Criteria to define proven and probable cases of IAPA
The distinction between proven and probable IAPA is important for clinical trials, while in clinical practice, people should not distinguish between proven and probable disease.
The criteria for proven disease include a patient fulfilling the entry criterion plus histological evidence of invasive fungal elements and mycological evidence for the presence of Aspergillus (obtained by Aspergillus PCR or culture from tissue). Tracheobronchitis (tracheal and/or bronchial ulcerations or nodules, pseudomembranes or plaques visualized at bronchoscopy), as also described in the EORTC/MSGERC definitions [10], is a separate entity. Although a tissue biopsy would normally be required to prove a case of IAPA, in tracheobronchitis cases hyphal elements suggestive of Aspergillus seen on sloughed-off pseudomembrane, and Aspergillus identified on culture or PCR, can also be considered proven disease (Table 1).
Table 1 Proposed case definition for IAPA in ICU patients
Entry criteria: influenza-like illness + positive influenza PCR or antigen + temporally relationship
Aspergillus tracheobronchitis IAPA in patients without documented Aspergillus tracheobronchitis
Proven Biopsy or brush specimen of airway plaque, pseudomembrane or ulcer showing hyphal elements and Aspergillus growth on culture or positive Aspergillus PCR in tissue Lung biopsy showing invasive fungal elements and Aspergillus growth on culture or positive Aspergillus PCR in tissue
Probable Airway plaque, pseudomembrane or ulcer
and at least one of the following:
Serum GM index > 0.5
or
BAL GM index ≥ 1.0
or
Positive BAL culture
or
Positive tracheal aspirate culture
or
Positive sputum culture
or
Hyphae consistent with Aspergillus A: Pulmonary infiltrate
and at least one of the following:
Serum GM index > 0.5
or
BAL GM index ≥ 1.0
or
Positive BAL culture
OR
B: Cavitating infiltrate (not attributed to another cause)
and at least one of the following:
Positive sputum culture
or
Positive tracheal aspirate culture
A patient fulfilling the case definition of probable IAPA is required to fulfill the entry criterion. A positive serum GM (GM index > 0.5) is important evidence for the diagnosis of IAPA, in patients with pulmonary infiltrates on chest X-ray or other imaging modality or bronchoscopic evidence of tracheobronchitis (Table 1). In patients with tracheobronchitis, an infiltrate is not required.
In patients with endobronchial plaques or pulmonary infiltrates, a positive BAL GM or culture of a tracheal aspirate is considered mycological evidence that supports a probable IAPA diagnosis. In patients with bacterial pneumonia where Aspergillus is cultured only from a sputum sample, there may be a risk of overdiagnosis and thus over-treatment. For clinical practice, clinicians should take into account that a positive culture of an upper airway sample may indicate IAPA, but that confirmation with serum or BAL GM or BAL culture should be pursued. However, one problem is that the background incidence varies in different regions, making it difficult to develop generalized guidelines that apply uniformly. The significance of a positive sputum culture thus depends on the background incidence in a specific unit. Although any Aspergillus-positive respiratory sample is in itself insufficient to classify patients as probable IAPA, a new pulmonary cavitating infiltrate is indicative of IAPA in patients who meet the entry criterion. Therefore, any Aspergillus-positive respiratory sample is sufficient evidence to classify patients as probable IAPA provided that a pulmonary cavitating infiltrate is present (Table 1; Fig. 1).
Fig. 1 Flowchart of probable IAPA classification. (*)If hyphae consistent with Aspergillus are documented in a biopsy of an airway lesion AND Aspergillus is grown from sputum or a tracheal aspirate, the case fulfills the definition of proven IAPA
A BAL GM index cutoff of ≥ 1.0 is recommended as this cutoff value ensures high specificity, without decreasing sensitivity significantly, which is also in line with other definitions and recommendations [10, 57]. Aspergillus PCR is not recommended as a primary diagnostic tool because of concerns about its reliability and positive predictive value for the diagnosis of IPA. However, Aspergillus PCR is recommended in the proven category because it enables Aspergillus identification in tissue samples.
In some patients, discordant results are obtained, for instance a positive sputum culture but negative BAL GM. For most situations, IAPA classification relies on a positive GM test, as a positive sputum culture with a negative GM result would be interpreted as a lower probability of IAPA (unless a pulmonary cavity or tracheobronchitis is present)(Fig. 1).