Sarcoidosis and Mold
Sarcoidosis has been associated with several different work and environmental exposures such as agricultural employment, insecticides at work and work environments with mold and mildew as reported by Newman, et al.
A separate investigation of respiratory morbidity in office workers in a a water-damaged building also reported a correlation between respiratory disease (asthma, Hypersensitivity Pneumonitis) and Sarcoidosis. The asthma rate increased from 1.9/1000 person years before occupancy to 14.5/1000 persons years after occupancy. Cases of HP and sarcoidosis were also associated with occupancy.
The question that arises is: What organisms are associated with sarcoidosis?
Recently, Aspergillus flavus and fumigatus were identified in the lungs of 10 patients from a retrospective cohort of 447 cases of sarcoidosis. The limitation of this report was that environmental exposures that may have led to the sarcoidosis in all patients was not done. Thus, it cannot be said which came first-- Aspergillus or sarcoidosis--as casually related to the disease. However, other published data show a causal relationship between pulmonary granulomas (sarcoidosis) and fungal infections.
Mukhopadhyay, et al, published their findings regarding causative agents in pulmonary granulomas in 500 patients with pulmonary granulomas. Specific cause was identified in 58 % of the cases (sarcoidosis in 27% and mycobacterial and fungal 28% of the 290 cases). Insufficient information was available for identification of cause in 210 of the 500.
Fungi were identified in biopsy specimens, while Mycobacteria were identified by culture. The identified mycobacterium
will be discussed in the review of bacteria infections in sarcoidosis published on this web site. Of interest, Mycobacteria were identified in 19% of the cases outside of the USA versus 8% within the USA.
In contrast, fungi accounted for 19% of cases in the USA versus 4% in other countries. No attempt was made to identify possible environmental sources of the microbial infections, e. g., workplace, water-damaged buildings.
Nonetheless, fungal and bacterial infections were identified as the probable cause of granulomas in these cases. However, several more recent papers have appeared in the literature that indicate that fungal exposure is causally related to the development of sarcoidosis. These data will be briefly reviewed below.
Fungi and Sarcoidosis
Increasing evidence has shown a positive correlation between exposure to microbes (particularly molds and Mycobacterium) and the hypersensitivity reaction leading to the development of granulomas and sarcoidosis.
Sarcoidosis historically has been treated with corticosteroids. However, some patients are refractory to this treatment.
Initially, a pilot study of refractory subjects involving 18 patients with sarcoidosis grades I and II was treated with antifungals (itraconazole, fluconazole, and ketonazole (all at 200 mg/day) along with corticosteroids. At 3-6 months, treatment resulted in a significant decrease of pulmonary infiltration. In addition the patients had significant increases in diffusion capacity and decreases in the severity of symptoms. The study suggested that antifungals are useful in certain cases of sarcoidosis associated with Aspergillus and Candida circulating antibodies.
A more recent study involved newly diagnosed sarcoidosis (n = 92) patients as follows: corticosteroids (n = 39), corticosteroids + antifungals (n = 31) and antifungals (n = 22). The patients had circulating antibodies against Aspergillus and Candida as well as biomarkers indicative of sarcoidosis (Angiotensin-converting enzyme and chitotriodases. X-ray score decreased significantly among all three groups, while antifungal treatment groups had greater improvement in X-ray findings when compared to the corticosteroid groups (p ,<0.001). It was concluded that antifungal treatment was as efficient as corticosteroid treatment against granulomatous and inflammatory manifestations of sarcoidosis.
Two additional observations support the role of fungi in the development of sarcoidosis. N-acetylhexosaminidase (NAHA), a fungal cell wall enzyme is a biomarker of fungal biomass and indoor mold exposure. NAHA levels were tested in homes where individuals had active and/or recurrent sarcoidosis.
Individuals with active and/or recurrent sarcoidosis had higher activities of NAHA in their homes vs control homes. The values were 33.6-39.9 U/cubic meter (patients) vs 10 U/cubic meter (controls). The second report involved the testing for proinflammatory cytokines in patients with sarcoidosis as well as the proinflammatory response of peripheral blood monocytes stimulated by particulate and soluble (S-glucan and P-glucan) Beta-glucans, chitin and lipopolysaccharide (LPS). The cytokines tested were TNF-alpha, IL-2, IL-10 and IL-12 in vivo and in vitro. The study involved 22 sarcoidosis patients vs 20 controls.
Briefly, the induced secretion of cytokines was higher from the peripheral blood mononuclear cells from subjects with sarcoidosis. P-glucan was more potent than soluble glucan (S-glucan) for inducing cytokine release. Among the subjects with sarcoidosis, there was a significant relation between the spontaneous production of LI-6, IL-13 and the NAHA levels in the homes. The X-ray findings of the Sarcoidosis patients were related to an increased secretion of cytokines after stimulation with LPS (endotoxins) and P-glucan. Subjects with sarcoidosis had a higher reactivity to the fungal cell wall agents in vitro and to home exposure.
Closing Comments: Although the above observations clearly implicate particulate glucans in the development of sarcoidosis, other factors must also be considered. These are (1) fine particulates less than one micron releases that contain beta-glucans and secondary metabolites of both mold and bacteria (12-16); and 2) multiple virulence factors have a role in the pathogenesis of both mold and bacteria in the development of lung disease and infection.
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