Invasive aspergillosis
Synonyms and keywords:

# Overview
Aspergillosis is a heterogenous group of infectious diseases caused by Aspergillus (commonly A. fumigatus), a ubiquitous fungus. Aspergillosis 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 first it was describe in animals later it was discovered in human.
- The exact date of discovery of aspergillus as pathogenic organism is unknown.

# Pathophysiology
- Aspergillus is primarily transmitted to the human  by inhalation of airborne conidia (usually dust exposure during building renovation or construction) or contaminated biomedical devices.
- Aspergillus is not transmitted from human to human.
- 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).
- Inhaled conidia  (Spore ) are met by the innate defenses provided by resident phagocytes, specifically, airway epithelial cells and alveolar macrophages.
- Macrophages, contribute to both conidial clearance and the production of secondary inflammation.
- These cells secrete inflammatory mediators after recognition of key cell wall components (eg, beta-D-glucan) exposed after conidial germination into hyphal forms.
- These mediators result in neutrophil recruitment and the activation of cellular immunity, which are important in killing potentially invasive microbial forms (hyphae) and determining the extent and nature of the immune response. Hence, risks for disease and the type of disease that occurs are the combined result of multiple cellular functions that impact proximal events in conidial clearance, production of inflammation, and killing of invasive forms.
- Inhibit phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, a key component in host defense against filamentous fungi.
- Inhibit macrophage phagocytosis and killing.
- Suppress functional T-cell responses.

# Risk Factor
Aspergillosis is cause by Aspergillus fumigatum, flavus and terreus.
respiratory system is root of entry. Aspergillus fumigatus is cause of invasive aspergillosis.
In an  immunosuppressed  host, infection present as allergic sinusitis, bronchitis or localized pulmonary infection.
- The major predisposing factor developing invasive aspergillosis are
- Agglutinating surface surfactant protein deficiency
- Deficiency of C3, C5 complement factors
- Inhibition of anti-conidial macrophage
- Thrombocytopenia and neutropenia
- Low count of CD4+ T lymphocytes
- Failure to produce IL-12 , Interferon or tumor necrosis factor
- Prolong antibiotic or  glucocorticoid use.

# Natural History, Complications, and Prognosis

## Pulmonary aspergillosis
- Invasive aspergillosis most commonly involves the lungs.
- . Patients can present with
- fever
- chest pain
- shortness of breath
- cough or hemoptysis
- The classic triad that has been described in neutropenic patients with pulmonary aspergillosis is fever, pleuritic chest pain, and hemoptysis.
- However, absence of this triad should not discourage consideration of this diagnosis in the patient with risk factors for disease since neutropenic patients frequently present with fever in the absence of localizing pulmonary symptoms. In such patients, lung imaging often reveals pulmonary nodules or infiltrates.
- Pulmonary aspergillosis present as single or multiple nodules with or without cavitation patchy or segmental consolidation or peribronchial infiltrates with or without tree-in-bud patterns on chest X- ray.

## Tracheobronchitis
- commonly in lung transplant recipients, but has also been described in other types of hosts (eg, recipients of other solid organ transplants, patients with hematologic malignancies, patients with HIV infection )
- Thick mucus plugs filled with Aspergillus hyphae are found in the airways, with little mucosal inflammation or invasion these finding called obstructive bronchial aspergillosis.
- Extensive inflammation and invasion of the tracheobronchial tree with a pseudomembrane composed of necrotic debris and Aspergillus hyphae overlying the mucosa which is called pseudomembranous tracheobronchitis.
- Ulcerative tracheobronchitis, in which there is focal invasion of the tracheobronchial mucosa or cartilage by fungal hyphae.

## Central nervous system
- CNS aspergillosis may occur in the setting of disseminated infection, as well as from local extension from the paranasal sinuses. Patients with CNS involvement with Aspergillus spp may present with seizures or focal neurological signs
- Finding in computed tomography and magnetic resonance imaging :
- Ring enhancing lesions consistent with brain abscesses
- Cerebral cortical and subcortical infarction with or without superimposed hematomas
- Mucosal thickening of a paranasal sinus with secondary intracranial dural enhancement consistent with direct extension from the sinuses
- CNS infection is associated with a very poor prognosis.

# Diagnosis

## Complete Blood Count
- Eosinophilia

## Electrophoresis
- Elevated concentration of serum immunoglobulin E (IgE)

## Biomarkers
- Positive galactomannan assay
- Positive beta-D-glucan assay

## Culture
- Positive culture and staining from sputum or from bronchoalveolar lavage (BAL)
- Culture can be performed on a variety of sterile specimens. Aspergillus typically appear as rapidly growing molds that are visible 1-3 days following incubation.
- Patients with invasive aspergillosis may have negative cultures.

# Medical Treatment

## Invasive pulmonary aspergillosis
- Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
- Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 35 mg/kg/day IV qd
- Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV qd
- Alternative regimen (3): Caspofungin 70 mg IV single dose then 50 mg/day IV qd
- Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
- Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV qd
- Alternative regimen (6): Micafungin 100150 mg/day PO qd
- Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

## Invasive sinus aspergillosis
- Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
- Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 35 mg/kg/day IV qd
- Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV qd
- Alternative regimen (3): Caspofungin 70 mg IV single dose  then 50 mg/day IV qd
- Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
- Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV qd
- Alternative regimen (6): Micafungin 100150 mg/day PO qd.