Can a Common Medical Practice Transform Candida Infections From Benign to Deadly? Joan Stephenson, PhD JAMA November 28, 2001 Vol 286, No. 20 pp 2499-2626 San FranciscoNew research hints that a common medical practicethe use of heparin in intravascular catheters to discourage blockages by blood clotsmay sometimes inadvertently trigger events that transform a benign fungal infection into a deadly illness. The microbe in question is Candida albicans, a yeast that often harmlessly colonizes patients. But C albicans has a darker side: it is also the leading cause of invasive fungal disease in premature infants and others with weakened immune systems, such as individuals infected with HIV, people recovering from surgery, and cancer or bone marrow transplantation patients. What transforms this microbial Dr Jekyll into a deadly Mr Hyde? Although many factors are likely to be involved, the new findingsthough preliminarysuggest that heparin in intravascular catheters may play a role by triggering a series of events that result in a life-threatening toxic shock-like reaction. TERMS OF ATTACHMENT The research, reported here at the 39th annual meeting of the Infectious Diseases Society of America, is part of an ongoing effort by Margaret K. Hostetter, MD, of Yale University School of Medicine, and colleagues to understand how and why C albicans can turn deadly. During the past two decades, the incidence of candidemia in patients in intensive care units (ICUs) has soared from 1.5 to 60 infections per 10 000 adult ICU admissions in adults and from 23 to 123 infections per 10 000 admissions to neonatal ICUs, noted Hostetter. Even with antifungal therapy, the mortality rate in patients with systemic C albicans infections approaches 30%. Although this yeast sometimes invades the bloodstream via a breach in the gut's epithelial barrier, researchers had long noted that in the majority of cases, patients who developed candidemia had central venous catheters in place for receiving infusions of antibiotics and other drugs, blood products, and other substances. Various Candida species on the skin of the patient or caregivers can insinuate their way into these catheters, adhere to the inside of the tubing, and form biofilmscomplex layers of yeast cells that can be dislodged and disseminated through the bloodstream to virtually every organ of the body, Hostetter explained. In previous research on virulence factors that allow C albicans to attach to host cells and form invasive hyphae, Hostetter and colleagues identified a gene called INT1, which encodes a C albicans surface protein, Int1p. Through a series of experiments, the investigators linked INT1 with adhesion, the ability to grow filaments, and virulence. Hostetter and colleagues also have recently found evidence in laboratory and animal studies that Int1p may yet another function: enabling C albicans to replicate in the kidney and in urine. "Knockout" mutants lacking INT1 are unable to proliferate in urinea hostile environment because of its high urea contentand they also have a somewhat impaired ability to grow and form normal filaments in mice. "Urea appears to be a potent trigger for replication and filamentation, and Candida albicans expressing INT1 can survive in this milieu," Hostetter said. If true, this may explain why uremic patients and patients undergoing peritoneal dialysis are susceptible to C albicans infections. LOOKING FOR A TOXIN The investigators suspected, however, that C albicans' ability to stake out the kidneys was not sufficient to explain why the microbe can be so lethal. "After all, a substantial proportion of patients dying from candidemia have no renal lesions whatsoever," said Hostetter. She and her colleagues turned their attention to searching for a toxin of some sort. Patients dying of candidemia have many of the same manifestations seen in patients stricken with bacterial sepsis: fever, shock, and soaring levels of cytokines such as tumor necrosis factor alpha(TNF-alpha) and interleukin 6 (IL-6). The researchers suspected that a microbial superantigen might fit the bill for several reasons, including the fact that such toxins are known to trigger a volcanic eruption of cytokines. Hostetter and colleagues conducted a series of experiments that provided evidence that INT1 is indeed linked with superantigenlike effects, while INT1-deficient C albicans is not. The protein Int1p is much larger than known superantigens, too large to be a candidate. But the investigators reasoned that perhaps (as is the case with at least one established superantigen), some unknown agent fosters the cleavage of Int1p into fragments, and that one of these fragments acts like a superantigen. A search of the literature turned up just such a candidate: heparin. The investigators found that heparinin concentrations equivalent to those in intravascular cathetersfacilitates the cleavage of a 263–amino acid peptide from Int1p. In vitro studies indicate that this cleavage product does indeed act like a superantigen, activating T lymphocytes and liberating cytokines TNF-alpha and IL-6, said Hostetter. AN "ACCIDENTAL" PATHOGEN? These provocative new findings await confirmation from animal studies, said Hostetter. But the work suggests that physicians may need to reevaluate the routine use of heparin in patients with intravascular catheters, especially those known to be colonized with Candida albicans. Hostetter tells of a recent encounter at a meeting of the European Society of Neonatology that adds weight to the notion that heparin may transform the yeast into a life-threatening pathogen. "I was astounded to learn that neonatologists in Germany and France don't use heparin in their intravascular catheters, and they see absolutely no candidemia," she said. Perhaps Candida albicans should be considered an "accidental" pathogen, mused Hostetter. "Candida doesn't 'want' to kill its host, but these events could be an accident of modern medical technology, a consequence of the use of heparin in central venous catheters," she said. Edward E. Rylander, M.D. Diplomat American Board of Family Practice. Diplomat American Board of Palliative Medicine.