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 |
---|
PID |
Infections |
||||||
---|---|---|---|---|---|---|---|
Invasive Aspergillosis |
Invasive Candidiasis |
Dimorphic Fungi Infections |
Cryptococcosis |
Pneumocystis jirovecii Pneumonia |
Deep Dermatophytosis |
||
Allergic Bronchopulmonary Aspergillosis |
A. fumigatus A. terreus A. niger A. flavus |
Asthma (2.5% asthmatic patients) Cystic fibrosis (1–15% of CF patients) |
|||||
Phagocytic defects |
CGD | 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 | |||||||
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 |
High |
Occasionally |
- |
- |
- |
A. fumigatus | |||||||
- | |||||||
Cladosporium | |||||||
spp. | |||||||
LAD-1 | |||||||
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 |
||||||||||
Mushroom worker’s lung |
P. chrysogenum C. herbarum A. alternata C. albicans Trichophyton spp. |
A. bisporus Rarely any underlying disease |
|||||||||||||
DOCK8 deficiency (AR-HIES) |
H. tessellatus L. edodes | 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 |
P. ostreatus Similar to severe asthma |
AR Partial or absent treatment response: consider biologicals (omalizumab, mepolizumab, benralizumab) and antifungal drugs (itraconazol) |
||||||||||
Exposure in spawning sheds |
53–64% |
Histoplasmosis Cryptococcosis PCP |
Staphylococcal infections, HSV, VZV, HPV, molluscum contagiosum virus |
Occasionally |
Occasionally |
- Eczema, food allergy and asthma, malignancies (lymphoma) |
- |
- |
- |
Thunderstorm asthma |
Alternaria spp. Cladosporium spp. Diatrypaceae D. exitialis P. nigran Sporobolomyces spp. |
Sensitization and exposure to aeroallergens (mainly pollen grains and fungal spores) Gender Ethnicity |
|||
Suberosis |
|||||||||||||||
PGM3 deficiency (AR-HIES) |
P. glabrum |
||||||||||||||
Congenital neutropenia |
AR C. sitophila |
Occasionally Asthma Allergic rhinitis Age |
The same as asthma |
Handling of damp cork |
Variable The same as asthma |
The same as asthma |
|||||||||
Variable |
Occasionally | HSV, CMV |
Eczema, asthma, neurologic impairment, leukocytoclastic vasculitis |
- |
- |
- |
- |
Allergic fungal rhinosinusitis |
|||||||
Maple bark stripper’s lung | |||||||||||||||
Defective Th17 immunity |
A. fumigatus A. flavus B. spicifera C. lunata A. alternata Other dematiaceous fungi |
||||||||||||||
Cellular and combined deficiencies |
C. corticale | Atopy |
STAT3 LOF mutation (AD-HIES) |
SCID, CIDs (e.g., AR-HIES, X-linked HIGM, IPEX) Stripping bark from logs |
AD |
Occasionally Nasal obstruction Loss of smell Nasal discharge Nasal crust Pressure sensation over the face sinus |
80% Double vision or visual loss (rare) Facial asymmetry and proptosis Sino–bronchial allergic mycosis syndrome |
SPT or elevated fungal-specific IgE |
Variable susceptibility (e.g., IPEX) 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 |
Aspergillosis Cryptococcosis Fungal hyphae in the mucus |
Histoplasmosis |
Variable susceptibility to Histoplasmosis, mostly in AR-HIES (DOCK8 deficiency) and HIGM Topical and oral corticosteroids Saline douching Sinus surgery Biologicals (dupilumab, omalizumab, mepolizumab) Allergen immunotherapy (?) |
|||
S. aureus | Variable, mostly in AR-HIES (DOCK8 deficiency) and HIGM |
Eczema, pneumatoceles, coronary aneurisms, hyperextensible joints |
High in patients with X-linked HIGM syndrome; variable in patients with SCID, AR-HIES, NEMO and MHC class II deficiency |
- |
Sequoiosis |
Graphium spp. Pullularia spp. A. pullulans |
Breathing damp sawmill dust |
||||||||
STAT1 GOF mutation |
AD |
||||||||||||||
Defective Th17 immunity |
AD-HIES (STAT3) |
100% |
High in patients with lung cavities Histoplasmosis Coccidioidomycosis |
Occasionally HSV |
Histoplasmosis Coccidioidomycosis Autoimmunity Cerebral and aortic aneurisms |
Occasionally |
Wood pulp worker’s lung |
Alternaria | |||||||
- | - |
CARD9 deficiency spp. |
|||||||||||||
STAT1 GOF mutation | Pulping contaminated wood |
||||||||||||||
AR |
. Variable |
Candida meningoencephalitis |
- Deep dermatophytosis |
Coccidioidomycosis Histoplasmosis None |
- None |
- |
- |
Malt worker’s lung |
|||||||
APECED A. clavatus | |||||||||||||||
CARD9 deficiency |
P. granulatum |
AD or AR P. citrinum R. stolonifer |
Handling moldy grain |
||||||||||||
. |
90–100% |
None |
Invasive CNS candidiasis None |
- |
-Hypoparathyroidism Adrenal insufficiency Vitiligo, alopecia, keratoconjunctivitis |
- |
High |
Wine grower’s lung |
B. cinerea |
||||||
IL-17F mutation |
AD |
Mold contamination |
|||||||||||||
Variable |
None |
None |
None |
Baker’s lung disease |
A. fumigatus |
||||||||||
IL-17RC mutation |
AR |
Handling contaminated flour |
|||||||||||||
Variable |
None |
None |
None |
Cheese worker’s lung |
P. roqueforti P. casei P. notatum P. viridicutum A. fumigatus A. niger A. pullulans |
Cleaning mold off cheese |
|||||||||
IL-17RA and ACT1 mutations |
AR |
Variable |
None |
Staphylococcal infections (dermatitis and blepharitis) |
None |
Salami Brusher’s disease |
|||||||||
RORC mutation | P. glabrum |
AR P. camemberti P. nalgiovense A. fumigatus |
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.
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][139].