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Biological particles, along with inorganic gaseous and particulate pollutants, constitute an ever-present component of the atmosphere and surfaces. Among these particles are fungal species colonizing almost all ecosystems, including the human body. Although inoffensive to most people, fungi can be responsible for several health problems, such as allergic fungal diseases and fungal infections. Worldwide fungal disease incidence is increasing, with new emerging fungal diseases appearing yearly. Reasons for this increase are the expansion of life expectancy, the number of immunocompromised patients (immunosuppressive treatments for transplantation, autoimmune diseases, and immunodeficiency diseases), the number of uncontrolled underlying conditions (e.g., diabetes mellitus), and the misusage of medication (e.g., corticosteroids and broad-spectrum antibiotics).
Disease |
Etiological Agent |
Risk Factors |
Clinical Manifestations |
Diagnosis |
Treatment |
---|---|---|---|---|---|
Allergic Bronchopulmonary Aspergillosis |
A. fumigatus A. terreus A. niger A. flavus |
Asthma (2.5% asthmatic patients) Cystic fibrosis (1–15% of CF patients) |
Worsening asthma Worsening cystic fibrosis Coughing paroxysms Mucoid impaction, with consolidation of the lung Recurrent ‘chest infections’ |
Total IgE > 1000 KIU/L SPT or specific IgE positive for Af Fleeting or fixed pulmonary opacities on chest radiograph Continuing respiratory symptoms Af IgG antibodies Eosinophilia (>500 cells/μL in steroid naïve patients) Filamentous fungal growth in sputum cultures or bronchial lavage fluid Sputum or bronchoscopy samples with positive PCR for Af |
Oral and inhaled corticosteroids Adjuntive oral antifungal medication (itraconazole, voriconazole) Biologicals (omalizumab, mepolizumab, benralizumab, dupilumab)—off label |
Severe Asthma with Fungal Sensitization |
A. fumigatus P. chrysogenum C. herbarum A. alternata C. albicans Trichophyton spp. |
Rarely any underlying disease |
Worsening asthma symptoms Need for a high dose of inhaled steroids and/or frequent courses of oral steroids |
Low FEV1 or peak flow (usually persistently) Total IgE < 1000 KIU/L SPT or specific IgE test positive for any fungus High-resolution chest CT: normal or minor alterations |
Similar to severe asthma Partial or absent treatment response: consider biologicals (omalizumab, mepolizumab, benralizumab) and antifungal drugs (itraconazol) |
Thunderstorm asthma |
Alternaria spp. Cladosporium spp. Diatrypaceae D. exitialis P. nigran Sporobolomyces spp. |
Sensitization and exposure to aeroallergens (mainly pollen grains and fungal spores) Asthma Allergic rhinitis Age Gender Ethnicity |
The same as asthma |
The same as asthma |
The same as asthma |
Allergic fungal rhinosinusitis |
A. fumigatus A. flavus B. spicifera C. lunata A. alternata Other dematiaceous fungi |
Atopy |
Nasal obstruction Loss of smell Nasal discharge Nasal crust Pressure sensation over the face sinus Double vision or visual loss (rare) Facial asymmetry and proptosis Sino–bronchial allergic mycosis syndrome |
SPT or elevated fungal-specific IgE Imagological findings (CT or MRI of the sinuses): opacification with centrally hyperdense content, nasal polyposis Histopathology showing eosinophilic mucin without invasion into the sinus tissue Fungal hyphae in the mucus |
Topical and oral corticosteroids Saline douching Sinus surgery Biologicals (dupilumab, omalizumab, mepolizumab) Allergen immunotherapy (?) Antifungal therapy (?) |
Af = A. fumigatus; CF = Cystic Fibrosis; CT = Computed Tomography; MRI = Magnetic Resonance Imaging; PCR = Polymerase Chain Reaction; SPT = Skin prick Test.
Disease |
Etiological Agents |
Risk Factors |
---|---|---|
Farmer’s lung |
Alternaria spp. A. fumigatus A. glaucus Botrytis spp. P. brevicompactum P. olivicolor |
Handling damp hay Opening bales for feeding livestock Threshing moldy grain |
Mushroom worker’s lung |
A. bisporus H. tessellatus L. edodes P. ostreatus |
Exposure in spawning sheds |
Suberosis |
P. glabrum C. sitophila |
Handling of damp cork |
Maple bark stripper’s lung |
C. corticale |
Stripping bark from logs |
Sequoiosis |
Graphium spp. Pullularia spp. A. pullulans |
Breathing damp sawmill dust |
Wood pulp worker’s lung |
Alternaria spp. |
Pulping contaminated wood |
Malt worker’s lung |
A. clavatus P. granulatum P. citrinum R. stolonifer |
Handling moldy grain |
Wine grower’s lung |
B. cinerea |
Mold contamination |
Baker’s lung disease |
A. fumigatus |
Handling contaminated flour |
Cheese worker’s lung |
P. roqueforti P. casei P. notatum P. viridicutum A. fumigatus A. niger A. pullulans |
Cleaning mold off cheese |
Salami Brusher’s disease |
P. glabrum P. camemberti P. nalgiovense A. fumigatus Cladosporium spp. |
Cleaning the white mold growing on salami surface using a manual wire brush |
Tobacco worker’s lung |
A. fumigatus |
Exposure to tobacco dust and molds dispersed in the air in cigarette production facilities |
Peak moss worker’s lung |
Monocillium spp. P. citreonigrum |
Handling contaminated peat moss |
Paprika slicer’s lung |
M. stolonifer |
Handling moldy paprika pods during slicing |
Summer-type HP |
T. cutaneum T. asahii T. mucoides |
Exposure to damp housing and furniture materials |
Humidifiers, heating, and ventilation systems |
Aspergillus spp. Cladosporium spp. Penicillium spp. A. pullulans Cephalosporium spp. Mucor spp. Rhodoturula spp. |
Humidifier ran continuously without cleaning and with water added periodically |
PID |
Inheritance |
CMCC Incidence |
Other Fungal Infections |
Non-Fungal Infections |
Noninfectious Complications |
|
---|---|---|---|---|---|---|
Cellular and combined immunodeficiencies |
SCID |
X-linked or AR |
30–35% |
Variable (e.g., PCP) |
Bacteria, viruses and mycobacteria |
|
DOCK8 deficiency (AR-HIES) |
AR |
53–64% |
Histoplasmosis Cryptococcosis PCP |
Staphylococcal infections, HSV, VZV, HPV, molluscum contagiosum virus |
Eczema, food allergy and asthma, malignancies (lymphoma) |
|
PGM3 deficiency (AR-HIES) |
AR |
Variable |
Variable |
HSV, CMV |
Eczema, asthma, neurologic impairment, leukocytoclastic vasculitis |
|
Defective Th17 immunity |
STAT3 LOF mutation (AD-HIES) |
AD |
80% |
Aspergillosis Cryptococcosis Histoplasmosis |
S. aureus |
Eczema, pneumatoceles, coronary aneurisms, hyperextensible joints |
STAT1 GOF mutation |
AD |
100% |
Histoplasmosis Coccidioidomycosis |
HSV |
Autoimmunity Cerebral and aortic aneurisms |
|
CARD9 deficiency |
AR |
Variable |
Candida meningoencephalitis Deep dermatophytosis |
None |
None |
|
APECED |
AD or AR |
90–100% |
None |
None |
Hypoparathyroidism Adrenal insufficiency Vitiligo, alopecia, keratoconjunctivitis |
|
IL-17F mutation |
AD |
Variable |
None |
None |
None |
|
IL-17RC mutation |
AR |
Variable |
None |
None |
None |
|
IL-17RA and ACT1 mutations |
AR |
Variable |
None |
Staphylococcal infections (dermatitis and blepharitis) |
None |
|
RORC mutation |
AR |
90–100% |
Disseminated mycobacterial infection |
None |
Legend: AD: autosomal dominant; APECED: autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy; AR: autosomal recessive; CARD9: caspase recruitment domain-containing protein 9; CMCC: Chronic mucocutaneous candidiasis; CMV: Cytomegalovirus; GOF: gain-of-function; HIES: Hyper-IgE syndrome; HPV: human papillomavirus; HSV: Herpes simplex virus; LOF: loss-of-function; PCP: Pneumocystis pneumonia; PGM3: Phosphoglucomutase 3; SCID: Severe combined immunodeficiency; STAT3: Signal transducer and activator factor of transcription-3; VZV: Varicella zoster virus.
PID |
Infections |
||||||
---|---|---|---|---|---|---|---|
Invasive Aspergillosis |
Invasive Candidiasis |
Dimorphic Fungi Infections |
Cryptococcosis |
Pneumocystis jirovecii Pneumonia |
Deep Dermatophytosis |
||
Phagocytic defects |
CGD |
High |
Occasionally |
- |
- |
- |
- |
LAD-1 |
Occasionally |
Occasionally |
- |
- |
- |
- |
|
Congenital neutropenia |
Occasionally |
Occasionally |
- |
- |
- |
- |
|
Cellular and combined deficiencies |
SCID, CIDs (e.g., AR-HIES, X-linked HIGM, IPEX) |
Occasionally |
Variable susceptibility (e.g., IPEX) |
Variable susceptibility to Histoplasmosis, mostly in AR-HIES (DOCK8 deficiency) and HIGM |
Variable, mostly in AR-HIES (DOCK8 deficiency) and HIGM |
High in patients with X-linked HIGM syndrome; variable in patients with SCID, AR-HIES, NEMO and MHC class II deficiency |
- |
Defective Th17 immunity |
AD-HIES (STAT3) |
High in patients with lung cavities |
Occasionally |
Histoplasmosis Coccidioidomycosis |
Occasionally |
- |
- |
STAT1 GOF mutation |
. |
- |
Coccidioidomycosis Histoplasmosis |
- |
- |
- |
|
CARD9 deficiency |
. |
Invasive CNS candidiasis |
- |
- |
- |
High |
Legend: AR: autosomal recessive; CARD9: caspase recruitment domain-containing protein 9; CGD: Chronic granulomatous disease CID: Combined immunodeficiency CNS: Central nervous system; HIES: Hyper-IgE syndrome HIGM: Hyper-IgM syndrome; IPEX: Immune dysregulation, polyendocrinopathy, and enteropathy, X linked; LAD: Leukocyte adhesion deficiencies; NEMO: Nuclear factor-kB essential modulator; SCID: Severe combined immunodeficiency; STAT1: Signal transducer and activator factor of transcription-1.
A better understanding of the cellular and molecular mechanisms critical for anti-fungal immunity can be helpful for the development of new drugs and preventive measures, including vaccines [35].