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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 73-77

Hemophagocytic lymphohistiocytosis: A cross talk between clinics and laboratory

1 Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
2 Department of Biochemistry, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India

Date of Web Publication13-Dec-2018

Correspondence Address:
Somanath Padhi
Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrsm.jcrsm_29_18

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How to cite this article:
Padhi S, Sarangi R. Hemophagocytic lymphohistiocytosis: A cross talk between clinics and laboratory. J Curr Res Sci Med 2018;4:73-7

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Padhi S, Sarangi R. Hemophagocytic lymphohistiocytosis: A cross talk between clinics and laboratory. J Curr Res Sci Med [serial online] 2018 [cited 2021 Apr 22];4:73-7. Available from: https://www.jcrsmed.org/text.asp?2018/4/2/73/247493

Hemophagocytic lymphohistiocytosis (HLH), also termed as hemophagocytic syndrome, is regarded as the tip of a hyperinflammatory iceberg of diverse etiologies, which results due to defective natural killer (NK) cell and cytotoxic T lymphocyte (CTL) function leading to excessive activation of benign macrophages, cytokine storm, histiocytic hemophagocytosis, multiorgan dysfunction syndrome (MODS), disseminated intravascular coagulation (DIC), and death, if not diagnosed and treated early.[1] Since the first description of cases coined as “histiocytic medullary reticulocytosis” by Scott Robin and Smith in 1939, there has been a sequential change in nomenclature, and the diagnostic criteria have been redefined or modified [Table 1].[2],[3],[4],[5] Although HLH occurring in pediatric setting has a well-documented genetic basis (the so-called primary or familial HLH), little is known about adult HLH (aHLH), which can occur at any age and is associated with a wide spectrum of underlying conditions mainly triggered by infectious diseases, malignancies (particularly leukemia and lymphoma), immunodeficiency, and autoimmune disorders (the so-called “macrophage activation syndrome” or MAS) that lead to an impaired ability of CTL and NK cells to kill target cells. Over the years, literature worldwide has been enriched with more influx of publications pertaining to aHLH, mostly in the form of sporadic case reports and case series [Figure 1].[1] India has also witnessed a rising trend in the awareness of aHLH cases. Both sporadic case reports and case series have been published from almost all corners of India. aHLH in the Indian subcontinent has been reported in association with disseminated tuberculosis, scrub typhus, dengue, typhoid fever, malaria (both Plasmodium vivax and Plasmodium falciparum), visceral leishmaniasis, leptospirosis, HIV/AIDS, and other sepsis syndrome [Table 2].[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] The pathophysiologic mechanism of HLH is complex and is the orchestrated events of impaired CTL and NK cell function in a genetically susceptible individual, leading to proliferation of macrophages in the reticuloendothelial organs such as bone marrow, spleen, liver, and lymph node; splenic upregulation of monocyte colony-stimulating factor (CSF)-producing splenomegaly; fever; cytokine-mediated liver injury masquerading as acute liver failure/dysfunction which in turn leads to hyperferritinemia as a part of acute-phase response, impaired lipoprotein lipase activity leading to hypertriglyceridemia, and hypofibrinogenemia; and finally culminating in MODS, DIC, and death, if uncontrolled and untreated [Figure 2].
Table 1: Hemophagocytic lymphohistiocytosis: Historical overview of nomenclatures (adopted from Hayden et al.)

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Figure 1: Hemophagocytic lymphohistiocytosis cases published from around the world

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Table 2: Hemophagocytic lymphohistiocytosis cases published from India during the last 5 years (2013-2018)

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Figure 2: Liver as a central organ in the pathophysiology of hemophagocytic lymphohistiocytosis

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There has been a paradigm shift of focus in the diagnosis of HLH since 2004 [Table 3].[1],[2],[3],[4],[5] Diagnostic criteria developed for the pediatric HLH-2004 protocol have been widely adopted in adult medicine without systematic validation. Both 2004 and 2009 guidelines incorporated mutational/genetic analysis as a “major criterion” which has subsequently been taken out, especially for aHLH case.[2],[3] Moreover, two important parameters that were incorporated in previous criteria such as “impaired NK cell activity” and “increased soluble interleukin 2 receptor” are likely to be removed sooner or later as these tests are available in only very few specialized centers all over the world and are very costly. Therefore, in practice, the necessary five out of eight criteria as per the HLH 2004 guidelines are actually five out of six parameters tested. In addition, the criteria of “bone marrow hemophagocytosis” is becoming increasingly less important nowadays as histiocytic hemophagocytosis has a poor specificity in the diagnosis of HLH, and this may not even be evident during initial marrow evaluation! In order to overcome these shortcomings, the French investigators proposed to adopt a new objective scoring system (HLH probability score or HScore). A total probability score of 169 was found to have a higher sensitivity and specificity for the diagnosis of HLH [Table 4].[4] Furthermore, simpler routine laboratory parameters (extended variables) have been incorporated to diagnose the disease early. These include peripheral blood monocytosis, hyponatremia, elevated lactate dehydrogenase, elevated β2 microglobulin, impaired coagulation parameters, and CSF pleocytosis.[5]
Table 3: The Hemophagocytic Lymphohistiocytosis Diagnostic Criteria: The changing paradigm

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Table 4: Hemophagocytic lymphohistiocytosis probability score (HScore) as proposed by Fardet et al.

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Another interesting change has been made in regard to the measurement of serum ferritin. A ≥500 μg/L cutoff among pediatric population (up to 18 years of age) was found to have 84% sensitivity in HLH-1994 trial and therefore was included in the HLH 2004 guidelines.[17] Subsequently, pediatricians have revised their ferritin cutoff value to ≥10,000 μg/L with a higher sensitivity and near 100% specificity for the diagnosis of HLH.[18],[19] On the contrary, recent reports from adult intensive care units (ICUs) have suggested a lower ferritin cutoff value of 3000–4000 μg/L with >80% sensitivity and specificity in HLH diagnosis.[20] While hyperferritinemia is not specific to HLH, the same in the clinical context of fever, worsening cytopenia(s), and splenomegaly is highly valuable in the ICUs where sepsis is the major overlapping clinical condition.[21]

In summary, the diagnosis of HLH is a multidisciplinary teamwork which requires a cross talk between the laboratory personnel (clinical pathologists, biochemists, and microbiologists) and the treating physicians/intensivists/critical care physicians/hemato-oncologists [Figure 3].[20] From a pathologist's perspective, it is highly essential to be aware of HLH as a differential diagnosis in the evaluation of prolonged fever, pancytopenia, and splenomegaly. Careful examination of a well-stained peripheral smear for possible evidence of DIC (in the form of schistocytes), reactive lymphoid cells, or blasts should be performed and correlated with coagulation parameters, liver enzymes, serum ferritin, triglyceride, and plasma fibrinogen. From a clinical perspective, it is imperative to make an early clinical judgment and go for early marrow evaluation; not only to add to the diagnostic criteria, but also to rule out the hiding lymphoma/leukemia or any infections. The usual culprit such as Epstein–Barr virus and cytomegalovirus and other common infections should be tested by antigenic assays. Finally, the goal of management in aHLH should be prioritized on a case-to-case basis and directed at controlling the cytokine storm in the form of immunosuppressive (corticosteroid) and/or immunomodulator (etoposide) therapy as well as treating the underlying cause aggressively. Only the patients will enrich our knowledge and understanding in this catastrophic syndrome in the days to come.
Figure 3: Hemophagocytic lymphohistiocytosis: The essential cross talks between the laboratories and the clinics

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  References Top

Hayden A, Park S, Giustini D, Lee AY, Chen LY. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev 2016;30:411-20.  Back to cited text no. 1
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 2
Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Program 2009;2009:127-31.  Back to cited text no. 3
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive Hemophagocytic syndrome. Arthritis Rheumatol 2014;66:2613-20.  Back to cited text no. 4
Tamamyan GN, Kantarjian HM, Ning J, Jain P, Sasaki K, McClain KL, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes. Cancer 2016;122:2857-66.  Back to cited text no. 5
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Nath UK, Sinha N, De D. Hemophagocytic lymphohistiocytosis secondary to Salmonella paratyphi: An infection presenting with severe pancytopenia and multiorgan dysfunction: The first case report. J Bone Marrow Res 2013;1:1000114.  Back to cited text no. 7
Basheer A, Padhi S, Boopathy V, Mallick S, Nair S, Varghese RG, et al. Hemophagocytic lymphohistiocytosis: An unusual complication of Orientia tsutsugamushi disease (Scrub typhus). Mediterr J Hematol Infect Dis 2015;7:e2015008.  Back to cited text no. 8
Padhi S, Ravichandran K, Sahoo J, Varghese RG, Basheer A. Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis. Lung India 2015;32:593-601.  Back to cited text no. 9
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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