This case study describes diagnosis and treatment performed in the HLH Center at Cincinnati Children’s. A 2-year-old girl was referred to us from the United Arab Emirates with a history of relapsing HLH.

Clinical History

At 18 months of age, the patient presented with fevers, skin rashes, irritability and loss of appetite. Soon after admission to the local hospital, she developed respiratory distress and severe swelling requiring mechanical ventilation and hemodialysis. She was found to be in liver failure with pancytopenia and persistently elevated blood markers of inflammation.

A bone marrow biopsy revealed hemophagocytosis (bone marrow cells “eating” normal blood cells). Treatment was started with steroids and chemotherapy. Although some symptoms improved initially, her condition worsened one month later, and a recurrence of active HLH followed soon after. The disease had spread to involve the brain.

Our Approach

Soon after, the family came to Cincinnati for additional diagnostic testing and curative treatment with hematopoietic stem cell transplantation (HSCT). Her siblings appeared to be suitable candidate donors based on preliminary data regarding their HLA type. However, not enough was known about a possible genetic cause of her disease. The possibility still existed that one of her siblings could also harbor a genetic defect and be at risk of developing HLH.

Our Diagnostic Immunology Laboratory (DIL) and the Molecular Genetics Laboratory at Cincinnati Children’s were involved in confirming an exact diagnosis. These clinical laboratories are the only ones in North America that can test for all known genetic causes of HLH. The causal gene defect was identified in the sick child and her siblings were found to be free of the disease. The patient’s older brother was identified as the best possible bone marrow donor.

In the meantime, the patient required ongoing intravenous chemotherapy, high-dose steroids, as well as intrathecal (directly into the spinal fluid) chemotherapy to control the HLH in her brain. She required months of high-dose steroid treatment which resulted in significant weight gain (Cushingoid changes), contributing to poor mobility, bed sores and heightened risk of infections.

The HSCT was performed at 2 years of age. Due to the patient’s condition, we used a reduced intensity conditioning (RIC) of pre-transplant chemotherapy. Studies performed at Cincinnati Children’s comparing outcomes of RIC vs. conventionally dosed chemotherapy prior to HSCT for HLH have shown that post-transplant survival following RIC is superior to the conventional approaches to pre-transplant chemotherapy (90 percent vs. 50 percent long-term disease-free survival).

Our patient achieved a full recovery with normal brain function in a matter of months despite still requiring intrathecal chemotherapy post HSCT. She was able to return to the U.A.E. before her third birthday, cured of HLH. A follow-up visit to Cincinnati Children’s one year later revealed her to be svelte and energetic – a normal, happy child.

Summary

Our patient was fortunate to have a suitable sibling donor for HSCT. However, not all patients with HLH will have suitable transplant donors. Therefore, our research is exploring alternative transplant strategies for these children. Additionally, current researchers at our facility are investigating novel agents that offer alternative pathways to cure or provide adequate long-term disease control. New biological agents have been developed that block the pro-inflammatory proteins, such as interferon gamma, which are significantly elevated in HLH:

Additional molecular studies are under way to unravel the complex immunology of active HLH disease in order to identify other targeted biologic agents with fewer side effects.

Once universally lethal, HLH is now curable.