Consider Chronic Granulomatous Disease Diagnosis in Children With HLH

Consider Chronic Granulomatous Disease Diagnosis in Children With HLH

Physicians should consider chronic granulomatous disease (CGD) in infants and children who present with hemophagocytic lymphohistiocytosis (HLH), as the latter can sometimes mask the former, according to a recent study.

Recognizing HLH in a feverish child is important in determining the appropriate immunosuppressive therapy. Best treatment strategies for such patients, however, are not well-understood.

The study, “Hemophagocytic lymphohistiocytosis in children with Chronic Granulomatous Disease – Single center experience from North India,” was published in The Journal of Allergy and Clinical Immunology: In Practice.

CGD is an inherited immune disorder caused by defects in the NADPH protein and mutations in the CYBB gene, which make patients more susceptible to bacterial and fungal infections. Repeated infections increase the risk of developing HLH.

HLH is a rare and life-threatening disease, in which natural killer and cytotoxic T-cells — two types of immune-related white blood cells — damage organs.

HLH can present as an inflammatory complication of CGD, but “optimal management strategies have not yet been identified in children with CGD who develop HLH,” wrote the researchers who conducted the study at the Postgraduate Institute of Medical Education and Research, in Chandigarh, India.

The team reviewed records of children diagnosed with CGD in a care center in North India for the past 20 years to analyze features of HLH in those who had both conditions.

Of 80 children at the center diagnosed with CGD, five also had HLH. All were boys, with a median age at CGD diagnosis of 2 months. Two of the children first presented with HLH.

All five patients showed clinical and laboratory signs of HLH, such as prolonged fever, elevated iron and triglycerides (a type of fat) levels, decreasing blood counts, and evidence of hemophagocytosis, a disorder in which blood cells attack other blood cells in the bone marrow.

Knowing what triggers a patient’s HLH affects the treatment strategy. In this case series, triggers identified by researchers consisted of microbial infections in three children, pneumonia in four children, and abscesses in the spleen in one child.

Fungal and/or bacterial infections included Candida albicans, a common fungal infection, and Burkholderia cenocepacia, an opportunistic bacteria. One child became infected with a bacteria called Francisella noatuensis,  known to infect only fish.

That boy, an 8-year-old with a known diagnosis of CGD, had been asymptomatic until a family trip to the beach shortly before arriving at the hospital. Despite treatment with broad spectrum antibiotics and antifungals, his respiratory distress worsened to the extent that he was transferred to an intensive care unit.

Lab findings showed evidence of HLH and a blood culture revealed an infection by Francisella noatunensis. The patient was given intravenous doxycycline and gentamicin — both are antibiotics — over two weeks, and antibodies and corticosteroids for five days, followed by a tapering dose of oral steroids for six weeks.

The boy responded well to the treatment and was discharged from hospital, having remained asymptomatic at one year follow-up, with no recurrence of HLH.

According to the team, this was the first recorded instance of human infection by Francisella noatunensis.

The two children who presented first with HLH both succumbed to their conditions. They were diagnosed with CGD after worsening HLH symptoms led doctors to suspect it.

Based on those case reports, the team argued for HLH to be considered in children with CGD who show broad dysfunction and progressively declining blood counts. Furthermore, physicians should consider testing for CGD in children with HLH, particularly when they have infections and a family history suggestive of the disorder.

“HLH can be a presenting manifestation of CGD, and workup for CGD must be considered in children with HLH,” the researchers wrote.

“Early recognition of HLH and infective triggers with timely institution of appropriate antimicrobials and immunosuppressive therapy are essential to prevent mortality,” they concluded.

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