What defines a fever in children. How does the body’s temperature normally fluctuate. What are the common causes of fever in children. How long do typical fevers last. What are the recommended home care treatments for fever.

Understanding Fever: Definition and Measurement

A fever is a common symptom that occurs when the body’s temperature rises above its normal range. But what exactly constitutes a fever? The definition can vary slightly depending on the method of measurement:

• Rectal temperature: Over 100.4°F (38.0°C)
• Oral temperature: Over 100.4°F (38.0°C)
• Axillary (armpit) temperature: Over 99.4°F (37.5°C)

It’s important to note that ear (tympanic) and temporal temperatures are not as reliable for children under 6 months old. The average oral body temperature is 98.6°F (37.0°C), but this can fluctuate throughout the day due to various factors.

Factors Affecting Body Temperature

Several external factors can cause mild temperature elevations (100.4° to 101.3°F or 38° to 38.5°C) without indicating illness:

• Physical exercise
• Excessive clothing
• Hot baths
• Warm weather
• Consumption of hot food or drinks

If you suspect these factors might be influencing your child’s temperature, it’s advisable to retake the measurement after 30 minutes.

Causes and Nature of Fever in Children

Fever is not a disease in itself but rather a symptom of an underlying condition. It serves as the body’s natural response to infections and plays a crucial role in activating the immune system. Most fevers in children range from 100° to 104°F (37.8° to 40°C) and are typically caused by:

• Viral illnesses (most common)
• Bacterial infections

Contrary to popular belief, teething does not cause fever. It’s crucial to understand that the height of the fever doesn’t necessarily correlate with the severity of the illness. The child’s overall behavior and symptoms are more indicative of the condition’s seriousness.

Duration and Intensity of Fevers

How long do fevers typically last in children? Most fevers associated with viral illnesses range between 101° and 104°F (38.3° to 40°C) and persist for 2 to 3 days. It’s reassuring to know that fever doesn’t cause permanent harm until it reaches 107°F (41.7°C), a level that the brain’s thermostat typically prevents in untreated fevers.

Home Care Strategies for Managing Fever

When your child has a fever, there are several home care strategies you can employ to provide comfort and support their recovery:

Hydration and Clothing

Encouraging fluid intake is crucial during a fever. Offer your child extra fluids, but avoid forcing them to drink. Popsicles and iced drinks can be particularly appealing. Why is hydration so important? Fevers cause increased sweating, leading to fluid loss.

Regarding clothing, less is more when dealing with fever. Most body heat is lost through the skin, so minimal clothing helps regulate temperature. Avoid bundling up your child, as this can lead to a higher fever. If your child experiences chills, provide a light blanket for comfort.

Medication for Fever Reduction

Acetaminophen is commonly used to reduce fever in children older than 2 months. However, it’s important to remember that fever plays a role in fighting infection. When should you use fever-reducing medication? Consider using these products only if the fever exceeds 102°F (39°C) or if your child is particularly uncomfortable.

Administer the correct dosage based on your child’s age every 4 to 6 hours, but not more frequently. Typically, these medications will reduce the fever by 2° to 3°F (1° to 1.5°C) within two hours. Keep in mind that the temperature may not return to normal unless it was only slightly elevated before medication.

Important Considerations in Fever Management

While managing your child’s fever, there are several crucial points to keep in mind:

Avoiding Aspirin

The American Academy of Pediatrics recommends against using aspirin for children and young adults (up to 21 years) with chickenpox or influenza symptoms. This recommendation stems from studies linking aspirin use to Reye’s syndrome, a severe condition affecting the brain and liver. Many pediatricians now avoid using aspirin for fever associated with any illness.

Alternating Medications

In some cases, your physician may recommend alternating acetaminophen and ibuprofen. This approach is typically used when:

• The fever exceeds 104°F (40°C) and doesn’t respond to a single medication
• A fever-reducing medication is needed every 4 hours

If alternating medications, it’s crucial to follow the prescribed schedule carefully and return to a single product after 24 hours. Be vigilant about dosage to prevent accidental overdose or poisoning.

Sponging Techniques for Fever Reduction

Sponging is not usually necessary for reducing fever and should be used judiciously. When is sponging appropriate? It’s recommended in emergency situations such as:

• Heatstroke
• Delirium
• Seizures caused by fever
• Any fever over 106°F (41.1°C)

In non-emergency cases, consider sponging only if the fever exceeds 104°F (40°C), remains high 30 minutes after administering acetaminophen or ibuprofen, and your child is visibly uncomfortable.

Proper Sponging Technique

If sponging is necessary, how should it be done? Always give acetaminophen or ibuprofen before sponging. Use lukewarm water (85° to 90°F [29° to 32°C]) for sponging, as it’s more effective than immersion. Sponging works by promoting heat loss through evaporation. However, be aware that sponging before medication takes effect may cause shivering, which is the body’s attempt to raise its temperature.

When to Seek Medical Attention for Fever

While most fevers can be managed at home, certain situations warrant medical attention. When should you contact a healthcare provider? Consider seeking medical help if:

• Your child is younger than 3 months and has a rectal temperature of 100.4°F (38°C) or higher
• The fever persists for more than 3 days
• Your child appears very ill, lethargic, or unresponsive
• The fever is accompanied by severe headache, stiff neck, or persistent vomiting
• Your child has a seizure
• The fever is over 104°F (40°C) and doesn’t respond to medication

Remember, trust your instincts as a parent. If you’re concerned about your child’s condition, don’t hesitate to consult a healthcare professional.

Debunking Fever Myths and Misconceptions

There are several common misconceptions about fever that can lead to unnecessary worry or inappropriate treatment. Let’s address some of these myths:

Myth: Fever is a disease

Fact: Fever is a symptom, not a disease itself. It’s the body’s natural defense mechanism against infections.

Myth: The height of the fever indicates the severity of the illness

Fact: The degree of fever doesn’t necessarily correlate with the seriousness of the condition. A child’s overall behavior and symptoms are more indicative of the illness’s severity.

Myth: Fever causes brain damage

Fact: Fever doesn’t cause brain damage unless it reaches extremely high levels (above 107°F or 41.7°C), which is rare due to the brain’s natural thermostat.

Myth: Teething causes fever

Fact: Despite popular belief, teething does not cause fever. If a teething child has a fever, it’s likely due to an unrelated illness.

Myth: Fever should always be treated with medication

Fact: Fever plays a role in fighting infection. Medication should be used judiciously, primarily for comfort when the fever is high or the child is uncomfortable.

Understanding these facts can help parents make informed decisions about managing their child’s fever and reduce unnecessary anxiety.

Preventive Measures and Long-term Health Considerations

While fevers are a common part of childhood, there are steps you can take to promote overall health and potentially reduce the frequency of fevers:

Boosting Immune Function

A strong immune system can help fight off infections that cause fever. How can you support your child’s immune system?

• Ensure a balanced diet rich in fruits, vegetables, and whole grains
• Encourage regular physical activity
• Ensure adequate sleep
• Manage stress levels
• Consider probiotics (consult with your pediatrician)

Hygiene Practices

Good hygiene can prevent the spread of infections that lead to fever. What are some key hygiene practices to emphasize?

• Regular handwashing, especially before meals and after using the bathroom
• Covering mouth and nose when coughing or sneezing
• Avoiding sharing personal items like utensils or towels
• Keeping living spaces clean and well-ventilated

Vaccination

Staying up-to-date with recommended vaccinations can prevent many illnesses that cause fever. Consult with your pediatrician about the appropriate vaccination schedule for your child.

Regular Check-ups

Regular pediatric check-ups can help catch and address health issues early, potentially preventing some illnesses that lead to fever.

By implementing these preventive measures, you can support your child’s overall health and potentially reduce the frequency of fevers. Remember, while fevers can be concerning, they are often a sign that your child’s body is effectively fighting off an infection.

Fever Instructions – Pediatric Associates of Madison

DEFINITION Your child has a fever if any of the following apply:

• Rectal temperature is over 100.4° F (38.0° C).
• Oral temperature is over 100.4° F (38.0° C).
• Axillary (armpit) temperature is over 99.4° F (37.5° C)
• Ear (tympanic) and temporal temperatures are not as accurate and should not be used in children less than 6 months.

The body’s average temperature when it is measured orally is 98.6° F (37.0° C), but it normally fluctuates during the day. Mild elevation (100.4° to 101.3° F or 38° to 38.5° C) can be caused by exercise, excessive clothing, a hot bath, or hot weather. Warm food or drink can also raise the oral temperature. If you suspect such an effect on the temperature of your child, take his or her temperature again in one-half hour.

Causes


Fever is a symptom, not a disease. Fever is the body’s normal response to infections and plays a role in fighting them. Fever turns on the body’s immune system. The usual fevers (100° to 104° F [37.8° to 40° C]) that all children get are not harmful. Most are caused by viral illnesses; some are caused by bacterial illnesses. Teething does not cause fever.

Expected Course


Most fevers with viral illnesses range between 101° and 104° F (38.3° to 40° C) and last for 2 to 3 days. In general, the height of the fever does not relate to the seriousness of the illness. How sick your child acts is what counts. Fever causes no permanent harm until it reaches 107° F (41.7° C). Fortunately, the brain’s thermostat keeps untreated fevers below this level.

HOME CARE:

Treat All Fevers with Extra Fluids and Less Clothing

. Encourage your child to drink extra fluids, but do not force him or her to drink. Popsicles and iced drinks are helpful. Body fluids are lost during fevers because of sweating.

Clothing should be kept to a minimum because most heat is lost through the skin. Do not bundle up your child; it will cause a higher fever. During the time your child feels cold or is shivering (the chills), give him or her a light blanket.

Acetaminophen Products for Reducing Fever.

Children older than 2 months of age can be given any one of the acetaminophen products. Remember that fever is helping your child fight the infection. Use drugs only if the fever is over 102° F (39° C) and preferably only if your child is also uncomfortable. Give the correct dosage for your child’s age every 4 to 6 hours, but no more often.

Two hours after they are given, these drugs will reduce the fever 2° to 3° F (1° to 1. 5° C). Medicines do not bring the temperature down to normal unless the temperature was not very elevated before the medicine was given. Repeated dosages of the drugs will be necessary because the fever will go up and down until the illness runs its course. If your child is sleeping, don’t awaken him for medicines.

Caution: The dropper that comes with one product should not be used with other brands. Dosages of Acetaminophen.

Avoid Aspirin


The American Academy of Pediatrics has recommended that children (through 21 years of age) not take aspirin if they have chickenpox or influenza (any cold, cough or sore throat symptoms). This recommendation is based on several studies that have linked aspirin to Reye’s syndrome, a severe encephalitis-like illness. Most pediatricians have stopped using aspirin for fevers associated with any illness.

Alternating Acetaminophen and Ibuprofen


If you are instructed by your physician to alternate both products, do it as follows:

• Use both if the fever is over 104° F (40° C) and unresponsive to one medicine alone.
• Give a fever medicine every 4 hours (acetaminophen every 8 hours and ibuprofen every 8 hours).
• Only alternate medicines for 24 hours or less, than return to a single product.

Beware of dosage errors and poisoning (especially if you give one or both products too frequently).

Sponging


Sponging is usually not necessary to reduce fever. Never sponge your child without giving him/her acetaminophen or ibuprofen first. Sponge immediately only in emergencies such as heatstroke, delirium, a seizure from fever, or any fever over 106° F (41.1° C). In other cases, sponge your child only if the fever is over 104° F (40° C), the fever stays that high when you take the temperature again 30 minutes after your child has taken acetaminophen or ibuprofen, and your child is uncomfortable. Until the acetaminophen or ibuprofen has taken effect (by resetting the body’s thermostat to a lower level), sponging will just cause shivering, which is the body’s attempt to raise the temperature.

If you do sponge your child, sponge him/her in lukewarm water (85° to 90° F [29° to 32° C]). Sponging works much faster than immersion, so sit your child in 2 inches of water and keep wetting the skin surface. Cooling comes from evaporation of the water. If your child shivers, raise the water temperature or wait for the acetaminophen or ibuprofen to take effect. Do not expect to get the temperature below 101° F (38.3° C). Do not add rubbing alcohol to the water; it can be breathed in and cause a coma.

Call our office immediately if:

• Your child is less than 3 months old and has a fever.
• The fever is over 105° F (40. 6° C).
• Your child looks or acts very sick.
  

Call our office within 24 Hours if:

• Your child is 3 to 6 months old.
• The fever is between 104° and 105° F (40° to 40.6° C), especially if your child is less than 2 years old.
• Your child has had a fever more than 24 hours without an obvious cause of location of infection.
• Your child has had a fever more than 3 days.
• The fever went away for more than 24 hours and then returned.
• You have other concerns or questions.

6 Fever Myths Debunked – Purohit Pediatric Clinic

When your little one comes down with a fever, it’s only natural for you to be concerned. However, there are plenty of misconceptions about fever that can cause you to panic needlessly. So before you worry too much, put your mind at ease with these six debunked fever myths.

Myth: All fevers require medical attention

Fact: A fever is simply the body’s natural reaction to an infection. In fact, fevers are a good sign that the immune system is working properly. Many times, a fever will run its course without any need for medical attention.

Rather than focusing solely on the fever, pay attention to the severity of other signs. If your child is eating, sleeping, and playing normally, then you can usually get by with home treatment. If the fever is accompanied by other symptoms – such as a sore throat, body aches, vomiting, cough, or ear pain – or if it persists for more than 48 hours, call your pediatrician.

Myth: All fevers should be treated with medicine.

Fact: While some parents are quick to give their children fever-reducing medication, it’s actually better to let the fever run its course. Remember, a fever is your body’s way of fighting an infection. If your child is acting fine and seems relatively unbothered, you don’t need to give them any medication.

If the fever rises above 102 or your child is obviously uncomfortable, you can give them some medication to help them rest and feel better. However, the goal is to *treat* the fever, not make it go away completely.

Also, no medicines will actually “break” the fever. The infection will have to run its course no matter what.

Myth: High fever means serious infection

Fact: A normal fever can range anywhere between 100.4 F and 104 F. The exact reading on your thermometer is not a true indicator of how sick your child is. Again, you want to pay attention to how your child looks and feels more than anything else.

Myth: High fevers can cause brain damage

Fact: Fevers from infections do not cause brain damage, even when they get up to the 104 – 106 range. The only time an elevated temperature can cause brain damage is when it reaches above 108 degrees, and this only happens when the air temperature is high – as is the case of children being left in hot cars.

Myth: Any elevated temperature above 98.6 is a fever

Fact: Your child’s temperature fluctuates throughout the day. Just because they may feel warm or have an elevated temp above 98.6 doesn’t mean they have a fever. Actual fever thresholds are as follows:

Myth: High fevers can cause dangerous seizures.

Fact: Febrile seizures, or seizures caused by fever, only affect about 4% of children. Even then, febrile seizures do not cause permanent harm, nor do they mean your child has a greater risk of developmental or cognitive disabilities.

Fever, fever (high body temperature): what is it, causes, symptoms, diagnosis, treatment, prevention

Fever; elevated temperature; hyperthermia; pyrexia; Febrile

What is a fever?

Fever is a temporary rise in body temperature, usually in response to an infection, inflammation, or other illness. This is often part of the body’s natural immune response and is not always a cause for concern. However, if the fever persists for more than a few days, a healthcare professional should be contacted to ensure proper treatment.

The child has a fever when the temperature is at or above one of the following levels: °F), measured in the mouth (oral)

An adult is likely to have a fever when the temperature exceeds 37.2 °C to 37.5 °C (99-99.5 °F), depending on time of day.

Normal body temperature can change throughout any day. It is usually highest in the evening. Other factors that affect body temperature are:

• Women’s menstrual cycle. In the second part of this cycle, its temperature may rise by 1 degree or more.
• Physical activity, strong emotions, food, heavy clothing, medicines, high room temperature and high humidity can increase body temperature.

Fever is an important part of the body’s defense against infection. Most bacteria and viruses that cause infections in humans thrive best at 37°C (98.6°F). Many infants and children develop high fevers due to mild viral illnesses. Although a fever signals that a battle may be taking place in the body, the fever fights for the person, not against them.

Brain damage from fever usually does not occur unless the temperature exceeds 42 °C (107.6 °F). Untreated fever due to infection rarely rises above 40.6°C (105°F) unless the child is overdressed or in a hot place.

Some children have febrile seizures. Most febrile seizures go away quickly and do not mean your child has epilepsy. These seizures also do no harm.

An unexplained fever that lasts for days or weeks is called a fever of unknown origin.

Causes of fever

Fever is most often caused by an infection or illness, such as a cold or flu. Other possible causes include:

• Immune system disorders
• Viral infections
• Bacterial infections
• Drug reactions
• Vaccines
• Tumors

900 13 Heatstroke

• Some diseases, such as lupus.
• Exposure to extreme temperatures

Almost any infection can cause fever, including:

• Bone infections (osteomyelitis), appendicitis, skin infections, or cellulitis and meningitis , mononucleosis, bronchitis, pneumonia and tuberculosis
• Urinary tract infections
• Viral gastroenteritis and bacterial gastroenteritis

Children and adults may have a low-grade fever for 1 or 2 days after certain vaccinations.

Teething may cause a slight fever in the baby, but not more than 37.8°C (100°F).

Autoimmune or inflammatory diseases can also cause fever. Some examples:

• Arthritis or connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus
• Ulcerative colitis and Crohn’s disease
• Vasculitis or periarteritis nodosa

The first symptom of cancer may be fever. This is especially true of Hodgkin’s disease, non-Hodgkin’s lymphoma, and leukemia.

Other possible causes of fever include:

• Blood clots or thrombophlebitis
• Medications, such as certain antibiotics, antihistamines, and anticonvulsants

Symptoms of fever

The most common symptom of fever is fever naya temperature, which is measured by measuring the temperature at person orally, rectally, axillary (under the arm), or with an ear thermometer. A temperature above 38 °C (100.4 °F) is usually considered a fever.

Other symptoms that may accompany fever include:

• Chills or shivering
• Chronic fatigue
• Headache
• Sweating
• Loss of appetite

9001 3 Muscle pain

• Dehydration
• Nausea and vomiting
• Cough
• Abdominal pain

When to see a doctor

Call your doctor right away if your child:

• is 3 months or younger and has a rectal temperature of 38°C (100.4°F) or higher
• Age 3 to 12 months and fever 39°C (102. 2°F) or higher
• 2 years or younger and fever lasting more than 24-48 hours
• Age over 2 years and fever lasting 48 to 72 hours.
• body temperature of 40.5 °C (105 °F) or higher, unless it resolves quickly with treatment and the person feels comfortable
• ear or cough.
• Has had a fever for a week or more, even if the fever is not very high
• Has a serious medical condition such as heart problems, sickle cell anemia, diabetes, or cystic fibrosis.
• Recently vaccinated
• Has a new rash or bruising
• Has pain when urinating
• Has a weakened immune system (due to long-term [chronic] steroid therapy, bone marrow or organ transplant, spleen removal, HIV/AIDS, or cancer treatment )
• Recently traveled to another country

Call your doctor right away if you are an adult and:

• You have a fever of 40.5°C (105°F) or higher unless it gets better with treatment
• You have a fever that persists or continues to rise above 39. 4°C (103°F)
• You have had a fever for more than 48-72 hours
• You have had a fever for a week or more, even if it is not very high
• A serious medical condition such as heart problems, sickle cell anemia, diabetes, cystic fibrosis, COPD, or other chronic lung conditions.
• Have a new rash or bruising
• Have pain when urinating
• Have a weakened immune system (due to chronic steroid therapy, bone marrow or organ transplant, spleen removal, HIV/AIDS, or cancer treatment)
• Recently traveled to another country

Call the emergency number if you or your child has a fever and:

• Child cries and cannot calm down
• Child or adult does not wake up and does not respond to stimuli
• Difficulty breathing persists even after the nose is cleared
• Blue lips, tongue or nails
• Very severe headache
• Stiff neck
• Child cannot move an arm or leg

9001 3 There is a seizure

Questions questions your doctor may ask

When you see your doctor to discuss a fever, they will likely ask you a series of questions to determine the underlying cause. These questions may include:

• What is your temperature?
• How long does the fever last?
• What other symptoms do you experience?
• Have you recently been vaccinated?
• Are you taking any medications?
• Has there been contact with a sick or infected person?
• Do you have trouble breathing?

In some cases, your doctor may order tests such as a blood test, urine test, or chest x-ray to look for any underlying causes or infections.

Diagnosis of fever

Once the cause of the fever is identified, the doctor will make a diagnosis and develop a treatment plan. The plan may include various treatments such as antibiotics, antivirals, fluids, and pain medication.

In some cases, your doctor may recommend lifestyle changes, such as getting more rest, drinking plenty of fluids, and avoiding highly processed foods.

Treatment of fever

Most moderate fevers do not require treatment. However, a doctor may suggest medications or other treatments to lower the fever and treat any associated symptoms. Common fever treatments include:

• Antihistamines . These medicines can help reduce the inflammation associated with a fever, as well as any associated discomfort.
• Antipyretics. These drugs lower fever by blocking inflammation-causing substances released by the body during an infection.
• Fluid . Drinking plenty of fluids will help keep you hydrated and cleanse your body of any bacteria or viruses that may be causing a fever.
• Rest. Rest and adequate sleep help the body recover faster and lower the temperature.
• Painkillers. If the fever is accompanied by pain, your doctor may recommend over-the-counter or prescription pain relievers to relieve discomfort.

Fever Home Treatment

A common cold or other viral infection can sometimes cause high fever (38. 9°C to 40°C or 102°F to 104°F). This does not mean that you or your child has a serious problem. Some serious infections do not cause fever or can cause very low body temperature, most commonly in infants.

If you have a mild fever and no other problems, you do not need treatment. Drink plenty of fluids and rest.

The illness is not likely to be serious if the child:

• Still enjoys playing and being active
• Eats and drinks well
• Attentive and smiles at you
• Has normal skin color
• Appearance it’s good when the temperature drops

Take steps to reduce fever if you or your child experience discomfort, vomiting, dryness (dehydration), or trouble sleeping. Remember that the goal is to reduce, not eliminate fever.

If you need to lower your body temperature:

• Do not wrap up someone who is chilly.
• Remove excess clothing or blankets. The room should be comfortable, not too hot or too cold. Try one layer of light clothing and one light blanket for sleeping. If the room is hot or stuffy, a fan can help.
• A warm bath or sponge bath can help cool a person with a fever. This is effective after the medicine is given, otherwise the temperature may rise again.
• Do not use cold baths, ice or alcohol rubs. They cool the skin, but often worsen the situation by causing chills, which increase the body’s core temperature.

Here are some suggestions for taking fever medication:

• Acetaminophen (paracetamol) and ibuprofen (Advil, Motrin) help reduce fever in children and adults. Sometimes doctors advise using both types of medications.
• Take acetaminophen every 4-6 hours. It works as if turning off the thermostat of the brain.
• Take ibuprofen every 6-8 hours. Do not use ibuprofen in children 6 months of age or younger.
• Aspirin is very effective for treating fever in adults. But don’t give aspirin to a child unless your child’s doctor tells you to.
• Find out how much you or your child weigh. Then check the instructions on the package to find the correct dose.
• For children 3 months of age or younger, call your doctor before giving any medicine.

Food and drink:

• Everyone, especially children, should drink plenty of fluids. Water, popsicles, soup, and jelly are all good choices.
• Do not give young children too much fruit or apple juice and do not give sports drinks.
• Do not force a child to eat if he does not want to.

Prevention of fever

Fever is usually caused by an infection or disease, so it is important to take steps to prevent these diseases from occurring. To reduce your risk of developing a fever, it is important to:

• Wash your hands often with soap and water or use an alcohol-based hand sanitizer.
• Do not touch your face or nose with your hands.
• Stay away from sick people.
• Do not share food, drink, or other personal items.
• Get recommended vaccinations
• Practice good hygiene, such as brushing your teeth and bathing regularly.
• Eat a healthy, balanced diet with plenty of fruits, vegetables, and whole grains.
• Exercise regularly and get plenty of rest.
• Avoid extreme temperatures.

By following these simple steps, you can help reduce your risk of developing a fever or other illness. It is also important to seek medical attention if you develop a fever that persists for more than a few days or if it is accompanied by other severe symptoms.

References and literature

Leggett JE. Approach to fever or suspected infection in the normal host. In: Goldman L, Schafer AI, eds. Goldman Cecil Medicine. 26th ed. Philadelphia, PA: Elsevier; 2020:chap 264.

Nield LS, Kamat D. Fever. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 201.

Systemic Mediterranean fever – National Association of Nephrology

Systemic Mediterranean fever

General information

Systemic Mediterranean Fever (FMF) ( Familial Mediterranean Fever, FMF ) is an autoinflammatory disease characterized by recurrent bouts of fever associated with aseptic peritonitis, sometimes pleurisy, skin lesions, arthritis, and rarely pericarditis ¹ .

Epidemiology

Among all autoinflammatory diseases, FMF is most characterized by ethnic predisposition. Representatives of four ethnic groups are most susceptible to the disease: Sephardic Jews (North African, non-Ashkenazi Jews), Turks, Arabs and Armenians ¹ . Knowing the ethnicity of the patient is of great help in establishing the diagnosis.

But as FMF was studied, it became clear that the prevalence of FMF was not limited to the above populations. Due to the migration of the population in the twentieth century, the disease has spread throughout the world: USA, Europe, Russia, Japan, South America, etc. ² . Thus, the disease was detected in representatives of fairly distant ethnic groups, which warns against making a diagnosis solely on the basis of a pedigree.

Etiology and pathogenesis

The etiological factor of FMF is a mutation of the MEFV gene, localized on the short arm of the 16th pair of chromosomes. The type of inheritance is autosomal recessive, respectively, if both parents are healthy heterozygotes, the probability of developing the disease in their offspring is 25% (Fig. 1). However, there is evidence of the possibility of an autosomal dominant type of inheritance in the presence of a mutation with high penetrance ³ .

Figure 1. Autosomal recessive inheritance pattern

FMF-associated mutations are gain-of-function mutations, i.e. they give a protein new or increased activity with the effect of a dose of the abnormal gene (i.e., increasing the number of copies of the abnormal gene gives greater effect). The MEFV gene normally encodes a protein (the so-called pyrin) that is expressed in circulating neutrophils ⁴ .

Pyrine is an integral structural component of the innate immune system and is involved in defense responses against bacterial toxins that depolymerize actin and activate inflammasomes. Bacteria that produce similar toxins include Clostridium difficile , Burkholderia cenocepacia , and Vibrio cholerae ⁴ . Pyrine is hypothesized to blunt the inflammatory response, possibly by inhibiting chemotaxis and neutrophil activation. Gene mutations result in altered pyrine molecules that do not inhibit inflammasome activation.

Impaired inflammasome function leads to spontaneous triggering of the inflammatory cascade and hyperactivation of the innate immune system for no apparent reason (in the absence of infection or autoimmune reaction), the main pathogenetic role in this process belongs to the pro-inflammatory cytokine IL-1β ^{4. 5} .

Interleukin-1β activates innate immune cells (neutrophils, monocytes; T-lymphocytes; osteoclasts), induces the expression of collagenases that destroy articular cartilage, stimulates the production of prostaglandin E2 in the hypothalamus, which leads to the development of central hyperthermia. By acting on the vascular endothelium, IL-1β promotes the development of a rash and stimulates atherogenesis in blood vessels, and also activates the synthesis of acute phase proteins in the liver ⁵ .

Clinical consequences of IL-1β overproduction are spontaneous attacks of systemic inflammation with an increase in the number of leukocytes due to neutrophils and acute phase blood counts.

CSL debuts, as a rule, before the age of 20. The main typical clinical signs of the disease include: fever, abdominal manifestations in the form of acute abdominal pain, arthritis, pleurisy, pericarditis, rash on the legs and feet, muscle manifestations and lesions of the genitourinary system3,6.

Clinical picture

FMF is characterized by recurrent attacks of systemic inflammation lasting 6–72 hours, manifested by febrile fever 38–40.5 °C and symptoms of inflammation of organs and systems ^6.7 . The main manifestations of the disease are shown in Fig. 2.

Figure 2. Clinical manifestations of FMF

Localization of the process occurs mainly in four main zones ³ :

• “acute abdomen”.
• Thoracic: with the development of aseptic pleurisy, in most cases unilateral.
• Articular: with the development of arthritis, mainly in the joints of the lower extremities.
• Dermal: the main manifestation is erysipelatous erythema, usually on the legs, over the ankle joint,
  in which there are signs of arthritis, and on the dorsum of the feet.

The frequency of FSL attacks varies, reflecting its severity: from 1–2 times a week to several times a year. During an attack, any combination of febrile fever with manifestations of inflammation from these systems is possible. Rarely, attacks can occur as an isolated fever. Almost always, febrile attacks are accompanied by a significant increase in the level of acute phase markers: ESR, CRP, serum amyloid A (SAA) ^8.9 .

The values ​​of acute phase markers are significantly reduced outside the attack, but approximately 63% of patients maintain an increased level of one or another acute phase indicator in the interval between attacks. Serum amyloid A (SAA) ^3.10 is currently the key and most sensitive marker of inflammation as an assessment of disease activity, treatment efficacy and risk of developing amyloidosis.

There are three ¹¹ variants of the course (phenotype) of FMF ^12.13 :

• FSL type I: proceeds in the form of typical attacks.
• Type II FMF: The first clinical manifestation of this phenotype is renal amyloidosis. Before the development of amyloidosis
  in such patients, only an increase in the level of acute phase markers can be detected.
• Type II FMF: The first clinical manifestation of this phenotype is renal amyloidosis. Before the development of amyloidosis in such patients, only an increase in the level of acute phase markers can be detected.

Complications

Renal amyloidosis is the main complication that determines the prognosis of the disease and leads to the development of chronic renal failure. Chronic renal failure due to amyloidosis is the cause of death in 90% of patients 14 with FMF ¹⁴ . The frequency of amyloidosis is 25-30% ¹ and may depend on the ethnic origin of the patient ¹⁵ . Thus, in untreated patients of Turkish origin, the frequency of amyloidosis reaches 60%, in Sephardic Jews – 75% ¹⁵ .

Risk factors for amyloidosis in FMF include male gender, presence of arthritis, delayed diagnosis, inadequate treatment, and family history of amyloidosis ¹⁴ .
Another complication that is significantly less important for the prognosis of the disease is adhesive disease.

Clinical consequences of chronic inflammation in FMF may include normocytic-normochromic anemia, splenomegaly, growth retardation in children, reduced bone density, male and female infertility, preterm birth, increased risk of cardiovascular disease ¹¹ .

Diagnosis

The diagnosis of FMF is possible on the basis of clinical findings, but molecular genetic testing is essential to confirm the diagnosis, and is particularly informative in evaluating atypical cases.

More information about the program of genetic diagnostics.

Genetic testing is used to confirm, but not rule out, a diagnosis of periodic illness. There are 5 major pathogenic mutations in the MEFV gene: M694V, M694I, M680I, V726A, E148Q. The largest number of mutations (up to 38%) falls on the 10th exon. Mutations in M694V lead to a more severe course of the disease with an early onset, frequent joint damage, and a high level of amyloidosis if left untreated. Patients homozygous for the M694V mutation are 6 times more likely to suffer from amyloidosis compared to other genotypes. Mutations are also found in exons 2, 3, 5 ^16,17,18 .

It should be noted that some patients with obvious phenotypic features of FMF have only one mutant gene, and sometimes there are no obvious mutations in the MEFV gene. Approximately 10-20% of patients who meet the diagnostic criteria for FMF do not have mutations in the MEFV gene, suggesting the presence of epigenetic and environmental factors contributing to the pathogenesis of the disease ¹⁹ . Non-specific signs include: an increase in the level of leukocytes with a predominance of neutrophils, ESR, C-reactive protein and fibrinogen. Urinary excretion of > 0.5 g of protein per day suggests the formation of renal amyloidosis ¹⁹ .

In the diagnosis of FMF, the clinical diagnostic criteria of the Tel Hashomer clinic are used – this is the “gold standard” (Table 1) ²⁰ .

Table 1. Diagnostic criteria for FSL clinic Tel Hashomer ²⁰

Major criteria	Typical attacks: 1. Peritonitis (generalized) 2. Pleurisy (unilateral) or pericarditis 3. Monoarthritis (hip, knee, head enostopic joints)
Small criteria	1–3. Incomplete attack involving ≥ 1 of the following sites: 1. Abdomen 2. Thorax 3. Joint 4. Stress pain in legs 5. Good response to colchicine therapy
Supporting criteria	1. Family history of FMF 2. Ethnicity 3. Age of onset <20 years 4–7. Attack characteristic: 4. Severe, bedridden 5. Spontaneous resolution of the attack 6. Presence of asymptomatic intervals 7. Elevation of laboratory markers of inflammation with increasing values ​​ * ≥ 1 of the following: * white blood cell count in a clinical blood test * ESR * serum amyloid A and/or fibrinogen 8. Episodes of proteinuria/hematuria 9. Unproductive laparotomy or removal of the “white” (without phlegmonous inflammation) appendix 10. Consanguineous marriage of parents

Diagnosis of FMF requires ≥ 1 major criteria, or ≥ 2 minor criteria, or 1 major + ≥ 5 supporting criteria, or 1 minor + ≥ 4 supporting criteria from the first 5.

Treatment

The goal of treatment for FMF is to achieve complete control of unprovoked seizures and minimize subclinical inflammation in the period between attacks ²¹ .

Currently, the main treatment for FMF is colchicine. Colchicine prevents disease attacks, reduces their frequency and severity. Also an important factor is a significant reduction in the risk of developing amyloidosis when using adequate doses of the drug ²² .

Today, colchicine is the only drug proven effective in preventing amyloidosis.
EULAR (2016) recommends that colchicine be given immediately after diagnosis of FMF (Evidence A) ²² .

Colchicine is effective in most but not all patients with FMF. In 20% of patients with FMF on colchicine
therapy, inflammatory attacks and latent inflammation between attacks persist. Why is this happening? More than 40% of patients
do not follow treatment recommendations, 2-5% report intolerance and serious side effects of colchicine therapy (severe diarrhea, neuropathy, rhabdomyolysis and bone marrow suppression) ²³ . In addition, there is the concept of “colchicine resistance”, when a patient with FMF does not respond adequately to therapy with the maximum allowable dose of colchicine. Colchicine resistance is diagnosed when ≥ 1 attack per month persists in compliant patients (received a maximum dose of colchicine ≥ 6 months) or when CRP/SAA levels persist between attacks ^21.24.25 .

The proportion of patients with true colchicine resistance reaches 15%. Such patients are indicated for the appointment of genetically engineered biological drugs (GIBP). Therapy with GEBAs blocking interleukin-1 is the most effective pathogenetic treatment option for patients with colchicine-resistant FMF ²¹ . The detection of AA-amyloidosis requires intensification of treatment with consideration of the possibility of biological therapy, regardless of the presence of
colchicine resistance in patients with FMF.

One of the IL-1 inhibitors is canakinumab, a monoclonal antibody to IL-1β. Canakinumab selectively binds to IL-1β and completely blocks its action. The drug has a long half-life (26 days), which makes it possible to use it in patients with colchicine-resistant FMF once every 4 weeks in the form of subcutaneous injections ²

controlled study CLUSTER (Canakinumab Pivotal Umbrella Study in Three Heredity Periodic Fevers) ^22.26 . Canakinumab is the only GIBP that is registered in the Russian Federation for FCL indications (as of 2021).

Conclusion

FMF is the most common monogenic autoinflammatory disease and has a distinct ethnic predisposition. Many representatives of ethnic groups (Armenians, Azerbaijanis, peoples of the North Caucasus) live in Russia, in which there is a high prevalence of the MEFV gene mutation and, accordingly, FMF. Thanks to the introduction of molecular genetic diagnostics into clinical practice, the detection of FMF is increasing.

The severity and prognosis of the disease are determined not only by attacks of systemic inflammation, but also by a high risk of developing secondary AA amyloidosis, which can lead to the development of chronic renal failure and death of the patient. Pathogenetic drug therapy with GIBD makes it possible to achieve significant progress in the management of such patients with improved prognosis, prevention of life-threatening complications, and improved quality of life.

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