What are the causes of recurrent fevers in children. How can physicians diagnose and manage periodic fever syndromes. What is the PFAPA syndrome and how does it differ from other causes of intermittent fever.

Understanding Recurrent Fevers in Pediatric Patients

Recurrent fevers in children are a common concern for parents and healthcare providers alike. Defined as three or more febrile episodes within a six-month period, occurring at least seven days apart without an apparent underlying medical cause, these fever patterns can be both puzzling and distressing. This article delves into the intricacies of intermittent fevers in children, exploring their potential causes, diagnostic approaches, and management strategies.

The PFAPA Syndrome: A Leading Cause of Periodic Fevers

Among the various causes of recurrent fevers in children, PFAPA syndrome stands out as one of the most common diagnoses. But what exactly is PFAPA?

PFAPA, an acronym for Periodic Fever, Aphthous ulcers, Pharyngitis, and Adenopathy, is a condition characterized by predictable episodes of high fever lasting three to six days and recurring every 21 to 28 days. This syndrome typically affects children under five years of age and is accompanied by some or all of the following symptoms:

• Periodic high fevers
• Aphthous ulcers (often small and relatively painless)
• Pharyngitis (sore throat)
• Cervical adenopathy (swollen lymph nodes in the neck)

Interestingly, children with PFAPA syndrome are generally well between episodes and remain relatively healthy even during febrile periods. This characteristic sets PFAPA apart from many other causes of recurrent fever.

Diagnosing PFAPA Syndrome

Diagnosing PFAPA can be challenging, as laboratory tests are only helpful during fever episodes. During these periods, physicians may observe:

• Leukocytosis (elevated white blood cell count)
• Increased erythrocyte sedimentation rate (ESR)

It’s worth noting that aphthous ulcers, a key symptom of PFAPA, are often overlooked due to their small size and relative painlessness. Therefore, a thorough examination of the oral cavity is crucial during evaluation.

Treatment Approaches for PFAPA Syndrome

While the exact cause of PFAPA remains unknown, several treatment options have shown efficacy:

1. Corticosteroids: A single dose of prednisone (2 mg per kg) at the onset of symptoms can provide significant relief.
2. Prophylactic cimetidine: This medication may improve symptoms in some children.
3. Tonsillectomy: In certain cases, surgical removal of the tonsils has been found to alleviate symptoms.

Other Causes of Recurrent Fevers in Children

While PFAPA syndrome is a common culprit, it’s essential to consider other potential causes of recurrent fevers in pediatric patients. These can be broadly categorized into two groups: those causing regular fever patterns and those resulting in irregular fever intervals.

Regular Fever Patterns

Besides PFAPA, other conditions that may cause regular fever patterns include:

• Cyclic neutropenia
• Relapsing fever

Cyclic neutropenia, in particular, can mimic PFAPA syndrome. How can physicians differentiate between the two?

Diagnosing cyclic neutropenia requires frequent leukocyte counts during both febrile and non-febrile periods. The goal is to document a significant decline in the absolute neutrophil count (less than 500 per mm3) followed by recovery to normal levels shortly after. A bone marrow examination during the neutropenic phase typically reveals myeloid line maturation arrest.

Irregular Fever Patterns

Recurrent fevers occurring at irregular intervals have a more extensive differential diagnosis, including:

• Infectious causes (viral, bacterial, parasitic)
• Inflammatory or autoimmune diseases
• Hereditary periodic fevers
• Lymphoma
• Factitious fever

It’s important to note that fungal infections have not been reported to cause recurrent fevers in otherwise healthy children.

Diagnostic Approach to Recurrent Fevers in Children

When faced with a child presenting with recurrent fevers, how should healthcare providers approach the diagnostic process?

The cornerstone of diagnosis lies in a thorough history and focused physical examination. Based on these findings, the initial laboratory workup for an apparently healthy child with recurrent fevers should include:

• Complete blood count (CBC) with differential and platelet count
• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP) testing
• Urine culture

For children who appear ill, additional tests may be necessary:

• Blood cultures
• Further testing based on potential exposures, clinical history, and physical examination findings

Does every child with recurrent fevers need extensive testing? Not necessarily. Children with normal initial evaluations and no additional signs or symptoms often do not require further testing. However, careful follow-up is crucial to identify any emerging symptoms that might indicate a more serious underlying condition.

Prognosis and Long-term Outlook

What is the typical prognosis for children with recurrent fevers? In general, the outlook is quite favorable. Many cases of recurrent fever resolve without any long-term adverse effects, especially when no underlying cause is identified. However, it’s important to note that some conditions causing recurrent fevers may require ongoing management.

For instance, in children with severe symptoms of cyclic neutropenia, treatment with granulocyte colony-stimulating factor can decrease the duration of neutropenia and the associated risk of infection. This highlights the importance of accurate diagnosis and appropriate management in cases where a specific cause is identified.

The Role of ESR in Differential Diagnosis

Erythrocyte sedimentation rate (ESR) testing plays a crucial role in the evaluation of recurrent fevers. How does ESR help in differentiating between various causes?

ESR is particularly useful in distinguishing between inflammatory and hereditary disorders. Elevated ESR levels often indicate the presence of inflammation, which can point towards conditions such as:

• Inflammatory bowel disease
• Juvenile rheumatoid arthritis
• Behçet’s disease

On the other hand, normal ESR levels in the presence of recurrent fevers might suggest hereditary periodic fever syndromes. This distinction can be invaluable in guiding further diagnostic steps and treatment decisions.

Viral vs. Bacterial Causes of Recurrent Fevers

When evaluating a child with recurrent fevers, it’s important to consider both viral and bacterial etiologies. How do these differ in their presentation?

Viral infections are more likely to cause fever without any other signs or symptoms. This “isolated fever” presentation is less common in bacterial infections, which often produce additional symptoms or physical findings.

However, it’s crucial to remember that this is not an absolute rule. Some bacterial infections can present with fever alone, while certain viral infections may cause additional symptoms. Therefore, a comprehensive evaluation, including laboratory tests when indicated, is essential for accurate diagnosis.

Management Strategies for Recurrent Fevers in Children

Given the diverse causes of recurrent fevers in children, what are some key management strategies that healthcare providers should consider?

1. Symptomatic treatment: Regardless of the underlying cause, managing the child’s comfort during fever episodes is crucial. This may include appropriate use of antipyretics and ensuring adequate hydration.
2. Targeted therapy: When a specific cause is identified, such as PFAPA syndrome or cyclic neutropenia, targeted treatments can be initiated as discussed earlier.
3. Watchful waiting: In cases where no clear etiology is identified and the child is otherwise healthy, a watchful waiting approach with regular follow-ups may be appropriate.
4. Patient and family education: Helping parents understand the nature of recurrent fevers and when to seek medical attention is an important aspect of management.
5. Multidisciplinary approach: In complex cases or when systemic diseases are suspected, collaboration with specialists such as rheumatologists or hematologists may be beneficial.

It’s important to tailor the management approach to each individual child, taking into account their specific symptoms, diagnostic findings, and overall health status.

The Importance of Follow-up Care

While many cases of recurrent fever in children resolve without long-term consequences, consistent follow-up care remains crucial. Regular check-ups allow healthcare providers to:

• Monitor the frequency and severity of fever episodes
• Assess the child’s growth and development
• Identify any new symptoms that might emerge over time
• Adjust management strategies as needed
• Provide ongoing support and reassurance to families

This continuity of care ensures that any changes in the child’s condition are promptly recognized and addressed, optimizing long-term outcomes.

Emerging Research and Future Directions

As our understanding of recurrent fevers in children continues to evolve, what are some areas of ongoing research and potential future developments in this field?

• Genetic studies: Research into the genetic basis of periodic fever syndromes may lead to more targeted diagnostic tests and treatments.
• Immunological investigations: Further exploration of the immune system’s role in recurrent fevers could unveil new therapeutic targets.
• Biomarker discovery: Identification of specific biomarkers for different causes of recurrent fever could streamline the diagnostic process.
• Novel treatment modalities: Development of new medications or treatment approaches, particularly for conditions like PFAPA syndrome, is an active area of research.
• Long-term outcome studies: More extensive follow-up studies of children with recurrent fevers will provide valuable insights into the natural history and long-term prognosis of these conditions.

These research efforts hold the promise of enhancing our ability to diagnose, manage, and ultimately improve outcomes for children affected by recurrent fevers.

The Role of Precision Medicine

As we look to the future, how might the concept of precision medicine impact the management of recurrent fevers in children?

Precision medicine, which aims to tailor medical treatment to the individual characteristics of each patient, could revolutionize the approach to recurrent fevers. This might involve:

• Genetic profiling to identify specific fever syndromes
• Personalized treatment plans based on individual immune system characteristics
• Targeted therapies designed to address the underlying mechanisms of fever in each child

While still in its early stages, the application of precision medicine principles to pediatric fever disorders represents an exciting frontier in this field.

Empowering Families: Education and Support

Beyond medical management, what role does patient and family education play in addressing recurrent fevers in children?

Empowering families with knowledge and support is a crucial aspect of managing recurrent fevers. This involves:

• Providing clear, accessible information about the nature of recurrent fevers
• Teaching parents how to accurately measure and record their child’s temperature
• Offering guidance on when to seek medical attention versus when home management is appropriate
• Addressing concerns and anxieties that often accompany recurring illness in children
• Connecting families with support groups or resources for specific conditions when applicable

By fostering a partnership between healthcare providers and families, we can ensure better outcomes and quality of life for children experiencing recurrent fevers.

The Impact on Family Dynamics

How do recurrent fevers in children affect family dynamics, and what strategies can help families cope?

Dealing with a child’s recurring illnesses can place significant stress on families. Some common challenges include:

• Disruption of daily routines and schedules
• Financial strain due to medical expenses and potential lost work days
• Emotional toll on parents and siblings
• Balancing the needs of the affected child with those of other family members

To help families navigate these challenges, healthcare providers can:

1. Offer resources for stress management and coping strategies
2. Provide information about financial assistance programs when applicable
3. Encourage open communication within the family about the impact of recurrent fevers
4. Suggest ways to maintain normalcy and routine as much as possible during fever episodes
5. Refer to family counseling services if needed

By addressing the holistic impact of recurrent fevers on the entire family unit, we can provide more comprehensive care and support.

Recurrent Fevers in Children: Differential Diagnosis

RICHARD SADOVSKY, M.D.

Am Fam Physician. 2003;67(4):863-864

Recurrent fevers are defined as three or more febrile episodes in a six-month period, occurring at least seven days apart, with no causative medical illness. These episodes can occur at regular or irregular intervals. John and Gilsdorf review the evaluation and differential diagnoses for recurrent fever. An overview is provided in the accompanying table.

Few diseases cause a regular pattern of recurrent fevers. The most common diagnosis associated with this fever pattern is PFAPA syndrome (i. e., periodic fever, aphthous ulcers, pharyngitis, and adenopathy). PFAPA is characterized by high fevers lasting three to six days and recurring every 21 to 28 days, accompanied by some or all of the signs noted in its name. The syndrome usually occurs in children younger than five years who present with regular fevers and cervical adenopathy. Aphthous ulcers, which are usually small and relatively painless, are the symptom most likely to be missed.

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Children with PFAPA syndrome are well between episodes and relatively well even during episodes. Laboratory tests are helpful only during episodes, when leukocytosis or elevated erythrocyte sedimentation rate (ESR) can be detected. The cause of PFAPA is unknown, although viral or autoimmune etiologies have been suggested. Treatment at the beginning of the symptomatic period with a single dose of prednisone (2 mg per kg) relieves symptoms. Use of prophylactic cimetidine or tonsillectomy also may improve symptoms in some children.

Other causes of recurrent fevers include rare diseases such as cyclic neutropenia (which has symptoms similar to those of PFAPA) or relapsing fever, or uncommon manifestations of common diseases such as Epstein-Barr virus infection. Diagnosis of cyclic neutropenia requires obtaining frequent leukocyte counts during febrile and nonfebrile periods to document a decline in the absolute neutrophil count (less than 500 per mm³ [0.5 × 10⁹ per L]), with recovery to normal shortly after. Marrow examination done at the time of neutropenia reveals myeloid line maturation arrest. In children who have severe symptoms with cyclic neutropenia, granulocyte colony-stimulating factor decreases the duration of neutropenia and the resultant risk of infection.

Recurrent fevers that occur at irregular intervals have a lengthy differential diagnosis. Infectious causes can include viruses, bacteria, and parasites. Fever without any other sign or symptom is more common with viral infections than with bacterial infections. Fungal infections have not been reported to cause recurrent fevers in healthy children. Inflammatory or autoimmune diseases, including inflammatory bowel disease, juvenile rheumatoid arthritis, and Behçet’s disease, as well as hereditary periodic fevers, lymphoma, and factitious fever, should be considered. ESR testing is useful in distinguishing inflammatory from hereditary disorders.

The laboratory work-up in children with recurrent fever depends on the history and physical examination. The apparently healthy child needs only a complete blood cell count (CBC) with differential and platelet count, and ESR and C-reactive protein testing. Urine cultures are also useful. If the child appears ill, blood cultures should be obtained, with additional tests as indicated by potential exposure, clinical history, and physical examination. Children with normal initial evaluations and no additional signs or symptoms do not require further testing. Recurrent fevers with no defined underlying cause have a very favorable prognosis.

The authors conclude that recurrent fever often occurs without any defined etiology. Diagnostic testing should be limited, depending on a careful history and focused physical examination. Careful follow-up will help in the early identification of other presenting symptoms of serious disease. Recurrent fever in children usually resolves without any long-term adverse effects.

Periodic Fever Syndromes | Duke Health

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Overview

Fevers that persist for several days and are accompanied by other symptoms such as sore throat, abdominal pain, and/or joint pain may indicate the presence of a periodic fever syndrome. Children may have recurrent episodes of fever and symptoms as often as every three to four weeks.

Duke pediatric rheumatologists are experts in identifying the many disorders that fall under the heading of periodic fever syndromes. They may recommend treatment to control symptoms so your child can return to daily activities. In rare cases, treatment may prevent potential complications from uncontrolled inflammation.

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Understanding Periodic Fever Syndromes

Content

Periodic fever syndromes are a group of rare, often inherited conditions; there may be a family history of similar episodes. The episodes of fever are not caused by infection and they are not due to an autoimmune disease such as systemic lupus erythematosus. Periodic fever syndromes typically involve episodes of unregulated inflammation, which is why they are also known as autoinflammatory conditions.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome
PFAPA is probably the most common disorder. It often appears in early childhood (between the ages of 2 and 5). Children have recurrent episodes of fever, mouth sores, sore throat, and swollen lymph nodes in the neck. There tend to be regular intervals between episodes. There are no long-term complications associated with PFAPA, and treatment is recommended to minimize or eliminate symptoms and allow a return to regular activities. PFAPA may last for several years, but it often goes away on its own during the second decade of life.

Familial Mediterranean Fever (FMF)
This genetic disease mostly affects people of Mediterranean and Middle Eastern descent. It causes recurrent fevers along with pain and swelling in the abdomen, chest, or joints. Painful, severe joint swelling can make it hard to walk. It typically affects children before the age of 10. Left untreated, FMF may result in a dangerous buildup of proteins, called amyloidosis, that may lead to organ failure.

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
This condition causes intermittent fevers plus a painful rash, chills, and muscle pain. Onset is often in childhood but may be delayed until mid-adulthood. In addition to symptoms common to other periodic fever syndromes, people with TRAPS often have associated eye symptoms including conjunctivitis and swelling around the eye. Amyloidosis may occur in some people. 

Hyperimmunoglobulin D Syndrome (HIDS)
This rare genetic condition is also known as Mevalonate Kinase-Associated Periodic Fever Syndrome. Symptoms usually start in the first year of life. It typically begins with an abrupt onset of high fever (up to 104). Associated symptoms may include skin rash, abdominal pain, vomiting, diarrhea, joint pain, and swollen neck glands.

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Diagnosis

Tests Overview

The first step will be to rule out other causes of recurrent fever, such as infection or an autoimmune disease that may have symptoms similar to periodic fever syndrome. The pediatric rheumatologist may also perform tests in order to better diagnose your child’s condition and recommend the most appropriate treatment. 

Physical Exam

Description

The doctor will examine your child’s body and look for signs associated with periodic fever syndrome, such as joint swelling, rashes, swollen glands, mouth sores, or swelling around the eyes. 

Blood and Urine Tests

Description

These and other tests determine whether infection or inflammation is present. They may include a white blood cell count, throat culture, and tests for erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Tests are often performed when your child is well, and again when your child is ill, to compare the degrees of inflammation.

Genetic Tests

Description

May help confirm a diagnosis if physical exams and lab tests indicate your child has an inherited syndrome.

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Treatments

Treatments Overview

The type of treatment your child may need will depend on the specific diagnosis. The main goal is to prevent episodes of fever and associated symptoms while minimizing the potential for side effects so your child can perform regular daily activities such as attending school. Some periodic fever syndromes require long-term treatment, including into adulthood, whereas others may resolve on their own as your child grows.

Corticosteroids

Description

PFAPA responds well to steroids like prednisone. A single dose given at the start of an attack can significantly shorten or end the attack. Steroids can also relieve symptoms caused by other periodic fever syndromes but are used on a limited basis to prevent side effects associated with long-term use.

Colchicine

Description

As the treatment of choice for FMF, colchicine reduces the severity of the attacks and helps prevent amyloidosis. It is safe to use for prolonged periods and in pregnancy.

Biologics

Description

Biologic therapy is indicated in certain periodic fever syndromes. Biologics are protein medications that are given as an injection under the skin, like an insulin injection, or by infusion through an intravenous (IV) catheter. In general, periodic fever syndromes are associated with increased inflammatory proteins. Biologics address these proteins more directly than corticosteroids.

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Content

Partners with Pediatric Specialists
When necessary, our pediatric rheumatologists partner with other Duke pediatric specialists including dermatologists, nephrologists, and ophthalmologists to manage your child’s condition.

Support for Your Child and Family
Periodic fever syndromes are especially disruptive to school-age children because they cause recurrent and painful attacks can last for days or weeks. If symptoms or treatment sessions are interfering with school, our dedicated social worker can arrange accommodations to help your child keep up with their schoolwork.

National Partners in Research and Treatment
Our rheumatologists participate in a national network of doctors devoted to expanding our knowledge of these rare conditions. When appropriate, we consult with our peers to help confirm a diagnosis or share treatment discoveries.

This page was medically reviewed on 10/30/2018 by

C. Egla Rabinovich, MD, MPH
| Pediatric Rheumatologist

Fever in children. Causes of development and methods of treatment

Body temperature is regulated by thermosensitive neurons localized in the preoptic and anterior hypothalamus. These neurons are responsible for changes in body temperature in the same way as neural connections with cold and heat receptors located in the skin and muscles. Thermoregulatory responses are highly variable, mediated through a variety of mechanisms, and include directing blood flow in the skin vasculature, increased or decreased sweat secretion, regulation of extracellular fluid volume (via arginine vasopressin), or behavioral responses such as seeking warmth or cool ambient temperature. Normally, there is a circadian temperature rhythm or diurnal variations in body temperature within adjustable limits. Body temperature is lower in the morning and approximately 1°C higher in the afternoon and late afternoon.

Fever is a controlled increase in body temperature through mechanisms that regulate normal temperature. The difference is that the “thermostat” of the body is reset to a high temperature. Depending on which disease accompanies fever (infectious, connective tissue disease, malignant process), regulatory mechanisms are triggered in response to endogenous pyrogens, which, in turn, trigger the production of cytokines such as interleukin (IL) 1β and IL-6 , tumor necrotizing factor α, β-interferons and interferon-γ. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens. The most well-studied lipid mediator is prostaglandin E2. Most endogenous pyrogenic molecules are too large to cross the blood-brain barrier. However, near the hypothalamus, the functions of the blood-brain barrier are insufficient, which allows neurons to contact circulating factors through a network of capillaries.

Microbes, microbial toxins and other microbial waste products are among the most common exogenous pyrogens that, when ingested, stimulate the functions of macrophages and other cells to produce endogenous pyrogens leading to fever. Endotoxin can directly influence thermoregulation in the hypothalamus and stimulate the release of endogenous pyrogens. Some substances formed in the body are not pyrogens, but are able to stimulate the formation of endogenous pyrogens. Such substances include antigen-antibody complexes in the presence of complement, as well as complement components, lymphocyte products, bile acids, and androgenic steroid metabolites. Fever can be the result of infections, vaccination, exposure to biological agents (granulocyte – macrophage – colony stimulating factor, interferons, interleukins), tissue damage (heart attack, pulmonary embolism, trauma, intramuscular injections, burns), malignant diseases (leukemia, lymphoma, metastatic diseases) , taking certain drugs (drug fever, cocaine, amphotericin B), diffuse connective tissue diseases, rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis), granulomatous diseases (sarcoidosis), endocrine (thyrotoxicosis, pheochromocytoma), metabolic disorders (uremia, gout) , genetic disorders (familial Mediterranean fever) and other unknown and poorly understood causes.

An increase in body temperature in response to microbial attack represents a response that has been observed in reptiles, fish, birds, and mammals. In humans, an increase in body temperature is accompanied by a decrease in the reproduction of microorganisms and an increase in the inflammatory response. Most of the evidence to date suggests that fever is an adaptive response and should only be treated in selected situations.

Although the nature of the temperature curve alone is not often helpful in making a specific diagnosis, observation of fever can provide useful information to the clinician. In general, a single isolated peak is not associated with an infectious disease. Such a peak can be observed with parenteral administration of blood products, drugs, certain procedures or catheter manipulations with an infected skin surface. Temperatures above 41°C are rarely due to an infectious cause. Very high fever (> 41°C) is most commonly central fever (due to CNS dysfunction involving the hypothalamus), malignant hyperthermia, drug fever, fever due to overheating.

Temperature below normal (< 36 °C) is most often associated with exposure to cold, hypothyroidism, overdose of antipyretics.

Intermittent or intermittent fever (daily fluctuations in t° max and t° min of at least 1 ° C, but the minimum body temperature never drops to normal values) is defined as hectic or may be due to sepsis. The remaining persistent fever is persistent, and fluctuations in t ° do not exceed 0.5 ° C per day. With relapsing (laxative) fever, fluctuations in t ° exceed 0.5 ° C during the day, but it does not return to normal. Recurrent (relapsing) fever is separated by intervals of normal temperature, for example, in three-day malaria, fever is observed on the 1st and 3rd days ( Plasmodium vivax ), four days – on the 1st and 4th days ( Plasmodium malariae ). The biphasic nature of Bactrian camel fever indicates the presence of a single disease with two definite periods of fever of more than 1 week. The classic example is polio. Biphasic fever is also observed in leptospirosis, dengue fever, yellow fever, African hemorrhagic fever.

The dependence of heart rate on body temperature can be quite informative. Relative tachycardia, when the pulse rises in proportion to body temperature, is usually observed in non-communicable diseases or infections in which the toxin determines the clinical manifestations. Relative bradycardia (dissociation of pulse and temperature), when the pulse remains low during fever, suggests drug fever, typhoid, brucellosis, leptospirosis. Febrile bradycardia may also be the result of conduction disturbances involving the heart in acute rheumatic fever, Lyme disease, viral myocarditis, and infective endocarditis.

Most infections lead to various lesions causing an inflammatory response and subsequent release of endogenous pyrogens. The appointment of etiotropic antimicrobial therapy can lead to rapid elimination of bacteria. However, if tissue damage is severe, the inflammatory response and fever may continue for several days after eradication of all microbes.

Fever occurs in various infectious diseases with a wide range of severity. In healthy children, benign febrile illnesses include viral infections (rhinitis, pharyngitis, pneumonia), bacterial infections (otitis media, pharyngitis, impetigo), which usually respond well to antibiotic therapy and are not life-threatening. Risk groups include young children, with chronic diseases, immunodeficiency states. Some bacterial infections such as sepsis, meningitis, pneumonia, pyelonephritis, if left untreated, can be severe and have poor outcomes.

Fever without a specific focus usually presents a diagnostic dilemma for pediatricians, especially in children of the first 1.5–2 years of life, making it difficult to differentiate between serious bacterial infections and viral diseases.

Fever in children under 3 months of age always suggests the presence of a serious bacterial disease (sepsis, meningitis, urinary tract infection, gastroenteritis, osteomyelitis, otitis, omphalitis, mastitis, etc. ). Bacteremia may be due to group B streptococcus, Listeria monocytogenes , Salmonella spp., Esherichia coli , Neisseria 15 Streptococcus pneumonia , Haemophilus influenzae type B, Staphylococcus aureus . Children under the age of 3 months with fever, symptoms of intoxication should be hospitalized, blood cultures, urine, cerebrospinal fluid should be examined and parenteral antimicrobial therapy should be started immediately. Unlike bacterial infections, viral diseases tend to be seasonal.

Regardless of age, a fever accompanied by a petechial rash indicates a high risk of life-threatening bacterial infections. 8-10% of patients with fever and petechiae had severe bacterial infections, 7-10% had meningococcal sepsis or meningitis. The disease caused by H.influenzae type B may also present with fever and a petechial rash. Treatment tactics include hospitalization, blood and cerebrospinal fluid culture, and the appointment of appropriate antimicrobial therapy.

Many physicians use the term “fever of unknown origin” for patients presenting for examination who do not have an obvious infection or a non-infectious diagnosis. In most of these children, the appearance of additional symptoms after a relatively short period of time makes the infectious nature of the disease obvious. Therefore, this term is more often used in patients with fever that is not identifiable after 3 weeks in the outpatient setting or after 1 week in the hospital.

The causes of the so-called fever of unknown origin can be infectious processes and diseases of the connective tissue (autoimmune and rheumatic). It is necessary to exclude a neoplastic process. Most cases of fever of unknown or unrecognized origin are the result of an atypical course of common diseases. Since at the beginning there may be no clinical and laboratory signs of a certain disease, the diagnosis in some cases is made only after prolonged observation. Causes of fever of unknown origin in a more detailed examination included salmonellosis, tuberculosis, syphilis, Lyme disease, atypical protracted course of common viral diseases, infectious mononucleosis, cytomegalovirus infection, hepatitis, histoplasmosis. Inflammatory bowel disease, rheumatic fever, Kawasaki disease can also cause fever of unknown origin. In these cases, it is recommended to re-examine the patient after a certain period of time.

In children under 6 years of age, fever of unknown origin is associated with infection of the respiratory or urogenital tract, localized infection (abscess, osteomyelitis), juvenile rheumatoid arthritis, rarely leukemia. Adolescents are more likely to have tuberculosis, an inflammatory process in the intestines, an autoimmune process, and lymphoma. The empiric use of antibiotics should be avoided. In unclear cases, hospitalization may be required for x-ray and laboratory examinations, closer observation, temporary relief from the anxiety of the child and parents. Once fully adequately assessed, antipyretics may be indicated for fever control and symptomatic treatment.

Fever less than 38–38.5°C in previously healthy children generally does not require treatment. If this level is exceeded, the state of health of patients worsens, and the appointment of antipyretics improves the condition. Antipyretics generally do not change the course of infectious diseases in normal children and are symptomatic. Heat production associated with fever increases oxygen consumption, carbon dioxide production, and cardiac output. Thus, fever may worsen heart failure in patients with heart disease or chronic anemia (eg, sickle cell anemia), pulmonary insufficiency in patients with chronic lung disease, and metabolic disorders in children with diabetes, congenital metabolic disorders. Moreover, in children between 6 months. and 5 years, the risk of febrile seizures is increased, and in children with idiopathic epilepsy, febrile illness may increase the frequency of seizures. Antipyretics are prescribed in high-risk patients, ie. having chronic cardiopulmonary diseases, metabolic, neurological diseases, and children with a high risk of developing febrile seizures. Hyperpyrexia (> 41°C) is associated with severe infections, hypothalamic disorders, and central nervous system hemorrhage and always requires antipyretics.

When choosing antipyretics for children, it is especially important to focus on drugs with the lowest risk of side effects. Currently, only paracetamol and ibuprofen fully meet the criteria for high efficacy and safety and are officially recommended by the World Health Organization and national programs in pediatric practice as antipyretics [1-3]. Acetaminophen, aspirin, and ibuprofen are hypothalamic cyclooxygenase (COX) inhibitors that inhibit the synthesis of PGE-2. These drugs are considered equivalent effective antipyretics. Since aspirin is associated with Reye’s syndrome in children and adolescents, it is not recommended for use in the treatment of fever. Paracetamol and ibuprofen can be prescribed to children from the first months of life (from 3 months of age). Recommended single doses: paracetamol – 10-15 mg / kg, ibuprofen – 5-10 mg / kg. Re-use of antipyretics is possible not earlier than after 4-5 hours, but not more than 4 times a day.

It should be noted that the mechanism of action of these drugs is somewhat different. Paracetamol has an antipyretic, analgesic and very slight anti-inflammatory effect, since it blocks COX mainly in the central nervous system and does not have a peripheral effect, it is metabolized by the cytochrome P-450 system. The delay in the excretion of the drug and its metabolites can be observed in violation of the functions of the liver and kidneys. If a child has a deficiency of glucose-6-phosphate dehydrogenase and glutathione reductase, the administration of paracetamol can cause hemolysis of red blood cells, drug-induced hemolytic anemia.

Ibuprofen has a pronounced antipyretic, analgesic and anti-inflammatory effect. Ibuprofen is effective against fever in the same way as paracetamol [4–6]. A number of studies have shown that the antipyretic effect of ibuprofen at a dose of 7.5 mg/kg is higher than that of paracetamol at a dose of 10 mg/kg and acetylsalicylic acid at a dose of 10 mg/kg [7]. Ibuprofen blocks COX both in the central nervous system and in the focus of inflammation (peripheral mechanism), which determines its antipyretic and anti-inflammatory effect. As a result, the phagocytic production of mediators of the acute phase, including IL-1 (endogenous pyrogen), decreases. A decrease in the concentration of IL-1 also contributes to the normalization of temperature. The analgesic effect of ibuprofen is determined by both peripheral and central mechanisms, which makes it possible to effectively use ibuprofen for mild and moderate sore throat, pain with tonsillitis, acute otitis media, and toothache [8]. An indication for the appointment of ibuprofen is also hyperthermia after immunization.

Due to its high toxicity, amidopyrine has been excluded from the nomenclature of drugs. The use of analgin in many countries of the world is sharply limited due to the risk of developing agranulocytosis. In urgent situations, such as hyperthermic syndrome, acute pain in the postoperative period, and others that are not amenable to other therapy, parenteral use of analgin and metamizole-containing drugs is acceptable.

Comparison in double-blind, randomized trials with multiple doses of antipyretics showed that the incidence of adverse events was similar between ibuprofen and paracetamol (8–9%) [3]. The results of a large randomized study of more than 80,000 children showed that the use of ibuprofen compared with paracetamol does not increase the risk of hospitalization associated with gastrointestinal bleeding, renal failure or anaphylaxis. When using ibuprofen and paracetamol in children with bronchial asthma [3], it has been shown that the use of ibuprofen, compared with acetaminophen, does not increase the risk of bronchospasm in children with bronchial asthma who do not have indications of aspirin intolerance, which indicates the relative safety of ibuprofen in children with bronchial asthma .

According to the experts of IC “MAKS” (Vladimir), paracetamol and ibuprofen are most often used in pediatric practice (Table 1).

We used Nurofen for children (ibuprofen) in 95 children aged 3 months and older. up to 10 years old. The indication was fever in acute respiratory infections, acute otitis media, tonsillopharyngitis, obstructive bronchitis, bronchiolitis, pneumonia. 43 children of the first three years of life were hospitalized in the regional children’s hospital due to the severity of the condition. In 20 children, acute respiratory infections occurred against the background of mild to moderate bronchial asthma without indications of aspirin intolerance, in 37 children obstructive bronchitis and bronchiolitis were diagnosed. The average value of the initial axillary temperature was 39.1 ± 0.6 °С. Nurofen for children was prescribed at the rate of 5 mg/kg, on the first day – 3-4 times, on the second day – 2-3 times; the third day and beyond – according to indications. Most children were prescribed the drug for no more than 2 days. In 40-60 minutes after taking the drug, the temperature decreased to 37.9 ± 0.4 °C, after 90-120 minutes – to 37.3 ± 0.5 °C. Adverse events were noted in 2 children in the form of an allergic rash, in 1 child – abdominal pain, exacerbation or provocation of bronchospasm was not observed in any case. In 6 children, the effect of taking ibuprofen was minimal and short-lived: 2 children were prescribed diclofenac, 4 others received parenteral lytic mixture. The drug was rated as effective 90.7% of physicians and 93.7% of parents.

In 84 patients, short-term use of ibuprofen and paracetamol did not increase the risk of developing toxic changes in the kidneys [3]. An increase in the level of urea nitrogen and creatinine occurs in children who initially had a risk of developing complications from the side of the kidneys due to relevant diseases (renal failure, congenital heart failure, liver dysfunction) or a pronounced clinical picture of dehydration.

Thus, when using antipyretics, it is necessary to clearly take into account the indications with the identification of the causes of fever, age dose, premorbid background.

Fever

The state of the body, characterized by a rise in body temperature above normal, is called fever. Normally, the temperature of the human body is maintained at a level of about 37 ° C, however, in some (often infectious) diseases, a protective and adaptive reaction occurs, which is based on an increase in body temperature with the obligatory preservation of the thermoregulation mechanism. This property is a hallmark of fever from hyperthermia (overheating). Pyrogens cause fever – substances that enter the body during infection (exogenous pyrogens) or are formed by cells of the immune system as a result, for example, of inflammation (endogenous pyrogens).

Fever always passes in three stages:

1. Rise in temperature – blood vessels constrict, skin becomes pale, chills, muscle tremors, metabolism in muscles increases. At this stage, heat production is much higher than heat transfer.
2. Temperature retention – the mechanisms of heat production and heat transfer are balanced – the temperature can be fixed for hours, days or weeks. Skin vessels dilate, the skin ceases to be pale and becomes hot to the touch, chills and trembling go away. At this time, a person experiences a feeling of heat.
3. Drop in temperature – either a sharp or gradual decrease in body temperature is possible. At this stage, heat transfer significantly exceeds heat production, profuse sweating occurs and diuresis increases. This stage begins in case of exhaustion of exogenous reserves or cessation of production of endogenous pyrogens.

There are several types of fever:

• Relapsing (laxative) type is characterized by diurnal changes in temperature, which does not drop to normal;
• Intermittent (intermittent) type characterized by rapid diurnal fluctuations in temperature, which falls to normal and rises again;
• Constant fever – slight fluctuations in elevated temperature during the day;
• Relapsing fever – constantly elevated temperature for one or more days, then its reduction to normal and repeated increase;
• Perverse fever – a rise in temperature in the morning is characteristic;
• Incorrect fever – temperature fluctuations during the day occur without any dependence.