Series Fungal infections 3 Pulmonary and sinus fungal diseases in non-immunocompromised patients David W Denning, Arunaloke Chakrabarti The human respiratory tract is exposed daily to airborne fungi, fungal enzymes, and secondary metabolites. The Lancet Infect Dis 2017 endemic fungi Histoplasma capsulatum, Coccidioides spp, Blastomyces dermatitidis, and Paracoccidioides brasiliensis, and Published Online occasionally Aspergillus fumigatus, are primary pulmonary pathogens 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 cell wall constituents and proteases, causing or See Online/Series exacerbating allergic disease. Increasing evidence implicates high indoor fungal exposures as a precipitant of asthma http://dx.doi.org/10.1016/ in children and in worsening asthma symptoms. Lung or airways infection by endemic fungi or aspergillus can be S1473-3099(17)30303-1, diagnosed with respiratory sample culture or serum IgG testing. Sputum, induced sputum, or bronchial specimens http://dx.doi.org/10.1016/ are all suitable specimens for detecting fungi; microscopy, fungal culture, galactomannan antigen, and aspergillus S1473-3099(17)30304-3, http://dx.doi.org/10.1016/ PCR are useful tests. Antifungal treatment is indicated in almost all patients with chronic cavitary pulmonary S1473-3099(17)30306-7, infections, chronic invasive and granulomatous rhinosinusitis, and aspergillus bronchitis. Most patients with fungal http://dx.doi.org/10.1016/ asthma benefit from antifungal therapy. Adverse reactions to oral azoles, drug interactions, and azole 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 acute S1473-3099(17)30308-0 surviving at body temperature and evading the host 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 immunity, 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 Cryptococcus 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 Aspergillosis 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- Microbiology, Postgraduate Institute of Medical Education 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 diabetes 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 inflammation and isolation of Aspergillus fumigatus are Academic Health Science Centre, 4,6 Manchester M23 9LT, UK and is somewhat controversially separated into different hallmarks of chronic invasive fungal rhinosinusitis. [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 flavus is 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 Pneumonia Coccidioidomycosis Miliary/ Chronic cavitary Primary/ dissemanated nodule Valley fever 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 lungs CGD Corticosteroids Sarcoidosis Bronchiectasis Asthma No overt immune Allogeneic HSCT AIDS/HIV Rheumatoid arthritis Airways damage Cystic fibrosis deficit Lung cancer Solid organ transplant Pneumothorax Figure 1: Spectrum of pulmonary fungal disease and mycoses Aspergillosis affects a broad range of patients. Aspergillosis and cryptococcosis 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 sinusitis, antibodies to aspergillus or precipitins can be useful in which might include facial pressure, headache, nasal monitoring therapy.7 Management consists of surgical stuffiness, and discharge.18 Patients often have a history of debridement, preferably endoscopically, and antifungal multiple surgeries and incomplete responses to therapy. Amphotericin B, itraconazole, or voriconazole 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 cortico steroids immediately after surgery, 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