Hemophagocytic lymphohistiocytosis: critical reappraisal of a potentially under-recognized condition

doi:10.1007/s11684-013-0292-0

Front Med

2013, Vol. 7

Issue (4) : 492-498 https://doi.org/10.1007/s11684-013-0292-0

RESEARCH ARTICLE

Hemophagocytic lymphohistiocytosis: critical reappraisal of a potentially under-recognized condition

Somanath Padhi¹(

), Renu G’ Boy Varghese¹, Anita Ramdas¹, Manjiri Dilip Phansalkar¹, RajLaxmi Sarangi²

1. Department of Pathology, Pondicherry Institute of Medical Sciences, Ganapathichettykulam, Kalapet, Puducherry 605 014, India; 2. Department of Biochemistry, Pondicherry Institute of Medical Sciences, Ganapathichettykulam, Kalapet, Puducherry 605 014, India

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Abstract

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially life threatening, hyper inflammatory syndrome of diverse etiologies. Cardinal signs include prolonged fever, organomegaly, and persistent unexplained cytopenias. In spite of the well known diagnostic criteria put forth by HLH society, this continues to pose great diagnostic challenge in both pediatric and adult intensive care settings. We describe 4 adult (2 males, 2 females, aged 19, 29, 40, and 17 years) and 3 pediatric (2 males, 1female, aged 1 month, 6 months, and 12 years) patients with secondary HLH who satisfied the HLH-2004 diagnostic criteria. Definite evidence of hemophagocytosis was noted in 4 patients on initial bone marrow examination. The underlying etiologies were as follows: Rickettsia tsutsugamushi (case 1), autoimmune disorder (case 2), systemic onset juvenile idiopathic arthritis (sJIA) (case 3), unknown bite (possibly a venomous snake) (case 4), Plasmodium vivax (case 5), Cytomegalo virus (case 6), and Mycobacterium tuberculosis (case 7). In one patient, hemophagocytosis was presumed to have been exacerbated by administration of granulocyte monocyte colony stimulating factor (GM-CSF) for severe neutropenia. Two patients died with disseminated intravascular coagulation (DIC) and multi organ failure within few days of HLH diagnosis. Immunosuppressive therapy was started in 3 patients, and etoposide was started in one patient only. Due to lack of specificity of diagnostic criteria, diagnosing and differentiating HLH from its closest mimickers like sepsis/septic shock may be quite challenging in critically ill patients. Therefore, increasing awareness among physicians is essential for early diagnosis and effective therapy to reduce the mortality.

Keywords hemophagocytic lymphohistiocytosis diagnosis therapy GM-CSF bone marrow

Corresponding Author(s): Padhi Somanath,Email:somanath.padhi@gmail.com

Issue Date: 05 December 2013

Cite this article:

Somanath Padhi,Renu G’ Boy Varghese,Anita Ramdas, et al. Hemophagocytic lymphohistiocytosis: critical reappraisal of a potentially under-recognized condition[J]. Front Med, 2013, 7(4): 492-498.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0292-0
https://academic.hep.com.cn/fmd/EN/Y2013/V7/I4/492

Patient characteristics	Case 1	Case 2+	Case 3	Case 4	Case 5	Case 6	Case 7
Age (years)/gender	19, female	29, female	12, male	40, male	1, male	6/12, female	17, male
Managing departments	ICU^(a)	ICU	Orthopaedics	ICU	ICU	ICU	ICU
Presumptive diagnosis	?Sepsis	?Sepsis	sJIA^(b)/leukemia/ tuberculosis	?Sepsis/SIRS^(c)	?HLH	?Storage disorder	?Sepsis, atypical pneumonia
HLH-2004 criteria
Fever	+^(d) (3 weeks)	+ (3weeks)	+ (6 months)	+ (2 weeks)	+ (1 week)	+ (2 weeks)	+ (2 months)
Splenomegaly±hepatomegaly	+	+	+	+	+	+	+
Cytopenia (≥2 cell lines)	+	+	+	+	+	+	+
? Hemoglobin≤90 g/L	+ (66 g/L)	+ (90 g/L)	+ (88 g/L)	+ (66 g/L)	+ (90 g/L)	+ (39 g/L)	+ (68 g/L)
? Platelet count≤100×10⁹/L	+ (80×10⁹/L)	+ (30×10⁹/L)	–^(e)	+ (40×10⁹/L)	+ (90×10⁹/L)	+ (68 x10⁹/L)	-
? Absolute neutrophil count (<1000/L)	+ (675/L)	-	+ (688/L)	+ (160/L)	-	-	+ (792/L)
Fasting serum triglyceride (>265 mg/dl)	760	503	-	Not done	277	660	-
Hypofibrinogenemia (<150 mg/L)	-	+	-	+	-	Not done	+ (>2000)
Hyperferritinemia (>500 μg/L)	+ (>30,000)	+ (>2000)	589	+ (>1000)	793	840	-
Hemophagocytosis in bone marrow	+	+ (marked)	+	+	not evident^(f)	(g)	Not evident
Natural Killer cell activity ^(h)	Not done	Not done	Not done	Not done	Not done	Not done	Not done
Soluble CD25⁽ⁱ⁾	Not done	Not done	Not done	Not done	Not done	Not done	Not done
Molecular testing^(j)	Not done	Not done	Not done	Not done	Not done	Not done	Not done
Supportive laboratory features^(k)
Liver transaminases (≥200IU/L)	+	+ (>1000)	-	+	-	-	-
Hyperbilirubinemia (mg/dl) (T/D)	1.285714286	1.607142857	-	1.428571429	-	-	-
Prolonged PT±aPTT	+	+	-	+	-	-	+
Lactate dehydrogenase (IU/L)	3000	Not done	267	889	Not done	Not done	903
Hypoalbuminemia (<3.5 g/dl)	2.5	2.2	-	2.8	-	-	2.2
Hyponatremia (<135 meq/L)	126	125	-	128	-	-	125
D-dimer (semi-quantitative)	-	800	-	+	-	Not done	-
Antinuclear antibody	-	+	-	-	-	Not done	-
Procalcitonin (ng/dl)	+ (>100)	+ (>100)	Not done	+ (>100)	Not done	Not done	+ (>100)
Etiology screen	Rickettsia tsutsugamushi (IgG ELISA) and secondary bacterial infection	Autoimmune ds with sepsis (MAS)^(l)	sJIA (MAS) HLA-B27 & IgM rheumatoid factor negative	? Viper snake bite, SIRS, GM-CSF^(m) aggravated	Plasmodium vivax (card test+)	CMV⁽ⁿ⁾ (IgG ELISA+)	Miliary TB^(o) and bone marrow caseating granulomas
Management	IV antibiotics, doxycyclin, ventilator support, vasopressor, steroids, etoposide	IV antibiotics, vasopressor, steroids, ventilator support, FFP^(p)	IV antibiotic+ tablet naproxen (10 mg/ kg) + low dose steroid	IV antibiotics, vasopressor, steroids, ventilator support, FFP	Syrup chloroquine+ primaquine+ IV antibiotic	Supportive care+ IV antibiotics	Ventilator support+ IV antibiotic+ ATT^(q)
Outcome	Alive, on follow-up	DIC^(r), MOF^(s), death	Alive, on follow-up	DIC, MOF, death	Alive	Alive, on follow-up	On follow-up

Tab.1 Clinicopathological features, management, and subsequent follow-up data of seven patients with hemophagocytic lymphohistiocytosis (HLH) diagnosed as per HLH-2004 criteria []

Fig.1 Bone marrow aspirate smears from a patient with miliary tuberculosis (case 7, 17 years, male) showing increased reticuloendothelial cells/histiocytes with engulfed debris and without evidence of hmophagocytosis (Black arrow) (May Grunwald Giemsa stain, 400×).

Fig.2 Aspirate smears from another patient with scrub typhus () (case 1, 19 years, female) with evidence of erythrophagocytosis.

Fig.3 Aspirate smears from case 2 with autoimmune disorder (29 years, female) with marked hemophagocytosis of all three elements (May Grunwald Giemsa stain, 400×).

Fig.4 Bone marrow trephine biopsy of a patient with systemic onset juvenile idiopathic arthritis (sJIA) showing sheets of foamy histiocytes (A, 200×) with hemophagocytosis (B, black arrow, 400×) (Hematoxylin and eosin). Note that histiocytic hemophagocytosis may not be detected on initial bone marrow aspirate smears; and may be in apparent on trephine sections compared to the aspirate smears [].

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