BAL Galactomannan to Diagnose Invasive Aspergillosis in the ICU

Abstract & Commentary

By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle

Dr. Luks reports no financial relationship to this field of study.

Synopsis: In immunocompromised ICU patients at risk for invasive aspergillosis, Galactomannan levels in bronchoalveolar lavage fluid are more useful markers for establishing or excluding the diagnosis of invasive aspergillosis than serum galactomannan, BAL culture, or direct examination.

Source: Meersseman W, et al. Am J Respir Crit Care Med. 2008;177:27-34.

Invasive aspergillosis (IA) is increasingly recognized as a source of infection in immunocompromised ICU patients, but accurate diagnosis remains challenging. (See Critical Care Alert, October 2007, pp. 50-52). Recent work in neutropenic patients has shown that detection of galactomannan—a polysaccharide fungal-cell wall component released during tissue invasion by aspergillus—in bronchoalveolar lavage (BAL) fluid may facilitate diagnosis in this patient population. Meerseman and colleagues sought to determine if BAL galactomannan levels could play a similar role in the diagnosis of IA in critically ill ICU patients with other forms of immunosuppression.

Patients were included in the study if they had persistent fever despite appropriate empiric antibiotic therapy, clinical signs of invasive mycosis (eg, pleuritic chest pain) or lower respiratory tract infection, and had one of several forms of immunosuppression including hematologic malignancy, cancer with recent chemotherapy treatment, solid organ transplant, recent use of corticosteroids or other immunosuppressive agents such as tacrolimus or methotrexate, cirrhosis or human immunodeficiency virus infection. Patients underwent bronchoscopy and bronchoalveolar lavage upon inclusion and then on a weekly basis, with galactomannan levels, direct microscopic examination and fungal cultures performed on all specimens. Serum galactomannan was performed twice weekly and autopsies were performed in all fatal cases. Antifungal treatment could be started at the discretion of the treating physician and was not protocol-driven.

Patients were classified as having proven, probable IA or possible IA based on previously published case definitions.1 A variety of statistical analyses were used to compare the results of cultures, serum and BAL galactomannan values between the different groups of patients. Sensitivity of the different techniques was calculated from the proven cases while specificity was determined using a biopsy or autopsy-proven negative group.

A total of 110 patients out of 1109 admissions during the study period were eligible for inclusion in the study, and there were 26 proven cases of IA. All 26 of these cases had at least one BAL galactomannan index > 0.5, the pre-defined cut-point for a positive test, with 23 of these positive levels being found on the first BAL sample. In 11 of 26 proven cases of IA, BAL culture and serum galactomannan remained negative. Thoracic CT scans performed in 15 proven cases showed no evidence of halos or air-crescent signs, classically described features of invasive pulmonary aspergillosis. Using an index cut-off value of 0.5, the sensitivity and specificity of BAL galactomannan were 88% and 87%, compared to 42% and 96%, respectively, for serum galactomannan. Using a cut-point of 0.5, the area under the ROC curve for BAL galactomannan was 0.898 (95% confidence interval 0.811 to 0.985). The specificity of BAL galactomannan remained high even in those patients treated with piperacillin-tazobactam, a widely used antibiotic known to cause false positive results on this assay.

Commentary

One of the striking aspects of this study was the fact that 26 of the 110 ICU patients (24%) with some form of immunosuppression, persistent fevers despite appropriate empiric antibiotics, and/or clinical evidence of lower respiratory tract infections, turned out to have IA. That is a high number that strongly suggests that we need to be looking more closely for this infection among the non-neutropenic immunocompromised patients admitted to the ICU who develop persistent fevers and evidence of pneumonia.

Until recently, proving this diagnosis pre-mortem has been challenging, as the sensitivity and specificity of BAL culture and direct examination have been limited. Radiologic imaging is also of limited utility, as demonstrated by the fact that none of the proven cases in this study had the classically described features of the disease.

The well-conducted study by Meerseman and colleagues strongly suggests that BAL galactomannan assays may alleviate some of these diagnostic problems. It is a minimally invasive test with superior test characteristics relative to serum galactomannan and BAL culture with a faster turnaround time than either cultures or biopsy specimens. It is also reassuring to know that piperacillin-tazobactam, a widely used broad-spectrum antibiotic, did not affect the specificity of the assay.

Further testing would be useful to confirm these results as this was a single center study and there were a few important methodological issues such as the fact that the authors did not regulate the use of antifungal medications (which can decrease the assay's sensitivity) by the treating physicians. Nevertheless, given the high morbidity and mortality associated with IA infections and the simplicity and minimal invasiveness of BAL galactomannan measurement, we should be using this test more often in immunocompromised patients with evidence of pneumonia and no response to empiric antibiotic therapy.

Reference

  1. Ascioglu S, et al. Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: An international consensus. Clin Infect Dis. 2002;34:7-14.