Basic information

HIDS – what are the symptoms?

People with HIDS suffer from ever-recurrent periods, “attacks”, of high fever. Such a fever attack often lasts about four to six days, but it can be shorter or longer. This is different from person to person, and also from attack to attack. Often, it is a high, spiking fever. In young children, the fever can get so high that it causes fever convulsions. Other symptoms that can occur during a fever attack:

  • exhaustion, tiredness
  • swollen lymph nodes, especially in the neck
  • stomachache, diarrhea, nausea, vomiting, loss of appetite
  • pain in muscles and joints
  • headache
  • small ulcers (aphthous ulcers) in the mouth
  • red spots on the skin

After the end of an attack these symptoms will disappear, although it sometimes takes a few days longer before all symptoms have disappeared. The severity of symptoms can be very variable in different attacks. Generally, outside the fever episodes, a person with HIDS does not feel ill.

Most persons with HIDS experience their first fever attack at a very young age, often in the first year of life. It can be manifested for the first time later in life, but almost always in the first few years of childhood. How often these fever attacks occur varies from person to person. Some people have an attack every month, or even more often. Others have a fever episode for example about six times a year. This can also change in the course of life. Sometimes, a person does not have any symptoms of disease for months, and then he gets a few attacks in a row. Children often have very frequent fever attacks. In many people the pattern of the disease changes during puberty or just after. Usually, attacks occur less often afterwards – but not always, and there may still come periods with frequent attacks.

Certain things seem able to provoke an attack. Many people with HIDS notice than a fever attack often starts at a time of physical or emotional stress. For example, often there will be an attack after an operation, or in an exam period. Women with HIDS sometimes notice a relation to the menstrual cycle, and for example no attacks during pregnancy, while delivery is followed by a major fever episode. Another often noted factor is vaccination – children or adults with HIDS almost always get a fever attack after vaccination.

HIDS is a rare disorder. Worldwide, about 200 patients are known with this disease. It occurs in both men and women with the same frequency. It is a hereditary disease, it can occur in several brothers or sisters from one family.

Complications are rare. About 5 patients in a total of 100 patients have developed organ damage due to amyloidosis or abdominal adhesions (because of recurring inflammation). HIDS patients live a normal life span as far as we know. It does not have a direct influence on the growth and development of a child, although the frequent episodes of illness can of course have an influence, for example through missed time at school.

How is the diagnosis made?

A fever attack is an inflammatory process. The results of laboratory examinations and other tests during such an episode will all fit with inflammation. For example a raised sedimentation rate and a high white blood cell count. But these results are not typical only for HIDS.

There are numerous causes of fever and inflammation. Most of these occur much more often than the rare disorder HIDS. HIDS is so rare that many doctors know little about it, and will not think of this diagnosis. Often, a lot of tests are done to exclude many possible causes of fever and inflammation. Often, these tests do not yield a clear result in people with HIDS, unless of course they have some other disease as well. Most people with HIDS can recount a childhood with numerous hospital admissions and countless medical examinations.

HIDS is part of a group of syndromes which have features in common, especially the recurrent fever. These are collectively known as “periodic fever syndromes” or “hereditary autoinflammatory syndromes”. Other examples of this group of disorders are Familial Mediterranean fever (FMF) and TRAPS. There are differences in symptoms, prognosis and treatment between the different periodic fever syndromes.

To make the diagnosis HIDS the first step is that the physician considers this rare disease. A suspicion of HIDS is strengthened by a typical disease course: lifelong recurrent fever attacks without a clear cause, which last a few days and resolve spontaneously, and sometimes similar symptoms in a brother or sister. Sometimes, however, the course of the disease is less characteristic.

Immunoglobulin D (IgD)

An important test is the determination of the concentration of immunoglobulin D (IgD) in the blood. HIDS patients usually have a very high concentration of IgD. For this test a blood sample is drawn. To be sure about the result, this examination is often done twice at different times. The patient does not need to have a fever at the time of drawing the blood sample. However, there are a small number of patients with HIDS who do not have an increased concentration of IgD. Also, IgD is not very specific: small increases in IgD can occur in numerous disorders – only a (slightly) raised IgD is not enough for the diagnosis HIDS.

DNA-analysis

Because it is known in which part of the inherited information the faults that cause HIDS are located, it is possible to prove the genetic disposition for this disorder by analysis of DNA. DNA is found in all cells of the body, which includes white blood cells. Most often a blood sample is used to perform the DNA analysis. Bear in mind that it can take some months before you get the results, because it is a time-consuming examination. The patient does not need to have a fever at the time of drawing the blood sample.

Mevalonic acid

It is also possible to measure the concentration of mevalonic acid in a urine sample to make a diagnosis. In HIDS patients, this concentration will be high during a fever attack. However, the concentration will be still to low for the routine assays; only specific assays will be able to detect the peak in mevalonic acid during the fever attack.

Some patients suffer from the typical fever attacks, but do not carry the expected defects in the specific bit of DNA. The DNA analysis in these persons will therefore not yield anything, and the mevalonic acid concentration in the urine during fever will not be high. These patients do have a form of periodic fever syndrome, but it is not known what the exact cause of the disease is in those cases.

Treatment

HIDS cannot be cured. It is caused by a defect in the genes that cannot be corrected. To control the symptoms of fever and pain many patients benefit from the use of non-specific drugs like paracetamol (acetaminophen). Some doctors report favorable effects of prednisone in children with HIDS (although not consistently, and in some it may increase the frequency of fever episodes). There is no consensus on treatment for HIDS. Because it is so rare it will be almost impossible to perform large medication trials. Recent developments have focussed mostly on simvastatin (in 2004) and in recent years on so-called “IL-1 blockers”.

Simvastatin

A randomized, placebo-controlled study in a group of adult HIDS patients showed that simvastatin will in most patients diminish the number of days of illness (although it did not stop all fever attacks). Simvastatin is a drug often used for other reasons, most often to lower cholesterol; it has relatively few side effects, and no side effects were observed in the HIDS patients. However, in clinical practice the effect of simvastatin is hardly noticeable for patients. Therefore, it is not routinely prescribed.

IL-1 blockers

Interleukin-1 (IL-1) is a very potent inflammatory protein that mediates a large part of the inflammation that is part of a HIDS fever attack. A drug that blocks the action of IL-1 called anakinra (or kineret) has been tried in patients with HIDS, and is often helpful. It needs be given by daily subcutaneous injection. Descriptions of continuous use of anakinra by patients with HIDS have been published on about 5 cases. Anakinra was generally successfull in strongly reducing the number and severity of HIDS attacks. In the Netherlands, we usually prescribe anakinra in an “on-demand” fashion: patients do not use the drug when they have no symptoms, but they have it in the house. As soon as they feel an attack coming on, they will use Anakinra for a few days. This will shorten the attack to 1-2 days, instead of 4-5 days. There are several longer-acting IL-1 blocking drugs currently in development, which may be promising for HIDS in future.

Visiting a doctor at time of fever?

A lot of people with HIDS who have suffered from fever attacks for a long time do not visit a doctor each time, because they know what is happening and how to deal with it. In case of a fever episode which is different from usual, more severe or with other symptoms, or which persists, we do recommend that you visit your family doctor or specialist. He or she can then determine whether there is not something else going on. For people with HIDS of course have as much chance to get another illness as others.

What is the cause of HIDS?

The exact answer to this question is not known yet. We know that a certain protein does not function properly in a person with HIDS because of a defect in the hereditary information (this protein is called mevalonate kinase, see also the background information in the next chapter). It is unknown what this protein has to do with inflammation and fever exactly.

It seems to be a defect in the control of inflammatory reactions. The body possesses a complicated inflammation and immune system. This system is so complicated that a lot of details are unexplained as of yet. One of its functions is to get rid quickly of substances that do not belong in the body. For example, imagine a splinter in your finger: if this remains in place, within a short time an inflammatory reaction will start at that spot to get rid of the splinter. You notice this because the spot will get hot and red, and will pulsate. If it gets worse, you can even get a fever. But as soon as the splinter drops out, the inflammation is not necessary any more and is only annoying. The body therefore has the ability to turn off an inflammatory reaction when it is not needed any more. Usually, this system is so well ordered that most problems, such as a small wound or bacteria, are resolved with a very small local inflammation, which you do not even notice yourself. This probably occurs every day. Only if the problem gets to big to deal with in such a manner, you start to notice it: you for example get symptoms of a cold because of a virus which you can not get rid of quickly enough or you get diarrhea after eating contaminated food.

It appears to be that in HIDS there is a defect of the turning off of the inflammatory system, which can more easily lead to an exaggerated inflammatory response. In a situation where another person will for example not even notice that his inflammatory system has got rid of a virus, in a person with HIDS the inflammation will get going and will keep on going, even after the virus has long since disappeared. This will lead to a severe inflammatory reaction with fever and for example pain in muscles and joints. Only after a longer period, the inflammation dies out. The exact reason for the attacks in HIDS is unclear yet.

To emphasize: patients with HIDS do not have an impaired immune system, they are not more prone than others to catch a bacteria or a virus. At the time of a fever attack there is an inflammatory reaction, but no bacteria. Antibiotics will therefore not help to dissolve all fever attacks. Of course, someone with HIDS can just as well as everyone be infected with a bacteria, but this does not happen more often than in healthy persons. Exposure to a bacteria can probably provoke a fever attack: the body tries to get rid of the bacteria by means of an inflammatory reaction, and that reaction is not stopped promptly, as explained in the previous paragraph. For example, many patients are sure to get a fever attack when there is flu going around: probably the flu virus is the triggering factor in that case.

Update: March 12, 2011

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