Pediatric Rheumatology

Symptoms, Progression, and Emergency Red Flags

At a Glance

AIFEC often begins in infancy with chronic diarrhea, recurrent fevers, intestinal ulcers, poor growth, rashes, or mouth sores. Seek emergency care for dehydration, shock, major bleeding, seizures, sudden confusion, or severe abdominal pain, and never assume a fever is only a flare.

Living with AIFEC means managing a condition that can change quickly. While many days may involve managing chronic symptoms like diarrhea or low-grade fevers, there are times when the inflammation can escalate into a medical emergency. Understanding the difference between a “typical” flare and a life-threatening complication is essential for your child’s safety.

Common Symptoms and Daily Challenges

In children with AIFEC, the immune system is persistently overactive, which primarily affects the digestive tract and the body’s temperature regulation.

Gastrointestinal Symptoms

The hallmark of AIFEC is enterocolitis, or inflammation of the small and large intestines. This can cause:

Chronic Diarrhea: Stools are often frequent and loose, and they may contain visible mucus or blood ^[1]^[2].
Intestinal Ulcers: Deep sores (ulcers) can form in the lining of the colon and ileum (the end of the small intestine), similar to what is seen in Crohn’s disease ^[1].
Poor Growth: Because the inflamed gut cannot absorb nutrients well, many children struggle with poor weight gain or “failure to thrive” ^[1].

Systemic and Skin Symptoms

Beyond the gut, the “stuck-on” immune response affects the whole body:

Recurrent Fevers: These may be periodic (coming and going) or nearly constant during a flare ^[3].
Rashes: Some children develop skin issues, such as urticarial (hive-like) rashes ^[2]^[4].
Mouth Sores: Painful aphthous ulcers (canker sores) in the mouth can occur ^[3]^[4].

How the Disease Progresses

The course of AIFEC is highly variable and unpredictable. Symptoms almost always begin in infancy, often within the first few months of life ^[1].

For some children, the disease remains a chronic struggle with bowel inflammation and fevers that require ongoing medication to manage. In the most severe cases, particularly in neonates, the inflammation can lead to bowel necrosis (death of intestinal tissue), which may require emergency surgery ^[5]^[6]. However, some children are able to achieve remission—a state where symptoms are minimal and the gut begins to heal—with the right combination of targeted therapies ^[1]^[3].

When to Seek Medical Care

In infants especially, deterioration can happen very fast. Crucially, you must work with your treating team to create a written, individualized emergency action plan. This plan should define your child’s specific baseline, detail exactly which symptoms require a same-day specialist call versus a 911 call, and provide the local emergency contact numbers. Do not wait for a lab result or a specialist callback if your child appears seriously unwell.

Emergency Services (Call 911 or Go to the ER)

Seek immediate emergency care if you notice signs of Macrophage Activation Syndrome (MAS), vasoplegic shock, or severe dehydration ^[2]^[6].

Signs of Dehydration: Markedly fewer wet diapers (or no urine for several hours), no tears when crying, a dry mouth, sunken eyes, sunken fontanelle (soft spot), or rapid breathing.
Signs of Shock: Extreme paleness, very fast heart rate, cold or “mottled” skin, and a child who is difficult to wake up, unusually floppy, or lethargic ^[2].
Signs of MAS: Unusual bruising and bleeding (from gums, or pinpoint red spots) or an abruptly worsening clinical state ^[6]^[7]. (Your doctor will use complex lab trends like falling platelets or rising ferritin to officially diagnose MAS).
Neurologic Changes: New seizures or sudden, extreme confusion ^[3].
Severe GI Bleeding: Large amounts of bright red blood in the stool or vomit that looks like coffee grounds.
Severe Abdominal Pain: Intense, worsening pain or a rigid, hard belly, which could signal a bowel perforation or obstruction ^[5].

Call Your Specialist Based on Your Action Plan

Contact your child’s rheumatology or immunology team if you see:

A “Falling” Platelet Count or Rising AST/ALT: If you have access to recent labs and see these trends, notify the team immediately. These are major warning signs of MAS that require clinician interpretation ^[8].
Inability to Hydrate: Frequent vomiting or diarrhea that prevents the child from keeping fluids down.
New Rash or Mouth Sores: These can signal that the current treatment is no longer controlling the underlying inflammation.

Discuss at Your Next Visit

Bring these up during your regular appointment:

Slow Growth: If your child is not gaining weight as expected.
Frequent “Mild” Flares: If the number of days your child feels unwell is increasing.
Joint Pain: New signs of stiffness or pain in the limbs (arthralgia) ^[4].

A Note on IL-18 and Infections: Many children with AIFEC have extremely high levels of a protein called IL-18 in their blood at all times ^[9]. While a high IL-18 level is used to help diagnose the disease, it does not always mean your child is in an emergency. Doctors look at the trend of other markers (like ferritin or platelets) and the child’s actual physical symptoms to decide if an emergency is occurring ^[9]^[8]. Furthermore, never assume a fever is just a flare. Children with AIFEC can develop a genuine infection and a flare at the same time. Always follow your specific infection action plan.

Common questions in this guide

What symptoms are common in children with AIFEC?

AIFEC commonly causes chronic diarrhea, sometimes with mucus or blood, along with recurrent fevers. Children may also develop intestinal ulcers, poor weight gain, hive-like rashes, or painful mouth sores.

When should my child with AIFEC receive emergency care?

Seek emergency care for markedly fewer wet diapers, no urine for several hours, a dry mouth, sunken eyes or soft spot, rapid breathing, extreme paleness, cold or mottled skin, or unusual difficulty waking the child. New seizures, sudden confusion, large amounts of blood, coffee-ground-like vomit, severe abdominal pain, or a rigid belly also require immediate evaluation.

Can a fever in a child with AIFEC be caused by an infection?

Yes. A child with AIFEC can have an infection and an inflammatory flare at the same time, so you should never assume that a fever is only a flare. Follow the infection action plan provided by your child’s medical team.

Which blood test changes may warn of macrophage activation syndrome?

Falling platelets, rising ferritin, or rising AST and ALT can be warning trends that require prompt review by your child’s medical team. Clinicians interpret these results together with the child’s physical symptoms and other laboratory findings rather than using one result alone.

How can AIFEC affect my child’s growth?

Inflammation in the intestines can interfere with nutrient absorption, leading to poor weight gain or failure to thrive. Ask the treating team to review the growth curve and whether a pediatric dietitian with experience in inflammatory bowel conditions could help.

Does a high IL-18 level always mean that my child is having an emergency?

No. IL-18 may remain very high in children with AIFEC, so clinicians also evaluate changes in markers such as ferritin and platelets and the child’s actual symptoms. A high IL-18 level by itself does not establish that an emergency is occurring.

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Key takeaways

AIFEC usually begins in infancy and commonly causes chronic diarrhea, recurrent fevers, intestinal ulcers, poor growth, rashes, or mouth sores.
The disease course can range from ongoing intestinal inflammation to remission, while severe neonatal inflammation can cause bowel tissue death.
Call emergency services for signs of dehydration or shock, major gastrointestinal bleeding, new seizures or confusion, or severe abdominal pain with a rigid belly.
Falling platelets, rising ferritin or liver enzymes, rapid worsening, and unusual bruising or bleeding require prompt clinical interpretation for possible macrophage activation syndrome.
A high IL-18 level alone does not prove an emergency; clinicians assess laboratory trends and physical symptoms, and fever may reflect infection as well as a flare.

References (9)

1
Autoinflammation with infantile enterocolitis associated with a novel CARD domain mutation in NLRC4: a case report and literature review.
Mao Y, Xie Y
Frontiers in pediatrics 2026; (14()):1878056 doi:10.3389/fped.2026.1878056.
PMID: 42534928
2
NLRC4 GOF Mutations, a Challenging Diagnosis from Neonatal Age to Adulthood.
Bardet J, Laverdure N, Fusaro M, et al.
Journal of clinical medicine 2021; (10(19)) doi:10.3390/jcm10194369.
PMID: 34640385
3
Three cases of autoinflammatory disease with novel NLRC4 mutations, and the first mutation reported in the CARD domain of NLRC4 associated with autoinflammatory infantile enterocolitis (AIFEC).
Asna Ashari K, Parvaneh N, Mirnia K, et al.
Pediatric rheumatology online journal 2024; (22(1)):90 doi:10.1186/s12969-024-01020-z.
PMID: 39425177
4
Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus.
Steiner A, Reygaerts T, Pontillo A, et al.
Journal of clinical immunology 2022; (42(2)):325-335 doi:10.1007/s10875-021-01175-4.
PMID: 34783940
5
Autoinflammation with infantile enterocolitis induced by a heterozygous variant (c.1357C > T) in the NLRC4 gene: a case report.
Wang X, Xiao Y, Ge T, et al.
Frontiers in pediatrics 2026; (14()):1822554 doi:10.3389/fped.2026.1822554.
PMID: 42290740
6
Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites.
Liang J, Alfano DN, Squires JE, et al.
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2017; (20(6)):498-505 doi:10.1177/1093526616686890.
PMID: 28403691
7
Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.
Hines MR, von Bahr Greenwood T, Beutel G, et al.
Critical care medicine 2022; (50(5)):860-872 doi:10.1097/CCM.0000000000005361.
PMID: 34605776
8
Characterization of Patients with Macrophage Activation Syndrome Secondary to Systemic Juvenile Idiopathic Arthritis.
Rogowska J, Kubicka J, Grabowska M, et al.
Clinical rheumatology 2025; (44(5)):2023-2029 doi:10.1007/s10067-025-07420-0.
PMID: 40146446
9
Free IL-18 in NLRC4-associated autoinflammatory disease without macrophage activation syndrome.
Willemsen M, Schoonbrood THM, Rodriguez E, et al.
Rheumatology (Oxford, England) 2026; (65(7)) doi:10.1093/rheumatology/keag363.
PMID: 42444142

This page is for informational purposes only and does not constitute medical advice about AIFEC. Use your child’s individualized emergency plan and contact the treating team or emergency services for urgent concerns.