Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU)
Influenza-associated pulmonary aspergillosis (IAPA) is a serious secondary infection that may affect 19% of patients admitted to ICU. Its mortality is almost doubled (51% vs 28%) compared to critically ill influenza patients without IAPA and may reach up to 90% mortality when it presents as Invasive Aspergillus Tracheobronchitis.
Prevention by an antifungal agent is a possible option. However, no licences are currently issued for prophylactic use in ICU patients. Posaconazole (POS) choice as possible prophylaxis was made because of its good safety profile, availability for intravenous administration, and favourable PK/PD characteristics.
From December 2017 to March 2017, the authors organised and conducted a multicentre, prospective, randomised, open-label, proof-of-concept trial, comparing prophylaxis with Posaconazole vs no prophylaxis (standard-of-care only, SOC) for IAPA in critically ill patients.
Inclusion criteria comprised admission to an ICU because of respiratory distress with PCR-confirmed influenza within 7 days prior or 48h after ICU admission with symptoms for less than 10 days before ICU admission. In addition, exclusion criteria were pregnancy, limited survival expectancy in ICU, documented IAPA infection at study screening, drug-related contraindications or prior enrolment in other interventional clinical trials.
Eligible patients were randomised to POS or SOC in a 1:1 ratio, without stratification and treatment allocations were open to all parties. Randomisation and diagnostic assessment for possible IAPA were performed in the first two days and then re-evaluated for the duration of participation, which included 90 days of follow-up.
Patients in the prophylaxis group received a loading dose of POS 300 mg intravenously twice daily on the day of randomisation (day 1), followed by a once-daily 300 mg from day 2 to day 7 (or less, in case of evidence of invasive fungal infection requiring treatment and/or an adverse event mandating discontinuation of study medication). All cases of fungal infections were individually assessed, classified and differentiated to “Early” and “Late” IAPA by two experienced physicians (who were blinded to the allocated arm), using a modified AspICU algorithm and the ICM2020 case definition.
The primary endpoint was the incidence of IAPA during ICU stay, while timing of IAPA, length of ICU and hospital stay, point mortality and mortality at 90 days were the secondary endpoints.
A modified intention-to-treat population (MITT) was used for the primary efficacy analysis. This group comprised patients in the POS arm who received at least one full dose without early IAPA. Enrolment of 110 patients in total was estimated to suffice patient inclusion in the MITT population.
Of the 252 critically ill influenza patients, 88 patients were randomised in the study, 15 of which were excluded from the MITT pool due to early IAPA infection, and the remainder MITT population was equally matched (37/73 received POS and 36/73 SOC).
The incidence of proven and putative IAPA was 5.4% in POS arm (2/37) and 11.1% in SOC [4/36, inter-population difference 5.7% (95% CI – 10.8 to 21.7); p = 0.32,]. IAPA diagnosis occurred later in POS patients [10 (IQR 8–12) vs. 5 (IQR 3–8) days after ICU admission], but the hazard ratio was statistically insignificant [0.46 (0.09–2.29), p = 0.36]. Hospitalisation duration and ICU stay were similar in both study arms. In a quarter of patients, POS prophylaxis was discontinued prematurely (for reasons unrelated to treatment) after approximately 4.6 days of administration (SD 1.2).
Early IAPA occurred in 15 cases (71% of all IAPA) and late IAPA in 6 (29% of all IAPA). All early IAPA patients required ventilator support, while a third (5/15) needed ECMO. IAPA tracheobronchitis was identified in 4 (27%) early IAPA cases. Antifungal treatment was initiated on average 3 days (SD 2) after ICU admission in early IAPA cases.
Regardless of the early diagnosis and treatment, mortality of early IAPA was 53% (8/15), while overall, IAPA cases had higher ICU mortality than non-IAPA patients (57% vs 18%, p = 0.0013). IAPA infection was found in four patients in the SOC group and two patients in the POS group (both receiving corticosteroids for prior illnesses) after completing the full 7-day course.
STUDY STRENGTHS & LIMITATIONS
– It is the first randomised clinical trial on anti-fungal prophylaxis in critically ill patients admitted to the ICU with respiratory failure due to influenza.
– Well-designed study with few inclusion biases, due to the strict nature of the protocol.
– It did not reach a definite conclusion on POS prophylaxis in IAPA patients.
– It was underpowered, mainly because of the large population excluded from the study due to early IAPA and timing constrictions.
– The diagnostic approach of the study is only feasible when bronchoscopy is safe and performed readily, and mycological tests are available with short turnaround times.
– Azole susceptibility was not routinely evaluated, despite increased regional resistance. Nonetheless, POS resistance was not verified in all 14 IAPA cases that were assessed.
– The diagnosis of IAPA was based on the modified AspICU, as was determined in the study protocol in 2017. In 2020 a team of experts announced a newer definition algorithm to improve homogeneity and increase enrolment in clinical studies. When this definition was applied to the patient pool, all cases of putative IAPA would be classified as probable IAPA, except for one.
It is recommended to develop an early diagnostic mycological protocol for influenza patients due to the inherently high incidence and mortality rate of early IAPA. This study suggests that the bulk of patients may suffer from IAPA as early as ICU admission, making IAPA primarily a co-infection in most ICU patients rather than a secondary infection. The high incidence of IAPA at admission, in conjunction with the lower than anticipated incidence in the MITT population, prevents an obvious verdict on the prophylactic use of Posaconazole.
This article review was prepared and submitted by Dimitrios Papadopoulos MD, MSc, PhD, Senior Consultant in Intensive Care Medicine, General Hospital of Larisa, Larisa, Greece, on behalf of the ESICM Journal Review Club.
Vanderbeke L. et al. “Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.” Intensive Care Medicine (2021), 47:674-686.
Verweij P.E. at al. “Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion.” Intensive Care Medicine (2020), 46, 1524–1535.