Increased mortality in young candidemia patients associated with presence of a Candida albicans general-purpose genotype

Abstract

The yeast Candida albicans causes life-threatening candidemia. A general-purpose genotype (GPG; corresponds to clade 1) causes more infections than other C. albicans genotypes. To investigate if GPG strains also cause higher mortality, we developed a duplex PCR assay which was 98% accurate in identifying GPG strains in an international collection of strains typed with probe Ca3. We applied the assay to 635 European C. albicans candidemia isolates. Of these, 18% conformed to the GPG genotype, 4% were of a borderline genotype, and 78% were of a non-GPG genotype, broadly consistent with genotype distributions in earlier studies. The prevalence of GPG strains was increased in females and in younger patients, exceeding 40% in infants aged ≤1 year. Logistic regression confirmed sex and age as significant determinants of GPG prevalence. Across the entire patient cohort, there was no difference in mortality for patients infected with GPG strains or other strains (36% versus 37%). However, mortality in patients aged ≤48 years was 33% for infection with GPG strains but only 15% for infection with other strains (z test; P < 0.01). Mortality rates associated with GPG and non-GPG strains were comparable in older patients (39% versus 46%). A logistic regression analysis confirmed the age-dependent impact of genotype on mortality. Thus, GPG strains may be more virulent than other strains in younger patients. Because candidemia is usually caused by endogenous strains, our PCR assay could potentially be used as a risk assessment tool for identifying younger patients most at risk of death from candidemia.

Fig. 1.

Duplex PCR assay. (A) PCR products for isolates from an international collection of isolates of known genotype (G=GPG, N=non-GPG, and B=borderline) (see Table S1 in the supplemental material) on which development of the assay was based. The GPG-specific MG1 and YWP1 products and their molecular weights are marked on the right, and molecular weights of bands of a 1-kb Plus ladder (MW) are shown on the left. (B) Example of a gel used to type isolates of unknown genotype, in this case a set of Italian isolates (see Table S2 in the supplemental material). Coamplified samples from previously typed GPG strains were included in every 4 to 5 lanes as controls [marked by “(G)” after the strain name]. Genotypes deduced from the assay are shown below each lane. A 100-bp ladder was loaded in the right lane (MW).

Fig. 2.

Prevalence of GPG strains. (A) Prevalence of GPG strains in female (black bars) and male (gray bars) patients in different age brackets. Age brackets were set to be consistent with those set for mortality analyses (see Fig. 4). Numbers in parentheses are the numbers of male and female patients in each age category. (B) Plot of dependence of prevalence on age for males and females, as deduced from logistic regression. Borderline strains were excluded from these analyses, as was one isolate where the age of the patient was unknown.

Fig. 3.

Higher mortality is associated with GPG isolates in young patients. (A) Mortality in different age groups of patients with GPG isolates relative to that of patients with non-GPG strains. The dashed line indicates a ratio of 1.0. (B) Overall mortality of patients of different ages. Numbers in parentheses after the age range are the numbers of GPG isolates and non-GPG isolates in the cohort. Age ranges were set so that at least 5 deaths of patients with GPG strains occurred in each cohort. (C) Plot of dependence of mortality on age, as deduced from logistic regression, for ICU patients, ICU patients who had undergone surgery (S+ICU), non-ICU patients who had undergone surgery (S), and non-ICU patients who had not undergone surgery (unlabeled). Solid lines indicate the mortality of patients with GPG strains, and dashed lines indicate the mortality of patients with non-GPG strains. Patients with borderline strains were excluded from these analyses.

Fig. 4.

Time dependence of survival probability of patients. (A) Time dependence of the probability of survival of patients aged 48 years or less with GPG isolates (solid line) and non-GPG isolates (dashed line). (B) Time dependence of the probability of survival of patients older than 48 years with GPG isolates (solid line) and non-GPG isolates (dashed line).