For two days this 3-year-old female had a poor appetite, a low grade fever, poor urinary output and abdominal pain with, in her mother’s words, “pink” stools, which prompted a visit to the pediatrician’s office and then to the ED at the local hospital, where the girl was admitted for IV rehydration and pain control. On discharge, Johns Hopkins pediatric resident Madiha Raees reported at a recent case conference, the patient’s appetite and blood stools had improved and she was urinating well. Then things got worse.
Over the next few days the girl suffered increasing abdominal pain—again with pink stools—fatigue and nausea, and the continuing problem of infrequent urination, or anuria. She was transferred to Johns Hopkins Children’s Center, where she appeared irritable and pale with dry mucus membranes. Most notable in the workup was a low blood pressure reading of 80/48. With the exception of a grandmother with hypertension, her history was unremarkable—she suffered no allergies, was not on any medications, and her immunizations were up to date. Any animal exposure? No. What was going on? Was this more than a case of acute gastroenteritis?
Along with the symptoms, a clue came when the mother was asked if her daughter had recently eaten anything unusual. Well, yes, both the mother and the girl had shared an unpasteurized drink at a local market. Interestingly, the mother had experienced a similar bout with diarrhea, though it had resolved and she now felt fine. So, pediatric residents at the case conference were asked, any thoughts on differential diagnosis? What further labs should be ordered?
Acute interstitial nephritis, cardiogenic shock, dehydration, glomerulonephritis, hemolytic anemia, and septic shock were among the responses. Overwhelmingly, however, the residents were leaning toward HUS, or hemolytic uremic syndrome. HUS typically develops in children after two to 14 days of diarrhea, often bloody and often due to infection with Escherichia coli (E. coli), which is found in contaminated meat or produce, or perhaps an unpasteurized drink. In HUS red blood cells are damaged and begin to clog the filtering system in the kidneys, which may lead to life-threatening kidney failure. But was HUS the culprit in this case?
“There were so many things at the outset that led us to HUS right away but you can’t ignore other possibilities,” said pediatric nephrologist Lauren Loeffler.
Confirmation of HUS, Loeffler explained, requires a triad of diagnostic criteria—hemolytic anemia, thrombocytopenia, and acute kidney failure—evidenced by elevated results in blood urea nitrogen and creatinine lab tests, among others. Because HUS is a systemic disease, Loeffler ordered other labs to obtain a baseline of other organs affected.
“What’s happening in the kidney is happening everywhere in the body,” said Loeffler. “There is a great deal of acute and chronic morbidity associated with this disease.”
She added that the classic clinical history and timeline of HUS—dehydration, bloody diarrhea, resolution of the diarrhea followed a day or two later by worsening symptoms of abdominal pain and fatigue—seals a diagnosis of HUS.
“That’s what happened with this child—everyone is relieved that the diarrhea is over, but about 15 percent of these exposed children go on to have HUS,” said Loeffler.
Children’s Center director and hematologist George Dover, citing the key question repeatedly raised by Johns Hopkins pediatrician-geneticist Barton Childs, asked, “Why did this child get this disease at this time?” In his book Genetic Medicine: A Logic of Disease, Childs, who died in 2010, argues that in the future all medicine must be based on the individuality of gene-environment interaction.
In the same vein, Dover also asked, “Why is it that only 15 percent of the people exposed to this bacteria get HUS? And why is it that the mother was exposed to the same bacteria but she’s fine?”
The answers, Loeffler said, are unknown, though some theories suggest a genetic link to dysregulation of the complement pathway in the immune system that leads to unchecked cell destruction, or lysis. Mutations in the complement regulators factor H, factor I and membrane cofactor protein have been associated with atypical HUS, which occurs without E. coli exposure and subsequent diarrhea.
“People wonder,” Loeffler said, “do patients who get diarrheal HUS have a less severe abnormality in their complement pathway?”
Regarding the patient’s mother, who didn’t develop HUS, Loeffler added, “Maybe the mom didn’t get as high a dose of the toxin as the child received? You have to get enough toxin to trigger the HUS.”
In the hospital, treatment of HUS includes fluid therapy and management of hypertension, hematologic disorders and acute renal failure—up to two-thirds of patients require acute dialysis. For community pediatricians, Loeffler said, the take-home message in this case is close monitoring of patients with diarrheal illness.
“Pediatricians need to give parents very clear advice on how to monitor for dehydration and to seek medical attention if their child is not improving within a couple of days of the diarrhea going away,” said Loeffler. “If they get better and then feel bad the next day, something may be going on.”