The description of these two cases, with different clinical and therapeutic outcomes, intends to reinforce the concept of HLH as an important diagnostic consideration in cases of fever of unknown origin4
as well as a possible cause of multiorgan failure syndrome,5
as it has been recently described.
Familial haemophagocytic lymphohistiocytosis (FHLH) is a group of genetically determined diseases, with an estimated incidence of 1:50 000 live births.6
Most cases (85%) occur within the first year of age, with 70% occurring before 6 months; however, late onset cases have also been described.1
As an autosomal recessive disease, it is more frequent in ethnic groups where consanguineous marriages are common,2
but despite its name, family history is often negative. Both our cases occurred in early infancy (the first after the first year) and in non-consanguineous families, with no past positive medical history.
Currently, there are four known forms of FHLH, three with causative genetic defects identified: mutations in the genes encoding for perforin (PRF1
, and syntaxin 11 (STX-11
). All of these proteins are involved in cellular cytotoxicity mediated by NK and T cells.1
These mutations interrupt the exocytotic process of polarisation, docking, priming, and fusion in NK/cytotoxic T cells, leading to defective cytotoxicity and subsequently HLH.7
Genetic analysis of children with primary HLH reveals a frequency of mutations around 30% to PRF, 20% to UNC3D and 10% to STX11, with approximately 40% of the patients not having a known genetic defect.7
According to the literature, the double heterozygosity for MUNC 13-4 identified in the second case had not been previously described.
Also, a rare finding in the first case was myelofibrosis on bone marrow biopsy and autoimmune haemolytic anaemia (AIHA), both previously described in association with HLH.8–10
Myelofibrosis in childhood may be primary or secondary to infections, drugs, toxins, autoimmune conditions, malignancies and trauma. However, it is most often associated with haematologic malignancies. The underlying mechanisms of bone marrow fibrosis are not fully understood, but evidence suggests that it is mediated through numerous cytokines and growth factors. Thus, the development of reversible (with immunosuppressive therapy) myelofibrosis in HLH (as it happened in our case) is conceivable in the setting of a hyperinflammatory state.8
In our case, myelofibrosis may be a primary effect of HLH, or secondary to a precipitating infectious agent such as HSV6 or autoimmunity. The cytokine overproduction in HLH might also be responsible for AIHA, since the mononuclear phagocytic system participates in the destruction of opsonised erythrocytes.10
Due to non-specific symptoms and signs, the diagnosis of HLH is difficult, and although the initial clinical presentation is highly variable, prolonged fever (up to 100%) and hepatosplenomegaly (30–90%) are the most frequent signs.4,11
In these two cases, these signs were present from the onset of the disease. The main differential diagnosis is a normal infection in an immune competent patient, but it is the severity and progression of symptoms that are important for differentiation.2
When a patient presents with prolonged fever unresponsive to antibiotics, hepatosplenomegaly and cytopenias, HLH should be considered. There is evidence that some patients do not meet all the diagnostic criteria and that many patients do so only late in the course of the disease, as in case 1, with five of eight criteria presenting only 44 days after the onset of disease. Furthermore, patients with a molecular diagnosis consistent with HLH do not need to fulfil the diagnosis criteria to start adequate therapy.3
FHLH is a fatal disease with a median survival of <2 months after diagnosis if untreated; mortality occurs mainly as a result of haemorrhage or opportunistic infections,12
but is also due to multiorgan failure.
The immediate aim in treatment is to suppress severe hyperinflammation, using drugs that neutralise the functions of activated macrophages/histiocytes and T cells.13
Current treatment includes chemotherapeutic (etoposide) regimens in association with dexamethasone and ciclosporin A.3
The second aim is to remove the infectious stimulus for the ongoing activation of cytotoxic cells; however, appropriate antimicrobial treatment will only sometimes modify the course of the disease. The ultimate aim is stem cell transplantation to correct the defective immune system by providing normally functioning cells. At present, HSCT is the only curative treatment, and partial chimerism appears to be sufficient to prevent reactivation of HLH in most cases.1
The follow-up study of HSCT in children treated with protocol HLH-94 revealed that marrow transplantation using matched related or unrelated donors offers a similar long term disease-free outcome (approximately 70% at 3 years). However, the success of HSCT depends on the extent of control of HLH before transplantation.1,13
Despite reactivation of HLH on the third week of protocol HLH-04, HSCT from a matched sibling was performed successfully in our first case.
The clinical outcome in HLH patients often depends on how fast and accurately the diagnosis is established. Therefore awareness of the clinical symptoms and diagnostic criteria is crucial to start appropriate therapy, which has changed the prognosis from uniformly fatal to a cure rate of >50%.2
- In cases of prolonged fever unresponsive to antibiotics, hepatosplenomegaly and cytopenias, haemophagocytic lymphohistiocytosis (HLH) should be considered.
- HLH might present as multiple organ dysfunction syndrome.
- It is important that paediatricians and paediatric intensivists know about the diagnostic criteria and possible clinical presentations of HLH so that treatment is promptly initiated
- Haematopoietic stem cell transplantation is the only curative treatment.