Aspergillus flavus

Aspergillus flavus on gypsum boardAspergillus flavus on woodAspergillus flavus on a ceiling tileAspergillus flavus on EM agarAspergillus flavus on RB agarAspergillus flavus - StereoscopyAspergillus flavus - Microscopy (EM Culture)

Basics

Taxonomy

Kingdom Fungi Order Eurotiales
Phylum Ascomycota Family Trichocomaceae
Class Euascomycetes (Eurotiomycetes) Genus Aspergillus

Aspergillus flavus has no known telemorph forms.

Habitat/Ecology

Aspergillus species are ubiquitous imperfect filamentous fungi. Of this genus, Aspergillus flavus has a worldwide distribution, mostly growing as a saprophyte in the soil {2428; 1797}. A. flavus is an opportunistic pathogen causing invasive and non-invasive aspergillosis in humans, animals and insects; this Aspergillus also infects agricultural crops and contaminates stored grains while producing the most toxic and potent carcinogenic metabolites such as aflatoxins and other mycotoxins {3527}.

A. flavus is able to cause diseases in economically important crops, such as maize and peanuts {2428; 2430}. It is common in groundnuts, spices, oil seeds, cereals and occasionally in dried fruits (e.g. figs) {725; 2431; 1056; 1552}. It is usually a contaminant commonly associated with mycotoxins, such as aflatoxins {412}.

More details

This ubiquitous species is however more common in warmer, subtropical and tropical climates than in the temperate areas of the world {725; 1552}.  A. flavus is particularly prevalent in the air of certain tropical countries; however, climatic conditions markedly influence its prevalence in outdoor air. In temperate countries, its prevalence is somewhat lower, as demonstrated by data from European countries {2428}. In desert countries, A. flavus is among the most common fungi in outdoor air; concentrations of up to 1.9 x 104 CFU/g of airborne dust particles have been reported in Saudi Arabia {930} and up to 1.39 x 105 in Egypt {1762}. A high prevalence of A. flavus has also been observed in other natural environments, such as in caves of Southern India where concentrations up to 3.4 x 104 CFU/g dry soil were recorded {1394}.

Growth requirements

A. flavus is a mesophilic fungus; it can grow between 17-19 °C and 47-48 °C, with optimal growth between 25 and 42 °C {989; 725; 2428}.  Optimum growth pH is 7.5 while optimum pH for conidia production is 6.5 {989}. A. flavus grows better with a water activity (Aw) between 0.86 and 0.96 {2428} although it has been reported to grow at an Aw between 0.78 to 0.80 according to some authors {989}. Optimal growth is obtained with a relative humidity of 80 to 85% {989}.  In nature, the fungus overwinters either as mycelium or as resistant structures known as sclerotia which can germinate to produce additional hyphae or conidia which, in turn, can subsequently be dispersed in the soil and air {2428}.

Water Activity:     Aw = 0.78 - 0.96

Growth on building materials or indoor environment

In addition to foodstuff and feed, Aspergillus flavus is known to be able to grow on paper, wood, painted building materials, textiles and leather; it has even been found on synthetic materials, varnishes and waxes as well as on electronic parts and photographic glass plates {989}. Indoor studies have shown that A. flavus is present in house dust, ventilation ducts and contaminated building materials.

More details

In a case study conducted during extensive renovation work in a building comprised of both offices and laboratories, A. flavus was present in 5.2% of suspended dust samples, far behind other fungi {1790}.

In a Danish survey, A. flavus was identified in 4 water-damaged schools but also in 2 control schools {550}. In a study conducted in Croatia, A. flavus was identified in 4% of samples from wall scrapings collected from damp dwellings {1589}. A. flavus was also identified in HEPA filters which can serve as a point source for indoor contamination in hospitals and commercial locations {306}.

In indoor air of selected houses in Saudi Arabia, the concentration of A. flavus ranged between 63 and 81 CFU/g of house dust {1756}. This fungus was also identified in water closet air of a University in Egypt, being found in 75% to 95% of samples (20 samples) at concentrations ranging from 421 to 499 CFU/agar plate (exposed for 5 minutes) {2193}.

A. flavus was recovered in 33% of pillow swatches, but was not among the most common fungi identified in such environment (Aspergillus fumigatus being present in all samples) {2223}.

Microbial contamination of dental office waterlines usually reveals the presence of a biofilm composed of a microbial complex, mostly bacteria such as Pseudomonas and Legionella; however, Göksay et al. did recover A. flavus is some dental offices in Istanbul (specific data not shown) {2427}. A. flavus has also been reported to contaminate irreversible hydrocolloids used in dental material; after 7days incubation at 37°C , A. flavus was isolated in four of the six offices studied {2408}.

In rural areas, fungal species constitute a major component of environmental contaminants in facilities where animals are housed; moreover, high intake of cereal material in the diet may have adverse effects on animals {1778; 2331} while handling of this contaminated material may also have an affect on the health of farmers {1215}.

Fulleringer et al. reported that A. flavus was the third most prevalent fungus in a turkey confinement house, with a mean concentration of 37 CFU/m3 {646}. Fungal cultures from poultry feed, litter and air revealed 2 species of Aspergillus,including A. flavus, reaching a mean concentration of 37 CFU/m3 air, with peak concentrations of up to 150 CFU/m3{646}.  In a large rural indoor cattle shed, A. flavus was the most prevalent airborne fungal contaminant, contributing between 24 and 28% of mean concentrations (up to 600 CFU/m3) leading the authors to emphasize that this fungus could represent a potent source of aflatoxins for cattle shed workers {2373} .

In one study investigating airborne fungi in agricultural and industrial environment, A. Flavus was found in only one of these environments, the grain mill, with a very low prevalence (0.4%) {854}.

Laboratory section

Normal laboratory precautions should be exercised in handling cultures of this species within Biosafety Level 2 practices and containment facilities.

Colony, macroscopic morphology

Colonies are fast growing, reaching a diameter of 3-5 cm within 7 days on Czapek agar at 25 °C; they usually consist of a dense felt of yellow-green conidiophores. Their texture is woolly to cottony to somewhat granular and the surface is flat, often with radial grooves, yellow at first but quickly becoming bright to dark yellow-green with age. Sclerotia, when present, are dark brown. A clear to pale brown exudate may be present in some isolates {2207; 1052}.

Colonies on malt-extract agar (MEA) grow even faster, but are otherwise similar.

Colonies on potato dextrose agar (PDA) at 25 °C grow rapidly, olive to lime green with a cream underside; texture is woolly to cottony to somewhat granular. A clear to pale brown exudate may be present in some isolates {816}.

Poor growth is observed on creatinine sucrose agar (CREA) and the reverse of the colony is orange on AFPA (Aspergillus flavus /A. parasiticus selective medium) {725; 1056}.

Microscopic morphology

Hyphae are septate and hyaline. Conidiophores are hyaline, coarsely roughened and may measure up to 1.0 mm (some isolates, up to 2.5 mm) in length. Vesicles are globose to subglobose, 25-45 mm in diameter. Phialides, borne directly on the vesicle or on the metulae, measure 6-10 x 4.0-5.5 mm {1056} and are uniseriate or biseriate, covering the entire vesicle and pointing out in a radial pattern {412}.

Conidial heads, generally 300-400 µm in diameter, are radiate becoming loosely columnar with age {816}. In fact, young conidial heads are typically radiate, later splitting into several loose columns; they are first yellow-green becoming dark yellow-green at maturity.  Conidia are globose to subglobose, 3.6 mm in diameter, pale green, and echinulate {2428; 816; 1056}. 

Some strains produce sclerotia in culture {3425}: these sclerotia can withstand extreme circumstances, hence allowing the dissemination and propagation of A. flavus {2428}.

Specific metabolites

Organics compounds (including VOCs)

A number of organic compounds, including microbial volatile organic compounds (mVOCs) from many fungal species have been identified in indoor air in damp buildings: some compounds are found in most fungal species and are thought to contribute to a variety of indoor air problems. Most identified metabolites are non-reactive and found in low concentration in the indoor air {594}. 

The mVOC profile for A. flavus is not well known. 

More details

Nonetheless, general knowledge regarding mVOCs still holds true and can be applied to A. flavus. Some species have a defined mVOC profile which may be subjected to considerable modification in response to external factors such as cultivation on different substrata. Cultivation on different substrata changes both the number and concentration of mVOCs {2968; 1148}{Fischer, 1999 2809 /id), whereas some volatiles are specific for a single species {2809}.

Mycotoxins

Aspergillus flavus produces many toxic metabolites including, alphabetically: aflatoxins B1, B2, M1, G1 and G2, agroclavin, aspergillic acid, aspertoxin, citrinin, cyclopiazonic acid, diacetoxyscirpenol (DAS) (a trichothecene), ergocryptin, ergoline, kojic acid, 3-nitropropionic acid, ochratoxine A, patulin, sterigmatocystin, T-2 toxin, versicolorin A and zearalenone {989}. 

Some strains of A. flavus produce a tremorgenic substance (unnamed) {3529}.    The strains of A. flavus likely to form sclerotia are frequently tremorgen-positive. Mature sclerotia may contain the toxin, whereas conidia do not. However, formation of sclerotia is not a prerequisite for toxin production, since non-sclerotiagenic cultures produce the toxin as well.

A. flavus is especially associated with aflatoxin B1 which is hepatotoxic for humans and animals when ingested and can cumulate over time {2426}. A. flavus toxins are produced from growth on a wide array of substrates in different circumstances, both in foodstuff and on building materials.

When associated with aflatoxin ingestion, mycotoxicosis can be fatal and/or manifest itself under multiple clinical patterns.

(See mycotoxicosis section)

More details

The A. flavus toxins occur naturally on several key animal feeds, including corn, cottonseed and peanuts. Occurrence of aflatoxins on some field crops tends to spike in  certain years when drought and insect damage facilitate invasion by causative organisms {1883; 2452}. Hay conservation methods from high moisture content are critical to avoid aflatoxin production {752}. Poor on-farm storage of corn and other grains is a primary contributing factor for the formation of aflatoxin, which continues during and after the milling process {3487}.

Mycotoxins, especially aflatoxins, are often produced on cereal grains used for livestock {2416} or in raw grain material during mill processing {1883}.  In pig feed, A. flavus was amongst the most prevalent species (along with A. fumigatusand Fusarium verticillioides); aflatoxins levels were detected in all feeds {2424}. In poultry feed mixtures, Labuda and Tancinova identified A. flavus in 30% of the 32 samples collected, as well as its mycotoxins {1778}.

Airborne dust collected from 8 farms during harvest revealed aflatoxin B1 concentrations of up to 92 ng/m3 and up to 5100 ng/m3 from an enclosed animal feeding building, thus demonstrating that farmers and farm workers may be exposed to potentially hazardous concentrations {1215}.  In a German study assessing health hazards in farm workers, measurement of A. flavus in chicken pens revealed concentrations of up to 8.4 x 105 CFU/m3 {1999}.

Aflatoxins and cyclopiazonic acid (CPA) produced by A. flavus often contaminate peanuts {2417}. Grains and rice stored under tropical conditions are reportedly a favorable milieu used by A. flavus to grow and produce aflatoxin B1 {2446} or other mycotoxins which have been shown to damage organs such as kidneys, liver and spleen in laboratory animals {1771}. A. flavus and aflatoxins B1 and B2 have also been found in cigarette tobacco, although these mycotoxins are seemingly trapped by the topping filter {1758}. 
The alkaloid fraction of Aspergillus flavus, namely clavines, agroclavines and elymoclavines, are formed in comparatively higher yields during the early phase of fungal growth, after which their concentration gradually decreases while production of the peptide alkaloid ergokryptine is enhanced. Ergokryptine is probably the principal product of the late stage of growth {3528}.   

Mycotoxins derived from Aspergillus flavus can be encountered indoors, both in domestic and occupational environments, and exposure to these toxins can lead to severe health hazards {804; 443}.  Some studies have recorded  A. flavusmycotoxins in the indoor environment and have identified important toxic or carcinogenic metabolites such as kojic acid, 3-nitropropionic acid, cyclopiazonic acid, aflatoxin B1 and B2 and aspergillic acid {725; 2431; 1056} . In vitro cultivation ofA flavus strains isolated from walls of mouldy dwellings and schools have been shown to produce aflatoxins B1, B2, G1 and G2 {2392}. Conversely, while Pieckova et al. reported that A. flavus produces certain chloroform-extractable toxic exometabolites (not specified) present in house dust, their study failed to detect aflatoxins {550}.

Adverse health reactions

A. flavus can cause diverse pathologies in humans, including allergies, asthma, allergic bronchopulmonary aspergillosis {412}, hypersensitivity pneumonitis, infection of the paranasal sinuses, pulmonary aspergilloma and invasive opportunistic infection {2428; 509; 1797}.

More details

A. flavus is the second most important Aspergillus species causing human infections. The importance of health effects may increase in regions with dry and hot climate: in countries with semi-arid and arid dry weather conditions, A. flavus is the main aetiological agent of invasive aspergillosis {2428}. Some reports suggest the disease process may be potentiated by aflatoxins, particularly in the immunocompromised and neutropenic host.

Health risks associated with mould exposure in water damaged buildings are well established, especially for upper and lower respiratory tract symptoms. Aspergillus flavus grows well in the indoor environment and can significantly contribute to a number of indoor air problems. 

Irritation and inflammation

Many fungal substances common to most or all moulds, such as glucans, can cause irritation and inflammation. However, none are reported relating specifically to A. flavus.

Allergic reactions

Aspergillus flavus is linked to Type I allergies, such as rhinitis {3443} and asthma as well as allergic sinusitis. In one study, 105 asthmatic patients with or without rhinitis were tested with a full screening panel of antigens: 33 (28.5%) patients showed immediate hypersensitivity to one or more Aspergillus antigens. Among these, 70% were sensitive to A. flavus {288}.

More details

Although A. fumigatus is responsible for the vast majority of allergic bronchopulmonary aspergillosis (ABPA), A. flavus has also been implicated in some case series {3396; 3407}. ABPA is caused by a Type I hypersensitivity reaction toAspergillus species and is most commonly observed in patients with asthma or cystic fibrosis.  

Allergic fungal sinusitis due to A. flavus is particularly frequent in certain geographical areas such as the Middle East and India {2428}. These sinusitis are typically diagnosed on the basis of Type1 hypersensitivity and presence of fungal hyphae in the secretions; they are different from sinus infections as these cases are without tissue invasion {2537}.

Allergic components and mechanism

Two allergens of A. flavus have been characterized and their mechanisms partly elucidated in experimental studies. In one controlled study, mice were treated three times a week with intranasal instillation of 100 micrograms of Aspergillus antigen containing A. fumigatus and A. flavus: animals developed pulmonary eosinophilia, observed in the bronchoalveolar lavage (BAL) and confirmed on histopathological examination. At week 3, eosinophils were the predominant inflammatory cells {3453}.

More details

The two allergens of A. flavus that have been characterized are Asp-fl-1 and Asp-fl-13.  A. flavus allergen (Asp fl 1) is an alkaline serine protease and was identified by immunoblotting with a serum pool of allergic patients {3495}.  A recombinant Asp fl 1 (rAsp fl 1) was also cloned and shown to have the same binding capacities;  rAsp fl 1 cross-reacted strongly with IgE specific for natural Asp fl 1 and Pen c 1, indicating that common IgE epitopes may exist between A. flavusand P. citrinum allergens.

The purified allergen, Asp-fl-13, a 34-kD alkaline serine proteinase, is a major allergen in the crude extract of A. flavus; it has been shown to have proteolytic activity with casein as substrate at pH 8.0 {3494}.

Hypersensitivity pneumonitis

Type III hypersensitivity pneumonites  (HP) due to Aspergillus flavus are well known in occupational settings involving rice and grain products.  However, in occupational and residential settings, it is often difficult to attribute HP to A. flavus alone primarily because the environment is often simultaneously contaminated with multiple species of Aspergillus and because of species cross-reaction in serological tests {3399}.

Nevertheless, a case of hypersensitivity pneumonitis associated with a home humidifier revealed positive serum precipitins for A. flavus and Phoma herbarum {1680}.

More details

After a latent period of 3 weeks following an intense inhalational exposure to mouldy corn, a farmer developed a pneumonitis apparent to the HP type. This illness was associated with the presence of serum precipitating antibodies against antigens contained in the mouldy corn as well as against purified antigens of Aspergillus flavus and A. fumigatus. Analysis of Aspergillus flavus cultured from the mouldy corn and of the purified Aspergillus antigen obtained from the patient's serum yielded identical precipitin bands. Signs of bronchiolitis obliterans organizing pneumonia were found in pulmonary tissue at autopsy; death was presumably attributable to pulmonary embolism. This case is believed to represent an occurrence of hypersensitivity pneumonitis following massive inhalation of the spores of the genus A. flavus possibly with transient respiratory infection with these organisms but without systemic invasion of the host {3431}.

Toxic effects (mycotoxicosis)

Many strains of A. flavus are active producers of toxins under given sets of growth conditions. The major toxins are aflatoxins: they are well known to cause mycotoxicosis in humans and animals ingesting contaminated food.  Food borne aflatoxicosis has reached epidemic proportions in certain developing countries and represent a public health burden for many low-income countries {2472; 3378; 3423; 3435}. Aflatoxicosis may be acute or chronic and multiple symptoms and multi-organ failure may be part of the clinical presentation.

Diet is the major means by which humans and animals are exposed to aflatoxins. In addition to this route, exposure to aflatoxin can occur through ingestion of contaminated milk containing aflatoxin M1 (metabolite of AFB1). Occupational airborne exposure to aflatoxins in agricultural workers, especially those working in vegetable oil mills and granaries, has been reported {1225}.  Recent studies have suggested that indoor exposure to airborne aflatoxin in contaminated buildings should be assessed.  In particular, special emphasis should be given to the assessment of indirect mycotoxin risk in heating, ventilation and air conditioning systems {443}; such exposure could be tested by means of toxin assays in urine {3551}.  Finally, aflatoxins are recognised as among the most potent natural carcinogenic substances known.

More details

Aflatoxins, a family of 18 closely related and biologically active mycotoxins, have been known as a prominent cause of animal disease for over 30 years {2452}.  
Metabolised by various microsomial enzymes, aflatoxins are eliminated as glycurono- and sulfo-conjugates in urine, milk and bile.  During aflatoxin metabolism, epoxidation reactions generate highly reactive epoxides. These strongly electrophile compounds react with DNA, inserting themselves between bases or proteins, thus acting as mutagenic and carcinogenic agents. Aflatoxins are also important teratogenic agents and can, at high doses, be fatal to the foetus within hours or days depending on the amount ingested and the sensitivity of the animal species to these toxins. Furthermore, aflatoxins play a role in the phosphorylation process and lipogenesis as well as displaying immunosuppressive proprieties.

Aflatoxicosis in animals is linked to morbidity and mortality in farm and wild animals and is of significant economic importance. 

In farm and laboratory animals, chronic exposure to aflatoxins compromises immunity and interferes with protein metabolism as well as that of multiple micronutrients which are critical to health and normal development {3488}.

Clinically in animals, acute aflatoxicosis is generally fatal; it causes a distinct overt disease marked by hepatitis, icterus, haemorrhaging, sometimes accompanied by depression, anorexia, diarrhoea or anemia, followed by death. Lesions are essentially hepatic and evolve into a hepatoma or carcinoma, over a long period of time.

Chronic aflatoxin poisoning produces very protean signs that may not be clinically obvious; reduced rate of gain in young animals is a sensitive clinical marker of chronic aflatoxicosis. The immune system is also sensitive to aflatoxin, resulting in suppression of cell-mediated immune responsiveness, reduced phagocytosis and depressed complement and interferon production. Acquired immunity from vaccination programs against certain diseases may be substantially suppressed.

No animal species is resistant to the acute toxic effects of aflatoxins.  A wide variation in LD50 values has been observed in animals tested with single doses of aflatoxins. For most species, LD50 ranges from 0.5 to 10 mg/kg body weight as reported by the Food and Agriculture Organization (FAO): animal species respond differently in their susceptibility to chronic and acute aflatoxin toxicity {3491}.

Clinically in humans, aflatoxicosis presentation may be acute, subacute or chronic and can incur multiple organ damage {3423}.  Epidemiological, clinical and experimental studies reveal that exposure to large doses (>6000 mg) of aflatoxin may cause acute toxicity with a lethal outcome, whereas exposure to small doses for prolonged periods is carcinogenic {3496; 3497; 3498}.

The discovery of aflatoxins in the early 1960s led to the resurgence of interest in human mycotoxicoses, especially in developing countries. The limited amount of information regarding repeated exposure in humans suggests that, at least in those locations where it has been studied, existing aflatoxin exposure results in nutritional and immunity changes.  
Airborne exposure to aflatoxins has also been well documented in the rural setting, leading some authors to suggest that such exposure could be possible in the residential setting, albeit in lower concentrations {3488}.

Aflatoxin B1 is reported to be a potent hepatocarcinogen associated with human hepatocellular carcinoma (HCC). HCC is the fourth leading cause of cancer-related death in the world. The underlying pathological mechanism appears to be a cumulative process, as revealed by AFB1 deposits in HCC liver tissue. Furthermore, an Indian study demonstrated that the degree of food contamination by aflatoxins and the prevalence of HCC were closely and significantly correlated {2446}.

In addition to foodborne and airborne exposures, some authors have reported the endogenic toxic potential of A. flavusinfections.  Thirty strains of A. flavus were isolated from clinical isolates from immunocompromised patients in a haematological unit: aflatoxin B1 and aflatoxin G1 were detected in 23% and 3% of these isolates, indicating a potential additional risk for these patients {299} (see virulence factor).

Infections and colonisations

A. flavus infections occur very rarely in immunocompetent subjects.  Many host risk factors have been well documented. Immunocompromised patients are particularly at risk of invasive aspergillosis including A. flavus infections {526}.  A. flavusinfections are seen in hospital settings as single cases or as part of outbreaks and may be linked to environmental contamination or iatrogenic exposure (see Nosocomial section). 

In immunocompetent patients A. flavus may be linked to infections of the sinuses and, occasionally, of the eyes and ears. After A. fumigatusA. flavus is the second leading cause of invasive aspergillosis and is the most common cause of superficial infection. Common clinical syndromes particularly associated with A. flavus include chronic granulomatous sinusitis, keratitis, cutaneous aspergillosis, wound infections and osteomyelitis following trauma and inoculation. Experimental invasive infections in mice show A. flavus to be 100-fold more virulent than A. fumigatus in terms of inoculum required.

Aspergillus species, including A. flavus, frequently colonise the lower respiratory tract and lungs in concomitance with localised underlying conditions such as healed tuberculous cavity, cystic fibrosis and bronchiectasis.  A. fumigatus causes the vast majority of cases of chronic cavity pulmonary aspergillosis and aspergilloma; A. flavus is rarely associated with these infections, although a few cases have however been reported {2428; 2429; 2451}.

More details

Outbreaks of aspergillosis involving the skin, oral mucosa or subcutaneous tissues are more often associated with A. flavus as opposed to other Aspergillus; however, clusters of invasive sinusitis or invasive pulmonary infections caused exclusively by A. flavus are uncommon {2428}.

Among fungal keratitis occurring predominantly in tropical and warm climates, and caused by Aspergillus spp., A. flavusaccounts for 80% of total cases; the major predisposing condition being trauma, generally with plant material. Some cases however have been reported associated after laser cataract surgery. Fungal endophthalmitis is rarely associated with A. flavus, although some cases have been reported, usually developing as a postoperative infection {2402; 1598}. A case of keratomycotic malignant glaucoma, occurring as a rare complication of a severe A. flavus corneal ulcer and aspergilloma following exenteration for an invasive eye tumour, has been reported {2403} {2447}. A case of A. flavusendophthalmitis associated with periodontis was also reported {1246}.

A. flavus is more likely to be recovered from the upper respiratory tract where it can cause invasive rhinosinusitis (both acute and chronic), chronic granulomatous and non invasive syndromes. In some countries, most cases of Aspergillussinusitis have been caused by A. flavus; a prospective study of 176 cases of fungal sinusitis in India revealed that A. flavus was the commonest isolate {1972}.

Chronic granulomatous sinusitis is a syndrome of chronic and slowly progressive sinusitis caused by A. flavus {2448}.  This species is also the most frequent agent of all forms of paranasal sinus mycosis {1972} and is quite prevalent worldwide in hot climates. In fact, in the largest series of fungal sinusitis described in the literature, A. flavus was the main aetiologic agent, representing 65% (11/17) of all cases {3530}.   

Case series of craniocerebral aspergillosis due to A. flavus in immunocompetent hosts have been reported mainly in Asian and African countries; this disease is a complication of granulomatous sinusitis, due to tropical environmental conditions (hot and dry weather), and poor hygiene conditions {2428}.

Aspergillar osteomyelitis caused by A. flavus in presumed immunocompetent adults has been reported {2412; 2423}. A review of such infections revealed that among adults, the majority of cases occurred in presumably immunocompetent hosts while in paediatric cases, the underlying cause was usually a severe immunocompromised state {2423}.

It is well known that peri-hospitalisation aspergillosis causes significant morbidity and mortality in neutropenic and immunocompromised hosts {2409; 509; 390; 489; 497}; significant Aspergillus flavus infections are strongly associated with defects in host defences, in particular phagocytic function {2412}. In immunocompromised patients, some very rare cases of infection have been reported: such as a case of primary aspergillosis affecting the tongue in a leukemic patient {2411}.

Organ transplantation is also a condition associated with higher risk of infection by A. flavus {2435; 397; 497; 2467}. A large review of invasive aspergillosis in both  haematopoietic stem cell transplants (4621 cases) and solid organ transplants (4110 cases) across 19 sites dispersed throughout the United States, revealed that A. flavus was respectively involved in 18.7% and 11.8% of cases {1412}. In a study of 417 lymphoma patients treated by bone marrow transplant, 3.4% had invasive aspergillosis caused by A. flavus {394}; this study showed that, even in a protected environment with HEPA air filtration, there was a significant risk of developing aspergillosis. Incidence of invasive aspergillosis is also well documented in patients with haematological malignancies {526; 344; 394; 2439; 2457}.

Virulence factors

A. flavus is more virulent than almost all other Aspergillus species. In the immunocompromised mouse model, the LD90 inocula for A. flavus are 100-fold lower than those required for A. fumigatus. However, while aflatoxins may contribute to the virulence of A. flavus, it seems that aflatoxins are not a major factor in disease development, since strains unable to produce these toxins are somewhat equally virulent {2428}.  A. flavus is extremely angio-invasive with resultant necrosis and infarction {1056}. 

More details

Aspergillus flavus culture filtrates cause minor damage to human respiratory ciliated epithelium in vitro without any significant slowing of ciliary movement; nevertheless, the damage to the epithelium may possibly contribute to the further proliferation and spreading of lesions in pulmonary aspergillosis {2531}.   

Specific settings

Nosocomial infections

Aspergillus flavus infections have been reported in the hospital setting. A. flavus is frequently isolated in the hospital indoor environment, being one of the most prevalent Aspergillus species {401; 342; 340}.

The presence of Aspergillus species in hospital air is considered a major risk factor for both invasive and allergic aspergillosis. The link between A. flavus infection and contamination of the environment has clearly been demonstrated by molecular typing methods {2428}. Almost all outbreaks of nosocomial aspergillosis in hospitals, including A. flavus, are attributed to airborne sources {344; 317}. The principal source of Aspergillus in hospitals is considered to be infiltration of conidia from the outside and the growth of the fungus on organic materials present throughout the hospital; acoustical ceiling tiles as well as plasterboard walls, when moistened, are excellent media for the growth and generation of airborne A. flavusconidia{526}. 

More details

Very specific measures must be undertaken to prevent contamination of areas at risk in hospitals. However despite such measures, air-path studies indicate that Aspergillus spores can enter the main hospital through doors, poorly sealed windows, and even walls {497}. However, source of contamination is not only from the outside, since A. flavus can be introduced by way of visitors, hospitalised patients {382} or damp building materials {509}.

In a new hospital, A. flavus was recovered from moistened material spawning airborne concentrations greater than 1 CFU/m3; this contamination was associated with an increased incidence of aspergillosis in immunocompromised patients {526}.

Contamination is often observed during active construction {497; 2465}  and several outbreaks of invasive aspergillosis have been associated with construction and/or renovation activities in and around hospitals. A comparative study of recent and older construction has demonstrated an occurrence of 80% of A. flavus in an old hospital wing compared with 23% in a contiguous newer wing {530}.

In a large hospital undergoing extensive indoor renovation and extensive demolition/building at several nearby sites, viable fungi samples (720 indoor samples) revealed that A. flavus was among the five most prevalent Aspergillus species with a mean concentration of 0.97 CFU/m3. In this study, three major incidents had contributed in increasing hospitalAspergillus concentrations, including improper sealing and water infiltration of a unit dedicated to bone marrow transplant patients {313}. Authors thereby concluded that multi-factorial preventive approaches should be undertaken, involving moisture/water control and sealed positive-pressure rooms; use of HEPA filters is also reported as an efficacious protective measure {313; 344}.

In a Greek hospital, surveillance air sampling performed in 4 departments with high-risk patients revealed that Aspergillusspp. were commonly recovered, including the presence of A. flavus in 17.7% of samples {2450}. A Brazilian study assessing fungal microbiota in air conditioners in intensive care units reported a prevalence of 40% for A. flavus, with fungal counts ranging between 104 and 234 CFU/m3 in the air {2445}.

In a four year Russian study, surveillance air samplings were also performed to investigate spread, species spectrum and quantity of Aspergillus spores in the air of a haematological hospital.  A. flavus was the third most prevalentAspergillus in the environment after A. fumigatus and A. niger.  In the haematological department, of the 33 patients who tested positive for Aspergillus, 42% were positive for A. flavus  {317}; A. fumigatus (44%), A. niger (8%), A. versicolor (3%) and Aspergillus spp. (3%) were also detected in these patients.  

A review of nosocomial Aspergillus sp. outbreaks in Germany affecting 458 patients revealed A. fumigatus (n = 154) andA. flavus (n = 101) as the most identified species.  A. flavus was reported in almost all cases involving superficial skin infections (24 patients in total) {2465}.

A. flavus has been reported as a cause of both native and prosthetic valve endocarditis, which is occasionally a manifestation of disseminated aspergillosis. In postoperative Aspergillus endocarditis, A. flavus accounted for 11% of cases {2428}. This species has  also been involved in 14 cases of endocarditis following implantation of cardioverter-defibrillators {2410}.  A. flavus was also recovered from sternal surgical-site infection in patients after cardiac surgery {509}.  Finally, a rare case of infection of breast implants by A. flavus has been reported {1797}.

It should be reminded that for some hospitalised patients, even concentrations of Aspergillus spp. below 1 CFU/m³ of air are considered sufficient to cause infection given the right set of circumstances {2465}.

Occupational diseases

Allergic and toxic health problems due to A. flavus exposure have been reported in the occupational setting. In particular, Type III hypersensitivity pneumonites due to Aspergillus flavus are known in occupational settings such as grain handling facilities.

More details

One study suggests that A. flavus could have played a role in the aetiopathology of bronchial asthma in asthmatic workers of a big cereal silo who were exposed to a high concentration of fungal species, including A. flavus. The airborne concentrations were assessed semi-quantitatively by passively exposing Petri dishes for 60 minutes: test results yielded 40 colonies of airborne A. flavus {2454}.

A. flavus was also a dominant species in fungal aerosol in a rural bakery in India (up to 1577 CFU/m3 of air). Antigenic extracts prepared from some of the dominant culturable fungi showed high levels of allergenicity in skin prick tests indicating that they may be responsible for allergic respiratory dysfunction in bakery workers {2401}.

A study of the environmental mycoflora of rice mills showed that of all the genera isolated, Aspergillus was predominant, with A. flavus being the most common isolate; total percentage of aflatoxin positive strains was 8%. This study indicates that rice mill workers are occupationally exposed to airborne dust containing A. flavus and its aflatoxins {1140}. Levels of airborne aflatoxins may also be significant as shown in a study of corn handling:  aflatoxin B1 and B2 concentrations in bulk corn were 223.9 and 17.5 ppb respectively, while gravimetric dust concentration in the air ranged from 7 mg/m3 to 417 mg/m³. The lesser concentration is that of respirable particles representing approximately 17% of total contaminated dust {1136}.

One study also reported suspected cases of aflatoxicosis in breeding budgerigars {3371} indicating the possibility of exposure to the toxins in birdfeed.

Diagnostic tools

Cultures

Direct examination of sinus secretions showing typical septate hyphal fragments is indicative of fungal sinusitis but must be followed by proper cultures to confirm A. flavus as the aetiological agent. 

The diagnosis of deep wound infections or of fistulae can be confirmed by definite microbiological diagnosis i.e. presence ofA. flavus on cultures of deep operative wound samples obtained from normally sterile tissues, such as cartilage or bone, during 1 episode or more {3531}. 

As for suspected ABPA cases, cultures may be negative or, when positive, are not sufficient to confirm the diagnosis: diagnosis is based on the characteristic clinical and laboratory findings of ABPA and specific hypersensitivity can be verified by immunodiagnostic tests (see Immunodiagnosis section).

Histopathology

The histological presentation of a deep sited infection due to A. flavus is typically that of an opportunistic fungal hyphal infection and cannot be distinguished from other aspergillosis. 

More details

Immunoperoxidase staining using the EB-A1 monoclonal antibody performs well on routinely processed tissue sections and enables the detection and generic identification of Aspergillus species, although it does appear overtly superior to conventional histopathology in identifying the presence of an infection. An additional advantage is that the immunostain may help provide an aetiological diagnosis when cultures remain negative {3450}.

Two anti-Aspergillus murine monoclonal antibodies (MAbs), designated 164G and 611F, have been produced; both specifically recognise cytoplasmic antigens of A. fumigatusA. flavus, and A. niger in enzyme-linked immunosorbent assays. The MAbs can identify Aspergillus spp, both in frozen sections by immunofluorescence and in paraffin-embedded clinical specimens by immunofluorescence and immunoperoxidase staining {3499}.

In some cases of deep sited infections, cultures and biopsies are not sufficient to identify the aetiological agent.  Such was the case of a child afflicted with acute myeloid leukaemia, who was treated with allogenic haematopoietic stem cell transplantation and developed cervicothoracic spinal osteomyelitis due to Aspergillus flavus. Diagnosis was difficult on a clinical basis, but made possible by conventional radiography and MRI {2404}.

Immunodiagnosis

Immunological tests detecting specific IgG may help in the diagnosis of infections and HP, whereas IgE assays and skin tests complement hypersensitivity diagnoses.  

More details

ABPA needs to be detected before onset of bronchiectasis because the occurrence of bronchiectasis is associated with poorer outcomes. Since many patients with early ABPA may be minimally symptomatic or asymptomatic, a high index of suspicion for ABPA should be maintained while managing any patient with bronchial asthma regardless of severity or level of control. This underscores the need for routine screening of all patients with asthma with an Aspergillus skin test.

When demonstration of specific IgG is required, immunodiffusion can be performed. The more sensitive ELISA method is also used but interpretation remains difficult: a larger number of sera from patients with well defined clinical types of aspergillosis and caused by various Aspergillus species, needs to be examined before any firm conclusions can be drawn as to ELISA titres and disease type. However, some patients do produce significant ELISA titres to antigenic extracts from species other than A. fumigatus in the absence of significant A. fumigatus ELISA titres {3532; 3520; 3533}.

Test IgE IgG Antigens Other
Skin Tests X      
RAST-IgE X      
RAST-IgG   Experimental    
ELISA-ELIFA   Experimental    
Immunodiffusion   X  Experimental  
Immunofluorescence      Experimental  
Complement fixation        
PCR        
Other      Experimental  

More details

A. flavus extracts for skin tests are not available commercially; experimentally-produced antigens have however been developed for use in sensitisation surveys. Aspergillus allergen mixes are commercially available for skin testing.

Antigenic extracts of Aspergillus flavus are available for IgE-RAST and double immunodiffusion tests as single extracts or pooled antigens.    

Aspergillus flavus antigens are part of the American  Food and Drug Administration (FDA) surveillance program and part of the Biological Product Deviation Reports mould list {3285}.

GJ08 - Aspergillus amsterdami
GJ09 - Aspergillus clavatus
GJ10 - Aspergillus flavipes
GJ11 - Aspergillus flavus
GJ12 - Aspergillus fumigatus
GJ13 - Aspergillus glaucus
GJ14 - Aspergillus nidulans
GJ15 - Aspergillus niger
GJ16 - Aspergillus ochraceus
GJ17 - Aspergillus restrictus
GJ18 - Aspergillus sydowi
GJ19 - Aspergillus terreus
GJ20 - Aspergillus ustus
GJ21 - Aspergillus versicolor

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July-28-16