This document discusses Aspergillosis and different types of fungal infections caused by Aspergillus species, including invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, fungal rhinosinusitis, sino-orbital-cerebral aspergillosis, and subacute invasive pulmonary aspergillosis. It covers the microbiology, epidemiology, clinical presentations, histopathology, diagnosis, and diagnostic tools for each type of infection.

1. Dr Venkat Ramesh
MD (Medicine), MRCP (UK)
Registrar (Fellow) in Infectious Diseases
Aspergillosis

2. Introduction
• The term "aspergillosis" refers to illness due to allergy, airway or lung invasion,
cutaneous infection, or extrapulmonary dissemination caused by species of Aspergillus
• Most commonly A. fumigatus, A. flavus, and A. terreus
• Aspergillus species are ubiquitous in nature
• Inhalation of infectious conidia is a frequent event
• Tissue invasion is uncommon
• Occurs most frequently in the setting of immunosuppression associated with therapy
for hematologic malignancies, HSCT/SOT

3. Microbial epidemiology
• Most invasive infections are caused by members of the A. fumigatus species complex
• 218 infections in 24 transplant centres (US):67 percent: A. fumigatus complex, followed
by A. flavus (13 percent), A. niger (9 percent), and A. terreus (7 percent)
• 1992 data: Vast majority of cases (90 percent) were secondary to A. fumigatus species
• Changes in microbial epidemiology, center-based differences, and/or changes in typing
methods.
Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002
Apr 1;34(7):909-17. Epub 2002 Feb 26. PubMed PMID: 11880955

5. Aspergillus species
• The commonest species implicated in IA is Aspergillus fumigatus
• Other Aspergilli including A. flavus, A. terreus, A. niger, A. ustus, and A. alliaceus
have been implicated as pathogens less commonly in patients with IA
• However, in developing countries A. flavus has been isolated comparatively at
higher frequency from sino-orbital aspergillosis or Aspergillus eye infections
• Few of those series reported A. flavus to be the exclusive agent or several times
more common than A. fumigatus

6. Aspergillus species
• Higher environmental contamination due to A. flavus may lead to increased
frequency of A. flavus infections in developing countries
• A. niger has been reported as the etiological agent in patients with
endophthalmitis, and endocarditis
• A. terreus and A. ustus have been isolated from patients with endophthalmitis
• A. terreus was also isolated from a case of aortic root abscess and
pseudoaneurysm post-cardiac surgery
• Rare cases of A. nidulans or A. glaucus isolation were reported from patients with
brain abscess

9. Spectrum of Aspergillus infection
1. Pulmonary: IPA, subacute IPA, CPA, ABPA
2. Rhino-sinusitis
3. CNS disease
4. Endophthalmitis
5. Endocarditis
6. Cutaneous
7. Gastrointestinal
8. Disseminated

11. Fungal rhinosinusitis
• FRS can be broadly divided into two categories based on histopathological
findings (depending on invasion of the mucosal layer)
1. Invasive
2. Non-invasive
• In the late 1990s, deShazo et al. proposed a new classification for tissue invasive
FRS based on the clinical condition, immune status, histopathology, and fungus
infection
1. Acute (fulminant) invasive
2. Granulomatous invasive
3. Chronic invasive types

12. Fungal rhinosinusitis
• Granulomatous invasive type: In chronic FRS cases from Sudan, India, and
Pakistan, where the patients are immunocompetent, almost exclusively identified
with Aspergillus flavus, and present as noncaseating granuloma with proptosis
• Chronic invasive FRS: Chronic course, often in subtly immunocompromised
patients, such as those with diabetes mellitus and corticosteroid treatment, with
dense accumulation of hyphae invading tissue, sometimes in association with the
orbital apex syndrome

13. Fungal rhinosinusitis
• 1965->one was non-invasive, behaving clinically like chronic bacterial sinusitis,
and the other invasive, in which the infection results in a mass that behaves like
malignant neoplasm, eroding bone and spreading into adjacent tissue
• 1980 -> immunocompromised patients: a fulminant form with rapid and
malignant course.
• 1976 -> nasal polyposis, crust formation, and sinus cultures yielding Aspergillus
species, resembles ABPA
• AFS/AFRS and EFRS

15. Non-invasive FRS
1. Saprophytic fungal infestation: Asymptomatic colonization of mucous crusts
within the nasal cavity
2. Fungal ball : non-invasive accumulation of dense conglomeration of fungal
hyphae in one sinus cavity, usually the maxillary sinus, although the disease
may affect other sinuses or rarely multiple sinuses
3. Fungus-related eosinophilic rhinosinusitis including AFRS: type I
hypersensitivity, nasal polyposis, characteristic findings on CT scan, presence of
fungi on direct microscopy or culture, and allergic mucin containing fungal
elements without tissue invasion

16. Sino-orbital-cerebral aspergillosis (Invasive fungal
rhinosinusitis)
• This clinical type is a highly prevalent disease in tropical countries, though much confusion exists
regarding its categorization
• The most commonly accepted classification divides invasive fungal rhinosinusitis (FRS) into
1. Acute invasive FRS
2. Granulomatous invasive FRS,
3. Chronic invasive FRS
• The prevalence of acute invasive FRS is more or less similar in the developed and developing world
• Developed world-> Hematological malignancy is the commonly associated underlying disease in acute
invasive FRS with higher isolation of A. fumigatus
• Uncontrolled diabetes is more commonly associated in developing countries with higher isolation of
Zygomycetes in such a setting. This may be due to the high prevalence of uncontrolled diabetes in these
countries

17. Granulomatous invasive FRS
• Granulomatous invasive FRS is primarily seen in Sudan, India, Pakistan, and Saudi
Arabia
• The disease is described by a time course of >12 weeks with enlargement of mass
in the cheek, nose, paranasal sinuses and the orbit in the immunocompetent host
• HPE: granulomatous inflammation and considerable fibrosis, with presence of
scanty hyphae, and A. flavus is the primary agent isolated

18. Chronic invasive FRS
• In contrast, chronic invasive disease is seen in any part of the world and is
characterized by dense accumulation of hyphae, presence of vascular invasion,
sparse inflammatory reaction
• A. fumigatus isolation in patients with diabetes and on corticosteroid treatment
• A. flavus is the common etiological agent of all types of FRS except acute invasive
type in Sudan and India

30. Chronic pulmonary aspergillosis
• Chronic pulmonary aspergillosis includes several disease manifestations, including
aspergilloma, Aspergillus nodules, chronic cavitary pulmonary aspergillosis, and chronic fibrosing pulmonary
aspergillosis
• Subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing aspergillosis) is on the spectrum
between chronic and acute forms of pulmonary aspergillosis
• A duration of disease longer than three months distinguishes chronic pulmonary aspergillosis from acute and
subacute pulmonary aspergillosis.

31. Chronic pulmonary aspergillosis
• The most common form of CPA is CCPA
• Untreated it may progress to chronic fibrosing pulmonary aspergillosis (CFPA)
• Less common manifestations of CPA include Aspergillus nodule and single aspergilloma
• All these entities are found in non-immunocompromised patients with prior or current
lung disease
• Subacute invasive pulmonary aspergillosis (formerly called chronic necrotising
pulmonary aspergillosis) is a more rapidly progressive infection (<3 months) usually
found in moderately immunocompromised patients

33. Aspergilloma
• Fungus ball composed of Aspergillus hyphae, fibrin, mucus, and cellular debris
found within a pulmonary cavity
• Aspergillomas arise in preexisting pulmonary cavities that have become colonized
with Aspergillus spp and are the result of growth of fungus on the cavity wall that
detaches into the cavity, often forming a rounded shape, sometimes with air
within it
• If the aspergilloma is single, the cavity stable over months, and the patient has
few symptoms (ie, a mild cough only) and little evidence of systemic
inflammation, a simple aspergilloma may be diagnosed.

36. Aspergillus nodule
• Aspergillus nodules occur in immunocompetent hosts, may be single or multiple,
and may or may not have cavitation within them
• The differential diagnosis includes carcinoma of the lung, TB/nontuberculous
mycobacterial infection, and coccidioidal or other fungal nodules
• Symptoms +/- , FDG avid
• Positive Aspergillus immunoglobulin IgG titer in the blood
• HPE: necrosis is surrounded by granulomatous inflammation with occasional
multinucleate giant cells; center of the necrotic material contains fungal hyphae.

38. Chronic cavitary pulmonary aspergillosis
• Immunocompetent patients
• Formation and expansion of one or more pulmonary cavities over months
• Do not use “Complex aspergilloma"
• Because more than 50 percent of such patients don't have an aspergilloma visible
radiographically
• Always Aspergillus IgG antibodies in the blood

40. Chronic fibrosing pulmonary aspergillosis
• Late-stage manifestation of chronic cavitary pulmonary aspergillosis
• Progression to marked and extensive fibrosis has occurred
• Sometimes called "destroyed lung"

42. Subacute invasive pulmonary aspergillosis
(chronic necrotizing pulmonary aspergillosis)
• Patients with some degree of immunocompromise who present with progressive
features over one to three months have subacute invasive pulmonary
aspergillosis (formerly known as chronic necrotizing pulmonary aspergillosis)
• Hyphal invasion of tissue is observed histologically or can be inferred based upon
radiographic findings, including cavitation
• Such patients usually have a single thin-walled cavity or area of cavitating
pneumonia/consolidation
• May have detectable Aspergillus antigen (galactomannan) or Aspergillus IgG
antibodies in blood.

43. Subacute invasive pulmonary aspergillosis
(chronic necrotizing pulmonary aspergillosis)
• Diabetes mellitus
• Malnutrition
• Alcoholism
• Advanced age
• Prolonged glucocorticoid use or other modestly immunosuppressive agents
• Chronic obstructive pulmonary disease
• Connective disease
• Radiation therapy
• Nontuberculous mycobacterial infection
• Human immunodeficiency virus (HIV) infection

44. Diagnosis
• The diagnosis of CPA requires a combination of characteristics
1. A consistent appearance in thoracic imaging ( preferably by CT)
2. Direct evidence of Aspergillus infection or an immunological response to Aspergillus spp. and
exclusion of some alternative diagnoses
3. In addition, by convention the disease will have been present for at least 3 months, even if
that duration is inferred and based on symptoms or progressive radiological abnormality
4. Patients are usually not immunocompromised by HIV-infection, cancer chemotherapy or
immunosuppressive therapy
A few patients have some level of immunosuppression and, arbitrarily, ESCMID recommend a
cut-off of 10 mg prednisolone daily (or equivalent) for clinical management
Intermittent higher levels of immunosuppression may accelerate progression of CPA, if not
controlled with antifungal therapy.

45. Diagnosis
• If a fungal ball is observed, then confirmation that Aspergillus is responsible
requires only an Aspergillus IgG or precipitins test to be positive, which it will be
in >90% of cases
• If antibody testing is not positive then other evidence of Aspergillus infection is
required
• Patients may have both CPA and other infections that occur concurrently.

46. Diagnosis
• In patients with one or more cavities consistent with CPA then any of the following can
be used to confirm the diagnosis, if other diagnoses have been excluded
• Aspergillus IgG or precipitins positive, strongly positive Aspergillus antigen or DNA in
respiratory fluids, percutaneous or excision biopsy showing fungal hyphae on
microscopy or growing Aspergillus spp. from a cavity
• If hyphae are seen to be invading lung parenchyma, the diagnosis is acute or subacute
invasive aspergillosis
• Respiratory samples showing hyphae consistent with Aspergillus and/or growing
Aspergillus spp. and/or with a positive Aspergillus PCR assay support the diagnosis, but
are not enough alone for a confirmed diagnosis of CPA as numerous other conditions
can yield Aspergillus in the airways.

48. Diagnosis of SAIA
• SAIA should be diagnosed according to established definitions of invasive
aspergillosis in immunocompromised patients (or highly debilitated patients)
• Slower course than acute invasive aspergillosis (1–3 months)
• Commonly with both detectable Aspergillus antibody and antigen in the serum
• Histological confirmation derives from seeing hyphae invading lung parenchyma.

51. Galactomannan in CPA
• The sensitivity and specificity of galactomannan Aspergillus antigen (GM) assay in
bronchoalveolar lavage
• BAL fluid specimens was 77.2% and 77.0%, respectively (with a cut-off level of
0.4), and in serum was 66.7% and 63.5%, respectively, with serum at a cut-off
level of 0.7 for the diagnosis of CPA
• In another study the BAL GM-antigen detection test had a sensitivity and
specificity of 85.7% and 76.3%, respectively, with a cut-off level of >0.5
• In a recent study, the sensitivity of serum GM was only 23%
• Thus BAL and not serum GM should be used in diagnosis of CPA.