Periodic Fever Syndrome in Children – Types, Diagnosis and Treatment by Dr. Sagar Bhattad

The Periodic Fever Syndrome is identified with the diagnosis of certain other disorders. These disorders are classified and defined based on several factors, including,

• Defects in Genes controlling inflammation
• Clinical Features
• Other affected body parts apart from repetitive fever
• The Child`s age when the syndrome occurs
• The place or the ethnicity of the children and the parents.

The Review of the molecular pathogenesis of these disorders helps us to identify and understand the process of regulating our immune system to fight the Periodic Fever Syndrome.

4 Main Types of Periodic Fever Syndrome in Children

Several types of disorders are associated with Periodic Fever Syndrome in children. While some of these disorders are hereditary, others might result from mutation or mistakes in the formation of genes. The various disorders associated with Periodic Fever Syndrome are Periodic fever, Aphthous-stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome, Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), HyperImmunoglobulin D Syndrome (HIDS).

These genetic defects might cause different problems for different children. It is essential to understand the problem to determine the treatment. Let us look at each of the disorders in detail.

1. Periodic Fever, Aphthous-Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome

PFAPA was first identified in the year 1987. PFAPA is a condition that occurs commonly among children aged between 2 to 5 years. It is characterized by,

• Repetitive Fevers (Periodic Fever) – fevers recur once in every 3-5 weeks in a predictable manner. Parents can exactly predict the occurrence of next episode due to the periodic nature of fever.
• Mouth Sores (Aphthous-Stomatitis)
• Sore throat with redness (Pharyngitis)

For children who are diagnosed with PFAPA,

• Aphthous-Stomatitis accompany 70%
• 72% also have Pharyngitis
• 88% have Adenitis

Causes PFAPA Syndrome in Kids

PFAPA is not hereditary or a genetic disorder. No infections are associated with PFAPA, so it is not a contagious disease. Children may take a few years to outgrow it. The patients may be expected to be healthy between two episodes.

Other Symptoms of PFAPA Syndrome

There are a few more symptoms associated with PFAPA. But, they are less common among children. They are as follows.

• Headache
• Joint Pain
• Abdominal Pain
• Nausea
• Vomiting
• Diarrhea
• Rashes

How is PFAPA Diagnosed?

No laboratory tests prove or confirm the existence of the disease. The diagnosis includes physical examination and existing symptoms. Children might have to undergo the following tests to rule out infection.

• Blood Test: To check the count of White Blood Counts.
• C-Reactive Protein or Erythrocyte Sedimentation Rate (ESR): To Check for General Inflammation.
• Strep Culture: To check if the child has Strep Throat.
• Genetic Tests: To Check and confirm if there are any other disorders associated with periodic Fever.

Top Treatment Offered For PFAPA Syndrome in Children

There is no specific treatment that can cure PFAPA Syndrome at once. The treatments aim to reduce the symptoms and the frequency at which the fever occurs—one or two doses of Prednisone help abort the PFAPA. The following are some of the common treatments provided by doctors,

• Steroids: They help in shortening the episode and end them soon.
• Medicines including Cimetidine or Colchicine: To prevent frequent episodes in the future.
• Surgery: To remove the tonsils.

[Read : Steroids in Children]

2. Familial Mediterranean Fever (FMF)

Familial Mediterranean Fever (FMF) belongs to the group of auto-inflammatory disorders. A defect in a specific gene, MEFV causes this disease. The Mutations are widespread among the Mediterranean, Middle East, Turks, Arabs, Jews, and Armenians. It usually begins in childhood and if untreated can cause damage to inner organs.

Causes of FMF in Children

FMF is passed on genetically. A Specific gene called MEFV affects a protein called Pyrin in the body. Pyrin is responsible for controlling inflammation naturally.

In case this gene gets defective, the pyrin cannot perform the function of controlling the inflammation, which leads to repetitive fevers and other related symptoms.

Primary and Rare Symptoms of FMF in Children

The primary symptoms of FMF are,

• Repetitive Fever
• Rash
• Abdominal Pain
• Joint Pain
• Chest Pain

It is essential to remember that every child may not experience all the symptoms.

Most of the symptoms go away without treatment within three to four days. Sometimes, few children suffer due to repetitive symptoms that hinder their growth. The most affected Joint due to FMF is the ankle or knee.

The ankle or knee might be swollen, making it difficult for the children to walk. In rare cases, swollen knee or ankle might be the sole symptom. This symptom may be misleading in diagnosing the disease as rheumatic fever or Juvenile Idiopathic Arthritis.

Some other rare symptoms among children include,

• Inflammation in the outer layer of the heart (Pericarditis)– causing chest pain
• Muscle Inflammation (Myositis)
• Inflammation of the brain and spinal cord membrane (meningitis)
• Testicular Inflammation (Orchitis)

In the worst-case scenario, FMF may lead to Amyloidosis if children are untreated. Amyloid protein gets stored in different organs of children who do not have proper control over inflammation. If untreated, the Amyloid might start attacking the kidney.

[Read :  Meningitis In Children]

How is FMF Diagnosed?

The Diagnosis of FMF is quite a challenging task. No direct tests show us that the child has been affected by FMF. It begins with the clinical tests. Children might not get repetitive episodes and still be affected by FMF. Some of the diagnostic procedures include the following.

• Closely examine the various episodes of fever. The parents might be asked to note the symptoms and timing of various episodes.
• Laboratory tests, including Sedimentation Rate (ESR) or a Complete Blood Cell Count, help show the signs of inflammation.
• A Sample of urine might be tested to check the presence of protein. Children with higher protein levels might alarm physicians to check for possible amyloidosis.
• If all the above tests suggest a diagnosis of FMF, then a genetic test could be conducted to check for gene mutation.

There are two possible outcomes for the test,

• Positive Result: The defect is found in both gene copies, often known as Homozygote.
• Negative Result: The defect is found only in one of the gene copies or without any defect in any of the gene copies.

How is FMF Treated in Children?

Colchicine is the best treatment available for FMF. While FMF can never be cured, Colchicine helps reduce the episodes of fever. Colchicine helps to prevent not only FMF episodes but also Amyloidosis. But, the patient should continue the medication lifelong. The risk of FMF and Amyloidosis might reappear if the patient discontinues the drug.

The doctors shall decide the dosage of the drug. Parents shall not change the dosage without discussing it with the doctors. The dosage might differ if there have already been a few episodes and the patient is currently having an active episode.

Along with the treatment, some minor side effects may come along. They are,

• Diarrhea
• Nausea
• Vomiting
• Abdominal Cramps
• Muscle weakness
• Decrease in Blood count

3. Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)

Tumor Necrosis Factor Receptor Associated Periodic Syndrome is also called Familial Hibernian Fever. It is a genetic disorder and might occur even if one of the genes is defective; it might lead to TRAPS. This is termed Autosomal Dominant. Either one of the parents might have been affected by the disease or have a defective gene, or the gene might have been defective for the first time in the child.

Causes of TRAPS in Children

TRAPS is a genetically passed down disorder. When a protein called Tumor Necrosis Factor Receptor (TNFR) is affected by a defect in the gene, the control over the inflammatory response goes out of control. The Tumor Necrosis Factor (TNF) blends with Tumor Necrosis Factor Receptor (TNFR) to control the inflammatory activities of the human body. TNF is a protein that causes inflammation. When TNFR is affected, TNF does not have the receptor to blend and overacts, increasing inflammation.

Other Major Symptoms of TRAPS

TRAPS can be identified with repetitive and periodic fevers. The following are some of the other symptoms associated with TRAPS.

• High fevers lasting for 3-4 weeks (episodes of TRAPS last much longer compared to other periodic fever syndromes)
• Diarrhea
• Abdominal Pain
• Muscle Pain
• Red skin rashes that migrate to different parts of the body
• Swelling around the eyes.

How is TRAPS Diagnosed?

TRAPS can be diagnosed based on physical examination, clinical symptoms, and verifying the family’s medical history. The doctors might test the blood to check for inflammation, if any. The doctors will confirm TRAPS only when the genetic test results show a defect in the TNFR gene.

How is TRAPS Treated?

No direct medication or treatment helps children get out of the disorder. However, medicines similar to TNF Receptor-Etanercept can be given to help prevent or cure repetitive episodes of fever and other symptoms. Steroids can help to get temporary relief. Long-term Steroid consumption might give adverse side effects.

4. Hyper Immunoglobulin D Syndrome (HIDS)

Hyper Immunoglobulin D Syndrome (HIDS) is a genetically inherited autosomal recessive disorder. It occurs when a protein called Mevalonic Kinase (MVK) affects the genes. MVK is solely responsible for producing cholesterol in the body by facilitating chemical reactions. When a child is affected with HIDS, the MVK enzyme stays active only in 1 to 10 percent of the regular activity. HIDS is also called Mevalonate Kinase Associated Periodic Fever Syndrome (MVK).

Causes HIDS in Children

HIDS is an inherited disease. The children receive two mutated genes from their parents. The parents are called the carriers. If one child has HIDS, there is a 25 % chance that the second child might also get HIDS. HIDS occurs when the protein called MVK is affected. But there is no sole proof validating the reason for the repetitive periodic fever. The disease occurs during infancy. Children who are affected by HIDS have a high amount of Immunoglobulin D.

Major Symptoms of HIDS in Children

The primary symptom is continuous fever episodes lasting between three to seven days. The fever might repeat very often, ranging from two to twelve weeks. This often begins in the first 6 months of life, but children may remain undiagnosed for years! The other symptoms include,

• Headache
• Abdominal Pain
• Loss of Appetite
• Joint pain/swollen joints
• Diarrhea
• Skin Rashes
• Mouth Ulcers
• Swollen Lymph Nodes

How is HIDS Diagnosed?

HIDS can be diagnosed through various tests, which include the following.

• During an episode of Fever, blood tests will be taken to check if there is inflammation. Children with HIDS will have high levels of Immunoglobulin D.
• A Urine test needs to be taken to check the levels of organic acid. High levels of mevalonic acid in urine may suggest HIDS.
• A genetic test will be conducted to check for any defect in MVK protein.

Only after the genetic tests will the HIDS be confirmed.

How Can HIDS be Treated in Children?

HIDS is a lifetime disorder, but the intensity of the disorder may come down over time. It can be treated with anti-inflammatory drugs including biologics, that help prevent future episodes of the disease.

Causes of Periodic Fever Syndrome in Children

Periodic Fever Syndromes are a group of less commonly diagnosed diseases. Most of them are genetic diseases caused by defects in proteins that control inflammation. Periodic Fever Syndrome is not caused by infection and is not an autoimmune disease. They involve unregulated inflammatory episodes.

Top 3 Ways to Treat Periodic Fever Syndrome in Children

The treatment for Periodic Fever Syndrome depends on the severity of the disease and the type of Periodic fever syndrome. The treatment’s primary aim is to reduce fever episodes and related symptoms. The various treatments include the following.

1. Corticosteroids

Steroids like prednisone can help control PFAPA. Steroids can help reduce repetitive fever and other symptoms if given during the initial stage of the attack. Using them on a limited basis is always recommended to avoid long-term side effects.

2. Colchicine

Colchicine is the best to treat FMF to reduce the severity of the fever and prevent Amyloidosis. It can be used on a long-term basis.

3. Biologics

Biologics are proteins that are injected below the skin or can be infused by an Intravenous (IV) catheter. Periodic Fever Syndrome is a result of unregulated inflammation in the protein. Biologics help in regulating proteins and reducing inflammation.

[Read : Biologics For Autoimmune Diseases]

Precautions to Take If Your Child Has Periodic Fever Syndrome

If your child is diagnosed with any disorders associated with Periodic Fever Syndrome, follow the directed medications to reduce the episodes.

When to See a Doctor?

When your child gets a fever that is acute and is more than 100 degrees Fahrenheit fever, connect to your child`s pediatrician. If the pediatrician suspects your child may be sick with Periodic Fever Syndrome, you may be referred to a specialist for further check-up.

When your little one gets a mild and short fever, there is nothing to worry about. Their body is perfectly working as it should by creating antibodies and boosting the immunity of your baby. They go away within a few days and never come back frequently. But, if your child gets repeated fevers without any clear identifiable cause, consult a doctor and get checked for Periodic Fever Syndrome.

Keep a note of all the episodes concerning the symptoms to monitor the progress of your little one. If you have any doubts regarding the condition and any other symptoms associated with the Periodic Fever Syndrome, always feel free to ask the doctor and get it cleared. A Pediatric Rheumatologist is a doctor who would be able to guide and treat in case your child has periodic fever syndrome. It is always better to know and accept challenges for Happy Parenting.

FAQ’s

1. How Do I Know if My Child Has Periodic Fever Syndrome?

If your child faces repetitive fevers that last for a few days, accompanied by other symptoms like sore throat, Joint Pain, and abdominal pain, the chances of Periodic Fever Syndrome are higher. These episodes tend to recur periodically and do not respond to antibiotics or regularly prescribed medications.

2. Does Periodic Fever Syndrome Go Away?

Some Periodic Fever Syndromes may fade over the years and go away by age 10 (eg: PFAPA).

3. What Causes Recurrent Fever in Children?

Children might get a recurrent fever because of a virus or bacterial infection. But, Periodic Fever Syndromes are not caused by any virus or bacteria. The primary cause is due to a defect in the gene.

Read Also: Recurrent Infections in My Toddler – When Should I Bother by Dr. Sagar Bhattad