History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors include allogeneic stem cell transplantation, prolonged severe neutropenia (>10 days), immunosuppressive therapy, chronic granulomatous disease (CGD), acute leukaemia, aplastic anaemia, and solid organ transplantation for invasive aspergillosis, and the presence of pre-existing cavities for aspergilloma.
uncommon
pleuritic chest pain
Invasive aspergillosis (IA): peripheral lesions in lung usually lead to this symptom. Pleuritic pain in a persistently neutropenic patient or stem cell recipient must raise the suspicion of IA.
pleural rub
The presence of a pleural rub in high-risk patients is highly suggestive of invasive aspergillosis.
nasal ulcer
Invasive aspergillosis: ulcer with an eschar or an anaesthetic area.
skin rash
Invasive aspergillosis: rapidly increasing erythematous, slightly tender, raised lesion, single or multiple with a necrotic, often ulcerated, centre (ecthyma gangrenosum) mostly seen in immunocompromised patients. May occur in the setting of disseminated disease or local invasion after trauma. Occasionally, burns or surgical wounds may be infected with Aspergillus.
Other diagnostic factors
common
cough
Invasive aspergillosis: usually non-productive, mild to moderate in severity, and frequently absent. Rejection of transplanted lung may present as cough.
Chronic pulmonary aspergillosis: may present with chronic productive cough.
headache
Invasive aspergillosis: may be related to sinus or intracranial disease.
fever
Invasive aspergillosis (IA): non-specific, suggestive of a systemic process. Suggestive of IA in neutropenic patients, particularly if fever is persistent despite broad-spectrum antibiotic coverage.
Chronic pulmonary aspergillosis: fever is an uncommon finding, but it may be present in patients with secondary bacterial infection.
congestion or sinus tenderness
Invasive aspergillosis: may be present in invasive sinus disease.
uncommon
haemoptysis
Invasive aspergillosis: usually absent. If present, it may suggest the presence of a lung lesion eroding into a neighbouring blood vessel. Catastrophic haemoptysis may occur, particularly with recovery of neutrophils after chemotherapy.
Aspergilloma: mild haemoptysis may occur in some patients, severe haemoptysis in only a few.
dyspnoea
Invasive aspergillosis: usually not present. If present, it is suggestive of extensive lung involvement. May be seen with rejection of transplanted lung.
facial pain
Invasive aspergillosis: pain over the maxillary or frontal sinuses with or without sinus drainage.
seizure
Invasive aspergillosis: indicative of an intracranial space-occupying lesion.
altered mental status
Invasive aspergillosis: indicative of an intracranial space-occupying lesion.
cranial nerve palsy
Invasive aspergillosis: indicative of an intracranial space-occupying lesion.
malaise
Patients with chronic pulmonary aspergillosis may present with malaise.
weight loss
Patients with chronic pulmonary aspergillosis may present with weight loss.
Risk factors
strong
allogeneic stem cell transplantation
Neutropenia during pre-engraftment and impaired T-lymphocyte function during post-engraftment are the primary risk factors for invasive aspergillosis (IA). Unrelated donor stem cell, HLA-mismatched allogeneic, and umbilical cord stem cell transplantations, as well as graft-versus-host disease (GVHD), contribute to poor or delayed immune reconstitution and thus have the greatest risk for IA.[28] The use of growth factors has diminished the duration of pre-engraftment neutropenia, thus reducing the risk during that period.
Post-engraftment, GVHD and its therapy with corticosteroids and/or monoclonal antibodies have become the most common risks.[29][30] IA should be strongly suspected in these patients in the presence of sinus- or lung-related symptoms.
Transplantation with T-cell-depleted or CD34-selected stem cells also poses a high risk for IA. Increased age, delayed engraftment, and viral infections such as cytomegalovirus greatly increase the risk in this patient population.[28][30]
prolonged severe neutropenia (>10 days)
As polymorphonuclear leukocytes (PMNs) provide an important phagocytic defence mechanism against the conidia and hyphae, a quantitative reduction in the circulating PMNs (<100/mm³) for 10 days or more significantly increases the risk for invasive aspergillosis (IA).[31] The risk is low to modest when the absolute PMN count is between 100 and 500/mm³ or if the duration of neutropenia is short. High-risk conditions include acute myelogenous leukaemia (AML), acute lymphocytic leukaemia, and, less commonly, lymphoma. During induction chemotherapy for AML, prolonged neutropenia and fever are common; sino-pulmonary symptoms or signs, cutaneous lesions, or central nervous system (CNS)-related symptoms should raise suspicion for IA. The risk diminishes sharply with bone marrow recovery and return of neutrophils.
immunosuppressive therapy
The use of high-dose corticosteroids, calcineurin inhibitors, anti-lymphocyte immunoglobulin preparations, TNF-alpha inhibitors, and cytotoxic drugs, as therapies for malignancies, transplantation, and autoimmune disorders (e.g., granulomatosis with polyangiitis [formerly known as Wegener's granulomatosis], Crohn's disease, ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis), increases the risk for invasive aspergillosis, particularly when these agents are used in combination.[32][33]
chronic granulomatous disease (CGD)
This rare, inherited disorder is characterised by severe, recurrent, or persistent bacterial and fungal infections. Invasive aspergillosis (IA) is the most important infectious cause of mortality. Frequency of fungal infection in CGD is at the rate of 0.1% per year. If IA is seen in the absence of classic risk factors, the patient should be evaluated for CGD.[34][35][36]
solid organ transplantation (SOT)
Lung transplant recipients are at highest risk among SOTs; the mortality is high (68%). Among other SOTs, the frequency of invasive aspergillosis is 5% in heart, 2% in liver, 2% in small bowel, and 1% in kidney transplants; mortality ranges from 65% to 90%.[37][38]
Risk factors in lung transplantation include single lung transplant and a history of Aspergillus colonisation prior to transplantation.[37][38] Among heart transplant recipients, the risks include re-operation and post-transplant haemodialysis.[39][40] Re-transplantation and renal dysfunction are risk factors in liver transplantation.[41]
High-dose corticosteroids, graft failure, haemodialysis, and potent immunosuppressive regimens are the major risks in renal transplantation. Infection/disease due to cytomegalovirus is a significant risk in all types of organ transplantation.[37][38][42]
acute leukaemia
Severe, prolonged neutropenia develops after induction chemotherapy for acute leukaemia. Presence/persistence of neutropenia is a critical risk factor for invasive aspergillosis. Previous episodes of neutropenia or refractory leukaemia suggest a high risk. Acute lymphocytic leukaemia poses a lower risk than acute myelogenous leukaemia.
aplastic anaemia
The presence of pancytopenia, mainly neutropenia, is the predisposing factor for invasive aspergillosis.
prior or current lung disease
Chronic pulmonary aspergillosis generally affects people who are not immunocompromised, but have underlying respiratory pathology with cavitation, for example, tuberculosis.[4][26] Other cavitary diseases predisposing to aspergilloma include sarcoidosis, bronchiectasis, bronchial cysts and bullae, ankylosing spondylitis, neoplasm, and pulmonary infarction. Occasionally, aspergilloma may occur within cavities caused by other fungal infections.[43][44][45][46] In patients with AIDS, aspergilloma can form after Pneumocystis pneumonia.[47]
weak
advanced chronic lung disease
Patients with severe COPD seem to be at increased risk for invasive aspergillosis (IA), particularly when corticosteroids are administered chronically. COPD is the underlying disease in 1% of IA patients. Aspergillus species are frequently recovered from the airways of COPD patients, making it difficult to distinguish colonisation from infection. With delayed diagnosis/therapy, mortality is high in these patients.[48][49]
influenza infection
Invasive aspergillosis (IA) is associated with severe influenza, particularly in patients recently admitted to the intensive care unit. It is associated with poor prognosis, so prompt diagnosis and management of IA is essential for improving outcomes.[50]
COVID-19 infection
COVID-19-associated aspergillosis may occur in people who are critically ill. In one study, aspergillosis was reported in 10.2% of COVID-19 patients admitted to intensive care.[51]
primary immunodeficiency
The lung cavities (pneumatoceles) of patients with hyper-IgE syndrome with recurrent infections (Job's syndrome) become colonised with Aspergillus species, leading to local invasion and, rarely, to disseminated infection. Other primary phagocyte disorders, T-cell disorders, and mitochondrial disorders are infrequently associated with invasive aspergillosis (IA). Severe combined immunodeficiency, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) syndrome, and Pearson's syndrome are also rarely associated with IA.[36]
HIV infection
Invasive aspergillosis (IA) in advanced HIV infection, frequently with CD4 counts 100/microlitre or less, may be seen and has a poor outcome. With the availability of antiretroviral therapy, the frequency of IA has greatly decreased. For reasons not well understood, the frequency of IA in patients with advanced HIV infection has remained low.[52][53][54][55]
diabetes mellitus
May predispose patients to invasive aspergillosis.[38]
cystic fibrosis
May predispose patients to invasive aspergillosis.[38]
severe burns
May predispose patients to invasive aspergillosis.[38]
malnutrition
May predispose patients to invasive aspergillosis.[38]
multiple myeloma
Carries a risk to develop invasive aspergillosis, even in the absence of neutropenia.[28]
immunocompetent patients
Rarely, invasive aspergillosis can occur in hospital intensive care unit patients who are considered immunocompetent.[56]
age >55 years
Increased age is a risk for invasive aspergillosis. In the US, the incidence of invasive aspergillosis hospitalisations was highest in the age groups 45-64 and 65-84.[57]
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