Haemophagocytic lymphohistiocytosis (HLH) is a rare, but potentially fatal, disease that occurs when normal histiocytes and lymphocytes become overactive and commonly occurs in infancy, although it has been reported in all age groups.1,2 The initial presentation of HLH is often comprises fever, hepatosplenomegaly, pancytopenia, lymphadenopathy and a rash.
Cutaneous involvement of HLH occurs in as many as 65% of patients, with various skin manifestations having been reported, including erythroderma, generalized purpuric macules and papules, and morbilliform eruptions.3 Detection of cutaneous involvement can assist in the initial diagnosis of HLH and potentially signify recurrences.
Primary HLH [i.e. familial erythrophagocytic lymphohistiocytosis (FEL)] is defined as an inherited form of HLH and is a heterogeneous autosomal recessive disorder that has been found to be more prevalent in cases of parental consanguinity. Secondary HLH (i.e. acquired HLH) occurs as a result of strong immunological activation, such as that which can occur because of systemic infection, immunodeficiency or underlying malignancy. Both forms of HLH are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematological alterations and, if untreated, death of the patient.4
We report on Kuwaiti twins who were less than 2 years old at the time of the presentation. The first twin, a female, presented at 20 months of age with fever, neck swelling, abdominal distension and a skin rash that had been present for 1 week. In addition, she also showed a poor intake of food, resulting in weight loss, lethargy and pallor.
The patient's history showed that she was a born to consanguineous parents and her mother was diabetic and also suffered from hypothyroidism, but was being treated for both. The patient was born prematurely at 36 weeks' gestation but the delivery was normal. The patient's birthweight was 2.3 kg and she had a history of seborrhoeic dermatitis since birth. The patient's twin and younger sister displayed almost the same clinical presentation.
On examination, the patient was febrile, irritable, pallid and emaciated with poor activity. Bilateral cervical lymphadenopathy was present as defined by large, tender and palpable cervical lymph nodes. The small inguinal lymph nodes were also bilaterally palpable. Hepatosplenomegaly, ascites and a purpuric rash were present all over the patient's body and a follicular erythematous rash was present all over the scalp.
Investigations revealed leucocytosis, thrombocytopenia, anaemia and high serum triglyceride and ferritin levels. The C-reactive protein test was positive, which, in combination with the clinical presentation and the leucocytosis, indicated an acute infection. This was expected as HLH can compromise the immune system. The patient was also found to have elevated liver enzymes.
The second twin presented 1 month after the first with an intermittent fever which had been present for 6 days, a maculopapular skin rash, a small purpuric skin rash on the trunk and thighs as well as congestion of the throat and swelling of the lips.
The patient had a history of bilateral otitis media with bleeding from the right ear. On examination, the patient was febrile, irritable, thin and her height and weight were both below the fifth centile for age. The right eardrum was perforated with purulent bloody discharge and the abdomen was distended with hepatosplenomegaly. The skin rash present on the trunk and thighs did not fade when pressure was applied, which is characteristic of a purpuric rash.
Like her twin, the results of various tests revealed thrombocytopenia, anaemia and high serum triglyceride and ferritin levels. The C-reactive protein test was positive, which, in combination with the clinical presentation and the leucocytosis, indicated an acute infection. This was expected as HLH can compromise the immune system. The patient was also found to have elevated liver enzymes. An ear-swab culture showed a heavy growth of Morganella morganii.
Bone marrow aspiration was performed in both twins and in both cases showed infiltration of the bone marrow with histiocyte-like cells that were S-100 and CD68 positive.
In view of the clinical presentation and the bone marrow pathological results in both twins, the patients were diagnosed as having HLH and treated accordingly. In addition to prescribing antibiotics for the bacterial infection present in both patients, they were kept under close observation and requested to attend follow-up sessions in the outpatient department of Hatta Hospital until clinical improvement could be detected.
Primary HLH (i.e. FEL) is defined as an inherited form of HLH and is a heterogeneous autosomal recessive disorder that has been found to be more prevalent in the children of consanguineous parents. Secondary HLH (i.e. acquired HLH) is the result of strong immunological activation, such as that which can occur alongside systemic infection, immunodeficiency or underlying malignancy. Both forms of HLH are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematological alterations and, if not treated, death of the patient.4
The pathological hallmark of this disease is the aggressive proliferation of activated macrophages and histiocytes, which phagocytose other cells (namely red blood cells, white blood cells and platelets), leading to the clinical symptoms of HLH. The uncontrolled proliferation of activated macrophages and histiocytes is not malignant and does not appear clonal, in contrast to the lineage of cells in Langerhans' cell histiocytosis. The spleen, lymph nodes, bone marrow, liver, skin and membranes that surround the brain and spinal cord are preferential sites for HLH involvement.5
A currently accepted in theory is that an inappropriate immune reaction caused by the proliferating and activated T cells results in macrophage activation and inadequate apoptosis of immunogenic cells, leading to HLH.6 Although the precise mechanism behind the occurrence of HLH remains unclear, many researchers have offered convincing reports for the role of perforin and natural killer cells in the manifestation of both primary and secondary HLH.7
The age at onset of primary HLH is usually before 1 year; however, the onset of secondary HLH can be later and usually occurs after 6 years of age. Although the primary form of the disease frequently affects infants from birth to 18 months of age,6 it has been reported in individuals as old as 8 years, and adult onset has been also reported.1,2
The diagnostic criteria enforced by the International Registry for HLH11 are given below; all five criteria must be met to establish a diagnosis of HLH:
fever – ≥7 days of a temperature as high as 38.5°C (101.3°F);
splenomegaly – a palpable spleen greater than 3 cm below the costal margin;
cytopenia – counts below the specified range for at least two of the following:
hypofibrinogenaemia or hypertriglyceridaemia – fibrinogen at a level of < 1.5 g/l or more than 3 SD below the age-adjusted reference range value, or fasting triglycerides at a level of > 2 mmol/l or more than 3 SD above the age-adjusted reference range value;
haemophagocytosis – tissue from the lymph nodes, spleen or bone marrow that does not show evidence of malignancy.
Other symptoms found in patients suffering from HLH are swollen or haemorrhagic gums, which can result in tooth loss, feeding problems (especially prominent in infants), abdominal pain, vomiting, diarrhoea, weight loss and a skin rash. A rash is found in more than half of patients and can present in a several ways, such as scaly and waxy lesions or rashes on the scalp and behind the ear. The skin can be involved in HLH in various ways and this is best characterized clinically as erythroderma, generalized purpuric macules and papules, or morbilliform eruptions.
One Swedish study reported that nearly 75% of patients suffering from HLH had some form of CNS involvement, with half showing neurological symptoms including seizures, ataxia, hemiplegia, mental status changes or simply irritability.10 Because of the predilection of the disease for certain tissues, such as the lymph nodes, lymphadenopathy is commonly found during physical examination. Other common findings, such as malaise, anorexia (with or without weight loss) and failure to thrive, have been reported.11 Findings in up to two-thirds of initial bone marrow aspirates may be non-diagnostic; therefore, a negative examination may not rule out HLH. Additional tests, including a lymph node biopsy, should be performed and treatment should not be delayed if all other criteria have been met.12 Although problematic in a patient with a coagulopathy, a liver biopsy providing results that would be expected in a case of chronic persistent hepatitis can support the diagnosis of HLH, as can the presence of mononuclear cells in the cerebrospinal fluid (CSF).
The initial therapy for patients with HLH consists of etoposide plus dexamethasone for 8 weeks. In the HLH-2004 protocol,13 it was recommended that cyclosporine be added at the start of treatment. Intrathecal methotrexate is used only as a treatment for cases with persistently abnormal CSF or progressive neurological symptoms. Resolved non-familial HLH does not require continuation of the therapy regime unless disease reactivation occurs after completion of the initial therapy, or unless patients are undergoing bone marrow transplantation. The remaining patients with either persistent non-familial HLH or the familial form of the disease should continue with therapy of intravenous etoposide infusions and dexamethasone pulses, and oral cyclosporine should be initiated at week 9 of treatment.14 HLH associated with malignancies demands prompt therapy directed at the neoplasm.
Bone marrow transplantation is performed if a suitable donor can be found and the patient is stable. A recent study reported on a group of patients given reduced-intensity conditioned treatment before stem cell transplantation from a matched family, unrelated or haploidentical donor.15 A total of 84% of patients with HLH were in remission at a median of 36 months following stem cell transplantation.15 In another study, reduced-intensity conditioned treatment was successful for 96% of patients.16 Reduced-intensity conditioned treatment compares favourably with conventional stem cell transplantation and provides long-term disease control in surviving patients with HLH.15 If the patient is experiencing life-threatening respiratory difficulties or uncontrolled hypersplenism, then splenectomy is an option.
Although the prognosis varies between studies and with different approaches to the treatment, HLH is invariably fatal if not treated. Patients suffering from HLH are at a high risk of early death and the median survival rate has been reported to be 2–6 months without treatment. However, steroids or intravenous immunoglobulin, or both, can be prescribed as a first-line therapy and may be sufficient to preserve life.17
Familial HLH is a rare disease that can affect several members of the same family, as seen with the twins in the case report discussed above. The diagnosis of HLH can be very difficult if it is not suspected from the beginning. Familial HLH can present in various non-specific forms and all paediatricians should consider rare diseases such as HLH if the clinical presentation does not fit a familiar and common disease.