Table of Contents

Whole Allergen

m2 Cladosporium herbarum

m2 Cladosporium herbarum Scientific Information

Type:

Whole Allergen

Display Name:

Cladosporium herbarum

Route of Exposure:

Inhalation

Family:

Davidiellaceae

Species:

C. herbarum

Latin Name:

Cladosporium herbarum (obsolete name Hormodendrum)

Other Names:

Byssus herbarum, Dematium herbarum, Heterosporium epimyces

Summary

Cladosporium species are phylloplane fungi and common plant endophytes. The most common species of the genus Cladosporium include C. herbarum, C. sphaerospermum, C. cladosporioides, and C. elatum. Cladosporium spp. are frequent airborne molds, which can be isolated from almost every environment and geographic location. They are present both in indoor and outdoor environments, but predominantly in the latter. C. herbarum is one of the most studied fungal species in allergy research after Aspergillus fumigatus and Alternaria alternata. C. herbarum is one of the major causes of fungal allergy in humans leading to respiratory symptoms, such as allergic rhinitis (AR) and asthma in addition to hypersensitivity pneumonitis. Sensitization is believed to occur through inhalation of dried mycelia in house dust or inhalation of Cladosporium spores. Cla h 8, a mannitol dehydrogenase, is the major allergen identified in C. herbarum. Potential cross reactivity is reported within the Cladosporium genus and with other fungi, yeasts, and bacteria.

Allergen

Nature

Cladosporium is a heterogenous genus of hyphomycetes, consisting of more than 772 names (1). Cladosporium species are phylloplane fungi that grow on dead plant material and plant surfaces and common plant endophytes, which are pathogenic to humans and have saprobic nutrition (1, 2). C. herbarum is one of the most commonly studied fungal species in allergy research after Aspergillus fumigatus and Alternaria alternata. The spores of this mold are mostly found in outdoor air, but are also present indoors. (3). Of note, other species have been demonstrated to form the major part of Cladosporium genus burden on indoor surfaces (2).

The conidiophores of Cladosporium have significant features; typically, they are olive colored, almost erect, branched, and floccose. They produce numerous branched dry conidia with smooth to rough surfaces. A distinct darkened coronate hilum, or conidial scar characterized by a thick rim surrounding a central convex dome is present. (4, 5). They are 250 µm in length and 3-6 μm in width, with terminal and intercalary swellings (7-9 μm diameter) (5). Since the conidia are small and usually formed in branched chains, they are well adapted to be spread easily in large numbers over long distances via wind (6, 7). Hyphae are creeping, septate on the surface or in the substrate. Blastopores are 1-2 celled, sometimes 3 celled, with variable shape and size. (5).

Habitat

Cladosporium spp. are frequent airborne molds, which can be isolated from almost every environment and geographic location (4). They are found both in indoor and outdoor environments, with C. herbarum mainly found outdoors, and other species comprising most of the indoor Cladosporium communities (2). Unlike Penicillium chrysogenum and Aspergillus versicolor, which are predominant in the indoor environment following water damage, Cladosporium spp. thrive in ambient environmental conditions (2).

Additionally, Cladosporium spp. are commonly found to thrive on withering or fallen dead leaves. Generally, they are isolated from air, soil, food, paints, textiles, and several other substrates. (5, 6, 8). The optimal growth temperature of Cladosporium spp. is 25°C. Growth was not found for most species at 4 to 10°C and at 37°C. (5, 6) Spore release usually happens during wet as well as dry weather, particularly dependent on fluctuations in humidity. Their outdoor counts are higher during hot weather and storms (9).

Taxonomy

There are about 500 species in the genus Cladosporium. The species most commonly associated with disorders in humans are C. cladosporioides, C. oxysporum, C. sphaerospermum in addition to C. herbarum (4, 9).Below is the taxonomical hierarchy of Cladosporium herbarum (9).

*Taxonomic tree of Cladosporium herbarum* (9)**
Domain	Eukaryota
Kingdom	Fungi
Phylum	Ascomycota
Class	Dothideomycetes
Order	Capnodiales
Family	Davidiellaceae
Genus	Cladosporium
Species	C. herbarum

Tissue

Fungi of the genus Cladosporium secrete various secondary metabolites such as thermostable mycotoxins, which persist during the normal preparation of food (5).

Epidemiology

Worldwide distribution

The prevalence of IgE reactivity to C. herbarum differs according to climate and the study population. In general population, including atopic subjects, the rate of sensitization to C. herbarum is around 8%, while asthmatic patients show higher figures, around 20% (10). In a European multicenter study with 877 subjects with nasal and/or bronchial symptoms of suspected allergy, 3–20% of all allergic patients were sensitized to C. herbarum in skin prick tests (SPT) (3, 11).

C. herbarum sensitization was found to be 5.8% among 1132 asthmatic patients across the globe in a multicenter cross-sectional epidemiological survey. Its distribution varied from 10.3% (n=39, Portland, United States), 9.9% (n=264, Northern Europe), 6.8% (n=205, United Kingdom and Ireland), 4.5% (n=335, Australia or New Zealand), 4.3% (n=139, Central Europe) to 0.7% (n=150, Southern Europe). (12). Another study found 2.7% (n= 175) prevalence of sensitization based on SPT to C. herbarum among 6376 Finnish patients referred for a suspicion of allergy (13). In Israel, 14% of 42 mold-allergic patients had positive SPT responses to C. herbarum (14).

C. herbarum sensitization is frequently found in China. In the Guangdong province, C. herbarum sensitization was present in 47.4% (771/1625) of patients with AR and in 3.6% (16/450) of children with asthma in Hainan province (15).

Pediatric issues

Childhood asthma is frequently associated with allergic sensitization to fungal spores. Daily fluctuations in ambient mold spores have been found to be directly associated with childhood asthma attacks leading to emergency visits for medical treatment. (16). A study in Kansas, United States found a correlation between childhood AR symptoms and indoor concentrations of Cladosporium spp., Epicoccum spp., yeasts and Aureobasidium spp. (17).

Risk factors

Both AR and asthma may be associated with exposure to fungal contamination in homes. A quantitative meta-analysis of 33 epidemiologic studies showed an increase of 30% to 80% in adverse respiratory health outcomes among building occupants because of dampness and mold exposure (18). Studies from California and Pennsylvania reported that asthma symptoms are increased on days when spore counts are high (19). However, health effects of C. herbarum cannot be directly inferred from exposure data, and some studies have even found a statistically protective effect against asthma in European general population (20).

Genetic susceptibility was suggested by the reported association of hypersensitivity pneumonitis to C. herbarum and the human leukocyte antigen (HLA) DRB1*13 allele (21).

Environmental Characteristics

Worldwide distribution

C. herbarum is cosmopolitan, with a slight increase in prevalence with increasing latitude (22). Similar to Alternaria and Aspergillus, Cladosporium spp. are abundant in tropical climate (such as Malaysia, Puerto Rico, and Singapore), temperate climate (Midwestern United States), and in arid or semi-arid climate (Finland; Kuwait; and Tucson, Arizona). In tropical and other hot, humid regions, spore counts typically exceed pollen counts by 100-fold (17). It is also widely distributed in China (15). In a multicentric European cohort of general population, the burden of C. herbarum in indoor dust was significantly higher in homes with pets such as dogs and cats (22). A study conducted in Riyadh (Saudi Arabia) identified the geographical distribution of Cladosporium spp. in forty sites located in north-east, north-west, south-east, south-west and middle of Riyadh. Cladosporium spp. was isolated from 12.4% of a total of 870 fungal colonies (1).

Route of Exposure

Main

Inhalation of fungal spores can induce respiratory allergic symptoms (5) and hypersensitivity pneumonitis, the latter occurring after domestic as well as occupational exposure (21, 23).

Clinical Relevance

Allergic rhinitis

Cladosporium spp. is one of the most common fungi responsible for causing AR in humans.(17). In a study in Finland, 27.5% of 40 (n= 11) patients showing positive SPT to C. herbarum exhibited AR (13).

Asthma

Prolonged exposure to elevated spore concentrations may elicit asthma and exacerbations of asthma. Cladosporium is a well-known trigger of asthmatic attack. Concentrations of 3000 Cladosporium spores per cubic meter of air are generally taken as the threshold concentrations for clinical significance (24). A cross-sectional study of 1,132 adults with asthma found that sensitization to C. herbarum increased considerably with asthma severity, with odds ratio (OR) of 1.21 [Confidence Interval (CI) 0.62 to 2.36] for moderate asthma to 3.20 (CI 1.72 to 5.94) for severe asthma (p<0.001). C. herbarum is found as a significant risk factor for severe asthma in several European countries (UK, Republic of Ireland, Northern, Central, and Southern Europe) and also in Australia, New Zealand, and USA (12). Tariq et al. (1996) addressed fungal sensitization in an Isle of Wight birth cohort of 981 children (4-year-old) at risk for atopic disease. Of these, 2.9% reacted to C. herbarum. In their study, C. herbarum together with A. alternata were found to be the third most common cause of sensitization after house dust mite (25). Mari et al. (2003) tested 4,962 patients having respiratory symptoms. The overall incidence of C. herbarum sensitization was 13% out of 621 fungi sensitized individuals, but within the group of monosensitized mold-allergic patients (n=482), sensitization to C. herbarum was only about 0.8% (26, 27). In a Finish study with allergic patients, out of 40 patients showing positive SPT for C. herbarum, 44% developed asthma (13).

Atopic Dermatitis

In a study involving 6,376 allergic patients in Finland, AD was present in 23 of 40 (58%) patients with positive SPT for C. herbarum (13).

Other diseases

A case of allergic broncho-pulmonary cladosporiosis was reported in a 6-year-old child. The child had febrile episodes of cough, wheezing, dyspnea, and green-brown sputum production. SPT reactions and specific IgE tests were positive to C. herbarum (28). Hypersensitivity pneumonitis cases associated with Cladosporium spp have been reported worldwide, following exposure at home, at work, and even in the car (21, 23, 29).

Prevention and Therapy

Prevention strategies

Avoidance

High humidity usually stimulates fungal growth. Thus, the growth of Cladosporium spp. could be reduced by keeping the indoor home environments (flats, apartment, or basements) dry. Also, a good ventilation system in the bathrooms and proper air circulation in the rooms is highly recommended. Further, susceptible individuals should avoid working at the allotment or gardens. Usually, the best time for walking during clear weathers is morning as the fungal spores in the air are least. Moreover, fungi presence test should be done on a regular basis in the living areas (5).

Molecular Aspects

Allergenic molecules

To date, 60 antigens from C. herbarum are identified, of which 36 react with IgE antibodies from patients' sera (3, 9, 30). However, only 8 allergenic molecules have been characterized and published officially by World Health Organization/International Union of Immunological Studies (WHO/IUIS) Allergen Nomenclature Sub-Committee for C. herbarum (31, 32). The table below provides detailed information on each of the allergenic protein identified by WHO/IUIS as of 25^th January 2021:

Allergens	Molecular Weight (kDa)	Biochemical name	Allergenicity
Cla h 2	23		Previously known as Ag-54. Positive immunoblot recognition by 43% of 62 C. herbarum sensitized patients (31, 32).
Cla h 5	11	Acid ribosomal protein P2	Previously known as Cla h 4. Positive immunoblot recognition by 22% of 62 C. herbarum sensitized patients (31, 32).
Cla h 6	46	Enolase	Minor allergen (31). Positive immunoblot recognition by 20% of 62 C. herbarum sensitized patients (31, 32).
Cla h 7	22	YCP4 protein (flavodoxin)	Previously known as Cla h 5. Positive immunoblot recognition by 22% of 62 C. herbarum sensitized patients (31).
Cla h 8	28	Mannitol dehydrogenase	Major allergen (33) The prevalence of IgE reactivity was found to be 57% in 21 C. herbarum allergic patients (33).
Cla h 9	45	Vacuolar serine protease	Minor allergen (34). Positive immunoblot recognition by 6% of 62 C. herbarum sensitized patients (31, 32). IgE reactivity prevalence of 15.5% in 110 C. herbarum allergic sera (34).
Cla h 10	53	Aldehyde dehydrogenase	Previously known as Cla h 3 (32). Considered as important allergen (31). Positive immunoblot recognition by 36% of 62 C. herbarum sensitized patients (31, 32).
Cla h 12	11	Acid ribosomal protein P1	Not available

kDa: kilodaltons, IgE: Immunoglobulin E

Cross-reactivity

There is extensive cross-reactivity among fungal genera. The dehydrogenase Cla h 8 is considered as a major allergen of C. herbarum with possible cross-reactivity to other dehydrogenase allergens, including Alternaria spp. and Aspergillus spp. Allergenic cross-reactivity among Cladosporium species C. cladosporioides, C herbarum, and C. sphaerospermum is reported (9, 35).

Cross-reactivity is seen between Alternaria and Cladosporium as a result of homologous allergens e.g., aldehyde dehydrogenase (Alt a 10 and Cla h 3/Cla h 10), acidic ribosomal protein P2 (Alt a 6 and Cla h 4/Cla h 5), Saccharomyces cerevisiae protein (YCP4) (Alt a 7 and Cla h 5/Cla h 7), and enolase (Alt a 11 and Cla h 6) (31).

Saccharomyces cerevisiae (baker's yeast) enolase exhibits high cross-reactivity to other fungal enolases, including C. herbarum (36). Extensive cross-reactivity is reported between the enolases of C. herbarum, A. alternata, S. cerevisiae, Candida albicans, and A. fumigatus (37).

Hev b 9, an enolase present in natural rubber latex, is cross-reactive with enolases from C. herbarum. (38).

A 45 kDa protein isolated from Fusarium solani shows cross-reactivity with, C. herbarum and A. alternata. (39).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Christian Fischer

Last reviewed: February 2021

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