Three questions arise when physicians face cultures positive to Aspergillus from lower respiratory samples in non-immunocompromised/non-neutropenic patients: Is there colonisation or infection?, should the patient be treated with antifungals?, and which is the prognosis?, that is, how to interpret and manage patients from which Aspergillus is obtained. The retrospective analysis of this series of 245 immunocompetent patients showing at least two respiratory cultures positive to Aspergillus, that were further categorised as colonised, probable or proven aspergillosis, tried to explore how these three questions are addressed in the clinical practice. The diagnostic categorization of patients was based on criteria adapted from those defined by Bulpa et al. for COPD patients because we expected that most of the non-neutropenic, non-transplant patients in our series were this type of patients.
The answer to the first question is important since an early diagnosis is crucial to improve prognosis
. It has been postulated that isolation of an Aspergillus species from respiratory samples in critically ill patients (even when immunocompetent) should not be routinely discarded as colonisation
, but in elderly patients (commonly having underlying diseases) isolation is usually interpreted as colonisation
. Confirmation of infection obliges the demonstration of histopathological evidence that is not usually feasible in this type of patients
. Early administration of antifungals may be life-saving, but overinterpretation of the potential clinical significance of Aspergillus isolation may drive to needless treatments, with their associated problems and costs
[5, 18]. How does clinicians solve the dilemma?
In this study 245 records from patients with at least two respiratory cultures positive to Aspergillus were identified, 139 of them (56.7%) classified as with Aspergillosis (probable + proven) following adapted Bulpa et al. criteria. This contrasts with other published series where the percentage of patients showing Aspergillosis was markedly lower
[3, 5, 10], probably due to the at least two positive cultures required as inclusion criteria in our study. In this sense, a recent study in our country reported 22.1% of probable invasive pulmonary aspergillosis among hospitalized COPD patients with at least one positive culture to Aspergillus. In addition to signs/symptoms suggestive of aspergillosis as cavitations in X-ray/CT scan, worsening of radiological findings and interaction of COPD and need for O2, according to the multivariate analysis performed, stay in the ICU, congestive heart failure and previous intake of steroids were also positively associated with Aspergillosis; all of them factors that had been previously described
[1, 6, 7]. Although clinical signs/symptoms and radiological findings are usually non specific in critically ill patients
, in our series requests of CT scan and the galactomannan test were significantly more frequent in patients further classified as with Aspergillosis than in those colonised, this suggesting a right clinical suspicion of colonisation/infection by treating physicians.
Initiation of antifungal treatment and time for initiation is a matter of considerable debate. Clinical manifestations of pulmonary aspergillosis may be initially indistinguishable from bacterial bronchopneumonia (fever, cough, purulent sputum)
. The recovery of the same Aspergillus species from several respiratory samples in the course of antibiotic-resistant pneumonia in patients with risk factors is clearly evocative of the diagnosis
. Therefore it has been proposed that the isolation of an Aspergillus species from the respiratory tract in critically ill patients with risk factors (COPD after corticosteroids exposure, severe underlying disease) and clinical features of pneumonia indicates prompt consideration of antifungal treatment
In our series (with 72.6% of pulmonary aspergillosis among patients with Aspergillosis) antifungal treatment was not initiated in 23.2% patients with probable aspergillosis while it was administered to 29.2% of patients classified as colonised. Administration of antifungals was negatively associated with the presence of severe liver disease, probably because of the renal and hepatic toxicity of antifungals
. ICU admission and days in the ICU were associated with prescription of antifungals, both in colonised and aspergillosis patients. Interestingly, in patients with Aspergillosis antifungal treatment was negatively associated with Gold III + IV and treatment with quinolones. The negative association with treatment with wide-spectrum quinolones could probably be linked to the commented similarity of initial clinical manifestations of pulmonary aspergillosis with bacterial bronchopneumonia. In addition this could be the reason for the significantly lower number of severe COPD patients found among treated vs. non-treated patients (65.3% vs. 88.0%) in our series when analysing patients with Aspergillosis. However the percentage of COPD patients with Aspergillosis (Table
5) that received antifungal treatment in our series was 75% (75 out of 100), a percentage similar to the one (71%) described in a published review of 65 cases
Voriconazole was the most frequent antifungal drug, with 74.5% of treated patients with Aspergillosis receiving this drug alone or in combined regimens. For primary treatment of invasive aspergillosis, the triazole voriconazole is recommended for most patients
 and, although its superiority over lipid formulations of Amphotericin B or echinocandins has not been proved in the subset of COPD patients
, the superiority of voriconazole versus Amphotericin B has been demonstrated in invasive aspergillosis in immunocompromised patients
The high mortality of invasive pulmonary aspergillosis in non-neutropenic critically ill patients has been attributed, at least partially, to difficulties in timely diagnosis caused by insensitive and non specific clinical signs and lack of unequivocal diagnostic criteria
 precluding the early needed treatment. In the present study, as expected, significant higher mortality was found in proven than in probable aspergillosis and in the latter than among colonised patients (78.6% vs. 41.6% vs. 12.3%). Interestingly, COPD was negatively associated with mortality in colonised patients but not in patients with Aspergillosis. Higher mortality rates (>90%) in invasive pulmonary aspergillosis than those found in the present study have been reported in previously published series in COPD patients, but including only patients in the ICU
[1, 22]. Although the strength of the present study resides in the description of clinical features of aspergillosis in a large series of patients with at least two positive lower respiratory samples, several study limitations should be considered. The retrospective nature of the study based on information (clinical, radiological reports…) recorded in clinical records from 29 different hospitals, implies bias derived from inter-hospital differences in patient’s management. This could specially affect the management of patients concomitantly presenting other hospital infections and/or organ dysfunction. In addition most patients in the Aspergillosis category were classified as “probable aspergillosis”, thus making difficult to establish firm conclusions due to the low number of proven cases or patients with CT scan images as halo sign or air crescent sign.