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How to have a rational approach to the FUO work-up



– When a child’s worried parents bring him back to be rechecked on his 8th day of fever, what’s next? If the initial work-up is unrevealing, when is it time to consider hospitalization? And which children can safely be managed as outpatients?

These tough scenarios are part of why “most pediatricians really don’t enjoy fever of unknown origin (FUO),” said Brian Williams, MD, speaking at a pediatric infectious disease update at the annual meeting of the American Academy of Pediatrics. “It can be really time consuming and frustrating to tease all of this out.”

As a pediatric hospitalist at the Rady Children’s Hospital, San Diego, Dr. Williams said he considers himself lucky. He usually picks up the patient from a pediatrician who’s already seen the patient for a couple of office visits and has done the basic work-up.

Dr. Williams comes into the picture when, for the pediatrician, “something about that history, that physical exam, and that lab work has them concerned that the child needs to be hospitalized for closer monitoring and a more extensive work-up.”

“There’s lots of variability for inclusion criteria in the studies for pediatrics,” said Dr. Williams, but most characterize FUO as a fever of at least 100.4° F for 8 days or longer with no clear diagnosis.

Understanding the epidemiology of FUO and having a systematic clinical approach can save you some grief, he said. “I think it’s one of those diagnoses where a thorough history and exam can oftentimes give you some clues that can help lead to your diagnosis.”

“It’s a diagnosis that always gets my full attention because sometimes you can find some pretty significant infections – an osteomyelitis or a severe pelvic abscess,” he said. “And there’s always the concern of some of these more serious underlying diseases, like rheumatologic diseases; there’s plenty of case reports of [inflammatory bowel disease] presenting with FUO.” Of course, he said, even more dire diagnoses like Hodgkin’s lymphoma and leukemia have to remain in the differential as well.

Although the broad diagnostic differential includes noninfectious causes, they are rarer by far than infections. When the etiology of FUO has been studied in the United States, said Dr. Williams, “infections pretty consistently dominate as the most common cause of FUO … as general pediatricians, it’s our job to really do a good evaluation for infection before we start going after some of these less common diagnoses – the rheumatologic and cancer diagnoses.”

A systematic approach is important, he said. “A really good fever history can, a lot of times, provide important and valuable information.” Take the time to get granular detail: Find out how often the fever is being checked and by whom, what symptoms accompany the fever, and how the fever is being measured.

And don’t forget to ask if there are fever-free days, he said. In an otherwise well-appearing child, a few days’ respite from fever can increase the likelihood that you’re really seeing back-to-back viral illnesses rather than a protracted unexplained fever.

A thorough head-to-toe review of symptoms and history is critical, too. Dr. Williams related the story of a well-appearing 9-year-old boy who’d had many days of high fever with accompanying elevated inflammatory markers. His exam was unremarkable, and the only untoward symptom he could recall was a few days’ worth of left upper quadrant tenderness when running in gym class. The child, said Dr. Williams, turned out to have nephronia. “Sometimes, really subtle clues from the history can guide you.”

Ask about exposures, including travel, animals, foods, insects, and sick contacts. “Obviously, children can get into just about anything,” said Dr. Williams. A detailed family and social history also may turn up clues.

An infection-focused musculoskeletal exam, to include the spine, is a must, as is a top-to-bottom search for lymphadenopathy as part of a complete physical exam.

At this point in the pediatrics office, said Dr. Williams, you’ve come to a decision point: “Does this work-up need to be initiated in the inpatient setting, or is this something that can be started in the outpatient setting?”

“There’s a lot of data to support that, initially, a lot of these patients can be worked up in the outpatient setting with close follow-up,” he said. The outpatient FUO work-up begins with some basic screening labs. In addition to a complete blood count, chemistries, and a urinalysis, labs should include blood and urine cultures, erythrocyte sedimentation rate, and C-reactive protein levels.

“I’ll actually rely pretty heavily on my ESR and CRP,” said Dr. Williams. “If I have an otherwise well-appearing child with a normal CRP and an unremarkable exam, I think it’s a pretty tough argument to keep that child hospitalized and do a more invasive work-up.”

The advent of the viral polymerase chain reaction panel has helped streamline the FUO work-up as well. In the setting of a well-appearing child with an unremarkable initial work-up, “a positive adenovirus can provide a lot of reassurance to the families.”

Dr. Williams usually also gets a chest radiograph at this point, knowing that pneumonia is in the differential for FUO. He said he’s seen mediastinal masses, as well as picked up dense right upper lobe infiltrates that were missed on exam.

If the answer is still unclear at this point, exam and laboratory findings from the first-tier inquiry can help guide the next steps.

Some less common infectious etiologies can be considered now, said Dr. Williams. These can include Epstein-Barr virus, cytomegalovirus, and cat scratch fever; the latter, he’s found, is the third-most-common cause of FUO in some case series. For the real mystery cases, next-generation sequencing is an option: A blood sample is used to search for DNA fragments from a huge variety of microorganisms. “It’s a little overwhelming,” and very expensive, he said.

If an oncologic process is suspected, second-tier labs can include lactate dehydrogenase, uric acid, ferritin levels, and a peripheral smear. A rheumatologic work-up can be started, with antinuclear antibody and complement levels. At this point, though, a general pediatrician would be considering consults, he said.

Empiric antibiotics can be a tempting diagnostic strategy in some cases. “Is a trial of antibiotics warranted? Usually we advise against it,” but a case can be made for a time-limited trial in certain circumstances, said Dr. Williams.

Dr. Williams is a consultant for Zavante Therapeutics, which markets fosfomycin.

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