PFAPA vs. HIDS

Pfapa vs hids

PFAPA and HIDS have more in common than just a recurring fever.

HIDS (hyper-IgD syndrome, also known as mevalonate kinase deficiency) and PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) are both periodic fever syndromes that generally start in childhood and have very similar symptoms. It can be difficult to distinguish PFAPA from HIDS clinically. This is because the fever length, frequency, and main symptoms including mouth ulcers, pharyngitis, and swollen cervical lymph nodes occur in both HIDS and PFAPA. In fact, one study showed 83% of HIDS patients meet PFAPA diagnostic criteria.

However, unlike PFAPA, HIDS is a lifelong condition that comes with serious risks if not treated. Getting a correct diagnosis and treatment greatly reduces possible serious complications from HIDS.

Below is a comparison of symptoms, labs, and other details of PFAPA vs. HIDS. This chart illustrates why genetic testing is such an important tool in helping to diagnose a patient with a suspected periodic fever syndrome, such as  HIDS or PFAPA.  It is recommended to do a complete genetic testing panel for periodic fevers, which includes testing for HIDS, TRAPS, FMF, CAPS, a few other disorders, and cyclic neutropenia, to rule out these other conditions. In some studies, many patients that met the clinical symptoms of PFAPA, actually had one of the other autoinflammatory diseases.

PFAPA may not yet have a genetic test available, but it is still important to run these tests to help with the diagnosis. Rheumatologists Dr. Lawson and Dr. Hersh state, “The various periodic fever syndromes have overlapping symptoms; therefore, a definitive diagnosis of PFAPA cannot be made until other periodic fever syndromes have been excluded via genetic testing…” Of all the periodic fever syndromes, HIDS and PFAPA can be the most easily confused. However, PFAPA can also overlap in symptoms with FMF, TRAPS, and CAPS. Click here to see the autoinflammatory disease comparison chart for more details. Click here to see PFAPA vs HIDS at autoinflammatory-search.org.

The Eurofever Classification Criteria is a good resource in evaluating patients who have PFAPA symptoms. This diagnostic questionnaire by the EUROFEVER project is really helpful for doctors considering symptoms when trying to diagnose some of the hereditary periodic fever (autoinflammatory) syndromes, like CAPS, TRAPS, HIDS and FMF. CAPS, TRAPS, HIDS, and FMF all have symptoms similar to PFAPA.

Keep in mind that in HIDS and PFAPA, disease severity and symptom presentation varies among patients. Not every patient has every symptom.

PFAPAHIDS
PFAPAHIDS
SymptomsFever accompanied by pharyngitis and at least one of the following symptoms for a diagnosis: mouth ulcers, and/or swollen neck lymph nodes.Fever with several other inflammatory symptoms. These can include: mouth ulcers, pharyngitis, swollen lymph nodes, joint swelling and pain, abdominal pain, diarrhea, vomiting, headaches, enlarged liver, and/or enlarged spleen. Some patients have a rash with flares.
Some have headaches, stomach pain, and possibly joint pain. Rashes are not typical.**Symptoms vary between individuals and between flares in the same individual.

Do symptoms occur outside of a fever?

No

Sometimes, in some patients. Some patients are completely healthy between flares.

Vaccine Reactions

None. Flares are cyclic and on a predictable schedule.

Most have flares within 24 hours after some or all vaccinations.

Age of Onset

Usually between 2 to 5 years old. Rarely before age 1.

Usually before age 1. Some adult onset cases reported, confirmed with genetic testing.

Prognosis

Most children outgrow PFAPA by age 10-11 or about 6 years after symptoms started.

Lifelong disease. Symptoms and flare frequency change throughout life and may decrease in adulthood.

Flare Frequency/Pattern

Average of once a month. Flares are cyclic and very predictable–some are predictable to the day.

Average of every 2 to 12 weeks in childhood. Some may have regular predictable flares occurring monthly and some flares may be erratic and unpredictable. Flares are often triggered by injury, illness, vacations, school, birthdays, etc.
Flare frequency spreads out as kids begin to outgrow PFAPA.Flare patterns often change throughout life.

Fever Length

Average 3 to 5 days. Rarely more than 7 days. No more than 10 days.

Average 3 to 7 days. May last 10 to 14 days.

Temperature Range

102-104+ degrees F

102-104+ degrees F

Response to Prednisone (Standard dosing starts at 1mg/kg for both PFAPA and HIDS.)

94% of PFAPA patients have full resolution of fever and flare symptoms with one dose.

Some HIDS patients have full resolution of fever and flare symptoms with one dose.
Some need a second or third dose to resolve all symptoms.Some need a second or third dose to resolve all symptoms.
In some, prednisone is never highly effective.
Use of prednisone may increase flare frequency.Use of prednisone may increase flare frequency.
Effectiveness of prednisone may decrease over time in some patients.

Most Effective Treatments

Ibuprofen and acetaminophen, prednisone, tonsillectomy. Off-label use of anakinra* and colchicine in some studies.

Prednisone, Off-label use of: anakinra*, canakinumab*, possibly tocilizumab*in some studies.

Genetics

Possibly genetic, but no genetic testing available to the general public as of 2016. Clinical research is ongoing, and there are cases of PFAPA with a family history of fever symptoms, so it is believed to have a genetic origin of some kind.

Genetic testing available for the MVK gene mutation. Most cases are autosomal recessive. However, some patients with HIDS disease have only one mutation found.

Blood Tests

High CRP, WBC, and ESR during fevers.

High CRP, WBC, and ESR during fevers.
Some have high IgD.Some have high IgD, also accompanied by elevated IgA in up to 80% in some studies, but IgD may be normal in some patients. IgD may not be elevated in young children and infants. IgD is not to be the sole diagnostic test for HIDS.
All blood tests will return to normal between flares.In some, all blood tests will return to normal between flares. In others, blood tests will remain high between flares. There is a spectrum of severity, and chronic inflammation within the diagnosis of HIDS.

Diagnosis

Clinical only, which includes ruling out similar conditions such as FMF, CAPS, TRAPS, and HIDS with genetic testing and comparison of symptoms.

Genetic testing available for the MVK gene. Most cases are autosomal recessive. However, some patients with HIDS have only one mutation found.

Risk of Severe Complications

None

Rare: Amyloidosis. Also, Henoch-Schonlein pupura (HSP), respiratory infections, and macrophage activation syndrome have been reported. Some patients have enlarged liver and/or spleen and gastrointestinal issues.

*These are not FDA approved treatments for HIDS or PFAPA.

**Dr. Beata Wolska-Kusnierz states that usually there are no skin changes in PFAPA and if there is a rash, “autoinflammatory illnesses other than PFAPA should be considered in the diagnostic process.” In this study, patients met the study definition of PFAPA only “if they did not have arthritis or a distinctive rash or documented neutropenia.”

**UpToDate Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome) authors state, “The following symptoms as a part of most attacks should trigger consideration of other diagnoses: cough, coryza, severe abdominal pain, significant diarrhea, rash, arthritis, or neuromuscular symptoms.”

Since there are specific treatments that benefit some of these diseases more than others, the right diagnosis–especially early in life can make a big difference. A common treatment for PFAPA is a tonsillectomy, which is painful, and all surgery has risks. So it would be helpful to best determine if a patient has PFAPA, and not some other periodic fever syndrome prior to surgery. If the doctor is not sure if they need to do genetic testing, many experts suggest using this online diagnostic tool to evaluate the probability of a genetic mutation for an autoinflammatory disease, which would warrant doing the testing. This tool was developed by leading experts on autoinflammatory diseases, and tested on hundreds of patients, which is described in this article in Pediatrics.

Did You Know?
An uncomplicated tonsillectomy costs $4,000 to $7,000.
Cost of a genetic fever panel testing 25 or more genes: Less than $1500.

However, a number of doctors treat patients with periodic fever symptoms as having PFAPA before exploring other fever syndromes. They only pursue genetic testing or other tests for known autoinflammatory diseases after a patient fails to have a reduction, or remission of symptoms after having a tonsillectomy, or they continue to have symptoms into their teenage years, or older. Some doctors cite challenges in getting insurance approval for genetic testing, or are concerned about if the insurance will consider the testing unnecessary if the results are negative for other autoinflammatory diseases.  The cost for the genetic testing is less than a tonsillectomy, and now there are a few laboratories doing the testing, so it is easier to get insurance approval. (More info on labs to use for the testing here.) Having a negative result on the genetic testing for other periodic fever syndromes actually would help to support the PFAPA diagnosis, if the patient also met the diagnostic criteria for PFAPA, so it is not a “wasted expense” for the test.

fever syndrome genetic testing

DNA photo by Mike_Kiev/Bigstockphoto.com

Even though PFAPA does not have a genetic test available to the public for testing at this time, more research is being done to try to find the genetic cause, and recent research has found some correlations with some genetic findings. Since HIDS and PFAPA have very different long-term risks and prognosis, it’s important that an accurate diagnosis be made for best treatment. It is also important to keep in mind that genetic testing is just one tool in the diagnostic process, and there are patients with all of these diseases that may clinically be diagnosed and respond to the suggested treatments for their disease that may not have a genetic mutation found for their disease.  So, having a genetic testing result with no mutations, but the patient fits the criteria for a certain disease should not rule out having that specific disease.  New advances in genetics are finding mutations for some of these diseases (especially CAPS) that were not found previously with the standard genetic testing process.

There are several factors that need to be considered in diagnosing any autoinflammatory disease, including both PFAPA and HIDS. These include collectively looking at symptoms, age of onset, blood test results, and genetic testing results. Also, patients with PFAPA do not have signs of chronic inflammation, or elevated inflammatory markers when not having flares of symptoms, so testing patients during a flare, and when they are not flaring is helpful.  Some autoinflammatory diseases can have signs of chronic inflammation between flares of fevers and more notable symptoms, so it is important to do a series of lab tests over a few weeks to get a bigger picture of what is going on.

If you are having difficulty getting the genetic fever panel test done, here are some resources that can help:

The questionnaire shows who is at high risk for having a positive genetic test for HIDS, TRAPS, FMF, and CAPS.

Learn how to pay for tests you need and appealing insurance company decisions here.

Learn here about myths and misconceptions with periodic fever syndromes, including those regarding the genetic testing available.


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References

  1. ACTA Paediatrica: A clinical review of 105 patients with PFAPA (a periodic fever syndrome)
  2. Children’s Mercy Kansas City: Diagnosing PFAPA in your clinical practice
  3. Nature Reviews Rheumatology: Clinical features and management of CAPS and PFAPA Table 2
  4. Healio: A 2-Year-Old Patient Has Had Recurrent Fevers For The Last Year. He Often Has A Red Throat, Adenopathy, And Stomatitis With His Fevers. I Am Concerned About Periodic Fever, Aphthous Stomatitis, Pharyngitis And Cervical Adenitis Syndrome. What Are The Treatment Options For This Diagnosis?
  5. PubMed.gov: PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre cohort.
  6. Pediatrics: Differentiating PFAPA Syndrome from Monogenic Periodic Fevers
  7. PubMed.gov: Elevated immunoglobulin D levels in children with PFAPA syndrome.
  8. PubMed.gov: First report of macrophage activation syndrome in hyperimmunoglobulinemia D
  9. Pediatrics: Mevalonate Kinase Deficiency: A Survey of 50 Patients
  10. SAID Support: Hyper-IgD Syndrome
  11. DermNet NZ: Hyperimmunoglobulinaemia D with periodic fever syndrome
  12. Cost Evaluation: How Much Does a Tonsillectomy Cost?
  13. To Make The PFAPA Syndrome More Familiar by Dr. Beata Wolska-Kusnierz
  14. BMJ: Recommendations for the management of autoinflammatory diseases
  15. UpToDate Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome)

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