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EMBARGOED FOR RELEASE Wednesday, April 1, to correspond with publication in the March issue of the Journal of Pediatrics.
TEST FOR NEONATAL INFECTIONS
MAY SAVE BABIES' LIVES, REDUCE HOSPITALIZATIONS
STANFORD -- Infants' immune systems are not fully developed at birth, so infections contracted before or during birth are extremely dangerous. But these infections are also hard to diagnose.
A new test devised at Stanford University Medical Center may allow rapid and reliable diagnosis of infections in newborns. This could reduce hospitalizations and antibiotic usage for uninfected babies, while saving the lives of babies whose infections might otherwise go undetected.
'Newborns can die within six hours if they are infected, but they don't have the usual signs of infection,' said Leonore Herzenberg, professor of genetics and senior author of a research report on the new test in the March Journal of Pediatrics.
'So we collaborated with our colleagues in pediatrics to devise a blood test that would identify infected newborns, using only a single drop of blood,' she said.
Knowing which babies to treat could save millions of dollars annually in unnecessary health care expenses. Every year, up to 300,000 newborns in the United States receive treatment for suspected infections, at a cost of more than $800 million -- even though only one in 17 has a confirmed infection, the researchers noted in their research paper.
Erica Weirich, a final-year medical student and the lead author of the paper, coordinated the study and conducted most of the laboratory work. In addition to Weirich and Herzenberg, the other authors are Dr. Ronald Rabin, now at the National Institute of Allergy and Infectious Disease; Dr. Yvonne Maldonado and Dr. William Benitz, both associate professors of pediatrics; Siv Modler, pediatrics study coordinator; and Leonard Herzenberg, professor of genetics.
Vague symptoms
'In neonates, it's hard to define what is an infection and what is not. The babies may act irritable, they may not feed well, or they may have a whole host of very minimal symptoms in the first day or so of life,' Maldonado said.
'You end up treating a lot of children for suspected bacterial infections when in fact they have either a benign viral infection or just variations in normal behavior. This involves a substantial cost in terms of hospital care and antibiotics. It's worth the cost if it saves lives, but you want to minimize a newborn's time in the hospital and away from parents,' Maldonado said.
The most direct way to diagnose a bacterial infection is by trying to grow the offending bug in a laboratory culture, starting with a sample of urine, blood or spinal fluid. Another way is to test for C-reactive protein (CRP), produced by the immune system in response to infection.
Both methods can take days to yield results. Bacterial cultures need at least 24 to 48 hours to grow, and CRP testing requires three consecutive days of negative results to rule out an infection, because the body can be slow to begin producing the protein. Meanwhile, antibiotic treatment and hospitalization must continue.
Bacterial cultures can also miss bacteria that fail to grow, and with the CRP test, stress from a difficult birth or other disease conditions can lead to false- positive results.
Speedy response
The new test measures a different protein, called CD11b. This protein rapidly appears on the outside of certain white blood cells, called neutrophils, as part of the immune system's response to infection. In test tube experiments, the amount of CD11b on the cell can increase within five minutes after exposure to bacteria.
With such a speedy response, the Stanford researchers were able to identify infections using blood samples collected from infants right after birth.
The researchers studied 106 infants who were being monitored for bacterial infection in the neonatal intensive care unit of Lucile Packard Children's Hospital at Stanford. Five of the babies had bacterial infections that were later confirmed by culturing the bacteria. All five of these infants showed high levels of CD11b when they were first admitted to intensive care, but did not show high CRP levels until later -- generally, one to two days after admission.
Two babies had confirmed viral infections. Both of them had high CD11b levels at admission, and neither had high CRP levels.
In 17 babies, doctors suspected bacterial infection because of outward symptoms, but cultures did not confirm the infection. Sixteen of these infants had high CD11b levels at admission. Fifteen later showed high CRP levels.
Of the remaining 82 babies with no evidence of infection, all had low CD11b levels at admission, although two later showed high CRP levels.
Thus, within six hours of birth, the CD11b test correctly predicted the diagnosis of all the babies with confirmed infections and all but one of those with suspected infections. The test also correctly excluded all babies who were infection-free.
Predictive value
This predictive value of 105/106 is extremely high, said Leonore Herzenberg. To confirm it, she and her colleagues propose a multicenter trial looking at up to 3,000 babies.
'A test like this has value in giving doctors more information about the infants they treat,' Herzenberg said. 'The second value may be in cutting down on intensive care admissions if we get the predictive values high enough. And the third issue is looking at all babies to catch infections that might be missed. At Packard Children's Hospital we tend to err on the side of safety, treating all babies who show any signs of infection, but that isn't possible in all places.'
The new test uses a flow cytometer, or FACS machine, to measure the amount of CD11b protein on the outside of each cell. The first flow cytometer was developed at Stanford in the early 1970s by a team led by Leonard Herzenberg. Although this is a complex technology, it is now widely available, used for everything from detecting cancer cells to measuring the levels of immune cells in AIDS patients.
Rigors, rewards
To collect a single drop of blood as soon as possible after each newborn in the study was admitted to neonatal intensive care, medical student Erica Weirich stayed on call for many, many hours.
'What she did required exceptional diligence and planning,' said Leonore Herzenberg.
'There was a lot of running between the neonatal intensive care unit and the laboratory,' Weirich recalled.
As part of a standard hospital protocol, however, the test should be simple to use, Herzeberg added.
'This may be a new and faster method to discriminate between infected and non-infected neonates,' commented Maldonado. 'It seems like a really nice way to keep children out of the hospital who don't need to be there.'
The study was supported by a National Cancer Institute Outstanding Investigator grant to Leonard Herzenberg and by Health and Human Services grant M01-RR00070 (General Clinical Research Centers, National Center for Research Resources, National Institutes of Health). The flow cytometry was done at the shared FACS facility in Stanford's Beckman Center for Molecular and Genetic Medicine.
Lucile Packard Children's Hospital at Stanford is part of UCSF Stanford Health Care.
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