Low Cryptococcus Antigen Titers as Determined by Lateral Flow Assay Should Be Interpreted Cautiously in Patients without Prior Diagnosis of Cryptococcal Infection

Abstract

Detection of Cryptococcus antigen (CrAg) is invaluable for establishing cryptococcal disease. Multiple different methods for CrAg detection are available, including a lateral flow assay (LFA). Despite excellent performance of the CrAg LFA, we have observed multiple cases of low-titer (Յ1:5) positive CrAg LFA results in patients for whom cryptococcosis was ultimately excluded. To investigate the accuracy of low-titer positive CrAg LFA results, we performed chart reviews for all patients with positive CrAg LFA results between June 2014 and December 2016. During this period, serum and/or cerebrospinal fluid (CSF) samples from 3,969 patients were tested with the CrAg LFA, and 55 patients (1.5%) tested positive. Thirty-eight of those patients lacked a history of cryptococcal disease and were the focus of this study. Fungal culture or histopathology confirmed Cryptococcus infection for 20 patients (52.6%), and CrAg LFA titers in serum and CSF samples ranged from 1:5 to Ն1:2,560. For the 18 patients (47.4%) without culture or histopathological confirmation, the CrAg LFA results were considered true-positive results for 5 patients (titer range, 1:10 to Ն1:2,560), due to clinical improvement with targeted therapy and decreasing CrAg LFA titers. The remaining 13 patients had CrAg LFA titers of 1:2 (n ϭ 11) or 1:5 (n ϭ 2) and were ultimately diagnosed with an alternative condition (n ϭ 11) or began therapy for possible cryptococcosis without improvement (n ϭ 2), leading to an overall CrAg LFA false-positive rate of 34%. We recommend careful clinical correlation prior to establishing a diagnosis of cryptococcal infection for patients with first-time positive CrAg LFA titers of 1:2.

Evaluation of low cryptococcal antigen titer as determined by the lateral flow assay in serum and cerebrospinal fluid among HIV-negative patients: a retrospective diagnostic accuracy study

“…Of note, our study showed that all false-positive cases were found in low serum titer cases, and more than a half (60.0%, 6/10) of them had predisposing conditions. Likewise, in the investigation by Dubbels et al, one or more co-existing predisposing factors were identified in 4 of 11 false-positive individuals with an overall rate of 36.4% (Dubbels et al 2017). However, the role of the immune status in the diagnostic accuracy of the CrAg LFA test remains unknown, though the incidence of false positives was higher in patients with predisposing factors.…”

“…With predisposing factors 33.3 CrAg titers were also identified in 20.0% (5/25) proven or probable cryptococcosis patients through an investigation at the Mayo Clinic (Dubbels et al 2017), indicating a potentially high incidence of low CrAg titer in HIV-negative patients, in whom the fungal burden may be lower. Early diagnosis, usually confirmed by CrAg titers in serum or CSF, is crucial for reducing the dissemination, disability and mortality of cryptococcosis (Sungkanuparph et al 2017).…”

“…Apart from the immune status, the other factors affecting false positives in the LFA are still unclear. Previous studies have reported that false positive results by the LFA may occur in patients with Trichosporon asahii, Paracoccidioides brasiliensis, and Aspergillus species infections (Vijayan et al 2013, Rivet Dañon et al 2015, Jitmuang et al 2016, Dubbels et al 2017. As for RF, the diagnostic interference of RF with the LFA has not been well recognized yet.…”

“…Only 2 culture-confirmed cryptococcal meningitis cases with low CrAg titers of 1:10 were reported in HIVinfected patients (Kabanda et al 2014). For patients without HIV infection, a retrospective study carried out by the Mayo Clinic reported that 13 of 18 cases with low CrAg LFA titers were found to be false-positive (Dubbels et al 2017). However, another study reported that 9 of 19 HIVnegative cases with low CrAg titer were identified to have pulmonary cryptococcosis (Erin et al 2019).…”

Very early‐onset ofCryptococcus neoformansdisease following liver transplantation: Report of two cases and a review of the literature

“…The role CrAg screening in cost‐saving and disease prevention in transplant recipients has been postulated but not yet defined. Further study is needed to determine whether there is an association between low‐positive CrAg titers in this setting and the risk of post‐transplant cryptococcosis, as well as the role of prophylactic antifungal therapy.…”