Fever of Unknown Origin in an Adult? Consider Periodic Fever Syndromes

Paul G. Auwaerter, MD


July 02, 2018

Hello. This is Paul Auwaerter, speaking for Medscape Infectious Diseases, from the Johns Hopkins University School of Medicine.

Fevers of unknown origin (FUO) are a not infrequent cause for ID consultation. Fellows, residents, or students often go straight to the usual definition of FUO, but I ask them to pause and consider whether the patient truly fits the FUO pattern that has been used since the early 1960s: unexplained fever lasting 3 or more weeks versus a longer-term pattern, such as episodic FUO which often have a benign diagnosis. Some fevers occur periodically and are not limited to a day or two. People might have fevers lasting 5-7 days at a time, and when you closely question them, it seems that they have fevers once or twice a month, or every 4-8 weeks. These fevers seem to have a periodicity.

We don't typically encounter periodic FUO in adult infectious diseases, but they can certainly occur and are worth considering, especially in the outpatient clinic. We've seen a number of these patients over the years and it's always gratifying if you can get to a diagnosis.

A recent patient—a 23-year-old, accompanied by his mother—had a history of problems as a youth with recurrent and severe sore throats that didn't seem to be due to Group A streptococcal infections. He had a tonsillectomy which seemed to solve this problem through his elementary and high school years; however, in college, he started to have very frequent sore throats. These were not Group A strep-related, and he had swollen glands and rather high fevers (up to 102-103˚ F), chills, sores in his mouth, and occasionally other complaints of feeling run down. This might last 5-7 days and then abate.

This patient was referred to us as having a FUO, but upon interviewing him, we learned that these fevers were occurring about once every 2 months, and then becoming even more frequent, occurring every 2-4 weeks. He has taken copious quantities of antibiotics which seemed to yield some benefit, but it was unclear whether this was just a time issue. When lab tests were done during these flare-ups, there were marked elevations in C-reactive protein levels and erythrocyte sedimentation rate.

Unlike children (for whom we have a long list of possible genetic bases for periodic fever), adults have their own menu of periodic fevers to consider. These include familial Mediterranean fever, the TNF receptor–associated periodic syndrome (known as TRAPS), or cryopyrin-associated periodic syndromes.[1] Many of these patients have other signs and symptoms, such as rash or abdominal complaints, and a positive family history with fairly high frequency. These fevers can be diagnosed using genetic means; however, there is one entity that deserves consideration for which this patient fit fairly well—periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome).

PFAPA was first described in children, but in 2008 it was described for the first time in adults.[2] We've diagnosed several of these patients and have referred some to the National Institutes of Health for further study. Of interest, these patients often have a history of frequent sore throats as a child, with improvement after tonsillectomy. As adults, they present once again with similar symptoms. They generally lack belly symptoms and often have an exclusive response to prednisone in the course of a few hours. The basis for this condition is not well understood. These patients may have disorders of innate immunity or IL-1-like responses.[3] The genetic basis isn't fully known, although it's generally helpful to exclude other genetic explanations. A number of companies are providing increasingly lower-cost genetic panels to assess for some of the other genetic syndromes. You can find out more about the availability of these genetic tests here, although insurers might not pay for them, even though the costs are dropping. A number of my patients have been willing to pursue this route.

The PFAPA syndrome is a diagnosis of exclusion if it fits. Some patients will not have all of the components, although our 23-year-old patient did. Patients are often gratified just to have the syndromic name, and some are willing to soldier on through, perhaps using nonsteroidal drugs. Sometimes, when they are feeling especially ill, a brief course of prednisone seems helpful. Others have suggested that cimetidine is helpful, although I haven't tried that.

In conclusion, there is certainly a rationale for taking some time to decide what kind of fever you might be evaluating, particularly in the outpatient setting. If there is a concern for periodic fever, take a step back and think about some of the periodic fever syndromes that might occur in adults. You might have to pursue genetic testing. If you can get a diagnosis, it's often gratifying to the patients, who are highly frustrated and might have been diagnosed with other conditions, such as fibromyalgia, chronic fatigue syndrome, or other somatic disorders. So, it is worth considering.

Thanks very much for listening.


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