Introduction
- Encompasses a variety of clinical syndromes depending on host immunity factors
Definition
Invasive Aspergillosis (IA)
- A rapidly progressive and frequently fatal invasive fungal disease (IFD) that occurs in highly immunocompromised individuals and critically ill patients
- Most common cause of infectious pneumonic mortality in patients undergoing hematopoietic stem cell transplantation (HSCT) and is a notable cause of opportunistic respiratory and disseminated infection in other immunocompromised patients
- Coronavirus disease 2019 (COVID-19) predisposes patients to secondary pulmonary aspergillosis known as COVID-19-associated pulmonary aspergillosis (CAPA)
- Please refer to COVID-19-associated pulmonary aspergillosis (CAPA) section
- Please see Coronavirus Disease 2019 (COVID-19) disease management chart for further information
- Coronavirus disease 2019 (COVID-19) predisposes patients to secondary pulmonary aspergillosis known as COVID-19-associated pulmonary aspergillosis (CAPA)
- Inhalation of etiologic agent is extremely common but disease is rare
- Any organ may be involved in the immunocompromised host, but sinopulmonary disease is the most frequent
Allergic Bronchopulmonary Aspergillosis (ABPA)
- A hypersensitivity reaction to Aspergillus antigens often due to A fumigatus and typically occurs in patients with long-standing asthma or cystic fibrosis
- It is believed that the pathogenesis involves Aspergillus-specific, IgE-mediated type I hypersensitivity reaction and specific immunoglobulin G (IgG)-mediated type III hypersensitivity reactions
Allergic Aspergillus Sinusitis (AAS)
- A hypersensitivity response to the presence of Aspergillus within the paranasal sinuses and is characterized by mucoid impaction similar to that of ABPA
Aspergilloma
- Conglomeration of intertwined Aspergillus hyphae, fibrin, mucus and cellular debris within a pulmonary cavity or an ectatic bronchus
- Most common pulmonary involvement due to Aspergillus
- Pre-existing lung cavity formed secondary to tuberculosis, sarcoidosis, bronchiectasis, bronchial cysts and bullae, ankylosing spondylitis, neoplasm or pulmonary infarction is the most common predisposing factor
Chronic Pulmonary Aspergillosis (CPA)
- Subtypes include chronic cavitary pulmonary aspergillosis (CCPA), chronic fibrosing pulmonary aspergillosis (CFPA), Aspergillus nodules, single (simple) aspergilloma, and subacute invasive pulmonary aspergillosis (previously known as chronic necrotizing pulmonary aspergillosis)
- CCPA is the most common manifestation of CPA, which may progress to CFPA when left untreated
- A pulmonary aspergillosis that commonly causes a slowly progressive inflammatory destruction of lung tissue in patients with underlying lung diseases and low-grade immunosuppression usually due to invasion by A fumigatus
- Present globally in 1.2 million patients with high incidence and prevalence rates in Africa, the western Pacific and Southeast Asia
- No vascular involvement or dissemination to other organs
Cutaneous Aspergillosis
- Primary cutaneous aspergillosis is usually resulting from a skin disruption site (eg intravenous [IV] devices, adhesive dressing, surgical wound, burn) creating access for the infection, or traumatic inoculation
- Secondary cutaneous aspergillosis results from hematogenous seeding from a primary source in immunocompromised patients
Otic Aspergillosis/Otomycosis
- Also called non-invasive Aspergillus otitis externa
- A condition of superficial colonization typically due toA niger and A fumigatus
- Usually occurs in patients with hypogammaglobulinemia, diabetes mellitus (DM), chronic eczema or human immunodeficiency virus (HIV) infection and those taking corticosteroids
COVID-19-Associated Pulmonary Aspergillosis (CAPA)
- A secondary form of invasive pulmonary aspergillosis in temporal proximity to a prior SARS-CoV-2 infection
- Associated with high mortality rate
- Leading fungal disease in COVID-19 patients with acute respiratory distress syndrome (ARDS)
Proposed Definitions for CAPA
- Proven CAPA: Tracheobronchitis or other pulmonary form of infection in patients with COVID-19 needing intensive care with ≥1 of the following:
- Direct microscopic or histopathological detection or both of fungal hyphae that are morphologically consistent with Aspergillus sp, showing invasive growth with associated tissue damage or
- Aspergillus sp recovered by culture, microscopy, histology or PCR obtained by a sterile aspiration or biopsy from a pulmonary site, showing an infectious disease process
- Probable CAPA
- Tracheobronchitis indicated by tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar, alone or in combination, seen on bronchoscopic analysis in patients with COVID-19 needing intensive care with ≥1 of the following:
- Microscopic detection of fungal elements in bronchoalveolar lavage (BAL), indicating a mold or
- Positive BAL or culture or PCR or
- 1 serum galactomannan index >0.5 or serum lateral flow assay (LFA) index >0.5 or
- BAL galactomannan index ≥1.0 or BAL LFA index ≥1.0
- Other pulmonary forms of infection are indicated by pulmonary infiltrate preferably documented by chest CT or cavitating infiltrate not attributed to another cause in patients with COVID-19 needing intensive care with ≥1 of the following:
- Microscopic detection of fungal elements in BAL, indicating a mold or
- Positive BAL culture or
- Serum galactomannan index >0.5 or serum LFA index >0.5 or
- BAL galactomannan index ≥1.0 or BAL LFA index ≥1.0 or
- ≥2 positive Aspergillus PCR in serum, plasma or whole blood or
- A positive Aspergillus PCR in BAL fluid (<36 cycles) or
- A positive Aspergillus PCR in serum, plasma, or whole blood and a positive Aspergillus PCR in BAL fluid (any threshold cycle)
- Tracheobronchitis indicated by tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar, alone or in combination, seen on bronchoscopic analysis in patients with COVID-19 needing intensive care with ≥1 of the following:
- Possible CAPA: Other pulmonary forms of infection indicated by pulmonary infiltrate preferably documented by chest CT or cavitating infiltrate not attributed to another cause in patients with COVID-19 with ≥1 of the following:
- Microscopic detection of fungal elements in non-bronchoscopic lavage indicating a mold or
- Positive non-bronchoscopic lavage culture or
- A non-bronchoscopic lavage galactomannan index >4.5 or
- Non-bronchoscopic lavage galactomannan index >1.2 and another positive non-bronchoscopic lavage mycology test (PCR or LFA)
Etiology
- Caused by Aspergillus, a ubiquitous, soil-dwelling, filamentous fungus that grows on soil, food, dead leaves, household dust, etc
- Grows best at 37°C, the small spores are easily inhaled and deposited deep in the lungs
- The most common pathogens are Aspergillus fumigatus, A flavus, A niger and A terreus
- Other species can also cause aspergillosis, including A nidulans, A lentulus and A clavatus
- In immunocompetent persons, aspergillosis can occur in previously damaged tissue or induce allergic responses
Signs and Symptoms
Invasive Aspergillosis (IA)
- Clinical manifestations include:
- Fever refractory to empirical broad-spectrum antibacterials
- Cough
- Pleural pain
- Paranasal sinus findings
- Hemoptysis
Allergic Bronchopulmonary Aspergillosis (ABPA)
- Patient usually presents with expectoration of brown mucus plugs, wheezing, fever and pleuritic chest pain
Allergic Aspergillus Sinusitis (AAS)
- Patient usually presents with nasal obstruction, rhinorrhea, headache and epistaxis
- May occasionally manifest as proptosis due to extension of fungal sinusitis into the orbit
Aspergilloma
- Aspergilloma may exist for many years without causing symptoms
- Hemoptysis that can be severe and life-threatening
- Chronic cough and dyspnea that are more likely due to underlying disease
- Fever (rare)
Chronic Pulmonary Aspergillosis (CPA)
- Chronic pulmonary symptoms (fever, cough with or without hemoptysis, dyspnea, fatigue, chest pain, sputum production, weight loss) of at least 3 months’ duration
Cutaneous Aspergillosis
- Erythematous indurated papules that progresses into ulcerative necrotic lesions
Otic Aspergillosis/Otomycosis
- Patient may usually present with ear pain, pruritus, hypoacusis and otic discharge
COVID-19-Associated Pulmonary Aspergillosis (CAPA)
- COVID-19 patients with refractory respiratory failure for >5-14 days despite receiving recommended therapy should be suspected of CAPA
- Onset of signs and symptoms is variable
- May present any of the following signs and symptoms:
- Refractory fever >3 days or new fever after a period of defervescence >48 hours during optimal antibiotic treatment not attributed to other causes
- Worsening respiratory function (eg tachypnea, increasing oxygen requirements)
- Hemoptysis
- Pleural friction rub or chest pain
Risk Factors
Invasive Aspergillosis (IA)
- Major risk factors include:
- Prolonged neutropenia (neutrophil count <100/μL for >10 days)
- Intensive cytotoxic chemotherapy or use of biologic agents
- Hematopoietic stem cell transplantation (HSCT) or solid-organ transplantation
- Acquired immune deficiency syndrome (AIDS)
- Chronic lung disease (eg asthma, chronic obstructive pulmonary disease [COPD], sarcoidosis, tuberculosis, nontuberculous mycobacterial infection, allergic bronchopulmonary aspergillosis [ABPA])
- Chronic granulomatous disease (CGD)
- Critical illness without documented immunodeficiency
- Hematologic malignancies
- Severe aplastic anemia
- Primary immunodeficiencies
- Prolonged corticosteroid use
- Cytomegalovirus disease
COVID-19-Associated Pulmonary Aspergillosis (CAPA)
- Severe lung damage during COVID-19 disease
- Use of corticosteroids for ARDS
- Use of broad-spectrum antibiotics
- Underlying medical conditions in particular presence of structural pulmonary defects