Latin name: Penicillium chrysogenum/P.notatum
Source material: Spores and mycelium
A mold, which may result in allergy symptoms in sensitised individuals.
Penicillium is the blue-green mold found on stale bread, fruits and nuts, and used for production of green and blue mold cheese.
Members of the genus Penicillium are almost all filamentous fungi. There are over 200 species, widely distributed in all environments. The most common species include Penicillium chrysogenum (also known as P. notatum), Penicillium frequentans, Penicillium citrinum, Penicillium janthinellum, Penicillium marneffei, and Penicillium purpurogenum. Penicillium molds prefer damp and dark places, but can occur elsewhere. Penicillium dominates in the soils of temperate climates, from which spores are easily released into the atmosphere. The molds are widespread in soil, decaying vegetation and compost, particularly in temperate-zone forests, grasslands and cultivated land.
The species vary from one geographic location to another. For example, P. citrinum is the most prevalent species in the Taipei area, whereas this and P. spinulosum, P. brevicompactum, P. oxalicum and P. notatum were the most frequently recovered species in Topeka, Kansas (1). Species belonging to this genus are prevalent indoor fungi as well (2). Penicillium contrasts with most other molds in that it has no big seasonal variations but reaches peak concentration in the winter and spring. It is a major cause of indoor mold allergy.
Colonies of Penicillium, with some exceptions, are rapidly growing, flat, and filamentous, and velvety, woolly, or cottony in texture. The colonies are initially white and become blue-green, gray-green, olive-gray, yellow or pinkish with time. The colour of the stains is not an accurate guide to the specific molds which have caused them.
The contamination of a bacterial culture by a stray asexual spore of P. notatum led to the discovery by Alexander Fleming that a substance was being produced which lysed the nearest organisms, and this led to the development of the Penicillin antibiotic (3). Secondary metabolites from members of the Penicillium genus have been revolutionary in combatting infectious diseases such as pneumonia and gonnorhoea.
Penicillium may be found in vineyards and wine cellars, in the soil of citrus plantations, among all types of stored seeds, and in barns, damp hay, dried fruit and fruit juice. Indoors it is the familiar blue-green mold found on stale bread, citrus fruits, and Apples. It is a contaminant in Rye flour in industrial bakeries. The Penicillium species may also be found in foam rubber mattresses, house dust, stuffed furniture, wallpaper, books, refrigerator doors and rubber tubing. Penicillium may cause the black spots on window sills. Two Penicillium strains are used in making blue and green mold cheese: P. camenbertii and P. roquefortii.
In an evaluation of 110 sites from 5 zoological institutions examined to determine whether fungi were associated with sick building syndrome, high levels of airborne P. notatum were found in 16 sites. Stachybotrys chartarum was recovered from surfaces at 2 institutions, and a wide range of other fungal species was recovered in low numbers from all institutions. The study concluded that poor indoor air quality in zoological institutions could affect animal and human health (4).
Studies examining the influence of mold on building-related symptoms in individuals working in damp and moldy buildings have found a number of molds to be present in such an environment. In one study, sensitisation to a number of molds was found in 37% of the individuals tested. The highest frequency of sensitisation was found to P. notatum, followed by Aspergillus species, Cladosporium sphaerospermum and Stachybotrys chartarum. The study concluded that the presence in serum of IgE specific to these fungi correlated with symptoms in individuals working in damp and moldy buildings, but whether the association was of a causal character required further investigation (5).
The first studies of the allergens in P. notatum identified allergenic proteins of 94 kDa, 43 kDa and 25 kDa (6). Subsequent studies identified, using sera from 19 allergic patients and 20 blood donors, a total of 11 allergenic components ranging in molecular size from 94 kDa to 20 kDa. The major allergen appeared to be an approximately 68 kDa protein that was recognised by IgE antibodies in 56% of the 39 sera analysed. This was probably the allergen now known as Pen ch 20. A 64 kDa component was recognised by IgE antibodies in 46% of the sera analysed (7) . In adults with perennial rhinitis and asthma and positive skin-specific IgE to P. notatum, a 52 kDa allergen was identified. Only 40% of the patients demonstrated serum-specific IgE to this allergen (8).
- Pen ch 13, previously known as Pen n 13 and also known as oryzin, a 32 kDa protein, an alkaline serine protease (9-14).
- Pen ch 18, previously known as Pen n 18 and also known as cerevisin, a 34 kDa protein, a vacuolar serine protease (10, 14, 15).
- Pen ch 20, a 68 kDa protein, an N-acetyl glucosaminidase (16-18).
Pen ch 13 has an 88% frequency of IgE binding to serum of patients hypersensitive to P. notatum. In a study evaluating IgE antibodies in serum from 35 allergic individuals, IgE binding occurred with at least 1 of the 11 peptide fragments of Pen ch 13 (9).9 Among the Penicillium allergens, the 32-34 kDa alkaline and/or vacuolar serine proteases have been identified as the major allergens of P. citrinum, P. brevicompactum, P. chrysogenum, and P. oxalicum (19). They have been designated as Group 13 for alkaline serine protease and Group 18 for vacuolar serine protease allergens. Immunoblotting data showed that IgE antibodies against components of these prevalent Penicillium species could be detected in the sera of about 16-26% of asthmatic patients (19).
In sera of 212 patients with hypersensitivity to P. notatum, 33% (69) showed IgE and/or IgG immunoblot reactivity to Pen ch 13. Significant differences in the prevalence of IgE and/or IgG antibody reactivity to Pen ch 13 were found among 8 different age groups of 212 asthmatic patients. The frequency of IgE-binding reactivity to Pen ch 13 increased significantly with the age of the patients. It was 7% for the group younger than 10 years and 42% for the group older than 70 (13).
Research has found that there are cross-reactive and allergen-specific IgE epitopes for Pen ch 18 and Pen ch 13, which suggests that both major allergens should be included in clinically diagnostic extracts of P. notatum (10). In a study of sera from 70 asthmatics, 18 (26%) and 17 (24%) had IgE reactivity toward components of P. oxalicum and P. notatum, respectively. The major allergens from both species were shown to be the 34 and 30 kDa proteins of P. oxalicum and the 34 and 32 kDa proteins of P. notatum.
An extensive cross-reactivity among the different individual species of the genus could be expected but has not been completely evaluated. Importantly, hypersensitivity to Penicillium mold bears no relationship with hypersensitivity to the antibiotic Penicillin.
A very early study reported no cross-reactivity between some major species of Penicillium (20). Subsequently, common antigenic determinants were suggested between P. solani and P. notatum (21). More recently, a great deal of information has cast more light on cross-reactivity among members of the family, and between this and other families.
In a study of Penicillium species, IgE cross-reactivity among the major allergens of P. oxalicum and P. notatum and the 33 kDa major allergen of P. citrinum was detected by immunoblot inhibition studies. The N-terminal amino acid sequences of the 34 kDa allergen of P. oxalicum and of the 32 and the 28 kDa allergens of P. notatum were shown to share homology with the vacuolar serine proteinase from Aspergillus fumigatus. The N-terminal amino acid sequence of the 34 kDa allergen of P. notatum demonstrated homology with that of alkaline serine proteinase from P. citrinum. Further investigation with monoclonal antibodies showed reactivity with the 34, 30 and 16 kDa IgE-binding components of P. oxalicum, and with the 34, 32 and 28 kDa IgE-binding components of P. notatum. Although IgE cross-reactivity occurs among the 33 kDa group major allergens of P. citrinum, P. notatum and P. brevicompactum, different allergenic profiles were demonstrated in the 3 different Penicillium species tested (22).
Further studies have demonstrated cross-reactivity between Pen ch 13 and Pen c 13 from P. citrinum and Asp fl 13 from A. fumigatus in a dose-related manner, indicating that atopic patients primarily sensitised by either of these prevalent fungal species may develop allergic symptoms by exposure to other environmental fungi, due to cross-reacting IgE antibodies (11-12).
Cross-reactivity has been demonstrated between Pen ch 18 and Pen c 18, a major allergen of P. citrinum (15).
Pen ch 20 was reported to be cross-reactive with P. frequentans and P. roseopurpureum, out of 10 Penicillium species tested, and with an allergen in Aspergillus fumigatus, A. terreus and A. flavus, out of 4 Aspergillus species tested, but not with components of 6 other fungi, including Alternaria porri, Cladosporium cladosporoides, Aureobasidium pullulans, Fusarium solani, Rhizopus arrhizus and Candida albicans (17).
Immunoblot inhibition experiments showed complete loss of IgE binding with the use of a self protein from Beauveria bassiana, an important entomopathogenic fungus currently under development as a bio-control agent; and partial inhibition using extracts from common allergenic fungi, including Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum, Candida albicans, Epicoccum purpurascens, and P. notatum (23).
In a study of cross-reactivity among antigens of 12 genera of airborne fungi, 13 species of Penicillium, and 5 species of Aspergillus using ELISA and 5 monoclonal antibodies against Penicillium notatum, cross-reactivity was demonstrated among the antigens of Penicillium, Aspergillus, and Eurotium species. Through the use of these monoclonal antibodies, cross-reactivity was not detected between antigens of Penicillium notatum and antigens of Fusarium solani, Alternaria porri, Cladosporium cladosporoides, Curvularia species, Nigrospora species, Aureobasidium pullulans, Wallemia species, Rhizopus arrhizus, and Candida albicans. Cross-reactivity among antigens of 11 species of Penicillium and 5 species of Aspergillus was detected by ELISA using 1 of the 5 monoclonal antibodies. The authors concluded that, as there may be cross-reactivity among antigens of closely related fungi species, this fact should be considered in the diagnosis and treatment of mold allergic diseases (24).
Penicillium has long been recognised as one of the molds most often producing positive skin test reactions in allergic individuals (25-28). Inhalation of Penicillium spores in quantities comparable with those encountered by natural exposure can induce both immediate and late asthma in sensitive persons (28). Sensitivity to Penicillium bears no relationship to sensitivity to the antibiotic Penicillin.
An early study reported that specific IgE antibodies were found in 90% of patients with hypersensitivity to P. notatum (29). As the prevalence of P. notatum varies among geographic locations, the prevalence of sensitisation will vary as well. In a Taiwanese study of 1070 patients with asthma, aged from 3 to 70 years, 77.9% were allergic to D. pteronyssinus, 40.0% to German cockroach, 9.6% to P. notatum and 10.4% to C. albicans. The highest prevalence of sensitisation to P. notatum, 18.9%, occurred in patients above the age of 61 years (30). In a study in the Netherlands of 137 children (5 months to 14 years), serum-specific IgE to Cladosporium herbarum was found in 18.2%, to Aspergillus fumigatus in 15.3%, to Alternaria alternata in 14.6%, and to P. notatum in 7.3% (31).
In a study in Singapore that evaluated sensitisation of 391 individuals (289 patients with asthma and/or allergic rhinitis, and 102 healthy controls) using skin-specific IgE determination to extracts of 6 species of local Dust mites and 10 other common indoor allergens, it was found that 18% of the subjects were sensitised to P. notatum (32). In 614 Turkish patients with respiratory allergy (72.6% with asthma and 27.4% with allergic rhinitis) evaluated for sensitisation to various molds by skin-specific IgE determination, sensitisation to Aspergillus fumigatus was found to be the most prevalent (26.0%), followed by sensitisation to Trichophyton rubrum, Mucor, Penicillium notatum, Aspergillus niger and Alternaria tenuis. In aerobiological studies, 26 species of mold were isolated, with Penicillium being the most prevalent one. This study concluded that in Turkey, molds can play an important role as causative agents for allergic rhinitis and asthma (33).
Sick building syndrome (SBS) was first described in 1982. Although no single cause is likely to be found, the presence of certain molds is becoming increasingly associated with this phenomenon. Symptoms most commonly are fatigue, runny nose, itchy eyes, sore throat, and headaches. Propagules of Penicillium and Stachybotrys species may be associated with sick building syndrome (34, 35).
Four workers in medical research laboratories located in a basement level of a University facility equipped with a humidifying air conditioning system complained of cough and/or asthma and/or rhinitis during their normal working activities. Aspergillus fumigatus and P. notatum were found in some laboratories. Of 26 laboratory workers investigated, 8, including the 4 symptomatic subjects, were found to be atopic. Specific IgE sensitisation to Aspergillus fumigatus was found in the 8 atopic and in 6 non-atopic workers, while P. notatum sensitisation was found in 7 atopic and 4 non-atopic subjects. The authors concluded that evaluation of immune parameters, along with monitoring of the working environment, may reduce the risk of sensitisation and/or allergic symptoms in atopic laboratory workers (36).
Allergic alveolitis caused by P. notatum and P. cyclopium was described in a married couple. It was caused by a leak in the central heating system of their home, which resulted in a heavy growth of these 2 fungi on the wet flooring and linoleum. P. notatum and P. cyclopium were isolated from the floorboards, linoleum, and settle plates. Antibodies against both these fungi were demonstrated in the serum of both patients (37).
P. notatum was isolated from 3 subsequent cerebrospinal fluid specimens of a 73-year-old male patient without immunological compromise (38). P. notatumendophthalmitis (39) and necrotising pneumonia have been reported (40).
Penicillium spp. are commonly considered as contaminants but may cause infections, including pneumonia, particularly in immunocompromised hosts. In addition to their infectious potential, some Penicillium spp. are known to produce mycotoxins (41). For example, P. verrucosum produces the mycotoxin, ochratoxin A, which is nephrotoxic and carcinogenic. The production of the toxin usually occurs in cereal grains at cold climates (42). Other mycotoxin-like compounds include patulin, citrinin, citroviridin, emodin, gliotoxin, verraculogen and secalonic acid D (43).
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