Autoinflammatory diseases are diverse: they are caused by different genes, present at various stages in life, and cause a variety of symptoms. Even in patients with the same disease, such as familial Mediterranean fever (FMF), attacks may differ widely; some can have severe abdominal pain while others develop headaches. As a result, measuring disease activity–how active the disease is and how severely the patient is affected–has been quite difficult.
Autoinflammatory diseases are a relatively new category of illnesses caused by disorders of one arm of the immune system. Many of these diseases are characterized by recurrent fevers, rash, chest and abdominal pain, and evidence of systemic inflammation on blood tests; these manifestations often mimic infectious or other illnesses, and it may take several years for the diagnosis to be made.
Most autoinflammatory diseases are genetic (inherited), start in childhood, and persist throughout adult life. These diseases are often present in several members of a family. Other autoinflammatory diseases appear to be acquired, perhaps due to the interplay of genetic and environmental factors, and can present at any time during childhood or adulthood.
The list of autoinflammatory diseases continues to grow every month. Here is a list of the autoinflammatory diseases as they stand so far:
- Familial Mediterranean Fever (FMF)
- TNF receptor associated periodic syndrome (TRAPS)
- Hyperimmunoglobulin-D syndrome (Hyper-IgD syndrome, HIDS, also known as mevalonate kinase deficiency, MVK)
- Cryopyrin-associated periodic syndromes (CAPS):
- Familial cold autoinflammatory syndrome (FCAS, also known as familial cold urticaria)
- Muckle-Wells syndrome
- Neonatal onset multisystem inflammatory disease (NOMID, also known as CINCA)
- Deficiency of the interleukin-1-receptor antagonist (DIRA)
- Deficiency of the interleukin-36-receptor antagonist (DITRA)
- Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA)
- Blau syndrome
- Pyogenic sterile arthritis, Pyoderma gangrenosum, Acne (PAPA)
- Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO)
- Adult-onset Still’s disease (AOSD)
- Macrophage activation syndrome (MAS)
- Behcet’s disease
- Schnitzler’s syndrome
- Chronic recurrent multifocal osteomyelitis (CRMO, also known as chronic non bacterial osteomyelitis (CNO))
- Deficiency of adenosine deaminase 2 (DADA2)
- STING-associated vasculopathy of infancy (SAVI)
When I was little, I used to get a lot of fevers. With my fevers, I would develop pain in one or both of my ears, and I felt so drained that I just wanted to be left alone to watch TV (or play Atari). If my fever spiked in the middle of the night, my parents would soak me in a tub of lukewarm water to lower my temperature (how I hated those baths!). On the following day, I would visit my pediatrician, who would invariably diagnose me with an ear infection. He prescribed a delicious bubble-gum flavored antibiotic that my parents kept at the top shelf in the refrigerator (out of my reach so I wouldn’t overdose). I’m not sure if it was the taste or the active ingredient, but this antibiotic always made me feel better. After what seemed like the millionth episode of fever, my pediatrician recommended that I get tubes in my ears, and the episodes of fever and ear pain subsided.
Recurrent infections, like those I had when I was a child, are the most common cause of frequent fevers in children. Usually, these infections are due to viruses, such as the ones that cause the common cold. Children with colds often develop symptoms attributable to the virus, including a runny nose, nasal congestion, or cough. Multiple infections, one after the other, are especially common in children attending daycare or school, where they trade viruses like I used to trade baseball cards with my friends. When I see these the worried parents of these children in my office, I have to remind them that it is normal for a child to have 9-12 colds every year. Fortunately, these children continue to grow and gain weight without difficulty, and they are healthy between episodes. “As your child grows,” I tell the parents, “her immune system will become better at fighting infections, and the frequency and severity of fevers will diminish.” Aside from stressing the importance of hand washing among all family members, there is not much that can (or needs) to be done about these episodes.
However, if the episodes do not clearly match the above description, other diagnoses should be considered. In this post, I will provide some tips that may help parents and physicians recognize a rare cause of fever in children: autoinflammatory diseases. The most common autoinflammatory disease in children is called PFAPA, which stands for Periodic Fevers, Aphthous stomatitis (canker sores or oral ulcers), Pharyngitis (sore throat) and Adenitis (enlarged glands in the neck). This disease usually presents in children less than 5 years of age, and causes episodes of fevers in addition to the features that make up the name of the disease (oral ulcers, sore throat, enlarged glands in the neck). The fever usually lasts about 4 days, and it recurs at regular intervals, usually every month. What is unique about PFAPA is that parents can usually predict when the child is “due” to get ill. The episodes of fever are so regular as to be predictable. This regularity is rare in most other diseases. PFAPA is commonly misdiagnosed as frequent Strep infections, and testing for Strep throat is usually negative. Patients do not readily respond to antibiotics, although their symptoms can disappear with one dose of steroids.
Another clue that the child may have an autoinflammatory disease is that all of the episodes of fever look alike. For example, if the child always develops abdominal and joint pain with the fevers, then he may have familial Mediterranean fever (FMF). If, in addition to fever, she always develops a painful rash, muscle pain, and red eyes, then she may have TNF-receptor associated periodic fever (TRAPS). If he develops fevers, rashes, and joint pain after exposure to cold weather, then the child may have familial cold-induced autoinflammatory syndrome (FCAS).
The length and frequency of fever, associated symptoms, and age at which the fevers began can help differentiate between these (and other) autoinflammatory diseases. Thus, it is very helpful to keep a fever diary, specifying the characteristics of each episode. Because many of these autoinflammatory diseases are inherited (genetic), there is often a history of other family members having similar symptoms. In addition, it is important to note that some autoinflammatory diseases are more common in people of certain ethnic backgrounds, such as FMF in Sephardic Jews, Turks, and Armenians.
In addition to autoinflammatory diseases, there are some features of recurrent fevers that should warrant a closer look by a child’s pediatrician. These include prolonged episodes of fever (more than one week), recurrent fever without symptoms attributable to a viral infection, difficulty growing or gaining weight, or if the child does not return to his baseline between episodes. Other causes of fever that should be considered in these instances include:
- Immunodeficiencies: problems in the immune system that makes the child more susceptible to infections
- Anatomic and metabolic abnormalities: abnormalities in certain organs that make them more prone to infections (like my ears), or diseases such as cystic fibrosis
- Inflammatory bowel disease: inflammation of the intestines
- Cancer: such as leukemia or lymphoma
With this knowledge, parents and pediatricians alike can help distinguish between the majority of children that develop recurrent fevers because of frequent viruses, from causes which may require additional workup or treatment.