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 Francisco
New 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 
(TNF-) 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- 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.