Postdiagnostic kinetics of the (1 3)dglucan assay in invasive aspergillosis, invasive candidiasis and pneumocystis jirovecii pneumonia

Post-diagnostic kinetics of the (1 fi 3)-b-D-glucan assay in invasiveaspergillosis, invasive candidiasis and Pneumocystis jirovecii pneumonia S. Koo1,2,3, L. R. Baden1,2,3 and F. M. Marty1,2,3 1) Brigham and Women’s Hospital, 2) Dana-Farber Cancer Institute, and 3) Harvard Medical School, Boston, MA, USA The kinetics of serum (1 fi 3)-b-D-glucan (BG) following the diagnosis of invasive fungal disease and administration of antifungal therapy are poorly characterized. It is unknown whether early BG changes have prognostic implications. We assessed the post-diagnostic kinet- ics of BG in patients with an initial serum BG ‡80 pg/mL and at least one additional post-diagnostic BG value in the setting of invasive aspergillosis (IA, n = 69), invasive candidiasis (IC, n = 40), or Pneumocystis jirovecii pneumonia (PCP, n = 18), treated with antifungal ther- apy. Clinical failure of antifungal therapy and mortality were assessed at 6 and 12 weeks, and Cox modelling was used to assess the haz- ard of initial BG and change in BG at 1 or 2 weeks for these outcomes. In patients with at least two BG values, median initial BG was >500 pg/mL (interquartile range (IQR) 168 to >500; range 80 to >500) in IA, 136 pg/mL (IQR 88 to >500; range 31 to >500) in IC and >500 pg/mL (IQR 235 to >500; range 86 to >500) in PCP. In patients with at least two BG values through to 1 week after diagnosis, overall 1-week decline in BG was 0 pg/mL (IQR 0–53) in IA, 0 (IQR ) 65 to 12) in IC and 17 (IQR 0–82) in PCP. Most patients withBG values through 6 and 12 weeks had persistent levels >80 pg/mL. Initial BG and the early trajectory of BG were not predictive of 6- week or 12-week clinical failure or mortality. Whereas BG eventually declines in patients with IA, IC and PCP, it lacks prognostic value within a clinically meaningful time frame.
Keywords: b-glucan, candidiasis, galactomannan, invasive aspergillosis, invasive fungal disease, kinetics, Pneumocystis jirovecii Original Submission: 7 October 2011; Revised Submission: 1 December 2011; Accepted: 14 January 2012 Article published online: 2 February 2012 Clin Microbiol Infect 2012; 18: E122–E127 sought to determine whether BG declines within a clinically Corresponding author: S. Koo, Division of Infectious Diseases, meaningful timeframe with antifungal therapy, and whether Brigham and Women’s Hospital, 75 Francis Street, PBB-A4, Boston,MA 02115, USA this decline has any prognostic value.
Although the diagnostic performance of serum (1 fi 3)-b-D- We identified all Brigham and Women’s Hospital/Dana-Farber glucan (BG) for invasive fungal disease (IFD) is fairly well- Cancer Institute patients from January 2005 to June 2009 who defined [1–4], its response to antifungal therapy is unknown.
fulfilled the following criteria: (i) proven or probable IA or In a murine invasive aspergillosis (IA) model, animals receiv- invasive candidiasis (IC) per 2008 European Organization for ing antifungal therapy had lower BG levels at censoring than Research and Treatment of Cancer–Mycoses Study Group untreated controls, and a decline in BG was associated with (EORTC/MSG) IFD diagnostic criteria [7], independent of BG improved survival [5,6]. In an analysis of its diagnostic perfor- results; or Pneumocystis jirovecii pneumonia (PCP) based on mance in a large cohort at our institution, BG sensitivity did host factors, a compatible clinical syndrome, and cysts in respi- not decrease in patients treated with antifungal agents for ratory tract specimens; (ii) BG ‡80 pg/mL at IFD diagnosis; over a week, suggesting relatively slow BG clearance [4]. We and (iii) receipt of antifungal therapy for IFD.
ª2012 The AuthorsClinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases Patients with concurrent invasive mycoses and patients 12 weeks and 6- and 12-week mortality. Cox modelling was exposed to factors associated with elevated serum BG in the used to generate unadjusted hazard ratios (HRs) for initial absence of IFD, such as intravenous immunoglobulin, albumin serum BG, change in BG after 1 and 2 weeks of antifungal or cellulose haemodialysis membranes, were excluded [4,8].
therapy, and other potential predictors of mortality or clini- No patients were bacteraemic with Pseudomonas aeruginosa, cal failure, including age, gender and IFD risk factors. Cox Alcaligenes faecalis or Streptococcus pneumoniae; in vitro culture modelling was also used to generate adjusted HRs for 6- supernatants of these organisms have been associated with week and 12-week clinical failure and mortality.
All analyses were performed with STATA 10 (STATA, Demographic, IFD and antifungal treatment details were College Station, TX, USA). The hospital’s Human Research recorded. The IFD host factors were assessed using the cur- rent EORTC/MSG definitions [7]. All BG values from IFD Serum BG levels were determined with the Fungitell assay (Associates of Cape Cod, East Falmouth, MA, USA) by a ref- We identified 88 patients with IA; 69 had at least two post- erence laboratory without knowledge of patient IFD status.
diagnostic BG values and 53 had BG measurements at least This assay is reported continuously for results between 31 1 week after diagnosis. Key patient characteristics are out- and 500 pg/mL, and as >500 pg/mL for values above this range. A value ‡80 pg/mL is considered positive. BG testing Of 69 patients with at least two post-diagnostic BG values, was performed at the discretion of clinical care teams.
19 had proven IA and 50 had probable IA. One patient had isolated sinus disease; the remaining 68 had pulmonary IA at minimum, and six had multifocal IA. The causative Aspergillus Mortality and cause of death were assessed in all patients at species was identified in 41 (59%) patients—32 A. fumigatus, 6 weeks, after which IFD-related mortality wanes [10], and four A. flavus, four A. terreus and one A. niger. Sixty-five (94%) at 12 weeks, a secondary time point for IA and IC outcome of 69 patients received voriconazole for treatment of IA dur- assessment that is recommended by the 2008 EORTC/MSG ing their BG follow-up period. The remaining four patients therapeutic outcome consensus statement [11]. Patients received amphotericin or echinocandin therapy.
were further classified as clinical ‘successes’ (complete or Actuarial data on rates of patient mortality and failure to partial response) or clinical ‘failures’ (stable response, pro- respond to antifungal therapy at 6 and 12 weeks are pre- gression of disease, or death) at 6 and 12 weeks according sented in Table 2. Eleven patients who were alive at 6 weeks to these consensus criteria for defining responses to antifun- had clinical outcomes that were discordant with their sur- gal therapy [11]. There is some controversy about whether vival status—while alive, they were considered clinical fail- to classify ‘stable response’ as clinical failure or success in ures because of either stable clinical response or evidence of these consensus criteria, so we assessed the endpoint of ‘fail- TABLE 1. Demographics and host factors in patients with at ure’ according to the standard definition and made a sepa- rate assessment reclassifying the six stable response cases as Change in BG at 1 and 2 weeks was calculated by linear interpolation from the two surrounding data points in patients with BG follow-up values extending through these time points. For the purposes of this analysis, 501 pg/mL was used for BG values reported as >500 pg/mL. Time to BG <80 pg/mL was estimated using linear interpolation in patients with values that eventually declined below this aMedian, interquartile range, range.
bAs defined by EORTC/MSG IFD diagnostic criteria [7].
We used the Kaplan–Meier method to estimate clinical HSCT, haematopoietic stem cell transplantation; GVHD: graft-versus-host dis-ease.
failure of antifungal therapy (as a binary outcome) at 6 and Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, E122–E127 Clinical Microbiology and Infection, Volume 18 Number 5, May 2012 TABLE 2. Clinical outcomes in patients with invasive asper- GM elevations at IA diagnosis; none had persistent GM ele- In 23 patients whose BG values eventually declined to <80 pg/mL, median time to this threshold was 7 days (IQR All invasive aspergillosis patients (n = 88) 3–11; range 1–162) in 11 patients with an initial BG <150 pg/ mL, 17 days (IQR 10–24; range 4–76) in five patients with Patients with at least two (1 fi 3)-b-D-glucan values (n = 69) initial BG 150–500 pg/mL, and 78 days (IQR 69–711; range 54–821) in seven patients with initial BG >500 pg/mL.
In nine lung transplant recipients with at least two BG val- ues following IA diagnosis, five with pleural involvement, As defined by 2008 EORTC/MSG consensus criteria for defining responses to median initial BG was >500 pg/mL (IQR >500 to >500; range At 6 weeks, 32 patients were considered clinical ‘successes’ (three complete clinical responses, 29 partial responses) and 56 were considered clinical ‘failures’ 229 to >500). All eight patients with BG follow-up values (six stable responses, five progressive disease, and 45 deaths).
dAt 12 weeks, 34 patients were considered clinical ‘successes’ (13 complete clin- through to 6 weeks and seven patients with BG follow-up ical responses, 21 partial responses) and 54 were considered clinical ‘failures’ (0 through to 12 weeks had persistently elevated BG values.
stable responses, two progressive disease, 52 deaths).
One patient’s serum BG eventually declined to <80 pg/mL 2.6 years after IA diagnosis; the remaining six patients with progressive infection. Only two patients with progressive dis- BG follow-up past 12 weeks had persistently elevated BG ease had clinical outcomes that were discordant with their values 0.4–1.8 years after diagnosis despite clinical IA resolu- tion and in most patients, cessation of antifungal therapy.
Median initial BG was >500 pg/mL (interquartile range In the whole cohort, initial BG was not predictive of 6- (IQR) 169 to >500; range 80 to >500) overall and >500 pg/ week mortality, either in three strata, <150, 151–500 and mL (IQR 168 to >500; range 80 to >500) in patients with at >500 pg/mL (HR 1.23; 95% CI 0.90–1.74), or continuously least two BG values. Patients with at least two BG values (HR 1.11 per 100 pg/mL increase; 95% CI 0.95–1.28). In the had 3 values (IQR 2–6; range 2–20) following IA diagnosis 53 patients with BG values through at least 1 week after IA over 19 days (IQR 7–109; range 1–964).
diagnosis, change in BG at 1 week (HR 0.99 per 10 pg/mL In the 53 patients with BG values extending through decline, 95% CI 0.95–1.04) or 2 weeks (HR 0.99 per 10 pg/ 1 week after IA diagnosis, BG decline was 0 pg/mL (IQR 0– mL decline; 95% CI 0.92–1.06) was not predictive of 6-week 53; range ) 347 to 160) at 1 week, with negative numbers mortality, either alone or accounting for initial BG. Neither representing an increase in BG levels. Table 3 summarizes initial BG nor change in BG at 1 or 2 weeks was predictive changes in BG at 1 week by initial BG strata.
of 12-week mortality, alone or adjusting for each other.
Twenty-seven patients had BG follow-up through to Initial BG did not predict clinical failure of antifungal ther- 6 weeks after IA diagnosis: 22 (82%) had persistent BG ele- apy at 6 weeks (HR 1.10 per 100 pg/mL increase; 95% CI vation, with a median interpolated BG of 221 pg/mL (IQR 0.94–1.28) or 12 weeks (HR 1.12 per 100 pg/mL increase; 116 to >500; range <31 to >501). Twenty-two had concur- 95% CI 0.95–1.31) in the cohort overall. In the 53 patients rent galactomannan (GM) elevations at IA diagnosis; only with BG values at least 1 week following IA diagnosis, change three (14%) patients had persistent GM >0.5 units at in BG at 1 week (HR 1.00 per 10 pg/mL decline; 95% CI 0.96–1.03) or 2 weeks (HR 1.00 per 10 pg/mL decline; 95% Twenty patients had BG follow-up 12 weeks after diagno- CI 0.95–1.04) was not predictive of 6-week mortality, either sis; 12 (60%) had persistently elevated BG with a median alone or accounting for initial BG. These HR estimates interpolated BG of 249 pg/mL (IQR 73 to >500; range <31 remained unchanged when the six patients with a stable to >500). In contrast, 15 of these patients had concurrent response at 6 weeks were classified as clinical ‘successes’ aNegative numbers indicate an interval increase in BG.
ª2012 The AuthorsClinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, E122–E127 rather than clinical ‘failures’. Neither initial BG nor change in 82–489; range 47 to >501). Ten (63%) of 16 patients with BG at 1 or 2 weeks was predictive of clinical failure in BG follow-up through 12 weeks had values >80 pg/mL, with response to antifungal therapy at 12 weeks, individually or a median 12-week interpolated BG of 140 pg/mL (IQR 70– adjusting for each other. Excluding patients with non-linear BG values (>500 pg/mL) within the first 1–2 weeks, initial In the whole IC cohort, initial BG was not predictive of 6- BG and change in BG at 1 or 2 weeks were still not predic- week mortality or clinical outcome (HR 0.87 per 100 pg/mL tive of 6-week or 12-week mortality or clinical failure, with increase; 95% CI 0.58–1.30). In the 40 patients with BG val- ues through at least 1 or 2 weeks after IC diagnosis, change in BG at 1 week (HR 1.00 per 10 pg/mL, 95% CI 0.96–1.05) or 2 weeks (HR 0.99 per 10 pg/mL, 95% CI 0.95–1.04) was We identified 75 patients with IC, 40 with at least two BG also not predictive of 6-week mortality or clinical outcome, values following IC diagnosis. Patient characteristics are out- either alone or accounting for initial BG. Initial BG and change in BG at 1 or 2 weeks were also not predictive of Of patients with at least two post-diagnostic BG values, 12-week mortality or clinical outcome, either alone or in 36 had proven IC and four had probable IC. Of the 36 pro- ven IC cases, 19 were caused by C. albicans, three by C. glab- rata, three by C. tropicalis, two by C. parapsilosis, two by C. krusei, one by C. guillermondii and one by Kodamaea (Pichia) We identified 38 PCP patients, 18 with at least two post- omeri. Three patients had concurrent candidaemia with more diagnostic BG values. Twenty-eight (74%) had an underlying than one species—C. albicans and C. tropicalis, C. albicans and malignancy and seven (18%) were HIV positive. Of patients C. glabrata, and C. tropicalis and C. parapsilosis. Two patients with at least two BG values, 16 (89%) received trimetho- had abundant yeast forms and pseudohyphae strongly sugges- prim–sulfamethoxazole, one received atovaquone and one tive of Candida species on visceral biopsy, with sterile biopsy had primaquine and clindamycin for PCP treatment.
Median initial BG was >500 pg/mL (IQR 410 to >500; Twenty-eight patients with at least two BG values range 86 to >500) overall and >500 pg/mL (IQR 235 to received fluconazole, eight received echinocandin and four >500; range 86 to >500) in patients with at least two BG val- had voriconazole maintenance therapy for IC treatment dur- ues. Patients with at least two BG values had 2 values (IQR 2–3; range 2–11) over 22 days (IQR 15–115; range 1–347) All-cause mortality was 0.24 (95% CI 0.15–0.35) at of BG follow-up. Median decline in BG was 17 pg/mL (IQR 6 weeks and 0.28 (95% CI 0.19–0.40) at 12 weeks overall, 0–82; range )343 to 205) 1 week after PCP diagnosis in 16 and 0.13 (95% CI 0.06–0.28) at 6 weeks and 0.21 (95% CI patients with BG follow-up through this time point.
0.11–0.37) at 12 weeks in the 40 patients with at least two Five of seven (71%) patients with BG values through to BG values. Clinical response at 6 and 12 weeks was concor- 6 weeks and four of six (67%) patients with BG follow-up dant with survival status in all IC patients—all patients had values through to 12 weeks after PCP diagnosis had BG val- either a complete or partial response or death at these time ues >80 pg/mL at these time points.
All-cause mortality was 0.22 (95% CI 0.11–0.39) at Median initial BG was 212 pg/mL (IQR 119 to >500; range 6 weeks and 0.33 (95% CI 0.20–0.51) at 12 weeks in all <31 to >500) overall and 136 pg/mL (IQR 88 to >500; range patients and 0.17 (95% CI 0.06–0.43) at 6 weeks and 0.28 31 to >500) in patients with at least two BG values. Patients (95% CI 0.13–0.54) at 12 weeks in patients with at least two with at least two2 BG values had three values (IQR 2–5; BG values. Clinical response at 6 and 12 weeks was perfectly range 2–9) following IC diagnosis over 51 days (IQR 24–124; concordant with survival status in all PCP patients—all patients had either a complete response or death at these Median decline in BG 1 week after IC diagnosis was 0 pg/mL (IQR )65 to 12; range )365 to 243) in 39 patients Neither initial BG (HR 1.05 per 100 pg/mL increase; 95% with BG follow-up extending through this time point.
CI 0.77–1.45) nor decline in BG at 1 week (HR 1.03 per Change in BG at 1 week by initial BG strata is summarized 10 pg/mL, 95% CI 0.94–1.13) or 2 weeks (HR 1.00 per 10 pg/ mL, 95% CI 0.93–1.06) was predictive of 6-week mortality or Sixteen (70%) of 23 patients with BG follow-up values clinical outcome, alone or in combination. Neither initial BG through 6 weeks had persistent BG elevations >80 pg/mL, nor decline in BG at 1 or 2 weeks was predictive of 12-week with a median 6-week interpolated BG of 138 pg/mL (IQR mortality or clinical outcome, alone or in combination.
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, E122–E127 Clinical Microbiology and Infection, Volume 18 Number 5, May 2012 further characterized at the time of testing, and original serum samples were unavailable for further analysis. We were therefore unable to explore the full impact of the rate Serum BG declined slowly in most IA, IC and PCP patients of BG decay because of this artificial truncation of the assay’s treated with appropriate antifungal therapy, and often per- linear range, creating a ceiling effect. Initial BG and early BG sisted above the usual threshold for positivity long after clini- changes were not predictive of clinical outcome when we cal resolution of the original infection. Neither BG height at restricted our analysis to values in the clinically reported lin- diagnosis nor early changes in BG levels were predictive of ear range of the assay, and given the extremely slow clear- clinical outcome or mortality at 6 or 12 weeks.
ance of BG in patients with initial values >500 pg/mL, often The rise and fall of serum BG remains poorly character- months to years after diagnosis, it is unlikely that these early ized in human IFD and probably depends on a range of incremental changes in BG would have provided useful prog- organism and host factors, including fungal species and bur- nostic information. Our study was also subject to the biases den, location of the infection, structure and molecular of non-systematic testing, as BG values were obtained at the weights of BG released into the bloodstream, timeliness of discretion of the clinical care teams.
IFD diagnosis, host immune status, rate of glomerular filtra- tion of low-molecular-weight BG, and rate of hepatic degra- value—BG often lingers in the serum past the clinical outcome dation of higher-molecular-weight BG [8,12,13].
of interest, and its early trajectory does not appear to predict In mammalian IA and PCP models, BG parallels fungal bur- clinical outcome. Unlike serum GM in IA [21], BG is not clearly den and declines with effective therapy [5,6,14–16]. Data on related to the hazard rate for mortality and does not capture post-diagnostic BG kinetics in humans are sparse, but the the net effects of IFD treatment on clinical outcome; it is available data are concordant with our findings. One study of therefore unlikely to be a useful surrogate marker for success- BG for IA diagnosis in neutropenic patients with haematolog- ful response to antifungal therapy in IFD patients [22,23].
ical malignancies reported persistent BG elevations in Although BG has no discernible prognostic value, it probably patients not responding to antifungal therapy and eventual retains its use as an IFD diagnostic test even after initiation of normalization in five IA patients who clinically responded to antifungal therapy, precisely because of its slow clearance.
antifungal therapy, although BG declined to <80 pg/mL after 6 weeks in patients whose values did eventually normalize [17]. In six haematopoietic stem cell transplant recipients with candidaemia, median time between clearance of candi- daemia and decline of BG to less than the diagnostic thresh- All authors contributed substantially to the conception and old for positivity was 48 days [18]. In 35 of 42 AIDS patients design of this study, reviewed the manuscript critically for with PCP, BG trajectory did not reflect the clinical course important intellectual content, and approved the final version after 3 weeks of therapy, and BG actually increased in nine of the manuscript. SK acquired and analysed the data and patients despite clinical improvement [19]. The authors reported the eventual normalization of BG values several months to years after treatment in all patients. In another recent retrospective study of BG in 17 AIDS patients with PCP, only three (18%) patients 4 weeks after PCP diagnosis and seven (41%) patients 6 weeks after PCP diagnosis had Part of this work was presented in abstract form at the BG values less than the diagnostic threshold for positivity Advances Against Aspergillosis conference in Rome, Italy in It is unclear why BG appears to behave differently in mammalian models compared with human infection—it may reflect earlier initiation of antifungal therapy in experimental models, before the onset of extensive invasive disease, whereas in our cohort, BG testing was generally driven by a This work was supported in part by Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH There are major caveats to consider when interpreting Award #UL1 RR 025758 and financial contributions from this study. Samples with values greater than the 500 pg/mL, Harvard University and its affiliated academic healthcare cen- the upper threshold the Fungitell assay reports, were not ters). All authors report no relevant conflicts of interest.
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