P - ISSN : 2349-6592    |    E - ISSN : 2455-7099
Year : 2016 | Volume : 3 | Issue : 4 | Page : :112-114
Source of Funding:None Conflict of Interest:None
Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disease caused by uninhibited hyperinflammatory reaction that can lead to fulminant, life threatening multi organ failure and whose pathophysiology and clinical characteristics are somehow similar to that of severe sepsis and septic shock. Here we present a case of a 5 months old baby, admitted in our PICU in shock and was being managed initially in the lines of septic shock but ultimately was diagnosed to be a case of Familial HLH type 2 due to a homozygous missense variation in exon 2 of the PRF1 gene that results in the amino acid substitution of Serine for Tryptophan at codon 129.
Key Words: HLH, Infant, Septic Shock, Fulminant
Septic shock is one of the leading causes of death in an ICU setting. The spectrum of sepsis ranges from microbial invasion of the bloodstream or intoxication with early signs of circulatory compromise—including tachycardia, tachypnea, peripheral vasodilation, and fever (or hypothermia)—to full-blown circulatory collapse with multiple organ dysfunction syndrome (MODS) and death. Elevations of pro-inflammatory cytokines during sepsis and septic shock have been identified including interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-18, interferon gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α) similar to that found in HLH.
HLH is a rare disorder characterized by widespread accumulation of lymphocytes and mature macrophages, sometimes with hemophagocytosis, primarily involving the spleen, lymph nodes, bone marrow, liver and cerebrospinal fluid1. The hallmark of HLH is an uncontrolled hyperinflammation, caused by unremitting activation of CD8+ T cells and macrophages, and excessive levels of cytokines2 similar to that in severe sepsis. The symptoms and signs may vary widely, but the most typical findings are prolonged fever, hepatosplenomegaly and cytopenias3. It can be either primary (genetic) or secondary (acquired). Secondary HLH may follow infections(Infecion associated HLH/IAHLH), autoimmune diseases (macrophage activation syndrome-MAS) or lymphoproliferative disorders, while primary HLH may be familial (FHL) or associated with primary immunodeficiency 4. FHL usually manifests in early infancy but can present at any age, and may follow an infectious trigger, like secondary HLH5, 6. Without treatment, FHL is invariably fatal, with a median survival of 2 months after diagnosis7, 8. Common genetic mutations associated with FHL are mutations in gene PRF-1 (FHL2), UNC13D (FHL3), STX11 (FHL4) and STXBP2 (FHL5). Our patient, a 5 month old male baby presented with characteristic clinical and laboratory features of septic shock and was ultimately found to be a case of FHLH2 being positive for the PRF1 gene mutation and ultimately succumbed just after 8 hours of admission.
A 5 month 15 day old, male baby, born of a non-consanguineous marriage, in a Hindu, Indian family, had an uneventful 1st 5 months of life. He developed fever with cough at the age of 5 month 6 days and was admitted in a hospital the next day as he refused to feed and became lethargic. There, he was diagnosed as sepsis, and started on IV antibiotics. On day 3 of fever, the child developed loose watery stool along with vomiting associated with decreased urine output. Even after 7 days of antibiotics, the baby’s condition kept deteriorating, so, he was referred to us. On admission, the baby was in shock with a weak pulse and cold, clammy extremities, had icterus and pallor along with hepatosplenomegaly, and a distended abdomen. The child was given multiple boluses of IV fluids without any improvement. Ionotropes were started and the child was given first dose of broad spectrum antibiotics(MEROPENEM & VANCOMCIN) along with other supportive measures. Initial blood investigations revealed a total WBC count of 4300/mm3 (45% neutrophils,52% lymphocytes) with haemoglobin 6.8gm/dl and a platelet count of 7000/mm3.CRP was 97mg/L( normal <6), Procalcitonin level was 54.22. LFT was deranged with a grossly abnormal coagulation profile (PT > 60 seconds, APTT > 120 seconds). 4 units platelets and 2 units fresh frozen plasma were transfused. A HLH panel of investigations were also sent to rule out the disease as there was unusual huge organomegaly ,icterus and cytopenias . Reports showed serum ferritin level of 66,015 ng/ml, LDH 5863 U/L, Triglycerides 417 mg/dl and Fibrinogen 0.9 g/L. IV Dexamethasone (0.6 mg/kg/day) and Intravenous Immunoglobulin (2gram/kg) were started after bone marrow aspiration.Despite all of our efforts, the baby suffered from pulmonary haemorrhage, went into refractory shock, and succumbed to death within just 8 hours of admission. Bone marrow later revealed plenty of hemophagocytes.
Since there was a high possibility of this FHL, blood samples of the baby were sent for genetic mutation analysis for FHL. A homozygous missense variation in exon 2 of the PRF1 gene (chr10:72360273; C>G, Depth: 49x) that results in the amino acid substitution of Serine for Tryptophan at codon 129 (p.W129S; ENST00000441259) was detected by targeted gene sequencing. Hemophagocytic lymphohistiocytosis-2 (OMIM#603553) caused by homozygous or compound heterozygous mutations in the PRF1 gene (OMIM*170280) has been diagnosed. The parents were called up again and genetic counselling was done. They were advised to go for a prenatal diagnosis by a Chorionic villous sampling and mutation analysis in the next pregnancy.
Clinically the features of septic shock and fulminant HLH, when both of them present late as MODS, are often indistinguishable. Both have somehow similar pathophysiology and are precipitated by microbial infection. HLH encompasses of a heterogeneous class of rare but potentially fatal disorders characterized by multisystem inflammation, which results from prolonged and intense activation of antigen- presenting cells (macrophages, histiocytes) and CD8+T-cells, and excessive proliferation and ectopic migration of T-cells2. It may have genetic causes or may be acquired under a variety of conditions. In infants and very young children, HLH is predominantly due to immune defects due to mutations in genes responsible for cytotoxic function of NK cells and cytotoxic T lymphocytes (CTLs). These are called as genetic or Familial HLH9. In older children, adolescents, and adults, HLH is associated more often with infections, malignancies, autoinflammatory and autoimmune diseases, and acquired immune deficiency states. However, even in a number of cases of late-onset HLH, many genetic defects are increasingly being identified10. Cardinal symptoms of HLH whether familial or acquired are prolonged fever coupled with hepatosplenomegaly and cytopenia as our index patient who presented with all of these three features. HLH is diagnosed based on the revised diagnostic criteria made by Histiocytic Society 11. Among the eight criteria (fever, splenomegaly, cytopenia, hypertriglyceridemia or hypofibrinogenemia, hyperferritenemia, increased soluble CD25, absent NK cell function and demonstration of hemophagocytes.) five should be present. Diagnosis can be established directly without necessitating such criteria if a known genetic defect has been identified. In our case we got the clinical and laboratory criteria as well as were able to demonstrate the PRF1 mutation.
Clinical features of HLH and sepsis are often overlapping and HLH basically a spectrum of disease that may start with an infection and end with a full blown HLH.(12) Fever, raised inflammatory markers, organomegaly, coagulopathy all are seen both in HLH as well as in sepsis. But depression of all the cell lines is unlikely in sepsis where it is the key laboratory features of HLH. As HLH has hypofibrionogenemia and thrombocytopenia, it sometimes behaves like DIC like our index case with grossly deranged coagulation parameters. But huge hepatosplenomegaly like our index case is rare in simple sepsis or septic shock .Most confirmatory differentiating features of sepsis from HLH is the hyperferritinemia. Though ferritin can be increased in sepsis as a marker of inflammation, but excessive high ferritin of more than 10,000ng/L are almost indicative of HLH.(13) In our index case, though the clinical presentations was initially like of a septic shock, but cytopenias and unusual huge organomegaly with falling ESR(due to hypofibrinogenemia) prompted us the think about HLH especially FHL. Though we diagnosed it and started immunosupressive therapy within 6 hours of admission, the kid was too sick to be salvaged and expire within 8 hours of admission. As the kid was deteriorating rapidly, in the penultimate hour we kept blood samples anticipating the possibility of genetic HLH and later on send the samples for whole genome sequencing that confirmed he diagnosis of FHL2 due to PERF1 Gene mutation.
Early establishment of the diagnosis of HLH and to differentiate it from sepsis has very important implications for timely commencement of the treatment, before overwhelming disease activity makes irreversible damage and a response to treatment less likely. Though the acquired HLH can be managed with low intensive therapy,(14) HSCT is the only curative option for FHL.
We thank the scientists at Medgenome Labs Pvt Ltd who contributed by performing the genetic analysis.
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