file · Web viewPulmonary and sinus fungal diseases in non-immunocompromised patients. David W....
Transcript of file · Web viewPulmonary and sinus fungal diseases in non-immunocompromised patients. David W....
Pulmonary and sinus fungal diseases in non-
immunocompromised patients
David W. Denning FRCP 1,2 and Arunaloke Chakrabarti MD 3
1Global Action Fund for Fungal Infections,
2The National Aspergillosis Centre, University Hospital of South Manchester, The
University of Manchester, Manchester Academic Health Science Centre, Manchester,
UK
3Department of Medical Microbiology, Postgraduate Institute of Medical Education &
Research, Chandigarh 160012, India
Corresponding author:
Professor David Denning FRCP FRCPath FMedSci
The National Aspergillosis Centre
University Hospital of South Manchester, the University of Manchester,
Manchester Academic Health Science Centre,
Manchester, UK
E-mail: [email protected]
Total number of words of the manuscript: 4300 words
Abstract: 198 words.
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Abstract
The human respiratory tract is exposed daily to airborne fungi, fungal enzymes
and secondary metabolites. The endemic fungi Histoplasma capsulatum,
Coccidioides spp., Blastomyces dermatitidis and Paracoccidioides brasiliensis, and
occasionally Aspergillus fumigatus, are primary pulmonary pathogens of
otherwise healthy people. The majority resolve such infections, few develop
disease. However, many fungi are directly allergenic by colonizing the
respiratory tract, or indirectly through contact with cell wall constituents and
proteases, causing or exacerbating allergic disease. Increasing evidence
implicates high indoor fungal exposures as a precipitant of asthma in children,
and in worsening asthma symptoms. Lung or airways infection by endemic fungi
or Aspergillus can be diagnosed with respiratory sample culture or serum IgG
antibody testing. Sputum, induced sputum or bronchial specimens are all
suitable specimens for detecting fungi; microscopy, culture, galactomannan
antigen and Aspergillus PCR are useful tests. Antifungal treatment is indicated in
almost all patients with chronic cavitary pulmonary infections, chronic invasive
and granulomatous rhinosinusitis and Aspergillus bronchitis. The majority of
patients with fungal asthma benefit from antifungal therapy. Adverse reactions
to oral azoles, drug interactions and azole resistance in Aspergillus spp. limit
therapy. Environmental exposures, genetic and structural pulmonary risk factors
probably underlie disease, but are poorly understood.
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Introduction
Different species of fungi may be inhaled; some are capable of surviving at body
temperature and evading healthy host defenses. A very small number of
pathogenic fungi causing pulmonary infection are true pathogens, notably those
causing the endemic mycoses – Coccidioides spp, Histoplasma spp., Blastomyces
dermatitidis, Paracoccidioides brasiliensis1. Others, such as Aspergillus spp. and
Cryptococcus spp. can overwhelm innate defenses when inhaled in substantial
quantities or patients can have specific defects in innate immunity what we
currently consider ‘normal’ defenses. Most of these subtle defense ‘holes’ are
poorly understood.
We review here the common upper and lower airway fungal diseases in non-
immunocompromised hosts – their frequency, the clinical and radiological
presentation, the mode of diagnosis and current therapy. Rare manifestations of
these infections are not addressed in any depth. We also describe some less well
understood issues, notably the presentation of fungal exposure in buildings or
through occupation. Treatment is addressed in a summary format only –
additional expert advice and in depth literature should be consulted.
Search strategy
We searched Medline and our own extensive article archives for relevant
material. The limit of 100 references has been maintained. There is no attempt to
formalize this review as any type of meta-analysis or other scoping/systematic
review, because of the breadth of subjects covered.
Fungal rhinosinusitis
Fungal rhinosinusitis (FRS) is now recognized more frequently, and somewhat
controversially separated into different phenotypes. Therapy varies by
phenotypes. As ~10% of the adult population suffers from chronic
rhinosinusitis2, and a small minority of these by FRS of different types, many
millions are affected3. A dysfunctional interplay between the human host and
fungi at the nasal and sinus mucosa results in a wide clinical spectrum of FRS3.
FRS can be classified into four broad clinical presentations4:
a) Immunocompromised – acute invasive phenotype with fulminant course.
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b) Mild or no discernable impairment of immunity – chronic invasive or
granulomatous phenotype with chronic course
c) Colonization of nasal passage and sinus – fungal ball phenotype with
chronic course
d) Atopic or genetic susceptible host – eosinophil-related FRS including
allergic fungal rhinosinusitis (AFRS) with chronic or occasionally acute
course.
Fungi can be present on nasal mucosa of any healthy person and invade the
mucous membrane in the first two types only5.
Chronic invasive or granulomatous FRS: It is not clear whether the two entities
are separate or different presentations of same phenotype. Chronic invasive FRS
is seen worldwide in patients with diabetes or on steroid therapy, whereas the
granulomatous type is seen in apparently healthy people in a geographically
restricted region extending from Sudan to India. Abundant hyphae with mixed
inflammation and isolation of Aspergillus fumigatus are hallmarks of chronic
invasive FRS4,6. Rarely dematiaceous fungi including Alternaria and Curvularia
spp. are isolated. In granulomatous FRS, A. flavus is more common and hyphae
are sparse in tissue and usually present inside giant cells. Both diseases have a
chronic course with marked orbital involvement. Diagnosis is established by
histopathology of endoscopically removed samples, and culture. Aspergillus IgG
antibodies or precipitins may be useful in monitoring therapy7. Management
consists of surgical debridement, preferably endoscopically, and antifungal
therapy. Amphotericin B, itraconazole or voriconazole for 6-12 weeks are
effective post-debridement 8-10.
Fungal ball: Fungi colonize the sinus mucosa and produce dense conglomeration
of hyphae in one sinus cavity, most commonly the maxillary sinus, occasionally a
sphenoid sinus6. The disease occurs worldwide but is prevalent in older women
in southern France11,12. Management consists of endoscopic removal4. Antifungal
therapy is not required for maxillary fungal ball, but may be advisable post-
operatively in those with sphenoid sinus disease13.
AFRS: Akin to allergic bronchopulmonary aspergillosis (ABPA), a profound Th2
response with eosinophilic mucin in the sinus is the hallmark of AFRS14. The
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disease is prevalent in arid and tropical region of the world. In north India, a high
rate of 110 AFRS patients per 100,000 population is documented especially
during the wheat-thrashing season (March-April)15. In Israel, a very high rate,
500/100,000, has been also described16. AFRS and ABPA may co-exist in the
same patient17.
Patients present with symptoms of chronic sinusitis, which may include facial
pressure, headache, nasal stuffiness, discharge18. Often there is a history of
multiple surgeries and incomplete responses to antibacterial therapy; AFRS
should be suspected in intractable sinusitis with nasal polyposis. Some patients
present with proptosis. CT scanning of the sinuses reveals opacification with
concretions and/or calcifications. Positive type I hypersensitivity is usual and the
presence of eosinophilic mucin containing fungal hyphae is diagnostic.
Dematiaceous fungi including Alternaria, Bipolaris, Curvularia are commonly
isolated from patients in western world. In contrast, A. flavus is isolated from
patients in south Asia, middle east and Sudan.
The cornerstones of management are removal of nasal polyps combined with
topical corticosteroids immediately post-operatively, short term antibiotic
therapy for concurrent bacterial infection (notably Staphylococcus aureus)19 and
nasal irrigation with saline. Relapse is common, and prevented in part by longer
term nasal steroids and saline20,21. In double-blind placebo-controlled studies,
there was limited benefit to local and systemic antifungal agents22-24; the benefit
is in relapsing cases25-27. Some patients benefit from a salicylate-free diet28.
Community acquired Aspergillus pneumonia
Massive exposures to Aspergillus conidia can overwhelm the innate immunity of
lung and acute disease follow (Figure 1)29,30. Lower levels of exposure following
influenza, prior lung disease, notably chronic obstructive pulmonary disease
(COPD), and corticosteroid therapy also predispose patients to community
acquired Aspergillus pneumonia31-33. An acute or subacute onset is typical. On
chest imaging a miliary, bilateral diffuse pattern or unilateral upper lobe cavitary
disease is seen. Aspergillus spp. may be isolated from respiratory tract specimens
and galactomannan is detectable on bronchoscopy fluid. Aspergillus IgG
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antibodies become detectable, but the time course is uncertain. Outcome is poor
in those with concurrent viral infection and also given corticosteroids32.
Complete resolution or development of chronic pulmonary aspergillosis (CPA)
occurs in other patients. Antifungal therapy is advised, with corticosteroids in
bilateral diffuse disease, but data are scant.
Chronic pulmonary aspergillosis
Chronic pulmonary aspergillosis (CPA) is a challenging disorder, complicating
several respiratory diseases34. The global estimate of burden is at ~3 million, of
whom about 1.2 million have had pulmonary tuberculosis 35-37. These patients are
not immunocompromised but have prior or current lung defects (Table 1)37.
By convention, CPA has been present for at least 3 months38. Slow progression
over time is common. Patients with CPA are commonly middle-aged men (60%)
with long standing constitutional symptoms of profound fatigue and weight loss,
pulmonary symptoms of productive cough, haemoptysis of variable degree, chest
discomfort and shortness of breath. Imaging, reveals one or more small or large,
thick or thin-walled cavities with or without an aspergilloma (most common), or
solid or cavitating nodules39 (Table 2), or rarely a large mass lesion or extensive
consolidation with limited air spaces (figure 2). Pleural thickening is
characteristic, but not universal. Aspergillomas are conglomerates of fungal
hyphae as biofilm within pulmonary cavities. Patients often have recurrent
infections with Streptococcus pneumonia or Haemophilus influenzae. Differential
diagnosis includes the other fungal entities discussed in this article, as well as
tuberculosis, non-tuberculous mycobacterial infection and lung carcinoma.
Subacute invasive pulmonary aspergillosis (previously chronic necrotizing
pulmonary aspergillosis) develops over 4-12 weeks usually in moderately
immunocompromised patients, which should be managed as invasive
aspergillosis40,41.
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The key diagnostic test for CPA is Aspergillus IgG antibody (or the less sensitive
precipitins), which is detectable in >90% of patients with cavitary disease42 but
about 60% of those with Aspergillus nodules. Inflammatory markers are raised in
almost all patients. Positive PCR or culture of Aspergillus or galactomannan from
respiratory samples is supportive evidence40,43, if the radiological findings are
typical. Some patients have raised total IgE or Aspergillus specific IgE, but may
not have asthma or ABPA.
Simple aspergillomas should be resected, if possible, preferably via video-
assisted thoracic surgery technique (table 3)40,41,44. Surgery may be required for
more complex patients with haemoptysis, un-responsive unilateral disease
and/or azole resistance. Each patient should be carefully risk assessed as
summarized by Farid et al44.
Long term oral antifungal therapy is recommended for most patients (Table
3)40,41. The objectives of therapy are to minimize symptoms45, notably cough,
sputum production, fatigue, weight and reduce the risk of haemoptysis.
Antifungal therapy does not improve breathlessness appreciably, unless they are
very deconditioned, and can exercise more; pulmonary rehabilitation may be
helpful. Patients with resected Aspergillus nodules and those with minimal
symptoms and no radiological progression over several months, need follow up,
without therapy.
Haemoptysis may be controlled with tranexamic acid and bronchial artery
embolization, rarely surgical resection, and may be a sign of therapeutic failure
and/or antifungal resistance. Acquired azole resistance may occur during
prolonged therapy, especially in those with low serum concentrations of azole, or
poor compliance and high burdens of infection. Currently such patients may have
to resort to intermittent or long term intravenous therapy.40
Pulmonary histoplasmosis
Histoplasmosis has 3 main pulmonary manifestations – acute disease after major
exposure to Histoplasma capsulatum (especially following cave exploration) and
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chronic cavitary diseases in immunocompetent people and disseminated disease
in the immunocompromised (Figure 1). Most exposures are sub-clinical leaving
small calcified granulomata in the lungs or spleen.
Acute pulmonary histoplasmosis follows a few days after a point exposure. The
diagnosis is usually made clinically, with consolidation on chest radiograph58.
Serological diagnosis is either or both of Histoplasma antigen or antibody,
especially antibody seroconversion59.
The annual number of new, symptomless infections can only be estimated by
skin test conversion, a rarely undertaken procedure, and varies substantially by
geography. For example in Mexico, the positive skin test rate varied from 11.2 to
–56.2 million of the estimated 112 million population60. Primary infection, with
or without symptoms appears to confer some immunity to re-infection, unless
profoundly immunocompromised.
Chronic cavitary pulmonary histoplasmosis is uncommon. Most frequently seen
in those with emphysema, ‘cavitation’ may represent focal areas of consolidation
surrounding bullae, initially58,61. It is usually bilateral, involving the upper lobes.
Patients present with productive cough, increasing shortness of breath, weight
loss, night sweats and sometimes fever over many months or years. Gradually
expanding cavities are seen on chest radiographs, progressing to local fibrosis61.
Respiratory samples usually yield a positive culture for H. capsulatum and IgG
antibody in >90% of patients62. The laboratory should be warned of the
possibility of Histoplasma as it is a class 3 pathogen. Long term itraconazole
therapy is advised (Table 3)46,47. Fibrosing mediastinitis and airway-obstructing
lymphadenopathy are rare complications, typically without concurrent
pulmonary disease.
Pulmonary coccidioidomycosis
Coccidioidomycosis is caused by Coccidioides immitis or Coccidioides posadasii
found in the environment in south-western USA, northern Mexico and pockets in
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Central and South America1. In the USA, about 60% of cases occur in Arizona, but
sporadic imported cases are reported across the world. Infection follows
inhalation of one or more arthroconidia.
Infection is asymptomatic in ~60%1. However, primary infection, often referred
to as ‘Valley Fever’ presents as flu-like symptoms including fever, chest pain,
cough or weight loss, sometimes associated with erythema nodosum or
erythema multiforme (Figure 1). Discrete nodules in the lower lobes, or
consolidation may be seen63. Sometimes primary pulmonary coccidioidomycosis
is severe with a prolonged, debilitating course. About 90% of patients have
detectable IgM antibody within 2 weeks of illness. Primary coccidioidomycosis
resolves or progresses to chronic and progressive pulmonary disease or
disseminates causing meningitis, skin, bone or lymph node disease.
Chronic pulmonary coccidioidomycosis presents with persistent cough, weight
loss and malaise. Usually there is a single, thin-walled cavity, but patients may
have enlarging or multiplying nodules or cavities63. Cavitary pulmonary disease
usually yields a positive sputum or BAL culture64.
A specific manifestation of coccidioidomycosis is the pulmonary nodule, with is
usually single, asymptomatic and benign (Table 2). Radiologically they do not
resemble carcinoma63, but in non-endemic areas are usually removed because
only histological confirmation minimises anxiety about the diagnosis.
The laboratory should be cautioned as Coccidioides spp. are classified class 3
pathogens. The fungus is white on agar and produces infectious arthroconidia,
rectangular microscopic structures. In tissue only spherules are seen - large,
thick walled circular structures containing endospores. The complement fixation
(CF) test for IgG antibodies is the usual means of establishing the diagnosis of
chronic pulmonary coccidioidomycosis as the titer correlates with the severity of
disease64, falling with successful therapy.
Primary coccidioidomycosis, is usually treated symptomatically; itraconazole or
fluconazole may shorten the duration of disease, but do not impact on relapse49.
Pulmonary nodules do not require antifungal therapy48. Chronic cavitary
pulmonary coccidioidomycosis requires prolonged therapy (Table 3)48, and
relapse is reported even after a year of therapy. There are no convincing data
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supporting the use of any one azole over another; echinocandins are ineffective.
Severe disease is treated with amphotericin B48,50. Relapse is more likely if the CF
antibody titer is >1:256. If relapse occurs, long term azole therapy is appropriate.
Pulmonary paracoccidioidomycosis
Paracoccidioidomycosis occurs in certain areas of Central and South America.
About 3,500 new cases occur in Brazil each year65. The dimorphic fungus
Paracoccidioides brasiliensis is acquired through inhalation. Initial infection is
usually subclinical; ill-understood factors or immunosuppression allow
reactivation.
A rare manifestation of paracoccidioidomycosis in those younger than 30 years
is acute, progressive infection (Figure 1) known as the 'juvenile' form,
characterized in the lung by adenopathy, unilateral pleural effusion and miliary-
like shadows51. Disseminated infection to other organs is typical. Untreated cases
may be fatal.
Chronic pulmonary paracoccidioidomycosis51 is often associated with disease in
other organs, notably the skin and mouth, lymph nodes, spleen, liver, adrenal
glands. Pulmonary lesions are granulomatous nodules that often cavitate but
rarely calcify. Co-existent pulmonary tuberculosis is frequent. Itraconazole is
superior to trimethoprim- sulphamethoxazole (Table 3)52.
Pulmonary blastomycosis
Pulmonary blastomycosis is usually seen with cutaneous blastomycosis. Almost
all cases occur in N. America, with rare cases reported from Africa and India. The
most common presentation is with cough, weight loss, chest pain, skin lesions,
fever and occasionally hemoptysis (Figure 1)53. Primary pulmonary
blastomycosis may be asymptomatic or present as acute or subacute pneumonia,
ranging from mild to severe. Itraconazole therapy is curative (Table 3).
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Cryptococcal pneumonia
Pulmonary cryptococcosis is rare, but probably underdiagnosed and more
common in immunocompromised patients (Figure 1). It is most often caused by
Cryptococcus neoformans var. grubii (worldwide) or C. gattii (geographically
restricted). C. gattii is found in eucalyptus and other large tropical trees in
tropical and sub-tropical regions expanding to include Australia, Asia, Europe
and the Pacific Northwest.
Patients may be asymptomatic and present with an abnormal chest radiograph66.
The most common symptoms are cough which is usually productive and
occasionally hemoptysis. Single or multiple peripheral nodules, sometimes in
association with areas of consolidation, are common, but occasionally pleural
effusion and consolidation are seen. Airways colonisation also occurs67. C. gattii
pulmonary infection includes multifocal areas of consolidation, both solid and
cavitary nodules, pleural effusion and endobronchial lesions. Hypoxemia is rare.
Patients may have disseminated disease with meningitis or a cerebral
cryptococcoma.
CT-guided or VATS lung biopsy or resection is the commonest means of
establishing the diagnosis. Culture from respiratory samples is often negative but
cryptococcal antigen is occasionally detected in serum (or CSF)67. Most patients
with C. gattii are not immunocompromised but may have ill-defined immune
deficits. If not resected, antifungal therapy with fluconazole is advised, unless
meningitis is also present (Table 3)54.
Fungal asthma
Current evidence links a proportion of asthma cases to fungi in two ways. First,
significant indoor dampness, mould odour and visible mould exposure can
trigger asthma, with an increased risk of 30-50%68. Second, many asthma
patients demonstrate sensitization to several fungi including Aspergillus,
Alternaria and Cladosporium and this is usually linked to worse asthma control69.
The latter is often referred to as ‘fungal asthma’54. Fungal sensitization is
common in severe asthma, at 33% or higher frequency70. Genetic factors
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probably play role in fungal asthma54,. Severe airway inflammation and multiple
hospital admissions are common70-72.
The clinical spectrum of fungal asthma is wide and includes ABPA 72. Fungal
asthma can manifest as fungal sensitization or fungal allergy. Fungal
sensitization is an exaggerated immune response to a fungus, without
inflammation or tissue damage, clinically documented by an elevated fungal-
specific IgE while fungal allergy is an immune-mediated inflammatory response
to a fungus causing tissue damage. Although many fungi can cause sensitization,
fungal allergy is predominantly due to thermotolerant fungi especially
Aspergillus fumigatus. ABPA is the most well characterized form of fungal
asthma72. Severe asthma with fungal sensitization (SAFS) denotes a phenotype of
severe asthma characterized by severe asthma and fungal sensitization but
exclusion of ABPA69.
ABPA presents as poorly controlled asthma, with exacerbations consisting of
increased amounts of sputum, with mucous plugs, together with malaise and
weight loss 72. Chest imaging may reveal mucous plugging, and, in later stages,
central bronchiectasis. Hyper-attentuated mucus is visible in a substantial
proportion of patients in India, and uncommon in elsewhere, for unclear reasons.
The diagnosis of various forms of fungal asthma is made on a combination of
clinical, radiological and immunological findings. A positive A. fumigatus specific
IgE is required for an ABPA diagnosis. A raised total IgE of >1,000 IU/L
arbitrarily distinguishes ABPA from SAFS55,72.
Management of fungal asthma includes inhaled and/or oral corticosteroids,
immunisation against S. pneumonia and H. influenzae, management of excess
mucus with therapeutic bronchoscopy (if severe plugging) and hypertonic saline
nebulisers and azithromycin as an airway anti-inflammatory agent55,56. Oral or
inhaled antifungal therapy is beneficial for the majority of patients, if tolerated
(Table 3). Complications of ABPA include bronchiectasis and pulmonary fibrosis
(including chronic pulmonary aspergillosis)56.
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Thunderstorm asthma: Thunderstorm asthma refers to an association between
high fungal spore counts, thunderstorms and severe asthma attacks73. Increased
humidity and high winds trigger increased spore release and dissemination.
Several fungi have been implicated including Didymella exitialis, Sporobolomyces
and Alternaria74 as well as grass allergens. Affected patients may be so ill as to
require ICU admission. It is not clear if there is a role for antifungal therapy.
Occupational asthma: There are a few cases described of occupational asthma
attributable to fungi. Examples include mushroom workers with positive IgE and
IgG to Pleurotus cornucopiae75., condom manufacturers where Lycopodium
clavatum was used as a dusting agent, a research microbiologist with asthma and
with specific IgE antibodies to Dictyostelium discoideum, a coal miner who
developed occupational asthma with specific IgE antibodies to Rhizopus
nigricans, following mine contamination with this fungus, coffee grinders and
plywood factory workers with specific IgE to Neurospora species and orchid
growers with sensitivity to Cryptostroma corticale, found in the bark chips used
in cultivating the orchids.
Aspergillus bronchitis
Aspergillus bronchitis is a chronic superficial infection of the lower airways,
characteristically in non-immunocompromised patients57,76. It may be caused by
any of the pathogenic species of Aspergillus. The majority of patients have
bronchiectasis or cystic fibrosis (CF). Approximately 10,000 adults with CF and
Aspergillus bronchitis are estimated worldwide77, but no estimate of the non-CF
burden has been made. The commonest clinical presentations in non-CF patients
are either chronic productive cough with tenacious mucus production and
dyspnoea or recurrent exacerbations of pre-existing airway disease with
incomplete response to antibiotics57. Mucous impaction requiring therapeutic
bronchoscopy is an occasional, dramatic presentation.
As Aspergilli may colonise the respiratory tree, the combination of symptoms
with microbiological demonstration of Aspergillus in the airways at least twice is
required for diagnosis57. Some patients have airway ulceration or membrane
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formation, some with obstructing, thick mucus, and microscopy and either
galactomannan or PCR is sufficient for diagnosis. Some patients have an elevated
Aspergillus IgG antibody test.
Oral azole therapy for ~4 months is effective in most patients (Table 3).
However, relapse is frequent and some patients need long term therapy.
Cystic fibrosis
Patients with cystic fibrosis may acquire fungi in their sputum, commonly
Candida spp, which is of limited import, A. fumigatus which may represent ABPA,
Aspergillus bronchitis or transient colonisation, Exophiala dermatiditis of
uncertain importance and Scedosporium spp78.. Those patients with Aspergillus in
their airways have a slightly more rapid decline in their lung function than those
without79. Infection of the airways is manifest as Aspergillus bronchitis and ABPA,
but many patients are not affected, or only sensitised to A. fumigatus80. The
optimal management of fungal infection and allergy in CF is uncertain.
Mouldy building exposure and building sickness syndrome
Poor quality buildings, water leaks and inadequate ventilation may lead to excess
fungal growth inside a building. In addition to precipitating or worsening
asthma, some patients develop other symptoms, dubbed ‘Building Sickness
Syndrome’ (BSS)81. Other names for this collection of syndromes include ‘Sick
Building Syndrome’ and Sick House Syndrome’ or the evocative ‘Toxic Black
Mould’, and may include patients with chemical intolerance (multiple chemical
sensitivity)82-85. As many of the symptoms are non-specific and there is no
diagnostic test available, the diagnosis rests on a careful history of the patient’s
symptoms and environmental exposures, and exclusion of other causes of
common symptoms such as fatigue83-85. A diagrammatic summary of the multiple
causes of BSS is shown in Figure S1.
Clinical clues to a positive diagnosis of BSS related to fungal or mould exposure
include three elements:
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An exposure history of visible mould or smell, usually with improvement
after leaving the building,
Eye, nose or throat irritation and hoarseness combined with difficulty in
concentration and sensitivity to odours is characteristic of exposure to
volatile organic compounds (VOCs),
Headache, dizziness, nausea, dry skin or pruritus, nasal stuffiness,
lethargy are common and sometimes weight loss and muscle pains,
Exacerbation or initiation of allergic rhinitis or asthma.
In addition to a empathetic ear and eradication of dampness and mould from the
house or office, patients need to be thoroughly examined, checked for alternative
diagnoses with an initial screen of inflammatory markers, anaemia, liver, renal
and thyroid abnormality and have a chest radiograph. Co-morbidity, especially
psychological, is common86. If allergic or pulmonary symptoms are prominent
then testing for fungal sensitisation and/or IgG testing is appropriate. Preferably
this should be combined with a careful evaluation of the home or workplace, by
an experienced professional, measuring fungal exposure. The Quick
Environmental Exposure and Sensitivity Inventory questionnaire may be
valuable in assessing patients87.
The cornerstone of management is avoidance. Repair of leaks, reduction in
condensation, and improvement in ventilation are key to clinical improvement.
Patients with evidence of chemical intolerance need advice on avoidance, which
can be challenging and may find cognitive behavioural therapy helpful88. No
evidence basis exists for any particular therapeutic strategy, partly because of
the highly individual nature of the exposures.
Extrinsic allergic alveolitis and other symptoms caused by fungi
Extrinsic allergic alveolitis (EAA) caused by fungi is well described (table S1)89,90.
Some cases of EAA follow complex microbial exposures, such as ‘grain fever’ or
‘organic dust syndrome’ which includes fungal material. Confirmation of a causal
relationship with any specific agent can be defined by a provocation test, often
difficult to undertake.
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As fungal exposure may be unobtrusive, EAA caused by fungi is probably more
common than realized. A well documented example was an outbreak of
pulmonary symptoms in several workers producing citric acid from Aspergillus
niger who had skin-prick positivity to Aspergillus91. Other examples include malt
workers’ lung92, tobacco workers lung93, bakers94 and stipatosis95. Many
individual case examples have not been given disease monikers yet, and so table
S1 is certainly incomplete. Many occupational exposures lead to pulmonary
symptoms, which do not fulfill criteria for asthma or EAA75,96.
There are no data published as to whether antifungal therapy is of any value for
either EAA or occupational asthma related to fungi. Some patients present late
with interstitial lung disease or pulmonary fibrosis. Generally, avoidance is
recommended, but for some patients this has significant economic consequences.
A trial of itraconazole may be worthwhile, as a corticosteroid-sparing agent, and
if subtle exposure continues and is unavoidable.
Conclusion
Airborne fungi cause a wide spectrum of lung and upper and lower airways
disease, some acute and others indolent or chronic. High exposure is a common
factor. Underlying lung or airway disease is a common antecedent factor, and the
course of fungal disease is highly variable – probably attributable to local airway
and lung defenses and genetic factors, which are not well understood. The
majority of infectious syndromes and some allergic manifestations improve with
antifungal therapy.
Author contributions: Both authors contributed equally to writing of this paper
Funding source: None
Potential conflicts of interest: DWD holds Founder shares in F2G Ltd a University of Manchester spin-out antifungal discovery company, in Novocyt which markets the Myconostica real-time molecular assays and has current grant support from the National Institute of Health Research, Medical Research Council, Global Action Fund for Fungal Infections and the Fungal Infection Trust. He acts or has recently acted as a consultant to Astellas, Sigma Tau, Basilea, Scynexis, Cidara, Biosergen Biosergen and Pulmocide. In the last 3 years, he has been paid for talks on behalf of Astellas,
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Dynamiker, Gilead, Merck and Pfizer. He is also a member of the Infectious Disease Society of America Aspergillosis Guidelines and European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines groups. AC has no conflict of interest, working full time in an Indian government sponsored autonomous medical institute.
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Figure legends
Figure 1 Spectrum of underlying disease and pulmonary mycoses. Aspergillosis
affects a broad spectrum of patients. Aspergillosis and cryptococcosis occur
worldwide, whereas endemic mycoses are geographically restricted.
Figure 2 CT scan showing moderate emphysema and a thin-walled right upper
lobe cavity containing intra-cavitary material and irregular wall laterally, with
pleural thickening. High titre A. fumigatus IgG antibodies were found.
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Table 1 Underlying conditions for chronic pulmonary aspergillosis37
Underlying condition
Frequency in series
Comment
Tuberculosis 17-80% Highest frequency probably soon after TB treatment is completed, but risk to persist for decades. Also seen in HIV positive patients
Emphysema/COPD 30-50% Bullous emphysema probably a key risk. Corticosteroids for exacerbations another risk
Non-tuberculous mycobacterial infection
<20% NTM may precede, be concurrent or follow CPA. Outcome determined by CPA not NTM
Pneumothorax or bullous lung disease
9-20% Often years before, but pleurectomy or talc pleurodesis also common history
ABPA and asthma 12-18% Radiological appearance of CPA in ABPA may differ with pleural fibrosis more common and cavities less common. Frequent corticosteroid courses may be a risk factor
Pulmonary fibrocystic sarcoidosis
9-17% Difficult to diagnose until aspergilloma apparent radiologically
Lung irradiation ~5%
Rheumatoid arthritis 2-4% May be Aspergillus-infected rheumatoid nodules
Ankylosing spondylitis
<5% Often isolated apical disease but very challenging surgically
COPD = chronic obstructive pulmonary disease, NTM = non-tuberculous
mycobacterial disease, CPA = chronic pulmonary aspergillosis, ABPA = allergic
bronchopulmonary aspergillosis
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Table 2
Differential diagnosis of a non-malignant pulmonary nodule – these differ by
geographical area. Exclusion of malignancy is important and can be impossible
without biopsy.
Cause of nodule/disease CT appearance
Coccidioidal nodule Usually single and in an upper lobe.
Occasionally calcified.
Aspergillus nodule Single or multiple. Any lobe may be
affected - upper lobes most common.
Occasionally calcified
Cryptococcal nodule Usually large and peripheral, single or
multiple and rarely cavitate or calcify.
Histoplasma nodule Single or multiple, small. Often calcified.
Non-tuberculous
mycobacterial nodule
Single or multiple. May be calcified.
Pneumocystis jirovecii Rare. Usually single but may be multiple,
usually immunocompromised
Nocardia spp. Single or multiple, usually
immunocompromised
Dirofilariasis ‘Coin lesion’. May be single or multiple
and may cavitate
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Table 3. Therapies for pulmonary fungal disease in non-immunocompromised patients
Pulmonary fungal disease Initial therapy Duration
(months)
Alternative therapy# Cautions References
Chronic pulmonary aspergillosis
Simple aspergilloma Surgical
resection
- None Sufficient respiratory
reserve, relapse possible40,41
Aspergillus nodule None if
asymptomatic
- Azole therapy if
progressive
If multiple, continued
imaging and possibly re-
biopsy, if progressive
39,40
Chronic cavitary and fibrosing Itraconazole or
voriconazole
>6, typically
long term
Posaconazole,
liposomal AmB (~3
mg/Kg), micafungin
Drug interactions,
especially rifampicin. Long
term toxicity - peripheral
neuropathy and skin
photosensitivity
(voriconazole)
40,41,45
Histoplasmosis
Acute pulmonary None,
Liposomal 1
None 46,47
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2
amphotericin B,
itraconazole 2-3
Chronic cavitary Itraconazole 12-24 Posaconazole 46
Coccidioidomycosis
Primary pulmonary None 2 Fluconazole,
itraconazole
Not of proven value, but
may be helpful in severe
cases, no impact on relapse
48,49
Coccidioidomycosis nodule None - 48
Chronic pulmonary Fluconazole,
itraconazole
12 Posaconazole,
liposomal AmB
Relapse rate ~50%48,50
Paracoccidioidomycosis
Juvenile Itraconazole 3-6 Liposomal AmB 51
Chronic pulmonary Itraconazole 6 Liposomal AmB 51,52
Blastomycosis None or
itraconazole
2-6 Liposomal AmB if very
unwell53
Cryptococcal pneumonia Fluconazole 6-12 Itraconazole or
voriconazole
Asymptomatic colonization
does not require therapy54
‘Fungal asthma’* Itraconazole 4-8 Nebulized AmB,
voriconazole,
Relapse rate ~50% 55,56
30
posaconazole
Aspergillus bronchitis Itraconazole 4 voriconazole,
posaconazole
Relapse rate ~50%57
* includes allergic bronchopulmonary aspergillosis (ABPA), severe asthma with fungal sensitization (SAFS).
AmB = amphotericin B,
# Careful monitoring of azole serum concentrations and possible toxicities and avoidance of drug interactions is recommended.
31
1
2
3
32
1