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30309-2 1 Series

Paracoccidioidomycosis Disseminated Chronic cavitary

Histoplasmosis Disseminated Chronic cavitary Acute

Cryptococcosis Pneumonia

Coccidioidomycosis Miliary/ Chronic cavitary Primary/ dissemanated nodule Valley

Blastomycosis Disseminated Acute

Chronic cavitary/ Acute Invasive Bronchitis Fungal asthma Aspergillosis nodule/aspergillma/ Community- ABPA chronic fibrosing acquired

Immune status and underlying pulmonary disease

Neutropenia T-cell dysfunction COPD Normal CGD Corticosteroids Asthma No overt immune Allogeneic HSCT AIDS/HIV Rheumatoid arthritis Airways damage Cystic fibrosis deficit Solid organ transplant

Figure 1: Spectrum of pulmonary fungal disease and mycoses Aspergillosis affects a broad range of patients. Aspergillosis and occur worldwide, whereas endemic mycoses are geographically confined. The coloured boxes represent groups of underlying diseases, with the more classical immunocompromising diseases to the left. ABPA=allergic bronchopulmonary aspergillosis. HSCT=haematopoetic stem-cell transplant. COPD=chronic obstructive pulmonary disease. CGD=chronic granulomatous disease.

of endoscopically removed samples and culture. IgG Patients present with symptoms of chronic , to aspergillus or precipitins can be useful in which might include facial pressure, , nasal monitoring therapy.7 Management consists of surgical stuffiness, and discharge.18 Patients often have a history of debridement, preferably endoscopically, and antifungal multiple and incomplete responses to therapy. , , or antibacterial therapy; allergic fungal rhinosinusitis should for 6–12 weeks are effective post-debridement.8–10 be suspected in intractable sinusitis with nasal polyposis. Some patients present with proptosis. CT scans of the Fungal ball sinuses will reveal opacification with concretions or Fungi colonise the sinus mucosa and produce a dense calcifications, or both. Positive type 1 hypersensitivity is conglomeration of hyphae in one sinus cavity, most common, and the presence of eosinophilic mucin typically the maxillary sinus but occasionally the containing fungal hyphae is diagnostic. Dematiaceous sphenoid sinus.6 The disease occurs worldwide but is fungi including Alternaria, Bipolaris, and Curvularia spp most prevalent in elderly women in southern France.11,12 are often isolated from patients in developed countries. By Management consists of endoscopic removal.4 Antifungal contrast, A flavus is isolated from patients in south Asia, therapy is not necessary for maxillary fungal ball but can the Middle East, and Sudan. be advisable post-operatively for patients with disease in The cornerstones of infection management are removal the sphenoid sinus.13 of nasal polyps combined with topical cortico­steroids immediately after , short-term antibiotic therapy Allergic fungal rhinosinusitis for concurrent bacterial infection (notably for Akin to allergic bronchopulmonary aspergillosis, a Staphylococcus aureus),19 and nasal irrigation with saline. profound Th2 lymphocyte response with eosinophilic Relapse is common but can be prevented, in part, mucin in the sinus is the hallmark of allergic fungal by long-term nasal steroids and saline.20,21 In double-blind, rhinosinusitis.14 Allergic fungal rhinosinusitis is placebo-controlled studies,22–24 local and systemic antifungal prevalent in arid and tropical regions of the world. The agents have been shown to have limited benefit—the prevalence in north India is reported to be 110 patients benefit is in relapsing cases (ie, preventing relapse).25–27 per 100 000 population during the wheat-thrashing Some patients benefit from a salicylate-free diet.28 season (March to April).15 In Israel, a prevalence of up to 500 patients per 100 000 population has been reported.16 Community-acquired aspergillus pneumonia Allergic fungal rhinosinusitis and allergic broncho­ Massive exposures to aspergillus conidia can overwhelm pulmonary aspergillosis can co-occur in the same the innate immunity of the lung and cause acute disease.29,30 patient.17 Low levels of exposure after , a history of

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lung disease, chronic obstructive pulmonary disease, and Frequency in Comments corticosteroid therapy also predispose patients to series community-acquired aspergillus pneumonia.31–33 An acute 17–80% Patients are probably at highest risk soon after or subacute onset is typical. Chest imaging will reveal a treatment for tuberculosis is completed, but the risk miliary, bilateral diffuse pattern or unilateral, upper lobe persists for decades; also seen in patients who are HIV cavitary disease. Aspergillus spp can be isolated from positive respiratory tract specimens, and galactomannan is Emphysema or chronic 30–50% Bullous emphysema is probably a key risk; detectable in bronchoscopy fluid. IgG antibodies to obstructive pulmonary corticosteroids for exacerbations is another risk disease aspergillus become detectable, but the time course is Non-tuberculous <20% Non-tuberculous mycobacterial disease might precede, uncertain. Outcome is poor in patients with concurrent mycobacterial infection be concurrent with, or follow chronic pulmonary viral infection and who are taking corticosteroids.32 Other aspergillosis; the outcome is determined by chronic patients will either have complete resolution or develop pulmonary aspergillosis, not non-tuberculous mycobacterial disease chronic pulmonary aspergillosis. Antifungal therapy is Pneumothorax or bullous 9–20% Often occurs years before chronic pulmonary advised, with corticosteroids in bilateral diffuse disease, lung disease aspergillosis, but pleurectomy or talc pleurodesis are also but data are scant. common in patients’ history Allergic bronchopulmonary 12–18% Radiological appearance of chronic pulmonary Chronic pulmonary aspergillosis aspergillosis and asthma aspergillosis in allergic bronchopulmonary aspergillosis Chronic pulmonary aspergillosis is a challenging disorder, might differ, with pleural more common and cavities less common; frequent corticosteroid courses 34 complicating several respiratory diseases. The global might be a risk factor burden is estimated at about 3 million people, of whom Pulmonary fibrocystic 9–17% Difficult to diagnose until become about 1·2 million have had pulmonary tuberculosis.35–37 sarcoidosis apparent by These patients are not immunocompromised but have a Lung irradiation About 5% ·· history of lung defects (table 1).37 Rheumatoid arthritis 2–4% Might be aspergillus-infected rheumatoid nodules Chronic pulmonary aspergillosis progresses slowly, Ankylosing spondylitis <5% Often isolated apical disease, but very challenging to and by convention, will have been present for at least resect surgically 3 months before diagnosis.38 Most patients with chronic None 2–10% Some patients have no discernable underlying disorder pulmonary aspergillosis are men aged 50–75 years (60%) Table 1: Underlying conditions for chronic pulmonary aspergillosis37 with long-standing constitutional symptoms of profound and , pulmonary symptoms of productive , haemoptysis of variable degree, chest Appearance on CT scan discomfort, and shortness of breath. Imaging reveals at Coccidioidal nodule* Usually single and in an upper lobe; occasionally calcified least one cavity, which can be small or large, thick or Aspergillus nodule Single or multiple; any lobe can be affected but upper lobes are thin-walled. Most often, the cavity appears with or most often affected; occasionally calcified without an aspergilloma (conglomerates of fungal Cryptococcal nodule Usually large and peripheral; single or multiple; rarely cavitate hyphae as biofilm within pulmonary cavities) or with or calcify solid or cavitating nodules (table 2).39 Occasionally, a large Histoplasma nodule* Single or multiple; small; often calcified mass lesion or extensive consolidation with limited air Non-tuberculous mycobacterial nodule Single or multiple; might be calcified spaces will have appeared (figure 2). Pleural thickening is Rare; usually single but occasionally multiple; usually appear in a characteristic feature of chronic pulmonary aspergillosis immunocompromised patients but not universal. Patients often have recurrent infections Nocardia spp Single or multiple; usually appear in immunocompromised with Streptococcus pneumoniae or Haemophilus influenzae. patients includes the other fungal Dirofilariasis* Coin lesion; single or multiple; might cavitate pathogens discussed in this Review, as well as *These types of pulmonary nodules differ by geographical area; exclusion of malignancy is important and can be tuberculosis, non-tuberculous mycobacterial infection, impossible without . and lung carcinoma. Table 2: Differential diagnosis of a non-malignant pulmonary nodule Subacute invasive pulmonary aspergillosis (previously known as chronic necrotising pulmonary aspergillosis) develops in 4–12 weeks, usually affects moderately aspergillus or the detection of galactomannan in immunocompromised patients, and should be managed respiratory samples is supportive evidence40,43 if the as invasive aspergillosis.40,41 radiological findings are typical. Some patients have The key diagnostic test for chronic pulmonary increased production of total IgE or IgE to aspergillus but aspergillosis is the detection of IgG to aspergillus (or the might not have asthma or allergic bronchopulmonary less sensitive precipitins), which is detectable in more aspergillosis. than 90% of patients with cavitary disease42 but only in Simple aspergillomas should be resected, if possible, about 60% of patients with aspergillus nodules. Almost preferably with the video-assisted thoracic surgery all patients show an increased production of technique (table 3).40,41,44 Surgery might be necessary in inflammatory markers. Positive PCR or culture of complex cases, such as patients with haemoptysis, www.thelancet.com/infection Published online July 31, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30309-2 3 Series

or (especially antibody seroconversion), or both.59 The annual incidence of symptomless infections can Right only be estimated by test conversion and varies substantially by geography. For example, in , the number of people who had a positive skin test varied from 11·2 to 56·2 million of the estimated 112 million population (based on a 2010 census).60 Primary infection, with or without symptoms, appears to confer some immunity from re-infection, unless the patient is profoundly immunocompromised. Chronic cavitary pulmonary is uncommon. Cavitation is most common in patients with emphysema and can, initially, represent focal areas of consolidation surrounding bullae.58,61 Disease is usually Figure 2: CT of moderate emphysema and a thin-walled right upper lobe bilateral, involving the upper lobes. Patients present with cavity containing intra-cavitary material and irregular wall laterally, with productive cough, increasing shortness of breath, weight pleural thickening High titre IgG antibodies to Aspergillus fumigatus were found. loss, , and sometimes fever that has lasted many months or years. Chest radiographs show gradually expanding cavities that progress to local fibrosis.61 For unresponsive unilateral disease, or azole resistance. Each more than 90% of patients, respiratory samples usually patient should be carefully risk assessed, as summarised yield a positive culture for H capsulatum and IgG by Farid and colleagues.44 antibody is detectable in serum.62 Histoplasma is a class 3 Long-term oral antifungal therapy is recommended for , so the laboratory should be prepared to handle most patients (table 3).40,41 The objectives of therapy are this safely. Long-term itraconazole therapy is to minimise symptoms,45 notably cough, sputum advised (table 3).46,47 Fibrosing and airway- production, fatigue, weight loss, and risk of haemoptysis. obstructing are rare complications, Antifungal therapy does not improve breathlessness typically without concurrent pulmonary disease. appreciably unless the patient is very deconditioned and can exercise more; pulmonary rehabilitation might be Pulmonary helpful. Follow-up without therapy is recommended for Coccidioidomycosis is caused by or patients with resected Aspergillus spp nodules and for , which exist in the environment patients with minimal symptoms and no radiological in southwestern USA, northern Mexico, and in progression in several months. geographical pockets throughout and Haemoptysis can be controlled with tranexamic acid and .1 In the USA, about 60% of cases occur bronchial artery embolisation; surgical resection is usually in , but sporadic, imported cases are reported unnecessary. Haemoptysis can be a sign of therapeutic across the world. Infection follows inhalation of one or failure or antifungal resistance, or both. Acquired azole more arthroconidia. resistance can develop, as is more likely, during prolonged Infection is in about 60% of cases.1 therapy (especially in patients for whom inadequate dosing However, primary infection, often referred to as Valley or drug bioavailability leads to suboptimum serum Fever, presents as influenza-like symptoms, which include concentrations of azole), poor compliance, and high fever, chest pain, cough, or weight loss, and is sometimes burden of infection. These patients might need associated with nodosum or erythema intermittent or long-term .40 multiforme (figure 1). Discrete nodules in the lower lobes or consolidation can occur.63 Primary pulmonary Pulmonary histoplasmosis coccidioidomycosis can be severe with a prolonged, Histoplasmosis has three main pulmonary manifestations: debilitating course. About 90% of patients have detectable acute disease after substantial exposure to Histoplasma IgM antibody within 2 weeks of illness. Primary capsulatum (especially after cave explorations), chronic coccidioidomycosis either resolves or progresses to chronic cavitary diseases in immunocompetent people, and and progressive pulmonary disease. Dissemination can disseminated disease in immunocompromised people lead to or skin, bone, or lymph node disease. (figure 1). Most exposures are subclinical and leave small Patients with chronic pulmonary coccidioidomycosis calcified granulomata in the lungs or spleen. present with persistent cough, weight loss, and . Acute pulmonary histoplasmosis appears a few days Patients usually have a single, thin-walled cavity, but after a point exposure. The diagnosis is usually made some patients can have enlarging or multiplying nodules clinically, with consolidation on .58 or cavities.63 Cavitary pulmonary disease usually yields a Serological diagnosis is based on histoplasma antigen positive sputum or bronchoalveolar lavage culture.64

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Initial therapy Duration Alternative therapy* Cautions Chronic pulmonary aspergillosis Simple aspergilloma40,41 Surgical resection ·· None Sufficient respiratory reserve, relapse is possible Aspergillus nodule39,40 None if asymptomatic ·· Azole therapy if progressive If multiple, continued imaging and possibly repeat biopsy if progressive Chronic cavitary and Itraconazole or >6 months, typically long , liposomal Drug interactions, especially fibrosing40,41,45 voriconazole term amphotericin B (about rifampicin; long-term toxicity include 3 mg/kg), micafungin peripheral neuropathy and skin photosensitivity (voriconazole) Histoplasmosis Acute pulmonary46,47 None if minor symptoms ·· None ·· Acute pulmonary46,47 Liposomal amphotericin B, 1–3 months None ·· itraconazole Chronic cavitary46 Itraconazole 12–24 months Posaconazole ·· Coccidioidomycosis Primary pulmonary48,49 None ·· , itraconazole Not of proven value but might be (2 months) helpful in severe cases; no effect on relapse Coccidioidomycosis nodule48 None ·· ·· ·· Chronic pulmonary48,50 Fluconazole, itraconazole 12 months Posaconazole, liposomal Relapse risk about 50% amphotericin B Juvenile51 Itraconazole 3–6 months Liposomal amphotericin B ·· Chronic pulmonary51,52 Itraconazole 6 months Liposomal amphotericin B ·· Blastomycosis53 None or itraconazole 2–6 months Liposomal amphotericin B ·· if very unwell Cryptococcal pneumonia54 Fluconazole 6–12 months Itraconazole or Asymptomatic colonisation does not voriconazole need therapy Fungal asthma†55,56 Itraconazole 4–8 months Nebulised amphotericin B, Relapse risk about 50% voriconazole, posaconazole Aspergillus bronchitis57 Itraconazole 4 months Voriconazole, posaconazole Relapse risk about 50%

*Monitor azole serum concentrations and possible toxicities and avoid drug interactions. †Includes allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitisation.

Table 3: for pulmonary fungal disease in non-immunocompromised patients

A specific manifestation of coccidioidomycosis is the cavitary pulmonary coccidioidomycosis (table 3),48 and pulmonary nodule, which is usually single, asymptomatic, relapse is reported even after 1 year of therapy. No convincing and benign (table 2). Radiologically, the nodules do not data exist to support the use of any one particular azole, and resemble carcinoma63 but are usually removed from echinocandins are ineffective. Severe disease is treated with patients living in non-endemic areas because only amphotericin­ B.48,50 Relapse is more likely if the antibody histological confirmation minimises anxiety about the titre in the complement fixation test is greater than 1/256. diagnosis. Long-term azole therapy is appropriate if relapse occurs. Coccidioides spp are classified as class 3 pathogens, so laboratories should be have the appropriate facilities. Pulmonary paracoccidioidomycosis The fungus is white on agar and produces infectious Paracoccidioidomycosis occurs in certain areas of Central arthroconidia (rectangular microscopic structures). America and South America. About 3500 new cases occur Tissue can contain spherules, which are large, thick in Brazil each year.65 The Paracoccidioides walled circular structures containing endospores. The brasiliensis is acquired through inhalation. Initial infection complement fixation test for IgG antibodies is the usual is usually subclinical; poorly understood factors or diagnostic test for chronic pulmonary coccidioidomycosis immunosuppression allow reactivation. since the titre correlates with the severity of disease64 and A rare manifestation of paracoccidioidomycosis in decreases with successful therapy. patients younger than 30 years is acute, progressive Primary coccidioidomycosis is usually treated sympto-​ infection (figure 1). This so-called juvenile form of matically; itraconazole or fluconazole can shorten the disease is characterised in the lung by adenopathy, duration of disease, but do not affect relapse.49 Antifungal unilateral , and miliary-like shadows.51 therapy is not necessary for pulmonary nodules,48 whereas Disseminated infection to other organs is typical, and prolonged antifungal therapy is necessary for chronic untreated cases could be fatal. www.thelancet.com/infection Published online July 31, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30309-2 5 Series

Chronic pulmonary paracoccidioidomycosis51 is often Second, many patients with asthma are sensitive to associated with disease in other organs, notably the skin several fungi, including Aspergillus spp, Alternaria spp, and mouth, lymph nodes, spleen, liver, and adrenal and Cladosporium spp, and this sensitivity is usually glands. Pulmonary lesions are granulomatous nodules linked to poor asthma control.69 The latter sensitivity is that often cavitate but rarely calcify. Co-existent often referred to as fungal asthma.54 Fungal sensitisation pulmonary tuberculosis is common. Itraconazole is is common in severe asthma, occurring in at least 33% of superior to compounded preparations of trimethoprim patients.70 Genetic factors are probably important in and sulphamethoxazole (table 3).52 fungal asthma.55 Severe airway inflammation and multiple hospital admissions are common.70–72 Pulmonary Fungal asthma has a broad range of clinical phenotypes Pulmonary blastomycosis is usually seen with cutaneous and includes allergic bronchopulmonary aspergillosis.72 blastomycosis. Almost all cases occur in North America, Fungal asthma can manifest as fungal sensitisation or with rare cases reported from Africa and India. The most fungal . Whereas fungal sensitisation is an common presentation is with cough, weight loss, chest exaggerated immune response to a fungus, without pain, skin lesions, and fever; haemoptysis is seen inflammation or tissue damage, and is clinically occasionally (figure 1).53 Primary pulmonary blastomycosis recognised by an increased production of fungus-specific might be asymptomatic or present as acute or subacute IgE, fungal allergy is an immune-mediated inflammatory pneumonia, ranging from mild to severe. Itraconazole response to a fungus causing tissue damage. Although therapy is curative (table 3). many fungi can cause sensitisation, fungal allergy is predominantly due to thermotolerant fungi, especially Cryptococcal pneumonia A fumigatus. Allergic bronchopulmonary aspergillosis is Pulmonary cryptococcosis is rare, but probably the most well characterised form of fungal asthma.72 underdiagnosed, and is most common in immuno­ Severe asthma with fungal sensitisation denotes a compromised patients (figure 1). It is most often caused phenotype of severe asthma characterised by severe by var grubii (worldwide) or asthma and fungal sensitisation but no allergic (geographically confined). C gattii is bronchopulmonary aspergillosis.69 found in eucalyptus and other large trees in tropical and Allergic bronchopulmonary aspergillosis presents as subtropical regions in Australia, Asia, Europe, and the poorly controlled asthma, with exacerbations consisting northwestern Pacific. of increased amounts of sputum containing mucous Patients might be asymptomatic and present with an plugs, malaise, and weight loss.72 Chest imaging might abnormal chest radiograph.66 The most common reveal mucous plugging, and, in later stages, central symptoms are cough, which is usually productive, and bronchiectasis. Hyperattenuated mucus is visible in a haemoptysis. Single or multiple peripheral nodules, substantial proportion of patients in India but is sometimes in association with areas of consolidation, are uncommon elsewhere, for unknown reasons. The common, but pleural effusion and consolidation are seen diagnosis of various forms of fungal asthma is based on a occasionally. Airway colonisation also occurs.67 C gattii combination of clinical, radiological, and immunological pulmonary infection includes multifocal areas of findings. IgE to A fumigatus is required for a diagnosis of consolidation, both solid and cavitary nodules, pleural allergic bronchopulmonary aspergillosis. A total IgE of effusion, and endobronchial lesions. Hypoxaemia is rare. more than 1000 IU/L arbitrarily distinguishes allergic Patients might have disseminated disease with bronchopulmonary aspergillosis from severe asthma meningitis or a cerebral cryptococcoma. with fungal sensitisation.55,72 CT-guided or video-assisted thoracoscopy lung biopsy or Management of fungal asthma includes inhaled or resection is the most common means of establishing the oral corticosteroids, or both, immunisation against diagnosis. Culture from respiratory samples is often S pneumoniae and H influenzae, management of excess negative, but cryptococcal antigen is occasionally detected mucus with therapeutic bronchoscopy (if plugging is in serum or .67 Most patients with C gattii severe), and hypertonic saline nebulisers and azithro­ infection are not immunocompromised but might have ill- mycin as an airway anti-inflammatory agent.55,56 Oral or defined immune deficits. If not resected, antifungal therapy inhaled antifungal therapy, if tolerated, is beneficial with fluconazole (table 3) is advised, unless meningitis is for most patients (table 3). Complications of allergic also present, in which case combination amphotericin B bronchopulmonary aspergillosis include bronchiectasis and is strongly recommended.54 and (including chronic pulmonary aspergillosis).56 Fungal asthma Current evidence links a proportion of asthma cases to Thunderstorm asthma fungal infections in two ways. First, substantial indoor Thunderstorm asthma refers to an association between dampness, mould odour, and visible mould exposure can high fungal counts, thunderstorms, and severe trigger asthma, with an increased risk of 30–50%.68 asthma attacks.73 Increased humidity and high winds

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trigger increased spore or conidia release and dissemination. Several fungi have been implicated in thunderstorm asthma, including Didymella exitialis, Sporobolomyces spp, and Alternaria spp74 as well as grass Physical factors Psychological factors allergens. Affected patients might become so ill as to • Low or high frequency noise • Excessive work stress or need intensive care. Whether antifungal therapy could be • Excess noise disaffection beneficial is unclear. • Poor lighting or over • Poor interpersonal reliance on relationships and fluorescent lighting poor communication Occupational asthma • Excess or very low humidity Occupational asthma has been attributed to fungi in a • Poor ergonomics few cases. Examples include workers with positive IgE and IgG to Pleurotus cornucopiae;75 people Causes of building Exposure to biological working in condom manufacturing, where Lycopodium sickness syndrome agents clavatum was used as a dusting agent; a research • Visible mould related to Ventilation problems leak or condensation/ microbiologist with asthma and with specific IgE • Inadequate ventilation and poor ventilaton antibodies to Dictyostelium discoideum; a coal miner who air changes • Insect or droppings • Dampness indoors or related to developed occupational asthma with specific IgE • Poor air conditioning ventilation intake antibodies to Rhizopus nigricans after a mine was • Excess volatile organic • Contaminated air contaminated with this fungus; people working in the compounds conditioning, system, • Temperature too high or low ducting, or individual coffee grinding industry or the plywood industry who • Cramping of space, offices, device have specific IgE to Neurospora species; and orchid or workplaces • Legionella • Carbon monoxide exposure contamination of water growers with sensitivity to Cryptostroma corticale, which • Exposure to external sources is found in the bark chips used to cultivate orchids. such as smoke, building exhausts, dust, external allergens Aspergillus bronchitis Aspergillus bronchitis is a chronic superficial infection of the lower airways, characteristically in non-immuno­ compromised patients.57,76 Any of the pathogenic Aspergillus spp can cause this form of bronchitis, and most patients Figure 3: Causes of building sickness syndrome have bronchiectasis or . About 10 000 adults Common sources of volatile organic compounds are mould, adhesives, new carpets, upholstery, copy machines, are estimated to have cystic fibrosis and aspergillus chipboard furniture, pesticides, and cleaning agents. bronchitis,77 but the burden of aspergillus bronchitis in people who do not have cystic fibrosis has not been represent allergic bronchopulmonary aspergillosis, estimated. The most common clinical presentations in aspergillus bronchitis or transient colonisation, Exophiala patients who do not have cystic fibrosis are either chronic dermatiditis, which is of uncertain importance, and productive cough with tenacious mucus production and Scedosporium spp.78 Those patients with aspergillus in dyspnoea or recurrent exacerbations of pre-existing airway their airways have a slightly more rapid decrease in disease with incomplete response to antibiotics.57 Mucous lung function than those without.79 Infection of the impaction necessitating therapeutic bronchoscopy is a airways manifests as aspergillus bronchitis and allergic rare, dramatic presentation. bronchopulmonary aspergillosis, but many patients are Since Aspergillus spp can colonise the respiratory tree, not affected or only sensitised to A fumigatus.80 The the combination of symptoms with microbiological optimal management of fungal infection and allergy in demonstration of aspergillus in the airways at least twice patients with cystic fibrosis is uncertain. is required for diagnosis.57 Some patients have airway ulceration or membrane formation, whereas other Mouldy building exposure and building sickness patients have obstructing, thick mucus. Detection of syndrome fungus by microscopy and either galactomannan assays Poor quality buildings, water leaks, and inadequate or PCR is sufficient for diagnosis. Some patients show ventilation can lead to excess fungal growth inside a increased production of IgG to aspergillus. building. In addition to precipitating or worsening Oral azole therapy for about 4 months is effective in asthma, some patients develop other symptoms, referred most patients (table 3); however, relapse is common, and to as building sickness syndrome.81 Other names for this some patients need long-term therapy. collection of syndromes include sick building syndrome, sick house syndrome, or the evocative toxic black mould. Cystic fibrosis This syndrome might affect patients with chemical Patients with cystic fibrosis are at risk of acquiring fungi intolerance (multiple chemical sensitivity).82–85 Since in their sputum, commonly Candida spp, which is many of the symptoms are non-specific and no diagnostic of limited importance, A fumigatus, which might test is available, the diagnosis relies on a careful history www.thelancet.com/infection Published online July 31, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30309-2 7 Series

Extrinsic allergic alveolitis caused by fungi is probably Search strategy and selection criteria more common than realised because fungal exposure We searched Medline and our own extensive article archives can be unobtrusive. A well documented example was an for relevant material. We considered articles that were written outbreak of pulmonary symptoms and skin-prick in English, French, and Spanish and published between Jan 1, positivity to aspergillus in several workers producing 91 1960, and Jan 1, 2016. Because of the breadth of topics citric acid from Aspergillus niger. Fungal exposure is also 92 93 94 discussed in this Review, we made no attempt to formalise it problematic for workers in the malt, tobacco, baking, 95 as a meta-analysis or other systematic review. and esparto manufacturing industries. Many individual case examples have not been given disease names yet, and many occupational exposures lead to pulmonary of the patient’s symptoms and environmental exposures symptoms that do not fulfil criteria for asthma or and exclusion of other causes of common symptoms extrinsic allergic alveolitis.75,96 such as fatigue (figure 3).83–85 Antifungal therapy has not been tested in patients with Clinical clues to a positive diagnosis of building either extrinsic allergic alveolitis or occupational asthma sickness syndrome related to fungal or mould exposure related to fungi. Some patients present late with include three elements: a history of exposure to visible interstitial lung disease or pulmonary fibrosis. Avoidance mould or smell, usually with improvement after leaving is generally recommended but could have serious the building (eye, nose, or throat irritation and hoarseness economic consequences for some patients. A trial of combined with difficulty in concentration and sensitivity itraconazole, as a corticosteroid-sparing agent, might be to odours is characteristic of exposure to volatile organic sensible if subtle exposure continues and is unavoidable. compounds); headache, dizziness, nausea, dry skin or pruritus, nasal stuffiness, and lethargy are common, and Conclusion weight loss and muscle pains are reported occasionally; Airborne fungi cause a wide range of disease in the lung and exacerbation or initiation of allergic or and upper and lower airways, some acute and others asthma. indolent or chronic. High exposure is a common factor. In addition to an empathetic ear and eradication of Underlying lung or airway disease is a common antecedent dampness and mould from the house or office, patients factor, and the course of fungal disease is highly variable— need to be thoroughly examined, checked for alternative probably attributable to local airway and lung immune diagnoses with an initial screen for inflammatory defences and genetic factors, which are not well markers, anaemia, liver, renal and thyroid abnormality, understood. Most infectious syndromes and some allergic and have a chest radiograph. Comorbidity, especially manifestations improve with antifungal therapy. 86 psychological, is common. If allergic or pulmonary Contributors symptoms are prominent, then testing for fungal DWD and AC contributed equally to the writing of this paper. sensitisation or IgG, or both, is appropriate. Preferably, Declaration of interests these tests should be combined with a careful assessment DWD and family hold Founder shares in F2G Ltd, a University of of fungal exposure in the home or workplace by an Manchester spin-out antifungal discovery company. He acts or has recently acted as a consultant to Astellas, Sigma Tau, Basilea, Scynexis, experienced professional. The Quick Environmental Cidara, Biosergen, Quintiles, Pulmatrix, Pulmocide, and Zambon. In the Exposure and Sensitivity Inventory questionnaire is past 3 years, he has been paid for talks on behalf of Astellas, Dynamiker, valuable in assessing patients.87 Gilead, Merck, and . He is a longstanding member of the Infectious The cornerstone of management is avoidance. Repair Disease Society of America Aspergillosis Guidelines group, the European Society for Clinical Microbiology and Infectious Diseases Aspergillosis of leaks, reduction in condensation, and improvement in Guidelines group, and the British Society for Medical Standards ventilation are key to clinical improvement. Patients of Care committee. AC declares no competing interests. with evidence of chemical intolerance need advice Acknowledgments on avoidance, which can be challenging, so cognitive DWD thanks the National Institute of Health Research, Medical behavioural therapy might be helpful.88 No evidence Research Council, Global Action Fund for Fungal Infections, and the exists for any particular therapeutic strategy, partly Fungal Infection Trust for grant support. because of the highly individual nature of the exposures. References 1 Vallabhaneni S, Mody RK, Walker T, Chiller T. The global burden of fungal diseases. Infect Dis Clin North Am 2016; 30: 1–11. 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