Aspergillus clavatus

# Overview
Aspergillus clavatus is a species of Aspergillus with conidia dimensions 3-4.5 x 2.5-4.5 micrometres. It is found in soil and animal manure.
Can produce the toxin patulin which may be associated with disease in humans and animals.
This species is only occasionally pathogenic. This agent has been implicated in Hypersensitivity pneumonitis.
Hypersensitivity pneumonitis (HP) is not a single disease but is a complex syndrome of varying intensity, clinical presentation, and natural history.
The syndrome was first described in Iceland in 1874 and termed heykatarr. The syndrome is caused by sensitization to repeated inhalation of dusts containing one of 300 organic antigens. These organic dusts come from a wide variety of sources but most commonly include:
- Dairy and grain products
- Animal dander and protein
- Wood bark
- Water reservoir vaporizers
The two most common antigens are:
- Thermophilic actinomycetes and
- Avian proteins
As a rseult of exposure to thee antigens, the two most common causes (i.e. diseases) are:
- Farmer's lung and
- Bird fancier's lung
Pathologically, the HP syndrome is associated with diffuse inflammation of lung parenchyma and airways.
Based on the length and intensity of exposure and subsequent duration of illness, there are 3 clinical presentations of HP:
- Acute
- Subacute (intermittent)
- Chronic progressive
Synonyms and related keywords: hypersensitivity pneumonitis, HP, bird fancier's lung, extrinsic allergic alveolitis, farmer's lung, Saccharopolyspora rectivirgula, S rectivirgula, Micropolyspora faeni, M faeni, Thermoactinomyces sacchari, T sacchari, Thermoactinomyces vulgaris, T vulgaris, Penicillium casei, P casei, Aspergillus clavatus, A clavatus, Mucor stolonifer, M stolonifer, Sitophilus granarius, S granarius, Cladosporium, heykatarr, bagassosis, grain handler's lung, humidifier lung, air-conditioner lung, bird breeder's lung, cheese worker's lung, malt worker's lung, paprika splitter's lung, mollusk shell hypersensitivity, chemical worker's lung, pulmonary disease, lung disease.

# Epidemiology and Demographics
- The prevalence of HP varies significantly by region, climate, occupation/exposure and farming practices.
- Farmers:
US: 8-540 cases per 100,000 persons per year among those at risk
UK: 420-3000 cases per 100,000 persons per year among those at risk
France: 4370 cases per 100,000 persons per year among those at risk
Finland: 1400-1700 cases per 100,000 persons per year among those at risk
- US: 8-540 cases per 100,000 persons per year among those at risk
- UK: 420-3000 cases per 100,000 persons per year among those at risk
- France: 4370 cases per 100,000 persons per year among those at risk
- Finland: 1400-1700 cases per 100,000 persons per year among those at risk
- Pigeon Breeders: 6000-21,000 cases per 100,000 persons per year
- Bird Fanciers: 20-20,000 cases per 100,000 persons per year
- Attack rates vary considerably, but can be high in sporadic outbreaks. For example a large proportion (52%) of office workers exposed to an infected humidifier were affected in one outbreak, and in another outbreak 27% of workers at a molding plant for polyurethane foam parts were affected.
- The male to female ratio is approximately 1.2:1.
- The mean age of the patients with HP is 61  0.7 years (epidemiologic data from Spain).

# Risk Factors
The following is a partial list of occupations and major causative antigens that put a patient at risk of HP:
- Farmers and cattle workers: These workers develop the most common form of HP which is caused by the antigen thermophilic actinomycetes.  It is important to note that while Farmer's lung is the most common cause of HP, it still must be distinguished from febrile toxic reactions to inhaled mold dusts (organic dust toxic syndrome, a nonimmunologic reaction) which occurs 30-50 times more often than HP.
- Poultry and other bird handlers: These workers are exposed to droppings, feathers, and serum proteins of pigeons and other birds.
- Ventilation workers and those exposed to water-related contamination: These workers may be exposed to microorganisms thatcolonize humidifiers, forced-air systems, hot tubs, whirlpools, and spas. The putative antigens are derived from Thermoactinomyces or Cladosporium.
- Veterinarians and animal handlers: These workers obviously have daily contact with a large variety of animals and organic antigens.
- Grain and flour processors and loaders: These workers are exposed to grain. Grain can become colonized with a variety of microorganisms and their antigens.
- Lumber mill workers and paper and wallboard manufacturers: These workers are exposed to wood which can become colonized with molds and then becomes aerosolized.
- Plastic manufacturers, painters, and electronics industry workers: These workers can be exposed to  diphenylmethane diisocyanate or toluene diisocyanate.
- Textile workers: These workers do develop lung injury but this is not a true form of HP. The injury is characterized by diffuse alveolar damage or airway dysfunction and includes diseases such as byssinosis and nylon worker's lung.

# Pathophysiology & Etiology

## Pathologic Findings

### Acute HP
There are noncaseating interstitial granulomas and mononuclear cell infiltration in a peribronchial distribution. Giant cells are prominent.

### Subacute or intermittent HP
The noncaseating granulomas are more well formed.  There is bronchiolitis with or without organizing pneumonia. Interstitial fibrosis is present.

### Chronic HP
There is chronic interstitial inflammation and alveolar destruction (honeycombing). There is dense fibrosis.  The pathologic findings of chronic HP that are often associated with a poorer prognosis include the following 3 patterns of fibrosis:
- Predominantly peripheral fibrosis: in a patchy pattern with architectural distortion and fibroblast foci similar to usual interstitial pneumonia (UIP)
- Homogeneous linear fibrosis: similar to fibrotic nonspecific interstitial pneumonia (NSIP)
- Irregular predominantly peribronchiolar fibrosis

## Pathophysiology of Immune Response
Exposure results in the development of circulating immunoglobulin G antibodies that are specific for the offending antigen. This antibody that forms is called the precipitating antibody, and it reacts with the specific putative antigen to form a precipitant.  Initially the disease process was thought to be immunecomplex-mediated. However, subsequent studies have demonstrated that cell-mediated immunity is more important.
In the acute phase, there is a local increase in neutrophils in the alveoli and small airways. This is followed by an influx of mononuclear cells which release proteolytic enzymes, prostaglandins, and leukotrienes.

# Natural History
- In general, the majority of patients recover completely after the inciting exposure ceases.
- The prognosis of Bird Fancier's Disease is worse than Farmer's Lung.
- Other varieties of HP have more variable outcomes.

# Diagnosis

## The 6 Diagnostic Criteria for Hypersensitivity Pneumonitis (HP)
When combined with the appropriate epidemiologic data and in areas of high prevalence, these criteria can establish the diagnosis of HP without the need for bronchoalveolar lavage (BAL) or biopsy (Lacasse, 2003).
- Exposure to a known offending antigen
- Positive precipitating antibodies to the offending antigen
- Recurrent episodes of symptoms
- Inspiratory crackles on physical examination
- Symptoms occurring 4-8 hours after exposure
- Weight loss

## Conditions That Can Mimic HP
Other diseases that are secondary to inhalation of organic agents but are not true forms of HP are as follows:
- Inhalation fever: Patients present with fever, chills, headache, and myalgias however there are not pulmonary findings (although mild dyspnea may occur). Onset is 4-8 hours following exposure.  There are no long-term sequelae occur.
- Organic dust toxic syndrome: This syndrome is the result of exposure to bioaerosols contaminated with toxin-producing fungi (mycotoxins). Patients present with fever, chills, and myalgias 4-6 hours after exposure. In contrast to inhalation fever, the chest X ray may show diffuse opacities. Bronchiolitis or diffuse alveolar damage may be present on lung biopsy specimens. This is not a true form of HP because no prior sensitization is required.
- Chronic bronchitis: This can result from chronic obstructive pulmonary disease, which is the most common respiratory syndrome among agricultural workers. The prevalence of chronic bronchitis is much higher  at 10%, compared with 1.4% for HP.
- Exposure to aerosolized Mycobacterium avium complex (MAC): A hypersensitivity pneumonitis like syndrome has been described in patients exposed to aerosolized Mycobacterium avium complex (MAC). Hot tub lung is a term used to describe these hypersensitivity pneumonitis-like cases because they have generally been associated with hot tub use. The syndrome has been linked to the high levels of infectious aerosols containing MAC organisms found in the water. Whether this syndrome represents a true MAC infection or classic HP remains controversial (Marras, 2005).

## Differential Diagnosis
By frequency of Interstitial Lung Diseases (Xaubet, 2004):
- Idiopathic pulmonary fibrosis (38.6%)
- Sarcoidosis (14.9%)
- Cryptogenic organizing pneumonia (10.4%)
- Interstitial lung disease associated with collagen vascular diseases (9.9%)
- Hypersensitivity Pneumonitis (HP) (6.6%)
- Unclassified (5.1%)
In alphabetical order:
Air-conditioner lung
Aspergillus clavatus
Bagassosis
Bird breeder's lung
Bird fancier's lung
Cheese worker's lung
Chemical worker's lung
Cladosporium
Farmer's lung
Grain handler's lung
Humidifier lung
Malt worker's lung
Micropolyspora faeni
Mollusk shell hypersensitivity
Mucor stolonifer
Paprika splitter's lung
Penicillium casei
Saccharopolyspora rectivirgula
Sitophilus granarius
Thermoactinomyces sacchari
Thermoactinomyces vulgaris

## History and Symptoms
History: The clinical presentation of HP is categorized as acute, subacute, or chronic, according to duration of illness.

### Acute HP
- Symptoms develop 4-6 hours following exposure to the inciting agent and then generally resolve spontaneously within 12 hours to several days upon removal of the inciting agent.
- Symptoms include the abrupt development of
fever
chills
malaise
cough
chest tightness
dyspnea
headache
malaise.
- fever
- chills
- malaise
- cough
- chest tightness
- dyspnea
- headache
- malaise.

### Subacute or Iintermittent HP
- Symptoms include the gradual development of
productive cough
dyspnea
fatigue
anorexia
weight loss
- productive cough
- dyspnea
- fatigue
- anorexia
- weight loss
- The same symptoms may be present in patients who experience acute attacks on multiple occasions.
Patients with subacute HP present similarly to patients with acute disease, but symptoms are less severe and last longer.

### Chronic HP
Patients often lack a history of acute episodes.
They have an insidious onset of cough, progressive dyspnea, fatigue, and weight loss.
Removing exposure results in only partial improvement.

## Physical Examination
In general, the signs of acute, subacute and chronic forms of the disease are similar except patients with the chronic form may have clubbing, weight loss and muscle wasting.

### Appearance of the Patient
Weight loss is present in the chronic form of the syndrome.

### Vital Signs
Fever and tachypnea are often present.

### Lungs
Diffuse fine bibasilar crackles

### Extremities
Clubbing is observed in 50% of patients with the chronic form of the syndrome.
Muscle wasting is also observed in the chronic form of the syndrome.

## Laboratory Findings

### Chest X Ray

### Other Imaging Findings

## Other Diagnostic Studies
A test to assess for precipitating antibodies to the offending antigen will be positive.

# Risk Stratification and Prognosis
- In general, the majority of patients recover completely after the inciting exposure ceases.
- The prognosis of Bird Fancier's Disease is worse than Farmer's Lung.
- Other varieties of HP have more variable outcomes.

# Treatment

## Pharmacotherapy

### Acute Pharmacotherapies

### Chronic Pharmacotherapies

## Primary Prevention

## Secondary Prevention