Summary

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.

Epidemiology

Worldwide distribution

Like other airborne molds, Penicillium spp. induce IgG and IgE production in humans. 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. In mold-sensitized subjects, sensitization to Penicillium spp. is associated with sensitization to other molds, mainly Alternaria spp. and Aspergillus spp.

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. Current sensitization rates to Penicillium range from 5 to 8% in general population and atopic patients and are much higher, usually up to 29%, in asthmatic patients. Accordingly, a 2016 study on 160 Japanese asthmatic adults found a 21.9% (35/160) prevalence of P. chrysogenum sensitization, 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. 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. 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.

A gender bias has been reported in some studies, with fungus, including P. chrysogenum, sensitization apparently more prevalent in male than in female subjects. 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.

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.

The use of molecular allergens instead of crude extracts for serum specific IgE testing is increasing. 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.

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).

Pediatric issues

Penicillium spp. is considered a causative agent of asthma and AR in children according to the American Institute of Medicine.

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. 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). 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.

Route Of Exposure

Main

The primary route of exposure to P. chrysogenum allergens is inhalation.

Secondary

P. chrysogenum can induce allergic reaction through ingestion or direct contact (cheilitis).

Clinical Relevance

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. 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. VOCs are responsible of the moldy odor, which can be perceived in presence of growing Penicillium. 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.

Allergic rhinitis

Penicillium spp. are reported to induce AR.

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.

Asthma

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

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. 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.

The association between indoor mold growth and wheezing episodes in children was also found in a Finnish pediatric cohort study. In adult asthmatic patients, multiple reports found that Penicillium sensitization was associated with poor asthma control or higher severity score for asthma. 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.

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. Current researches from the US, Europe, and World Health Organization (WHO) indicated damp indoor environment to be an important factor in inducing asthma.

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. IgE-mediated effects include histamine degranulation, which can be demonstrated in vitro through basophil activation triggered by Pen ch 13.

Atopic Dermatitis

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. 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).

Other diseases

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.

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.

Other topics

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. P. chrysogenum is reported to cause black esophagus, endophthalmitis, and keratitis.

Cross-Reactivity

P. chrysogenum protein (33 kDa) was found to be cross reactive with P. brevicompactum’s 33 kDa protein. Serine proteases are thought to be the major pan-fungal allergen group found in most of the airborne fungal species. 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.

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. 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. Pen ch 13 and Pen ch 18 are homologous to Asp f 13 and Asp f 18 with considerable sequence similarity. 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.