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INTRODUCTION
Hemophagocytic syndrome is an extremely rare condition in adults reported in only 116 cases in the literature since 1983.
It is differentiated into primary or secondary, based on whether an underlying genetic disorder or underlying conditions, such as viral illness, are present.
Of the 116 case reports found in the literature, all had speculated underlying or associated etiology.
DEFINITION
Hemophagocytosis :
DEFINITION
Hemophagocytic Syndrome :
- (aka) Hemophagocytic lymphohistiocytosis (HLH) - life-threatening hyper-inflammatory syndrome caused by severe hypercytokinemia due to a highly stimulated but ineffective immune process. - HLH is not a single disease, but a clinical syndrome associated with a variety of underlying conditions leading to the same characteristic hyper-inflammatory phenotype.
ETIOLOGY
PATHOPHYSIOLOGY
When immune system is triggered in a healthy person, histiocytes, Natural Killer (NK) cells, and cytotoxic T lymphocytes (CTL) are all activated which then mutually stimulate each other by receptor interaction as well as by secretion of inflammatory cytokines and chemokines. In healthy individuals this leads to killing of infected cells, removal of antigen, and then termination of the immune response.
In HLH, there is an inherited or acquired defect of the NK and CTL cells, so they are unable to cope effectively with the infectious agent or antigen. This results in accumulation of activated T-lymphocytes and activated histiocytes producing increasingly high levels of cytokines.Key cytokines found at extremely high levels in the plasma of patients with HLH include TNF-alpha, interleukins IL-6, IL-8, IL-10, IL-12, IL-18 and soluble IL-2 receptor (CD25).
HLH Pathophysiology (contd) Why is the cytotoxic activity of the NK cell and CTL cell impaired?
The killing function is mediated by a secretory pathway involving the activation, polarization, and release of cytoxic granules into the immunological synapse This process is blocked in HLH This results in accumulation of activated T-lymphocytes and activated histiocytes with increasingly high levels of cytokines
No laboratory test or mode of presentation provides a means to distinguish between primary or secondary
Natural history are similar for both i.e. if untreated - fatal with few exceptions. Death is usually secondary to infection from prolonged neutropenia or multiorgan failure
primary HLH is restricted to babies and young children (80% of time presents when < 1 year old) In adults almost all cases are secondary
Virus are the predominant pathogensEBV, CMV, Measles, HHV-8, HIV. EBV associated HLH with increased prevalence in Asia
CLINICAL FEATURES
Prolonged fever ( due to hyper-cytokinemia) Hepatosplenomegaly (due to organ infiltration by activated immune cells) Cytopenias (due to marrow suppression by TNF-alpha and INF-gamma and consumption by hemophagocytosis) Neurologic (organ infiltration by activated immune cells) - Seizures, cranial nerve palsies - LP in more than half of patients with slightly elevated cell count and/or moderately increased protein
- Elevated LDH
- Depressed fibrinogen (Increased levels of plasminogen activator secreted by activated macrophages) Impaired NK cell activity Elevated soluble IL-2 receptor (sCD25) Transaminitis
Clinical/laboratory criteria
Fever Splenomegaly
Cytopenia (at least 2 cell lines) Hb < 9 Platelets < 100,000 ANC< 1000
Hypertriglyceridemia > 265mg/dl Serum fibrinogen < 150 mg/l Hemophagocytosis in bone marrow, CSF, or lymph nodes Decreased/absent NK cell activity Serum Ferritin > 500 ug/l Soluble CD25 > 2400 U/ml
Need 5 of 8 above clinical/laboratory criteria (do not need to fulfill this if have a family history or molecular diagnosis that is consistent with HLH).
- It is common that the first bone marrow examination does not reveal hemophagocytosis.
Clinical findings and diagnosis Elusive diagnosis (postmortem diagnosis is not unusual). Presentation is generally nonspecific. Janka G. Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr 2009 Sep;221(5):278-85
Ferritin
Differential diagnosis when ferritin > 10,000 is rather limited to HLH, histiocytic malignancies and adult-onset Stills disease
Ferritin (contd)
Very nice recent publication by Allen et al.* Performed chart review on all patients with a ferritin > 500 at Texas Childrens Hospital from January 10, 2003 through January 10, 2005 in 330 patients Sensitivity and specificity for ferritin > 10,000 in diagnosis of HLH in this select population approached a Sensitivity of 90%, Specificity of 96%
Allen, C. E., X. Yu, et al. (2008). "Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis." Pediatr Blood Cancer 50(6): 1227-35.
Lab specimen requires special handling and will take 1-2 weeks for results (send out lab).
Functional assay that allows direct measurement of the NK cell defect (inherited or acquired), which is a central theme in HLH pathophysiology
THE HEMOPHAGOCYTE
Hemophagocyte in bone marrow :
Although it has been considered the gold standard for HLH, it is not required for diagnosis of HLH. One Study reported 64.5% of ICU patients with fatal sepsis had hemophagocytosis on autopsy
THE HEMOPHAGOCYTE
The hallmark pathologic finding in the bone marrow is histiocytic hyperplasia with prominent phagocytosis of mature and immature hematopoietic elements.
The histiocytes show abundant cytoplasm containing the phagocytized cells; cytoplasmic vacuoles and granules are also seen.
Prognosis of HLH Analysis of 34 adult HLH cases in 1997 by Kaito et al. showing the Risk factors associated with death Kaito, K., M. Kobayashi, et al. (1997). "Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases." Eur J Haematol 59(4): 247-53.
Treat the triggering agent, if exist (infection, neoplasm, etc.) It is usually not sufficient to only treat the triggering agent
Longer term goals : If genetic, replace the defective immune system via allogenic SCT
Duration of therapy :
8 weeks of therapy for secondary non-genetic disease For genetic disease continue therapy after week 8 until SCT
Rituximab
ATG
IVIG Plasma exchange
3.
Learning points
HLH in adults has a poor prognosis Ferritin levels are very useful in early stages Aggressively pursue tissue diagnosis Because so many immunologic, neoplastic, genetic, and infectious disorders may be associated with HLH, clinicians should work closely with pathologists and microbiologists to clearly define precipitating or underlying illnesses
The diagnosis of hemophagocytic syndrome must be included in the fever of unknown origin (FUO) workup, especially in those patients with pancytopenia and organ failure. In 20% of reported cases there is no evidence of hemophagocytosis on the first bone marrow examination, and multiple bone marrow biopsies were performed before the diagnosis was made.
Treatment can and should be initiated immediately if the diagnosis of hemophagocytosis is suspected and the criteria are fulfilled.
FUTURE TRENDS
Although knowledge of hemophagocytic syndrome in childhood forms has increased, much needs to be learned about this disease in adults, as the mortality rate of hemophagocytic syndrome remains high (50%).
Further studies are needed to advance the diagnosis of hemophagocytic syndrome in adults, and therapeutic guidelines need to be established. GENOMICS - It would be of interest to see whether polymorphisms in genes of cytotoxic effector pathways contribute to the pathogenesis of hemophagocytic syndrome in adults, as was recently described in patients with tuberculosis-associated hemophagocytic syndrome.
HLH in India
From the 1Department of Pediatric Medicine, Institute of Post Graduate Medical Education and Research, Kolkata, India
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