Clinical Manifestations of Human Exposure to Fungi

Clinical Manifestations of Human Exposure to Fungi: Comparison

Please note this is a comparison between Version 1 by Jose Laerte Boechat and Version 2 by Peter Tang.

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).

allergens
allergy
fungal diseases
fungi
hypha
immunodeficiency
spores

1. Introduction

Biological particles, along with inorganic gaseous and particulate pollutants, constitute an ever-present component of the atmosphere and surfaces. Among these bioparticles are fungal spores and hyphae ^[1][2][1,2] that colonize almost all terrestrial [3] and aquatic ecosystems ^[4][5][4,5], and even the inside and outside of the human body ^[6][7][8][6,7,8]. This diverse kingdom is composed of approximately 150,000 known species, and it is estimated that nearly a thousand times more species are yet to be described [9].

Fungal spores rarely exceed 20 µm in diameter, ranging from 3 to 8 µm [10]. Smaller fungal spores can travel greater distances than larger spores [11]. Due to their small size, most allergenic fungal spores can penetrate lower airways [12], acting as sub-pollen particles from rupturing pollen grains [13].

2. Allergic Fungal Diseases

Exposure to fungal particles (i.e., spores, hyphae, and metabolites) is associated with several allergic diseases, such as allergic bronchopulmonary aspergillosis (ABPA; estimated globally in approximately 4,800,000 adults), severe asthma with fungal sensitization (SAFS; some 6,000,000 persons), and allergic fungal rhinosinusitis (AFRS; approximately 12,000,000 individuals) [14]. Allergic fungal diseases can be divided into two groups. The first group includes allergic responses to aeroallergens (e.g., Alternaria spp. and Cladosporium spp.) that may present significant seasonal airborne concentrations inducing acute allergic exacerbations. The second group includes an allergic response to thermotolerant filamentous fungal genera (e.g., Aspergillus spp.) that not only act as aeroallergens but can also germinate in the airway, colonizing the lung and leading to a persistent allergenic stimulus that damages lung tissue [15]. Worldwide fungal allergy prevalence has been estimated to be between 3 and 10% [1], being higher for allergic sensitization when evaluated by skin prick tests in allergic (19–45%) and asthmatic patients (up to 50%) ^{[16][17][18][19]}[16,17,18,19]. Fungal spores play a significant role as aeroallergens in asthma development, exacerbation, and severity. About 120 individual fungal allergens from thirty-one mold genera have been identified (http://www.allergen.org/, accessed on 16 January 2023). Among the most well-known fungal sensitizing agents for asthmatic patients are Alternaria alternata, Aspergillus fumigatus, and Cladosporium herbarum [20]. The following sub-section provides further information concerning allergic fungal diseases, such as ABPA, SAFS, thunderstorm asthma (TA), AFRS, and occupational lung diseases (Table 1 and Table 2).

Table 1.

Overview of the most common allergic fungal diseases.

Disease	Etiological Agent	Risk Factors	Clinical Manifestations	Diagnosis	Treatment

125,133].

Table 4. Primary immunodeficiencies (PID) and invasive fungal disease ^[21][29].

Primary immunodeficiencies (PID) and invasive fungal disease [125,133].

PID		Infections
PID		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.

Table 2.

Overview of the most common occupational fungal diseases.

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

3. Association of Immunodeficiencies and Fungal Diseases

Invasive fungal infections are associated with high morbidity and mortality. These infections primarily occur in patients with secondary or acquired immunodeficiency (e.g., patients subjected to hematopoietic stem cell or solid organ transplantation, chemotherapy and immune-modulatory treatment for malignancies, hospitalization in an intensive care unit (ICU), or presenting AIDS or autoimmune disorders). More rarely, patients with primary immunodeficiency diseases (PIDs, also known as inborn errors of immunity), mainly seen in children and young adults, are genetically predisposed to recurrent, unusual, prolonged, and more severe invasive fungal infections ^{[21][22][23][24]}[125,126,127,128].

Candida spp., Aspergillus spp., Cryptococcus spp., and Pneumocystis spp. are responsible for more than 90% of reported deaths due to invasive fungal disease (IFD) ^[25][129]. These infections are often associated with iatrogenic immunosuppression ^[26][130].

Invasive candidiasis is a disease of critically ill hospitalized patients and originates from the patient´s flora following iatrogenic breaks of the skin or mucosal barrier. Using an intravenous catheter is the leading risk factor for candidaemia, the most common manifestation of invasive candidiasis ^[25][129].

Invasive pulmonary aspergillosis, secondary to inhalation of Aspergillus spores, is the main problem in immunocompromised hosts, accounting for >85% of invasive fungal diseases in humans. Risk factors for invasive aspergillosis include hematological malignancy, prolonged severe neutropenia, ICU patients (mainly chronic obstructive pulmonary disease and severe alcoholic liver disorders) and some forms of primary immunodeficiency ^[25][129].

Cryptococcosis is the most prevalent fatal fungal disease worldwide ^[27][131]. Cryptococcal meningitis is the most common manifestation, presenting as an opportunistic infection mainly in HIV-positive patients with low CD4 cell counts or iatrogenically immunosuppressed ones; immunocompetent patients are more likely to have the pulmonary disease ^[25][129].

In the pre-antiretroviral therapy era, Pneumocystis jirovecii pneumonia (PCP) was the most common opportunistic infection in HIV-positive patients. Nowadays, iatrogenically immunocompromised patients (malignancy, transplantation or rheumatological disease) are the leading risk group for PCP ^[25][129]. Usually, it is unclear if the disease results from recent reinfection or the reactivation of latent infection ^[28][132].

Primary immunodeficiency diseases include a diverse group of diseases caused by inherited expression defects in more than 485 genes, generally resulting in a reduced or absent function in one or more components of the immune system ^{[29][30][31][32]}[133,134,135,136]. The number of identified PIDs is increasing with the developments of genetic detection methods, such as next-generation sequencing. The 476 described PIDs are grouped according to the immune system malfunction component and commonly divided into disorders of adaptive immunity (e.g., T-cell immunodeficiency, B-cell immunodeficiency, combined immunodeficiencies and severe combined immunodeficiency), innate immunity (e.g., phagocyte defects and complement defects), and immune dysregulation (e.g., autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy, Chediak Higashi Syndrome) ^[30][33][34][134,137,138].

Severe combined immunodeficiency (SCID), some combined immunodeficiencies (CIDs) (e.g., autosomal recessive (AR) Hyperimmunoglobulin E syndrome (HIES), Nuclear factor-kB essential modulator (NEMO) deficiency) and PIDs with defective Th17 immunity (e.g., autosomal dominant (AD) HIES, Caspase recruitment domain-containing protein 9 (CARD9) deficiency and AR Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) are examples of inborn errors of immunity associated with chronic mucocutaneous candidiasis (CMCC) (Table 3) ^[21][29][125,133].

Table 3. Primary Immunodeficiencies (PID) associated with chronic mucocutaneous candidiasis ^[21][29].

Primary Immunodeficiencies (PID) associated with chronic mucocutaneous candidiasis [125,133].

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.

PIDs associated with increased susceptibility to invasive fungal disease can be classified as phagocytic defects (Chronic granulomatous disease (CGD), Leukocyte adhesion deficiencies (LAD) and congenital neutropenia), cellular and combined immunodeficiencies (e.g., SCID, CIDs) and PIDs with defective Th17 immunity (AD-HIES, CARD9 deficiency). CGD and HIES are PIDs most frequently associated with IFDs (Table 4) ^[21][29][

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].

4. Fungal Infections

The role of fungi as pathogens has been neglected since most are associated with opportunistic infections causing considerable morbidity and mortality. Recently, with the increase in the elderly population, improved treatments of immunosuppressed and transplanted patients, and premature neonates, the study of fungal diseases has gained special attention ^[36][140].

At the end of October 2022, the World Health Organization released its first Fungal Priority Pathogens List. In this List, fungal pathogens were divided into three categories: the critical priority group (Cryptococcus neoformans, Candida auris, A. fumigatus, and Candida albicans), the high priority group (Candida glabrata, Histoplasma spp., eumycetoma causative agents, Mucorales, Fusarium spp., Candida tropicalis, and Candida parapsilosis) and medium priority group (Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Candida krusei, Cryptococcus gattii, Talaromyces marneffei, P. jirovecii, and Paracoccidioides spp.). According to this document, all stakeholders (e.g., policymakers, public health professionals, medical mycologists, pharmaceutics, and diagnostics technicians) should concentrate efforts to improve the overall response to fungal pathogens through strengthening laboratory capacity and surveillance, increasing the investments in research, development, and innovation, and improving epidemiology ^[37][141].

Worldwide estimations have revealed that nearly one billion patients are affected by superficial mycoses, 135 million suffer from mucosal infections, and several million present severe invasive infections frequently associated with extremely high mortality rates ^[38][142]. Moreover, invasive fungal infections are increasing yearly since new and rare pathogens are emerging and causing new diseases, such as Kazachstania spp. (also known as Arxiozyma spp.) ^[39][143], Volvariella volvacea ^[40][144], and Rigidoporus cortisol ^[41][145], among many others. All fungi-related diseases are responsible for approximately 1.6 million deaths yearly ^[38][142]. Although some of the fungal infections overlap between categories, for simplification, they may be divided into three distinct groups according to the infected tissue. The first group includes diseases that affect the skin and/or the mucosal surfaces; the second group includes those that affect subcutaneous tissues and the underlying tissues and organs; finally, the third group includes invasive and disseminated diseases.