Type:
Whole Allergen
Whole Allergen
Whole Allergen
Penicillium chrysogenum
Inhalation
Trichocomaceae
Penicillium chrysogenum
Penicillium chrysogenum
Penicillium notatum
Penicillium species are outdoor and indoor environmental fungi. P. chrysogenum is one of the most important and well-known Penicillium species due to its use for the production of penicillin. Species belonging to Penicillium genus are ubiquitous soil and airborne fungi; however, the abundance of fungal spores fluctuates depending on rainfall and location. They thrive near organic material or damp building environment but can survive with very little water. P. chrysogenum spores are smooth and spheroidal. Prevalence of IgE sensitization to Penicillium spp. was found to be 1.5% and 7.3-22% in general population and atopic individuals, respectively. The primary route of exposure to allergens of P. chrysogenum is inhalation, while exposure may occur rarely through ingestion and skin contact. P. chrysogenum can induce respiratory allergic symptoms, such as allergic rhinitis, asthma, and allergic broncho-pulmonary mycosis in sensitized individuals. Penicillium sensitization in children is less frequent than in adults, usually below 10% among asthmatic or atopic subjects. Pen ch 13 and Pen ch 18 (serine and/or vacuolar proteases) are major allergens of P. chrysogenum, but they are not species-specific due to their cross-reactivity with other molds. Of note, there is no cross-reactivity between Penicillium sensitization and drug allergic reactions to β-lactam penicillin, which is a fungal secondary metabolite, synthesized only under specific circumstances.
The genus Penicillium consists of more than 250 ubiquitous filamentous fungi. Some of them are causal agents for allergies and opportunistic infections (1). They are easily recognizable as blue-green molds (2). Penicillium species are both outdoor and indoor environmental fungi; however, they are more predominantly indoor fungi (2, 3). They are employed in the food industry to produce blue mold cheese (2), commercially as enzymes and in the drug industry for the production of compounds against bacteria, fungi or viruses as well as anti-cancer compounds (1). Penicillium chrysogenum (P. chrysogenum) is the most important and well-known species (spp.) due to its use in the production of penicillin (4). Its name reminds of the yellow pigment chrysogine produced during prolonged growth (from chrysos, the Greek word for gold) (5).
Airborne Penicillium spores comprise asexually produced conidia, a major allergenic component of the airborne fungal burden, and ascospores, resulting from sexual reproduction (1, 3).
Penicillium genus spp. are soil and airborne fungi, which prefer moderate to cool climate; however, the abundance of fungal spores fluctuates depending on rainfall and location (4, 6, 7). The fungal spore count of airborne Penicillium spp. is usually found to increase with higher temperature and humidity (6, 7). Indoor factors associated with an increase in airborne Penicillium are poor ventilation, higher temperatures, less sunlight, water seepage, and presence of pets (2). The seasonal variability of indoor Penicillium spp. levels is less marked than for other genera because house dust and indoor mold act as reservoirs of spores and allergenic materials (7, 8).
Sources of Penicillium are rotting vegetables and foods, dead plants, and moldy wood (1, 9). Penicillium spp. are usually found near organic material or in humid environments, but some of them can survive with scarce water too (9). Penicillium spp. is a component of human microbiota, and its relative enrichment among fungal communities was reported in bronchial samples from asthmatic patients compared to healthy controls (10). Penicillium spp. has also been detected in healthy human gut, coming from diet or environment as they are unable to grow at 37°C and colonize the gut (11).
The Penicillium genus belongs to the Ascomycota phylum of fungi, which is characterized by meiotic ascospores and mostly airborne conidia. Penicillium conidiophores appear like a paintbrush, hence the name Penicillium was derived from the Latin for paintbrush, “penicillus”, that also gave the name “pencil”. Penicillium spp. are among the most common airborne fungi causing allergy (9). The genus Penicillium comprises of a large variety of species, with 354 accepted as of 2014 (12). P. chrysogenum is closely related to P. rubens, and both were earlier known collectively as P. notatum (9).
Taxonomic tree of Penicillium chrysogenum (9) | |
---|---|
Domain | Eukaryota |
Kingdom | Fungi |
Phylum | Ascomycota |
Class | Eurotiomycetes |
Order | Eurotiales |
Family | Trichocomaceae |
Genus | Penicillium |
Species | P. chrysogenum |
P. chrysogenum spores are smooth and spheroidal in shape with a size of 3 μm and cylindrical projections (phialides) of 7 μm diameter. Conidiophore branching pattern is bi, ter, and quarterverticillate, with a cylindrical outermost branch (metulae) of 10 μm size (1).
Like other airborne molds, Penicillium spp. induce IgG and IgE production in humans (13). Serum specific IgE and SPT can be used to demonstrate Penicillium sensitization, but the agreement between the two methods is low, varying from 29% to 44% as a function of the fungal extract and the study population (14, 15). In mold-sensitized subjects, sensitization to Penicillium spp. is associated with sensitization to other molds, mainly Alternaria spp. and Aspergillus spp. (16, 17).
A review of data from 1980-2000 reported that the prevalence of IgE sensitization to Penicillium spp. in general population was 1.5%, and 7.3% to 22% in atopic individuals (18). Current sensitization rates to Penicillium range from 5 to 8% in general population and atopic patients (19) and are much higher, usually up to 29%, in asthmatic patients (14, 19). Accordingly, a 2016 study on 160 Japanese asthmatic adults found a 21.9% (35/160) prevalence of P. chrysogenum sensitization (20), while 27% (7/26) of Canadian adult patients with allergic rhinitis (AR) or asthma had positive SPT to at least one species of Penicillium, mainly P. chrysogenum (21). A higher prevalence was recently reported in a Chinese study of asthmatic patients sensitized to Aspergillus fumigatus (A. fumigatus), 80% of whom exhibited P. chrysogenum co-sensitization (22). The prevalence of P. chrysogenum sensitization was also higher in a targeted population of patients with suspected mold allergy: 41% in asthmatic patients, and 23% in non-asthmatic ones (14, 19).
A gender bias has been reported in some studies, with fungus, including P. chrysogenum, sensitization apparently more prevalent in male than in female subjects (20, 23). This difference was related to asthma severity, which might be a confounding factor. Conversely, other studies did not find gender-related differences in fungal sensitization (24).
Studies addressing age-related variations of P. chrysogenum sensitization showed that a maximum was reached at 6-8 years, followed by a decrease during adulthood and a subsequent increase in elderly (23-25).
The use of molecular allergens instead of crude extracts for serum specific IgE testing is increasing (19). IgE immunoblot reactivity to Pen ch 13, a major allergen from P. chrysogenum, was found in 17% (35/212) of asthmatic patients (age 3 to 94 years) from Taipei (Taiwan). The prevalence of IgE reactivity to Pen ch 13 increased with age, from 7% in patients ≤10 years to 42% in >70 years, confirming sensitization to airborne Penicillium species is a common finding in older asthmatic patients (25).
Penicillium sensitization is associated with increased prevalence of upper and lower respiratory symptoms including poorer asthma control, and with severe asthma with fungal sensitization (SAFS) (1, 19, 20) .
Penicillium spp. is considered a causative agent of asthma and AR in children according to the American Institute of Medicine (26).
A cross-sectional study by Nolles et al. (2001) addressing sensitization to fungi among 137 atopic (asthma, AR, or eczema) children from the Netherlands, aged 5 months to 14 years, found a 7.3% prevalence for specific IgE to Penicillium (24). A similar figure of 12.8% was obtained with SPT with P. notatum among 7565 mold-sensitized Mexican children aged 2-18, addressed for asthma, AR, or atopic dermatitis (AD) (27). Other pediatric studies reported higher figures for the prevalence of sensitization to P. chrysogenum, e.g. 7% among 100 Brazilian asthmatic children aged 4 to 14 years assessed with serum specific IgE in 2007 (28).
In allergology, Aspergillus spp. and Penicillium spp. are the main indoor allergenic fungi (2, 17). Penicillium spp. are more frequent in indoors as compared to outdoor air, although they are found in large number in the soil (2, 3, 7). The prevalence of detectable airborne Penicillium spp. in homes is found to be at least 1 colony forming unit (CFU)/m3 , which is up to 41% (8).
Penicillium species shows geographical variation. P. citrinum was the most common Penicillium species found in Taipei (Taiwan), while five other species P. chrysogenum, P. spinulosum, P. oxalicum, and P. brevicompactum were commonly found in Topeka, Kansas (USA) (29).
A Nigerian study detected Penicillium and Aspergillus to be the most frequently occurring airborne fungal species in five different locations in Lagos State, Nigeria. They were found to be most abundant during the wet season in all locations (6). Another study in urban, suburban and forest areas of Nanchang, China reported a relatively higher abundance of allergenic fungal communities of Penicillium along with Alternaria, and showed the effect of air quality of the three areas (30).
The amount of airborne Penicillium spp. is subjected to variations resulting from global climate changes and new domestic environmental practices. Flooding causes damp indoor spaces, leading to increased levels of airborne Penicillium, even after apparent damage remediation (31). Similarly, a study conducted in Colorado, United States (US), showed that Penicillium was among the most abundant fungi in flooded homes (32). On the contrary, airborne dust in Kuwait conveyed minimal, stable levels of Penicillium (1.15%) (33). The possible effect of green walls and roofs has been reported as beneficial for both outdoor and indoor airborne fungal communities (31, 34).
The primary route of exposure to P. chrysogenum allergens is inhalation (35).
P. chrysogenum can induce allergic reaction through ingestion (35) or direct contact (cheilitis) (36).
Penicillium genus is one of the most important fungal allergenic sources, associated mainly with upper and lower respiratory allergy including asthma, AR, allergic fungal sinusitis, and allergic broncho-pulmonary mycosis. It is also responsible for opportunistic infections, onychomycosis, keratomycosis, and non-allergic, non-invasive, fungal sinusitis (1, 33). Beside sensitization, allergy and opportunistic infections, Penicillium spp. release volatile organic compounds (VOCs) and mycotoxins, which can pose health threats through inhalation or ingestion, e.g., ingested mycotoxins from fermented cheese (37). VOCs are responsible of the moldy odor, which can be perceived in presence of growing Penicillium (38). Data on exposure to Penicillium spp., especially in indoor environments, are best interpreted in the context of multiple microbial communities. Indeed, fungal and microbial load and diversity may mitigate immune responses, especially during early life (39).
Penicillium spp. are reported to induce AR (18).
A study by Kołodziejczyk et al. (2016) addressed the clinical presentation and natural course of AR in outpatients from Poland. Patients (n= 229) sensitized only to molds were compared to patient’s mono- or polysensitized to other airborne allergens. Among the 239 mold-allergic patients, only 14 (5.9%) were sensitized (SPT or specific IgE) to P. chrysogenum, a far lower prevalence than A. fumigatus or Cladosporium herbarum. The study concluded that in mold allergic patients AR is milder, but with significant predisposition for bronchial asthma (40).
Exposure to Penicillium spp. is a risk factor for asthma at all stages of its natural history inluding development, persistence, and severity, both in adults and in children (3, 41)
A prospective birth cohort study was conducted with 880 infants at high risk for developing asthma (defined as at least one older sibling with physician-diagnosed asthma) from Connecticut and western Massachusetts, USA. In this study, higher indoor concentrations of Penicillium spp. were linked with an increased rate of wheeze [RR =2.46; 95% Confidence Interval (CI) 1.63-3.70] and persistent cough (RR= 1.84; 95% CI 1.22-2.80) during the first year of life, after adjustment for potential confounding factors such as seasonal and housing characteristics, maternal asthma, and socio-economic status (2, 8). The same research group confirmed these findings in a cohort of 1233 asthmatic children (age 5-10 years): exposure and sensitization to any indoor airborne Penicillium species conveyed a higher risk of wheeze [Odds ratio (OR) 2.12, 95% CI 1.12-4.04], persistent cough (OR 2.01, 96% CI 1.05-3.85), and elevated asthma severity score (OR 1.99, 95% CI 1.06-3.72) in comparison to those who were not sensitized or exposed to Penicillium species (42).
The association between indoor mold growth and wheezing episodes in children was also found in a Finnish pediatric cohort study (3). In adult asthmatic patients, multiple reports found that Penicillium sensitization was associated with poor asthma control or higher severity score for asthma (20, 43). According to a cross sectional study by Woolnough et al. (2017) a significant correlation was observed between IgE sensitization to filamentous fungi and lung damage in asthma patients (44).
Similarly, a meta-analysis of 33 epidemiologic studies observed that adverse respiratory outcomes were increased by 30-50% in houses with damp indoor environment and mold growth (45). Current researches from the US, Europe, and World Health Organization (WHO) indicated damp indoor environment to be an important factor in inducing asthma (3).
At the pathophysiological level, Penicillium allergens exert both IgE-dependent and IgE-independent actions with synergistic effects. The alkaline serine proteases of Penicillium group 13 allergens (e.g., Pen ch 13) disrupt interepithelial tight junctions through direct action on occludin and induce bronchial epithelial cells to release proinflammatory cytokines (46, 47). IgE-mediated effects include histamine degranulation, which can be demonstrated in vitro through basophil activation triggered by Pen ch 13 (47).
P. chrysogenum was commonly found in homes from Canada, which may be responsible for upper or lower respiratory tract infection and also skin reactions in allergic individuals (21). Among patients from Taiwan (n= 133, 1-67 years) with fungal sensitization, Penicillium sensitization was found in 74.6 % (44/59) patients with isolated AD and in 71% (22/31) of those diagnosed with both AD and respiratory disease (asthma or AR), at higher levels than in patients with isolated asthma or AR (41%, 18/43) (48).
A study evaluating fungi in sick building syndrome among 48 schools in the US found Penicillium spp. in 5.2% of samples, with P. chrysogenum as the predominant species (49).
Penicillium spp. has been linked to the development of hypersensitivity pneumonitis, often in the context of occupational allergies in highly diverse fields: wind instrument players, food industry workers, foresters, mushroom producers (50, 51).
Penicillium spp. are also reported to produce several mycotoxins such as ochratoxin, citrinin, cyclopiazonic acid, mycophenolic acid, rubratoxin B, and patulin. These mycotoxins, especially ochratoxin and citrinin, can cause acute lesions and further can develop into cancer (52). P. chrysogenum is reported to cause black esophagus, endophthalmitis, and keratitis (35).
Fungi contain numerous and varied antigens (3). As of 25th January, 2021, six allergenic molecules have been identified, characterized and published officially by World Health Organization/International Union of Immunological Studies (WHO/IUIS) Allergen Nomenclature Sub-Committee for P. chrysogenum. The table below provides detailed information on each of the allergenic protein (2, 4, 53):
Allergens | Molecular Weight (kDa) | Biochemical name | Allergenicity |
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Pen ch 13 | 34 | Alkaline serine protease |
|
Pen ch 18 | 32 | Vacuolar serine protease |
|
Pen ch 20 | 68 | N-acetylglucosaminidase |
|
Pen ch 31 | Calreticulin |
|
|
Pen ch 33 | 16 |
|
|
Pen ch 35 | 36.5 | Transaldolase |
|
P. chrysogenum protein (33 kDa) was found to be cross reactive with P. brevicompactum’s 33 kDa protein (47). Serine proteases are thought to be the major pan-fungal allergen group found in most of the airborne fungal species (41, 47). Cross reactivity among serine protease allergens from the species such as P. oxalicum, P. chrysogenum, P. citrinum, P. brevicompactum, A. fumigatus, A. flavus, A. oryzae, R. mucilaginosa, and C. cladosporioides is reported. Serine protease Pen ch 13 and Pen ch 18 identified in P. chrysogenum are reported to be the most cross-reactive proteins (47).
Further, studies have demonstrated cross-reactivity between Pen ch 13 (P. chrysogenum) and Pen c 13 (a major allergen of P. citrinum) with Asp f 13 (A. fumigatus) and Asp fl 13 (A. flavus) in a dose-related manner (46, 47). This IgE cross reactivity among the serine proteases of different fungal species indicated that atopic patients primarily sensitized by either of these prevalent fungal species may develop allergic symptoms by exposure to other environmental fungi (47). Pen ch 13 and Pen ch 18 are homologous to Asp f 13 and Asp f 18 with considerable sequence similarity (2). Pen ch 18 has shown about 63-83% homology with other allergens of the same class (vacuolar serine protease) of A. fumigatus, Saccharomyces cerevisiae, and P. oxalicum (41).
Author: Turacoz Healthcare Solutions
Reviewer: Dr. Christian Fischer
Last reviewed: February 2021