Aspergillosis overview

# Overview
Aspergillosis is a heterogenous group of infectious diseases caused by Aspergillus (commonly A. fumigatus), a ubiquitous fungus. Apergillosis may be classified according to the clinical syndrome it causes into allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, aspergilloma, chronic pulmonary aspergillosis, invasive aspergillosis, or cutaneous aspergillosis. Aspergillus is primarily transmitted to the human host by either inhalation of airborne conidia (usually during dust exposure during building renovation or construction) or by contaminated biomedical devices, but not from one individual to another. The pathogenesis of aspergillosis varies according to the associated clinical syndrome. Allergic bronchopulmonary aspergillosis and allergic Aspergillus rhinosinusitis are thought to be caused by both type I and type III hypersensitivity immune responses. On the other hand, the development of aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis is directly related to the growth and expansion of the Aspergillus hyphae in the lungs. Lastly, cutaneous aspergillosis may result either from direct access of the Aspergillus through a skin break (primary) or dissemination of the Aspergillus to the skin from a distant infected organ (secondary). Immunocompromised status (e.g. organ or stem cell transplant recipient) and history of prior lung disease are the most important risk factors in the development of aspergillosis. Other risk factors include history of asthma, burn or surgical site wounds, and exposure to healthcare settings or construction sites. Following transmission, the majority of patients do not develop any clinical manifestations. The incubation of Aspergillosis is highly dependent on the host immune factors. The incubation period may range from a few days to years, during which the host is asymptomatic. Among immunocompetent hosts, Aspergillosis may result in a localized pulmonary infection, allergic bronchopulmonary aspergillosis, or allergic Aspergillus sinusitis. Accordingly, patients usually appear healthy but develop symptoms of asthma or sinusitis. Among immunocompromised hosts, Aspergillosis progresses faster and has a more invasive course, and patients are often sick-looking and lethargic. If aspergillosis among immunocompromised patients is left untreated, it often progresses, and patients report worsening fever, chest pain, and hemoptysis. Specifically, invasive aspergillosis eventually disseminates to non-pulmonary organs and results in life-threatening complications. PCR is the method of choice for the diagnosis of aspergillosis. A single negative PCR result is sufficient to rule out aspergillosis, whereas two positive test results are required to confirm the diagnosis. Laboratory findings consistent with the diagnosis of aspergillosis include positive aspergillus antibody test, positive galactomannan test, elevated concentration of IgE immunoglobulin, and positive culture from sputum or bronchoalveolar lavage. Imaging may also be helpful, particularly in the diagnosis of aspergilloma, whereby a mobile mass (fungus ball) within a pulmonary cavity is characteristic. Treatment usually includes antifungal pharmacotherapy. Steroid administration and surgical intervention may also be indicated in some clinical syndromes. There is no vaccine against Aspergillus. Effective preventive measures include avoiding exposure to Aspergillus by personal protective equipment in dusty environments around construction sites, avoiding activities that require exposure to soil (such as yard work or gardening), and properly cleaning wounds. Prophylactic antifungal drugs is not recommended for the general population. Pharmacologic prophylaxis may be helpful in individual cases among immunocompromised patients.

# Historical Perspective
Aspergillus is an ancient mold that has first been described in animals before it was discovered to be also pathogenic in humans. The exact date of discovery of Aspergillus as a pathogenic organism is unknown.

# Classification
Apergillosis may be classified according to the clinical syndrome it causes into allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, aspergilloma, chronic pulmonary aspergillosis, invasive aspergillosis, or cutaneous aspergillosis.

# Pathophysiology
Aspergillus is primarily transmitted to the human host by inhalation of airborne conidia (usually dust exposure during building renovation or construction) or contaminated biomedical devices. Aspergillus is not transmitted from one individual to another. The pathogenesis of aspergillosis varies according to the associated clinical syndrome. Allergic bronchopulmonary aspergillosis and allergic Aspergillus rhinosinusitis are thought to be caused by both type I and type III hypersensitivity immune responses. Aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis are directly related to the growth and expansion of the Aspergillus hyphae in the lungs. Lastly, cutaneous aspergillosis may result either from direct access of the Aspergillus through a skin break (primary) or dissemination of the Aspergillus to the skin from a distant infected organ (secondary).

# Causes
Aspergillosis is caused by the fungus Aspergillus, commonly A. fumigatus. Aspergillus is ubiquitous in the environment.

# Differential Diagnosis
Aspergillosis must be differentiated from other diseases that cause fever, chest pain, dyspnea, sinusitis, allergic symptoms, and elevated IgE concentrations. Differential diagnosis includes other infections (fungi, bacteria, viruses, and parasites), non-infectious pulmonary diseases (such as asthma, COPD, interstitial lung disease, bronchiectasis, and lung tumors), cardiac diseases (such as pericarditis, endocarditis, or myocarditis), facial diseases (such as infectious sinusitis, sinus tumor, or nasal polyps), systemic diseases (such as Hyper IgE syndrome, Churg-Strauss syndrome, granulomatosis with polyangiitis, Goodpasture's syndrome), congenital diseases (such as cystic fibrosis or ciliary dyskinesia), transplant-related complications (such as GVHD), diseases with cutaneous manifestations (such as eczema, scabies, deep vein thrombosis, cellulitis), and adverse drug reactions.

# Epidemiology and Demographics
The true incidence of aspergillosis is unknown since aspergillosis is not a reportable disease in the USA. The annual incidence of allergic bronchopulmonary aspergillosis is estimated to be 5 million worldwide. In contrast, invasive aspergillosis is much less common with an incidence of approximately 1 to 2 cases per 100,000 individuals. There is no gender predilection for the development of aspergillosis. Individuals of all age groups may be affected with aspergillosis. Elderly patients with long-standing chronic lung diseases and neonates are more likely to develop aspergillosis. With the advancement of immunosuppressive therapy and higher rates of transplantation, the incidence and detection of aspergillosis is increasing in developed countries.

# Risk Factors
Immunocompromised status and history of prior lung disease are the most important risk factors in the development of aspergillosis. Other risk factors include history of asthma, burn or surgical site wounds, and exposure to healthcare settings or construction sites.

# Natural History, Complications and Prognosis
Following transmission, the majority of patients do not develop any clinical manifestations. The incubation of Aspergillosis is highly dependent on the host immune factors. The incubation period may range from a few days to years, during which the host is asymptomatic. Among immunocompetent hosts, Aspergillosis may result in a localized pulmonary infection, allergic bronchopulmonary aspergillosis, or allergic Aspergillus sinusitis. Clinical manifestations may vary depending on the clinical syndrome. Among immunocompromised hosts, on the other hand, Aspergillosis progresses faster and has a more invasive course. If left untreated, aspergillosis in immunocompromised patients often progresses, and patients report worsening fever, chest pain, and hemoptysis. Invasive aspergillosis eventually disseminates to non-pulmonary organs results in life-threatening complications.

# Diagnosis

## Diagnostic Criteria
Diagnostic criteria are available for allergic bronchopulmonary aspergillosis and for allergic fungal rhinosinusitis. Major and minor diagnostic criteria are based on clinical, laboratory, and radiological findings.

## History and Symptoms
Symptoms of aspergillosis are dependent on the clinical syndrome and extent of disease invasion. Patients with allergic bronchopulmonary aspergillosis or sinusitis have symptoms typical of asthma and sinusitis, respectively. Symptoms of invasive pulmonary aspergillosis include spiking fever, pleuritic chest pain, productive cough, dyspnea, and hemoptysis. Symptoms of chronic pulmonary aspergillosis include chronic fever, weight loss, productive cough, and hemoptysis.

## Physical Examination
Patients with invasive pulmonary aspergillosis often appear sick-looking, lethargic, and fatigued. In contrast, patients with pulmonary aspergilloma, allergic bronchopulmonary aspergillosis, or allergic sinusitis often appear healthy. Physical examination of patients with pulmonary or invasive aspergillosis is usually remarkable for decreased breath sounds, wheezes, rales, and increased tactile fremitus. Physical examination of patients with cutaneous aspergillosis is usually remarkable for either single or multiple erythematous-to-violaceous cutaneous papules, macules, nodules, or plaques.

## Laboratory Findings
PCR is the method of choice for the diagnosis of aspergillosis. A single negative PCR result is sufficient to rule out aspergillosis, whereas two positive test results are required to confirm the diagnosis. Laboratory findings consistent with the diagnosis of aspergillosis include positive aspergillus antibody test, positive galactomannan test, elevated concentration of IgE immunoglobulin, and positive culture from sputum or bronchoalveolar lavage.

## Chest X Ray
Chest X-ray may be helpful in the diagnosis of aspergillosis. Chest X-ray may be remarkable for recurrent pulmonary infiltrates in allergic bronchopulmonary aspergillosis. Findings on chest X-ray suggestive of aspergilloma include a well demarcated, round soft tissue mass located inside an air space cavity of the lungs. Multiple cavities with evidence of fibrosis are suggestive of chronic pulmonary aspergillosis, whereas focal nodules and infiltration are suggestive of invasive aspergillosis.

## CT Scan
Chest CT scan may be helpful in the diagnosis of aspergillosis. Findings on chest CT scan suggestive of aspergillosis include a well formed cavity, a central soft tissue attenuating oval shaped, well circumscribed mass surrounded by an cresent of air (Monad sign).

## Other Diagnostic Studies
Skin biopsy may be helpful in the diagnosis of cutaneous aspergillosis.

# Treatment

## Medical Therapy
Patients with allergic bronchopulmonary aspergillosis require antifungal pharmacotherapy, as well as oral steroids and optimization of asthma control. Patients with allergic Aspergillus rhinosinusitis require de-obstruction, nasal drainage, oral steroids, immunotherapy against allergens, and allergy control. Aspergilloma fungus ball usually requires surgical resection. Chronic pulmonary aspergillosis, invasive aspergillosis, and cutaneous aspergillosis may be treated with antifungal pharmacotherapy. Surgery may be required in severe cases of cutaneous aspergillosis for debridement or amputation.

## Surgery
Surgery is required for the treatment of an aspergilloma fungus ball. Endocarditis caused by Aspergillus is treated by surgical repair of the heart valve.

## Primary Prevention
There is no vaccine against Aspergillus. Effective preventive measures include avoiding exposure to Aspergillus by personal protective equipment in dusty environments around construction sites, avoiding activities that require exposure to soil (such as yard work or gardening), and properly cleaning wounds. Prophylactic antifungal drugs is not recommended for the general population. Pharmacologic prophylaxis may be helpful among individual cases of immunocompromised patients.