Pediatric Secondary Hemophagocytic Lymphohistiocytosis

What is pediatric secondary hemophagocytic lymphohistiocytosis?

Pediatric secondary hemophagocytic lymphohistiocytosis (often shortened to secondary HLH) is a rare but serious condition in which a child’s immune system becomes dangerously overactive. Instead of switching off after fighting an infection or another threat, certain white blood cells keep multiplying and releasing large amounts of inflammatory chemicals called cytokines. This is sometimes described as a cytokine storm. The overactive cells can also begin to engulf, or eat, healthy blood cells, which is where the word hemophagocytic (blood-cell eating) comes from. Lymphohistiocytosis refers to the two main cell types involved: lymphocytes and histiocytes, which are both part of the immune system.

Doctors divide HLH into two broad groups. Primary, or familial, HLH is caused by an inherited genetic change and most often appears in infants. Secondary, or acquired, HLH develops in a child who does not have a known inherited cause but whose immune system is pushed into overdrive by a trigger, such as a severe infection, a cancer, or an autoimmune disease. Secondary HLH can occur at any age in childhood, from toddlers to teenagers, and it is generally more common than the inherited form in older children. The line between the two types is not always sharp, because some children with secondary HLH are later found to carry genetic changes that made them more vulnerable.

Because the condition affects the blood, the bone marrow, the liver, the spleen and sometimes the brain, care usually involves a team of specialists. In many hospitals, including Acibadem, a pediatric hematologist (a doctor who specializes in blood disorders in children) coordinates diagnosis and treatment, often working with infectious disease, rheumatology, intensive care and oncology teams.

Pediatric secondary hemophagocytic lymphohistiocytosis symptoms

Pediatric secondary hemophagocytic lymphohistiocytosis symptoms can look very much like a severe infection, which is one reason the condition is easy to miss at first. The key difference is that the child does not improve, or gets worse, despite treatment that would normally help. Common signs include:

• Persistent high fever that lasts for many days and does not respond well to fever medicine or antibiotics
• Enlarged spleen (splenomegaly), which a doctor may feel as fullness in the upper left abdomen
• Enlarged liver (hepatomegaly), sometimes with yellowing of the skin or eyes (jaundice)
• Swollen lymph nodes in the neck, armpits or groin
• Unusual paleness, tiredness and weakness caused by a low red blood cell count (anemia)
• Easy bruising, nosebleeds or bleeding gums caused by a low platelet count
• Skin rash, which may be patchy, red or purple
• Poor feeding, vomiting or diarrhea, especially in younger children
• Swelling of the legs, face or abdomen (edema) from fluid leaking out of blood vessels
• Neurological changes, such as unusual drowsiness, irritability, confusion, seizures or problems with balance

Early in the illness, fever and general unwellness may be the only noticeable features. As the inflammation progresses, blood counts tend to fall, the liver and spleen enlarge, and problems with blood clotting can appear. In the later or most severe stage, several organs may begin to fail at once, and the child may need intensive care to support breathing, blood pressure and kidney function. Not every child has every symptom, and the pattern can differ depending on the trigger. For example, when HLH develops in a child with a rheumatologic disease such as systemic juvenile idiopathic arthritis, doctors often use the term macrophage activation syndrome (MAS), and joint pain or a characteristic rash may be prominent.

Causes and risk factors

Pediatric secondary hemophagocytic lymphohistiocytosis causes are usually described as triggers, because the underlying problem is an immune response that fails to shut down. The most frequently identified triggers in children are:

• Infections. Viruses are the most common trigger. Epstein-Barr virus (EBV, the virus that causes infectious mononucleosis or glandular fever) is the single most frequently linked infection, but cytomegalovirus, other herpes viruses, influenza, adenovirus and many other viruses have been reported. Bacterial, fungal and parasitic infections, including tuberculosis and leishmaniasis in some regions, can also trigger HLH.
• Cancers. Certain blood cancers, particularly lymphomas and some leukemias, can set off HLH. In children this is less common than infection-related HLH, but it is important because the treatment plan is different.
• Autoimmune and autoinflammatory diseases. Conditions in which the immune system attacks the body, such as systemic juvenile idiopathic arthritis, systemic lupus erythematosus (lupus) and Kawasaki disease, can be complicated by HLH. In these settings it is often called macrophage activation syndrome.
• Immune deficiency. Children whose immune systems are already weakened, whether by an inherited immune disorder, HIV infection or medicines that suppress immunity after a transplant, are at higher risk.
• Medicines and treatments. Rarely, some drugs and newer cancer immunotherapies can provoke an HLH-like reaction.

Risk factors include having one of the conditions listed above, being on long-term immune-suppressing medication, and having a family history of HLH or of unexplained severe illness in infancy. Some children who develop secondary HLH after an infection are found to have subtle inherited changes in genes that control how immune cells switch off. These changes may not cause disease on their own but can lower the threshold at which a trigger sets off HLH. Because of this overlap, genetic testing is often part of the workup even when a clear trigger is found.

Pediatric secondary hemophagocytic lymphohistiocytosis diagnosis

Pediatric secondary hemophagocytic lymphohistiocytosis diagnosis is challenging because no single test proves the condition. Doctors instead look for a combination of clinical findings and laboratory results, and they weigh these against other possible explanations such as sepsis (a severe bloodstream infection) or leukemia. Most centers use internationally recognized diagnostic criteria, which require a set number of features to be present. These features include:

• Fever that is persistent and unexplained
• Enlarged spleen, found on physical examination or ultrasound
• Low blood counts affecting at least two of the three main cell lines: red blood cells, white blood cells and platelets
• Abnormal blood fats or clotting proteins, specifically high triglycerides (a type of fat) or low fibrinogen (a protein needed for clotting)
• Hemophagocytosis, meaning immune cells seen engulfing blood cells in a sample of bone marrow, spleen, liver or lymph node
• Very high ferritin, a protein that stores iron and rises sharply during severe inflammation
• Low or absent natural killer (NK) cell activity, measured in a specialized immunology laboratory
• Elevated soluble CD25 (also called soluble interleukin-2 receptor), a marker of T-cell activation

To gather this information, your child’s doctors may order a complete blood count, liver function tests, kidney tests, clotting studies, and blood levels of ferritin, triglycerides and fibrinogen. A bone marrow aspirate and biopsy, in which a small sample of marrow is drawn from the hip bone under sedation, is commonly performed both to look for hemophagocytosis and to rule out leukemia or lymphoma. Imaging such as abdominal ultrasound checks the size of the liver and spleen, while a chest X-ray or CT scan may be used to look for infection or enlarged lymph nodes. If there are neurological symptoms, an MRI of the brain and a lumbar puncture (a sample of spinal fluid taken from the lower back) may be recommended.

Searching for the trigger is a central part of the diagnostic process. This usually involves testing blood and other samples for EBV, cytomegalovirus and other infections, checking for signs of autoimmune disease, and, when indicated, biopsies to look for cancer. Genetic testing for the known HLH-related genes is often sent at the same time, because the results influence long-term decisions, including whether a stem cell transplant might eventually be needed. Because results from some specialized tests take time, treatment is frequently started before every test has returned when the clinical picture strongly suggests HLH.

Pediatric secondary hemophagocytic lymphohistiocytosis treatment

Pediatric secondary hemophagocytic lymphohistiocytosis treatment has two main goals: to calm the overactive immune system quickly so that it stops damaging organs, and to identify and treat the underlying trigger. Watchful waiting alone is generally not an option, because untreated HLH can worsen rapidly. The specific plan depends on how sick the child is, what the trigger is thought to be, and how the child responds to initial therapy. Options your child’s team may discuss include:

• Corticosteroids. High-dose steroids such as dexamethasone are usually the first step. They dampen inflammation across the whole immune system and often produce improvement within days.
• Chemotherapy-type medicines. Etoposide, a drug originally developed for cancer, is a core part of standard HLH protocols because it removes the overactivated immune cells. It is typically given in courses over several weeks, with the intensity adjusted to the child’s response.
• Other immune-modulating drugs. Cyclosporine, intravenous immunoglobulin (IVIG, a purified antibody product) and biologic medicines that block specific cytokines may be used. Anakinra, which blocks interleukin-1, is often chosen when HLH is linked to a rheumatologic disease. Emapalumab, an antibody that blocks interferon gamma, is an option in some situations, particularly when standard treatment has not worked.
• Treatment of the trigger. This may mean antiviral or antibiotic medicines for an infection, rituximab (an antibody that removes B cells) for EBV-driven disease, cancer treatment for a lymphoma or leukemia, or adjustment of therapy for an underlying autoimmune condition.
• Therapy directed at the brain and spinal cord. If spinal fluid tests or MRI show that HLH is affecting the nervous system, medicine may be injected directly into the spinal fluid (intrathecal therapy).
• Supportive care. Many children need transfusions of red blood cells, platelets or clotting factors, treatment for infections that take advantage of the weakened immune system, nutritional support and, in severe cases, intensive care.
• Hematopoietic stem cell transplant. A transplant of blood-forming stem cells from a donor essentially replaces the child’s immune system. It is not usually needed for secondary HLH that responds well to treatment and has a clear, treatable trigger. It may be recommended when HLH keeps coming back, does not respond to medicines, or when genetic testing shows a change that makes recurrence likely.

There is no surgery that treats HLH itself, although procedures such as bone marrow biopsy, placement of a central venous line for medicines and, rarely, biopsy of the spleen or lymph nodes are part of care. After the acute illness, some children benefit from rehabilitation, including physical therapy to rebuild strength after a long hospital stay and neurological follow-up if the brain was involved. Treatment for pediatric HLH is complex and is generally managed in a specialized center; at Acibadem, this falls under the Hematology Department working alongside pediatric intensive care and other subspecialties.

Living with pediatric secondary hemophagocytic lymphohistiocytosis and outlook

The outlook for a child with secondary HLH depends heavily on how early the condition is recognized, what triggered it, and how well the inflammation responds to treatment. Without treatment, HLH is life-threatening. With prompt therapy, many children with infection-triggered or rheumatology-associated HLH recover fully once the inflammation settles and the trigger is controlled. Outcomes tend to be more guarded when HLH is associated with cancer, when organ damage is already advanced at diagnosis, or when the disease does not respond to first-line medicines. Your child’s team can give you the most realistic picture for your specific situation, and honest uncertainty is a normal part of these conversations.

Recovery is often gradual. Hospital stays can last weeks, and children may feel weak, lose weight and fall behind in school during this time. Steroids and other medicines can cause side effects such as mood changes, increased appetite, high blood sugar, high blood pressure and a greater risk of infection, most of which improve as doses are reduced. Regular follow-up blood tests are usually needed for months to watch for relapse, which is possible even after apparent recovery. Families are often asked to watch for the return of fever or other early warning signs and to seek care quickly if they appear.

Children who required a stem cell transplant face a longer recovery and additional monitoring for complications. Those found to carry a genetic predisposition may be offered genetic counseling for the whole family. Emotional support matters as well; a sudden, severe illness is frightening for children and parents alike, and psychological support, school liaison and connection with patient support organizations can be valuable parts of the recovery process.

Frequently asked questions

What is the difference between primary and pediatric secondary hemophagocytic lymphohistiocytosis?

Primary HLH is caused by an inherited genetic change that prevents immune cells from switching off, and it most often appears in infancy. Secondary HLH develops when a trigger such as an infection, a cancer or an autoimmune disease provokes the same kind of uncontrolled immune response in a child without a known inherited cause. In practice the two can overlap, so doctors usually recommend genetic testing even when a trigger is identified.

What are the first pediatric secondary hemophagocytic lymphohistiocytosis symptoms parents might notice?

The earliest sign is usually a high fever that persists for many days and does not settle with standard treatment. Parents may also notice unusual tiredness, pale skin, a swollen belly, easy bruising or a rash. Because these features overlap with common childhood infections, HLH is generally suspected only when a child fails to improve or worsens despite appropriate care.

What are the most common pediatric secondary hemophagocytic lymphohistiocytosis causes?

Infections are the most frequent trigger in children, with Epstein-Barr virus the best-known example. Other viruses, some bacteria and parasites, blood cancers such as lymphoma, and autoimmune diseases such as systemic juvenile idiopathic arthritis and lupus are also recognized causes. In some cases no clear trigger is ever found, even after thorough testing.

How is pediatric secondary hemophagocytic lymphohistiocytosis diagnosis confirmed?

There is no single confirmatory test. Doctors use a combination of clinical findings, such as fever and an enlarged spleen, and laboratory results, such as low blood counts, very high ferritin, abnormal triglycerides or fibrinogen, and signs of hemophagocytosis in bone marrow. Specialized immune tests and genetic testing are often added, and testing for the underlying trigger runs in parallel.

Is pediatric secondary hemophagocytic lymphohistiocytosis treatment always chemotherapy?

Not always. High-dose steroids are the usual first step, and etoposide, a chemotherapy-type drug, is part of standard protocols for many children. However, some children, especially those whose HLH is linked to a rheumatologic disease, are treated mainly with steroids and targeted biologic medicines. The plan is tailored to the trigger, the severity of illness and how the child responds.

Can pediatric secondary hemophagocytic lymphohistiocytosis come back after treatment?

Yes, relapse is possible, particularly if the trigger has not been fully controlled or if the child carries a genetic predisposition. This is why follow-up blood tests continue for months after recovery and why families are asked to report new fevers promptly. Children with repeated episodes or a confirmed genetic cause may be considered for a stem cell transplant.

Is pediatric secondary hemophagocytic lymphohistiocytosis contagious?

HLH itself is not contagious. It is an abnormal immune reaction, not an infection. However, some of the infections that trigger it, such as Epstein-Barr virus, can spread from person to person. Only a very small proportion of children who catch these common infections go on to develop HLH.

When to see a doctor

Any child with a fever that lasts more than a few days without a clear cause, or who seems to be getting sicker rather than better, should be assessed by a doctor. If your child has already been diagnosed with HLH or is recovering from it, follow the monitoring plan given by the treating team and report new symptoms early. Seek emergency care immediately if a child shows any of the following red-flag signs:

• High fever together with extreme drowsiness, difficulty waking, or confusion
• A seizure, or new weakness, stiffness of the neck or severe headache
• Difficulty breathing, rapid breathing or bluish lips
• Widespread bruising, a purple or red rash that does not fade when pressed, or bleeding that will not stop
• Yellowing of the skin or eyes together with a swollen or painful abdomen
• Very pale or gray skin, cold hands and feet, or a very fast heartbeat
• Refusal to drink, no urine for many hours, or signs of dehydration
• A return of fever in a child who is being treated for or has recently recovered from HLH

Pediatric secondary hemophagocytic lymphohistiocytosis can progress quickly, and early recognition is one of the most important factors in a child’s recovery. When in doubt, it is safer to have a child evaluated promptly than to wait.