Fever of unknown origin: Clinical practice

Fever is one of the most common complaints in children.

Now, fever of unknown origin, or FUO, is defined as a temperature higher than 101ºF or 38.3ºC that lasts for at least eight days and has no underlying cause in spite of a formal evaluation.

Okay, so, causes of FUO can be divided into two large categories: infectious and non- infectious.

Infectious causes include generalized infections, especially bacterial ones, like Brucellosis, Cat scratch disease caused by Bartonella henselae infection, Lyme disease caused by Borrelia infection, Mycobacterial infections such as tuberculosis, Salmonellosis causing typhoid fever, Typhus caused by Rickettsial infections, Tularemia caused by Francissela tularensis, Psittacosis caused by Chlamydophila psittaci, Pasteurella along with various others infections from Campylobacter, Yersinia Legionella infections, Vibrio parahaemolyticus or vulnificus.

Likewise, there are viral infections, including Adenovirus, Influenza, CMV, EBV, arboviruses, and HIV; there are parasitic infections, like Malaria, Toxoplasmosis, and Babesiosis; and there are fungal infections like Blastomycosis, Cryptosporidiosis, Histoplasmosis, and Coccidioidomycosis.

But there are also localized infections, like pneumonia, bone and joint infections, such as osteomyelitis and septic arthritis, infective endocarditis, meningitis or encephalitis, intra abdominal abscesses, hepatitis, upper respiratory tract infections such as mastoiditis and sinusitis, dental infections, and urinary tract infections such as pyelonephritis.

Non-infectious causes include inflammatory conditions like Kawasaki disease, autoimmune conditions like Juvenile idiopathic arthritis, rheumatoid arthritis, polyarteritis nodosa, and systemic lupus erythematosus; neoplasms like leukemia and lymphoma; inflammatory bowel disease; immunodeficiencies; familial dysautonomia, and periodic fever syndromes like familial Mediterranean fever, cyclic neutropenia, and periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome or PFAPA.

FUO can also be induced by medications, including antimicrobial agents like acyclovir, carbapenems, cephalosporins, and tetracyclines; anticonvulsants like barbiturates, carbamazepine and phenytoin, antidepressants like doxepin, antineoplastic agents like interferons, 6-mercaptopurine and bleomycin, cardiovascular drugs like clofibrate, furosemide and heparin, histamine-2 blockers like cimetidine, Immunosuppressants like azathioprine, and NSAIDs like ibuprofen and salicylates.

And those fevers typically resolve within a few days of stopping the medication.

Another cause of FUO is neurologic injury that causes the hypothalamus to dysregulate a child’s temperature.

Finally, some portion of FUO cases remain undiagnosed and often resolve spontaneously.

Managing FUO begins with asking the family to keep a fever diary that records the date and time of fevers, the height of fevers, associated symptoms, and any medications that were given.

Sustained or continuous fevers generally persist throughout the day with less than 1 ºC of variation.

They are usually seen with typhoid fever, or typhus.

Fevers that fluctuate more than 1 ºC throughout the day are called intermittent and remittent fevers.

Where intermittent fevers descend back to normal temperature, while remittent fevers always persist above normal.

Intermittent fevers typically suggest a pyogenic bacterial infection, like an abscess, but may be also seen with Juvenile Idiopathic Arthritis, whereas remittent fevers are associated with viral infections but may be seen with some bacterial infections like infective endocarditis.

If the child remains afebrile for more than 24 hours between febrile episodes, the fever pattern is called relapsing or recurrent.

In relapsing fevers, the afebrile periods last for several days and suggest malaria, Borrelia infection, or lymphoma.

In recurrent fevers, there are afebrile periods of more than 7 days, seen with Periodic Fever Syndromes, Cyclic neutropenia and immunodeficiency states.

Next, it’s important to identify additional complaints.

Moving from head to toe, there could be a history of conjunctivitis with limbus sparing, which means red eyes with a white margin right around the iris in Kawasaki disease, in which case there’ll also be a rash, which starts polymorphous, but later desquamates, or flakes off; adenopathy, or enlarged lymph nodes, especially concerning the cervical lymph nodes; a strawberry tongue, which is when the top layer of cells on the tongue sloughs off, giving the tongue a very red, strawberry-like appearance; their hands and feet might develop a rash and swell; and finally, five or more days of high fever that doesn’t resolve with antipyretics.

Just remember that these Kawasaki patients C-R-A-S-H and burn.

We should also ask for nasal discharge in case of sinusitis or epistaxis in case of leukemia, oropharyngeal symptoms like pharyngeal hyperemia in case of CMV or EBV infection, recurrent pharyngitis with ulcerations in case of PFAPA syndrome and dental abscesses related to sinusitis.

There might also be lymphadenopathy in case of infectious mononucleosis, cat- scratch disease, tuberculosis or lymphoma, respiratory symptoms like cough in case of bronchitis or pneumonia, gastrointestinal complaints like abdominal pain or loose stools in case of Salmonellosis, an intraabdominal abscess, or inflammatory bowel disease, genitourinary symptoms like flank pain, dysuria, and frequent urination in case of genitourinary tuberculosis or brucellosis and musculoskeletal symptoms, like limb or bone pain in case of leukemia or osteomyelitis.

Another important thing to ask for is specific exposures. These include contact with animals, like birds for Chlamydia psittaci, Cryptosporidium, and Histoplasma capsulatum; household cats or kittens for Bartonella Henselae and Toxoplasma gondii; dogs for Brucella and Pasteurella; farm animals like cows, sheep and goats in case of Brucella; fish, water mammals, oysters or clams for Vibrio parahaemolyticus, Vibrio vulnificus, Legionella, and some Mycobacterium species.

There are also associations with more exotic animals like ferrets for Salmonella, Campylobacter, cryptosporidium and Leptospira; squirrels for Toxoplasma and Rickettsia; horses for Salmonella, Campylobacter, Cryptosporidium and Brucella; rabbits for Salmonella, Francisella tularensis, Yersinia, Pasteurella and Babesia; rodents for Francisella tularensis and Leptospira; and reptiles, like turtles, in case of Salmonella.

Recent travel to endemic places can also be a clue for malaria, tuberculosis, Lyme disease, as well as fungal diseases, like Histoplasmosis, Blastomycosis and Coccidioidomycosis.

Tick bites are also risk factors for tularemia, Lyme disease, Rickettsia and Babesiosis, while mosquito bites are rιsk for arboviruses infections and malaria.

There’s also often history of consumption of raw meat and unpasteurized milk in case of Brucellosis, or raw shellfish or unwashed vegetables in case of toxoplasmosis.

A history of pica, like eating dirt, might be also seen in case of toxoplasmosis.

And then, medical treatments may raise suspicion of drug fever, in case of medication consumption, or intra abdominal abscess especially if there’s a history of abdominal surgery.

Finally, several conditions are more common regionally.