Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 31st International Symposium on Intensive Care and Emergency Medicine (ISICEM)

Brussels, Belgium / March 22-25, 2011

There have been incremental improvements in a variety of diagnostic tools for identifying fungal infection, including better definition of characteristic radiological signs and better recognition of the significance of galactomannan (GM) and beta-D-glucan (BDG) tests in the context of host features.

Diagnostic Delays and Mortality Rates

No diagnostic tool is definitive without histopathological confirmation, but symptoms and test results can be combined to upgrade the likelihood of a specific fungal pathogen from possible to probable. This is critical for invasive aspergillosis (IA), a highly lethal invasive fungal infection in the intensive care unit (ICU) for which clinical cure is strongly influenced by the speed at which the optimal antifungal agent is introduced. “The mortality associated with aspergillosis in the ICU is staggering,” stated Dr. Dirk Vogelaers, Department of Infectious Diseases, University Hospital Ghent, Belgium. He cited studies that place the mortality for proven or probable IA in the ICU in the range of 60% to 90%.

The key issue is not the efficacy of available therapies for IA. Rather, “there are problems with every component of the diagnosis, and this delays therapy,” Dr. Vogelaers told delegates. Indicating that the path to better outcomes is more rapidly assembling the signs and symptoms so that first-line therapy is initiated, Dr. Vogelaers concluded, “The frequency with which patients are not treated or treated late accounts for much of the morbidity and mortality associated with this pathogen.”

Consequently, efforts to combine signs and symptoms that will permit clinicians to consider pre-emptive therapy while attempting to upgrade a “possible” to a “probable” diagnosis of IA are important. By accelerating the time to a guideline-mandated antifungal drug, there may be an important opportunity to improve outcomes.

The current first-line therapeutic strategy for IA is voriconazole according to several guidelines, including those issued by the Infectious Diseases Society of America (IDSA) which has characterized the level of evidence for this assertion as A-1. In a multicentre trial that randomized IA patients to voriconazole or amphotericin B deoxycholate (the only other antifungal licensed for primary treatment of IA in several countries), treatment success was achieved in 52.8% of the voriconazole group and 31.6% of the amphotericin B group. Although no hazard ratio (HR) was calculated for treatment success, the survival rate at 12 weeks was 70.8% and 57.9%, respectively (HR 0.59; 95% CI, 0.4-0.88; P=0.02).

In the comparative study, patients were eligible if they had definite or probable IA. Definite IA was defined by a clinically compatible disease with findings that included a positive culture from a sterile site, an involved organ or bronchoalveolar lavage (BAL). Probable IA, which signifies a non-culture-based diagnosis, was defined by a clinically compatible disease combined with a selection of clinical signs such as a characteristic halo or air-crescent pulmonary formation identified on computed tomography (CT); hyphae from BAL consistent with aspergillosis; or tracheobronchial lesions on bronchoscopy with a positive biopsy specimen.

Ambiguity in Diagnosis

While definite IA simplifies the initiation of treatment, clinicians typically face ambiguous signs of the underlying pathogen and must assemble numerous clues on which to base a possible or probable diagnosis in order to initiate therapy. Some signs, such as the characteristic halo pattern of pulmonary infection on CT scan, are associated with a good specificity but unfortunately, these are only found in a minority of patients. Serum assays for BDG, which is found in the cell wall of fungi, have good sensitivity for invasive fungal infection but are not specific for IA. GM, which is a component of the cell wall of Aspergillus, can be very useful in patients with neutropenia but “have very little predictive value in non-neutropenic populations,” Dr. Vogelaers noted.

Key Host Susceptibility Factors

The key issue for suspecting IA is the presence of host susceptibility factors, particularly immune suppression. Dr. Vogelaers noted that the specific susceptibility of ICU patients explains why fungal spores, which are routinely cleared from the respiratory tract of healthy individuals, are able to colonize and produce invasive infections. He listed the key host factors as a neutrophil count <500 cells/mm3; a hematological or solid malignancy being treated with cytotoxic agents; corticosteroid treatment equivalent to >20 mg/day of prednisone; and congenital or acquired immunosuppression. In such individuals, a probable diagnosis of pulmonary IA can be made if there is abnormal radiology, if a positive culture can be obtained from the lower respiratory tract, and if the patient has consistent signs of fungal infection such as fever refractory to antibiotics, pleuritic chest pain, dyspnea or hemoptysis.

While these characteristics best capture the immunocompromised patient, Dr. Vogelaers stressed that more attention is needed to produce earlier diagnosis of IA in non-classic critical illnesses, such as chronic obstructive pulmonary disease (COPD) and liver cirrhosis. In these, IA is also a life-threatening pathogen, but biomarkers such as GM are not typically useful. Symptoms consistent with a fungal infection, particularly fever unresponsive to antibiotics, should provide a basis for aggressive efforts to conduct histopathological study and culture for a definitive diagnosis.

Improved Survival with Pre-emptive Therapy

Although patients who develop fungal infection secondary to a critical illness such as COPD represent a minority of IA cases, preemptive therapy may also favourably affect survival. “There is good evidence that survival is greater when therapy is started before microbiological confirmation of the disease compared with a delay for a positive mycology,” reported Dr. Vogelaers, citing an influential retrospective study of 289 IA cases collected over a 9-year period (Nivoix et al. Clin Infect Dis 2008;47:1176-84). While an underlying malignancy, disseminated aspergillosis, renal impairment and solid-organ transplant were among factors associated with increased mortality in this study, pre-emptive therapy based on clinical signs emerged as a predictor of survival in multivariate analysis. The authors of this study also noted that survival from IA increased in the years that followed the introduction of voriconazole. The increase in survival relative to earlier years of data collection, when amphotericin B was the most commonly used therapy, was identified by the authors as being consistent with the randomized trial comparing these agents.

Consistent with this study, the IDSA guidelines also advocate presumptive antifungal therapy in patients with strongly suspected IA. Primary therapy with amphotericin B is no longer recommended, although it can be considered as an alternative. Rather, voriconazole in intravenous or oral form is the preferred agent. Treatment should be continued for a minimum of 6 weeks, but the guidelines note that an optimal duration has not yet been well defined and much longer courses may be appropriate in immunocompromised patients. In patients who are part of a treatment protocol and develop IA, the IDSA guidelines suggest a prophylactic course of antifungal therapy may be appropriate for any planned re-initiation of immunosuppression.

However, the challenge is not the selection of therapy but how best to develop protocols for increasing suspicion of IA. Dr. Vogelaers suggested that criteria differ for different populations. “We need to think about the sensitivity and specificity of each diagnostic component in the context of the host factors. This is the challenge in the treatment of IA,” he told delegates.

Summary

Life-threatening fungal infections in the ICU are likely to become more common due to increasing use of immunosuppressive therapies for such procedures as stem-cell and solid organ transplantation. Consequently, improved protocols to rapidly identify suspected cases of IA are essential for reducing the risk of infection-related mortality. Due to the delay in achieving a definitive diagnosis of IA, pre-emptive therapy has been identified as appropriate in patients strongly suspected of IA. In most major guidelines, the first-line therapy in these cases, as in definitive IA, is voriconazole. The effort to isolate appropriate candidates for preemptive therapy with this agent has the potential to play a significant role in mortality reduction.