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Hemophagocytic lymphohistiocytosis in the ED
American Journal of Emergency Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Hemophagocytic lymphohistiocytosis in the ED☆,☆☆,★ Abstract Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by tissue invasion of liver, spleen, and lymph nodes by benign lymphocytes and hemophagocytosing macrophages with marked release of inflammatory cytokines. The result is a cytokine storm with systemic inflammatory response syndrome, multiorgan dysfunction, and often death. Patients present with fever, hepatospenomegaly, unexplained cytopenias, marked hyperferetinemia, liver dysfunction, coagulopathy, central nervous system dysfunction, and/or renal dysfunction. An infectious or malignant trigger is often found. We describe here a case that presented to the emergency department with fever, jaundice, a change in mental status, acute kidney injury, and severe pancytopenia. The patient was admitted to the intensive care unit, and hemophagocytic lymphohistiocytosis was diagnosed. Recovery occurred with supportive therapy. Emergency medicine physicians need to be aware of this syndrome to obtain confirmatory testing and appropriate subspecialty consultation in a timely manner and to initiate the search for triggering infections. Chemoimmunotherapy of the hyperinflammatory state and specific treatment of triggering infections may be lifesaving. Hemophagocytic lymphohistiocytosis (HLH) is a frequently fatal, hyperinflammatory syndrome resulting from exuberant proliferation of CD8 + cytotoxic T-lymphocytes (CTL) and benign macrophages with tissue invasion involving lymph nodes, liver, and spleen [1]. There is marked release of proinflammatory cytokines, resulting in a “cytokine storm,” with severe systemic inflammatory response syndrome, multiorgan dysfunction syndrome, and often death. Autosomal recessive, primary familial HLH (FHL) as well as X-linked forms usually present in infancy or early childhood [2]. Secondary HLH (sHLH) can occur at any age, triggered by infection, malignancy, immunosuppression, or flare of rheumatologic disease (known as macrophage activation syndrome) [3]. Cases of sHLH not uncommonly also have an underlying genetic predisposition. Clinical manifestations include unremitting fever; rash; lymphadenopathy; hepatosplenomegaly; and dysfunction of liver, kidney, lung, and/or central nervous system. Bicytopenia or pancytopenia is characteristic along with markedly elevated ferritin, abnormal liver function tests, coagulopathy, hypofibrinogenemia, hypertriglyceridemia, and hyponatremia. Bone marrow aspiration (BMA) usually, but not always, reveals hemophagocytes (HPCs), macrophages that have phagocytosed red cells, leukocytes, and/or platelets, and their precursors.
☆ Funding: None. ☆☆ Conflicts of interest: None. ★ Disclosures: None.
There is nothing pathognomonic of HLH, including HPCs. Rather, diagnosis rests on a constellation of clinical and laboratory findings but most importantly requires suspicion. As HLH can be fatal, therapy to quell the hyperinflammation is often critical. This syndrome usually evolves over days to weeks as opposed to minutes to hours. Emergency medicine physicians, however, must be aware of HLH to obtain confirmatory testing and subspecialty input in a timely manner and to begin the search for identifiable and treatable triggers. A previously oriented 72-year-old man with a history of hypertension, coronary artery disease, and chronic obstructive pulmonary disease presented to the emergency department (ED) with a change in mental status and jaundice. He had a 50 pack-year history of cigarettes but did not drink alcohol or use illicit drugs. On examination, he was confused, icteric, and febrile (38.7°C), with normal pulse and blood pressure. Initial laboratory values revealed severe pancytopenia, abnormal liver function tests, and elevated serum creatinine (see Table 1). Haptoglobin was normal, and no schistocytes were present. Ferritin was markedly elevated. Lactate dehydrogenase was elevated, and fibrinogen was low but triglycerides were normal. Chest x-ray was unremarkable, and head computed tomography revealed a subacute left temporal lobe infarct. Broad spectrum antibiotics were administered, and the patient was admitted to the ICU. Infectious disease workup was negative, including blood and cerebrospinal fluid (CSF) cultures and blood polymerase chain reaction (PCR) for babesiosis, Rickettsia, Lyme, parvovirus B19, and HIV. Serologic testing revealed latent Epstein-Barr virus (EBV) infection. Polymerase chain reaction of CSF was negative for West Nile virus and herpes simplex. Bone marrow aspiration revealed HPCs. Abdominal computed tomographic scan showed splenomegaly. Hence, the patient satisfied Histiocyte Society criteria for diagnosing HLH in the pediatric age range (6 of 8 criteria, see Table 2) as well criteria developed for diagnosing reactive sHLH in adults (H-score of 224 giving a 97% chance of having sHLH). He was treated with supportive therapy only and gradually recovered to his baseline status. Presumably, this self-limiting episode of HLH was triggered by an unknown viral illness that resolved spontaneously. Our patient presented with fever, hepatosplenomegaly, and severe pancytopenia. Hemophagocytic lymphohistiocytosis was diagnosed with additional laboratory evaluation, including measurement of serum ferritin, fibrinogen, and liver function tests. In addition, BMA revealed HPCs. A viral trigger seems likely, although none were identified. Surprisingly, the patient recovered without any specific chemoimmunotherapy, illustrating the variable course this often fatal syndrome can manifest. Diagnosis of HLH requires satisfaction of multiple criteria, although FHL can also be diagnosed by genetic testing, family history, or possibly consanguineous parents. The Histiocyte Society published clinical criteria for diagnosing FHL in the pediatric age range (HLH-2004) [4]. Although never validated in adults, our patient satisfied these criteria,
0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034
2
J. Cesarine et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Table 1 Laboratory values Presentation
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Hemoglobin (14.0-18.0 g/dL)/hematocrit (42%-52%)
12.2/36.4
8.1/23.9
8.3/24.8
8.1/23.8
0.38 0.37
0.38
0.67
1.97
3.24
Platelets (150-400 × 103/μL)
86
28 53a
49
65
95
147
Ferritin (15-400 ng/mL) Fibrinogen (134-351 mg/dL)
1826 257 11.9
10.0/30.3 10.1/30.6 9.3/27.2 0.59 0.51 0.49 32 32 32 12 596 119
8.4/24.6
0.98
9.3/27.0 9.5/27.3 9.4/27.3 0.49 0.50 0.43 33 34 31
8.6/25.1 7.9/23.6
WBC (4.5-11.0 × 103/μL)
11.6/33.9 10.0/29.0 10.1/29.7 0.91 0.71 0.68 60 54 40 4836
(b0.50 μg/mL) AST (10-35 U/L)/ALT (6-45 U/L) Total bilirubin (0.0-1.2 mg/dL)/direct bilirubin (0.0-0.3 mg/dL) LDH (110-230 U/L) Triglycerides (b50.0 mg/dL) Sodium (135-145 mmol/L)
D-Dimer
75/39 2.9/0.7
106/38 2.1/0.8
466
732
134
123 134
135
135
Bicarbonate (23-30 mmol/L)
21
20
21
22
Creatinine (0.6-1.2 mg/dL)
1.53
1.54
1.36
1.21
a
14 995
134 135 23 23 1.30 1.34
136
135
138
139
24
23
24
24
1.35
1.26
1.09
1.04
Transfused 2 units of platelets before interventional radiology-guided BMA and biopsy.
having the 6 of 8 positive. Fardet et al [5] published criteria specifically for diagnosing adult sHLH, available online at http://saintantoine.aphp. fr/score/. Our patient's H-score was 224 (HLH probability of 97%). Different criteria may apply to diagnosing HLH with acute flares of rheumatic diseases such as systemic juvenile idiopathic arthritis [6]. In these instances, baselines levels of leukocytes, platelets, and fibrinogen may be significantly elevated so that the thresholds of HLH-2004 may
be too stringent. Relative decreases with higher cutoffs may be more appropriate, with published criteria specifically for systemic juvenile idiopathic arthritis available (Table 2). Emergency medicine physicians should be aware of these nuances of diagnosis to most effectively recognize potential cases presenting to the ED. Equally important to establishing a diagnosis of HLH is defining any potentially triggering agent(s). The most common triggers in adult HLH
Table 2 Diagnostic and classification criteria for HLH HLH2004 diagnostic criteriaa
H-score diagnostic criteriab
Macrophage activation syndromec
The diagnosis of HLH can be established by a molecular diagnosis consistent with HLH or by meeting ≥5 of the following 8 clinical and laboratory diagnostic criteria:
A higher score is associated with a higher risk for HLH, as calculated based on the following criteria and scoring system
A patient with known or suspected systemic juvenile idiopathic arthritis is classified as having macrophage activation syndrome if the following criteria are met: Fever
1. Fever 2. Ferritin ≥500 ng/mL
3. Cytopenias (affecting ≥2 of 3 lineages in peripheral blood): Hemoglobin b90 g/L Platelets b100 × 109/L Neutrophils b1.0 × 109/L 4. Splenomegaly
5. Hypertriglyceridemia and/or hypofibrinogenemia: Fasting triglycerides ≥265 mg/dL Fibrinogen ≤150 mg/dL 6. Soluble CD25 ≥ 2400 U/mL 7. Low or absent NK-cell activity
8. Hemophagocytosis in bone marrow or spleen or lymph nodes
Temperature (°C): 0 (b38.4), 33 (38.4-39.4), or 49 (N39.4) Ferritin (ng/mL): 0 (b2000), 35 (2000-6000), or 50 (N6000) No. of cytopenias (hemoglobin ≤ 9.2 g/dL and/or leukocytes ≤5000/mm3 and/or platelets ≤110 000/mm3): 0 (1 lineage), 24 (2 lineages), or 34 (3 lineages) Organomegaly: 0 (no), 23 (hepatomegaly or splenomegaly), or 38 (hepatomegaly and splenomegaly) Triglyceride (mg/dL): 0 (b132), 44 (132-353), or 64 (N353) Fibrinogen (mg/dL): 0 (N250) or 30 (≤250) Serum glutamic oxaloacetic transaminase (IU/L): 0 (b30) or 19 (≥30) Known underlying immunosuppression due to human immunodeficiency virus or long-term immunosuppressive therapy: 0 (no) or 18 (yes) Hemophagocytosis features on bone marrow aspirate: 0 (no) or 35 (yes)
Ferritin N684 ng/mL Plus any 2 of the following: Platelets ≤181 × 109/L
Triglycerides N156 mg/dL Fibrinogen ≤360 mg/dL Aspartate aminotransferase N48 U/L
a
Henter J-E, Horne A, Aricó M, et al. Pediatr Blood Cancer. 2007;48:124–31. In a development and validation study, the probability of having reactive hemophagocytic syndrome was less than 1% with an H-score less than 90% to greater than 99% with an H-score greater than 250; the median H-score for a positive diagnosis was 230 (interquartile range, 203-257), and the median H-score for a negative diagnosis was 125 (interquartile range, 91-150) [5]. c Cron RQ, Davi S, Minoia F, Ravelli A. Expert Rev Clin Immunol. 2015;11:1043–53. b
Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034
J. Cesarine et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
are infections and malignancy (usually lymphomas or leukemia) with flares of rheumatic disease found in about 10%. Multiple triggers may exist in up to one third [3]. Almost any infection can trigger HLH, but viruses are most notable [7]. The single most common virus is EBV, but other herpes viruses are also prominent, including cytomegalovirus, herpes simplex, HHV-6, and HHV-8. Other viruses to consider testing for include parvovirus B19, hepatitis (A, B, and C), dengue, adenovirus, measles, mumps, and rubella. Importantly, HLH had a prominent role in mortality from 2009 influenza A (H1N1). The most common bacterial infections triggering HLH include intracellular bacteria such as tuberculosis and Rickettsia, but pyogenic bacteria such as Staphylococcus and Escherichia coli have been reported. The most common parasite is leishmania, and diagnosis may require PCR of BMA fungi such as histoplasmosis have also been reported. Malignancy underlies up to half of adult cases of sHLH and becomes especially prominent in the elderly [8]. Active malignancy can trigger HLH, or it can occur during chemotherapy-induced remission typically associated with infection. The most common malignancies involve lymphocytes, including T- and natural killer (NK) cell lymphomas or leukemias, diffuse large B-cell lymphoma, or Hodgkin's. Immunosuppression is a significant risk factor, secondary to HIV [9] or following either solid organ or hematopoietic stem cell transplantations (HSCTs) [10]. In these cases, infections are the usual triggers, but malignancy can be as well. The pathogenesis of HLH is incompletely understood. In FHL, defective cytotoxic degranulation or reduced perforin synthesis impairs the ability of CTLs and NK cells to lyse target cells [11]. Infected or malignant cells cannot be effectively killed initially. Similarly, antigen presenting cells cannot be appropriately eliminated upon resolution of the initial challenge. In sHLH, acquired transient defects occur. In either case, CTLs release large quantities of interferon γ, which then results in macrophage activation and proliferation. Overproduction of inflammatory cytokines (interleukin [IL] 1, IL-6, IL-18, tumor necrosis factor α, among others) occurs, with the resulting “cytokine storm” driving the syndrome. Hemophagocytes may actually be reactionary, as these alternatively activated M-2 macrophages release the anti-inflammatory IL-10, and by catabolizing heme produce further anti-inflammatory factors (carbon monoxide, biliverdin, and ferritin) [12]. Our patient illustrates the dilemma with treating a potentially infected or immunosuppressed patient with further chemoimmunotherapy. Fortunately, he recovered without specific therapy. No published randomized controlled trials exist. Recommended therapy for FHL (the HLH-2004 protocol) includes dexamethasone, etoposide, and cyclosporine with the intent of HSCT when a suitable donor becomes available [4]. Etoposide has special benefit given its activity against CD8+ CTLs. Utilization of an earlier version of HLH-2004 changed 5-year survival of FHL from less than 5% without therapy to more than 50% [13]. The approach to treatment of the adult with sHLH depends on the particular circumstances given its heterogeneity and the variability in mortality [3]. Our patient recovered with only supportive therapy, and no specific trigger was identified. In the critically ill patient with multiorgan dysfunction syndrome, some form of immunosuppression is usually administered to quell the hyperinflammation as hospital mortality exceeds 50% [14]. High-dose steroids (methylprednisolone or dexamethasone if central nervous system involvement) may be combined with additional agents, such as cyclosporine, anakinra, or intravenous immunoglobulin [15]. Plasmapheresis has also been used. The mortality of HLH complicating rheumatic disease is much lower than FHL or other causes of sHLH such as malignancy or infection, perhaps around 10% [16]. Steroids and cyclosporine are typically used, but cytokine inhibitors such as anakinra or tocilizumab may be tried. Etoposide is usually reserved for severe or refractory cases [16]. Epstein-Barr virus requires special consideration. It is the most common infectious trigger, and it may occur with primary infection or
3
reactivation of latent disease. Mortality is substantial. Etoposide is indicated as EBV may predominantly infect T cells in this circumstance, and it should be started within 4 weeks of onset [17]. Hematopoietic stem cell transplantation has been used for refractory cases, and rituximab may be considered. Because hypomorphic mutations in the genes responsible for FHL can be found in a significant minority of adult sHLH cases, screening by flow cytometry for intracellular perforin and surface expression of CD107 (indicating normal T-cell degranulation) should be performed in all cases of sHLH [18]. If abnormal, genetic testing can follow. An underlying genetic defect would signify possible recurrence if the patient survives, and hence, the possible need for HSCT. Such testing is indicated in our patient. Hemophagocytic lymphohistiocytosis is a severe, potentially fatal hyperinflammatory syndrome that may present unsuspectedly to the ED. Physicians should be aware of its features to both ensure timely ordering of confirmatory tests for diagnosis as well as to initiate appropriate evaluation of triggering agents. Hemophagocytic lymphohistiocytosis should be in the differential diagnosis of a febrile patient with unexplained bicytopenia/pancytopenia or abnormal neurologic function. Ferritin, fibrinogen, LDH, and liver function tests should be immediately obtained, along with evaluation for splenomegaly. Bone marrow aspiration should not be delayed if features are consistent. Our patient serves to illustrate these issues. Joseph Cesarine MD Lisa M. Filippone MD Department of Emergency Medicine Cooper Medical School of Rowan University, Camden, NJ Edward J. Filippone MD Division of Nephrology, Department of Medicine Sydney Kimmel Medical College at Thomas Jefferson University Philadelphia, PA 19107 ⁎Corresponding author. 2228 south Broad St, Philadelphia, PA 19145 Tel.: +1 215 467 8955; fax: +1 215 467 8955 E-mail address: [email protected]
http://dx.doi.org/10.1016/j.ajem.2016.03.034
References [1] Janka GE, Lehmberg K. Hemophagocytic syndromes—an update. Blood Rev 2014; 28(4):135–42. [2] Degar B. Familial hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 2015;29(5):903–13 [08]. [3] Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. The Lancet 2014;383(9927):1503–16. [4] Henter J-, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. 2007;48:124–31. [5] Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chawan D, et al. Development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome. 2014;66:2613–20. [6] Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005;146:598–604. [7] Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7(12):814–22. [8] Lehmberg K, Nichols KE, Henter J-, Girschikofsky M, Greenwood T, Jordan M, et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica 2015;100: 997–1004. [9] Fardet L, Lambotte O, Meynard J, Kamouh W, Galicier L, Marzac C, et al. Reactive haemophagocytic syndrome in 58 HIV-1–infected patients: clinical features, underlying diseases and prognosis. AIDS 2010;24:1299–306. [10] Ponticelli C, Alberighi ODC. Haemophagocytic syndrome—a life-threatening complication of renal transplantation. Nephrol Dial Transplant 2009;24(9):2623–7. [11] Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol 2013;161(5):609–22. http://dx.doi.org/10.1111/bjh.12293 [Accessed 17 February 2016].
Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034
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J. Cesarine et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
[12] Canna SW, Costa-Reis P, Bernal WE, Chu N, Sullivan KE, Paessler ME, et al. Brief Report: Alternative Activation of Laser-Captured Murine Hemophagocytes. 2014;66:1666–71. [13] Trottestam H, Horne A, Aricò M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long-term results of the HLH-94 treatment protocol. Blood 2011;118:4577–84. [14] Barba T, Maucort-Boulch D, Iwaz J, Bohe J, Ninet J, Hot A, et al. Hemophagocytic Lymphohistiocytosis in Intensive Care Unit: A 71-Case Strobe-Compliant Retrospective Study. Medicine 2015;94:e2318. [15] Simon DW, Aneja R, Carcillo JA, Halstead ES. Plasma exchange, methylprednisolone, IV immune globulin, and now anakinra support continued PICU equipoise in management of hyperferritinemia-associated sepsis/multiple organ dysfunction syndrome/
macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis syndrome. Pediatr Crit Care Med 2014;15(5):486–8. [16] Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. 2014;66:3160–9. [17] Imashuku S, Kuriyama K, Sakai R, Nakao Y, Masuda S, Yasuda N, et al. Treatment of Epstein–Barr virus–associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: A report from the HLH study center. Med Pediatr Oncol 2003;41:103–9. [18] Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 2013;160(3):275–87.
Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Hemophagocytic lymphohistiocytosis in the ED☆,☆☆,★ Abstract Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by tissue invasion of liver, spleen, and lymph nodes by benign lymphocytes and hemophagocytosing macrophages with marked release of inflammatory cytokines. The result is a cytokine storm with systemic inflammatory response syndrome, multiorgan dysfunction, and often death. Patients present with fever, hepatospenomegaly, unexplained cytopenias, marked hyperferetinemia, liver dysfunction, coagulopathy, central nervous system dysfunction, and/or renal dysfunction. An infectious or malignant trigger is often found. We describe here a case that presented to the emergency department with fever, jaundice, a change in mental status, acute kidney injury, and severe pancytopenia. The patient was admitted to the intensive care unit, and hemophagocytic lymphohistiocytosis was diagnosed. Recovery occurred with supportive therapy. Emergency medicine physicians need to be aware of this syndrome to obtain confirmatory testing and appropriate subspecialty consultation in a timely manner and to initiate the search for triggering infections. Chemoimmunotherapy of the hyperinflammatory state and specific treatment of triggering infections may be lifesaving. Hemophagocytic lymphohistiocytosis (HLH) is a frequently fatal, hyperinflammatory syndrome resulting from exuberant proliferation of CD8 + cytotoxic T-lymphocytes (CTL) and benign macrophages with tissue invasion involving lymph nodes, liver, and spleen [1]. There is marked release of proinflammatory cytokines, resulting in a “cytokine storm,” with severe systemic inflammatory response syndrome, multiorgan dysfunction syndrome, and often death. Autosomal recessive, primary familial HLH (FHL) as well as X-linked forms usually present in infancy or early childhood [2]. Secondary HLH (sHLH) can occur at any age, triggered by infection, malignancy, immunosuppression, or flare of rheumatologic disease (known as macrophage activation syndrome) [3]. Cases of sHLH not uncommonly also have an underlying genetic predisposition. Clinical manifestations include unremitting fever; rash; lymphadenopathy; hepatosplenomegaly; and dysfunction of liver, kidney, lung, and/or central nervous system. Bicytopenia or pancytopenia is characteristic along with markedly elevated ferritin, abnormal liver function tests, coagulopathy, hypofibrinogenemia, hypertriglyceridemia, and hyponatremia. Bone marrow aspiration (BMA) usually, but not always, reveals hemophagocytes (HPCs), macrophages that have phagocytosed red cells, leukocytes, and/or platelets, and their precursors.
☆ Funding: None. ☆☆ Conflicts of interest: None. ★ Disclosures: None.
There is nothing pathognomonic of HLH, including HPCs. Rather, diagnosis rests on a constellation of clinical and laboratory findings but most importantly requires suspicion. As HLH can be fatal, therapy to quell the hyperinflammation is often critical. This syndrome usually evolves over days to weeks as opposed to minutes to hours. Emergency medicine physicians, however, must be aware of HLH to obtain confirmatory testing and subspecialty input in a timely manner and to begin the search for identifiable and treatable triggers. A previously oriented 72-year-old man with a history of hypertension, coronary artery disease, and chronic obstructive pulmonary disease presented to the emergency department (ED) with a change in mental status and jaundice. He had a 50 pack-year history of cigarettes but did not drink alcohol or use illicit drugs. On examination, he was confused, icteric, and febrile (38.7°C), with normal pulse and blood pressure. Initial laboratory values revealed severe pancytopenia, abnormal liver function tests, and elevated serum creatinine (see Table 1). Haptoglobin was normal, and no schistocytes were present. Ferritin was markedly elevated. Lactate dehydrogenase was elevated, and fibrinogen was low but triglycerides were normal. Chest x-ray was unremarkable, and head computed tomography revealed a subacute left temporal lobe infarct. Broad spectrum antibiotics were administered, and the patient was admitted to the ICU. Infectious disease workup was negative, including blood and cerebrospinal fluid (CSF) cultures and blood polymerase chain reaction (PCR) for babesiosis, Rickettsia, Lyme, parvovirus B19, and HIV. Serologic testing revealed latent Epstein-Barr virus (EBV) infection. Polymerase chain reaction of CSF was negative for West Nile virus and herpes simplex. Bone marrow aspiration revealed HPCs. Abdominal computed tomographic scan showed splenomegaly. Hence, the patient satisfied Histiocyte Society criteria for diagnosing HLH in the pediatric age range (6 of 8 criteria, see Table 2) as well criteria developed for diagnosing reactive sHLH in adults (H-score of 224 giving a 97% chance of having sHLH). He was treated with supportive therapy only and gradually recovered to his baseline status. Presumably, this self-limiting episode of HLH was triggered by an unknown viral illness that resolved spontaneously. Our patient presented with fever, hepatosplenomegaly, and severe pancytopenia. Hemophagocytic lymphohistiocytosis was diagnosed with additional laboratory evaluation, including measurement of serum ferritin, fibrinogen, and liver function tests. In addition, BMA revealed HPCs. A viral trigger seems likely, although none were identified. Surprisingly, the patient recovered without any specific chemoimmunotherapy, illustrating the variable course this often fatal syndrome can manifest. Diagnosis of HLH requires satisfaction of multiple criteria, although FHL can also be diagnosed by genetic testing, family history, or possibly consanguineous parents. The Histiocyte Society published clinical criteria for diagnosing FHL in the pediatric age range (HLH-2004) [4]. Although never validated in adults, our patient satisfied these criteria,
0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034
2
J. Cesarine et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Table 1 Laboratory values Presentation
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Hemoglobin (14.0-18.0 g/dL)/hematocrit (42%-52%)
12.2/36.4
8.1/23.9
8.3/24.8
8.1/23.8
0.38 0.37
0.38
0.67
1.97
3.24
Platelets (150-400 × 103/μL)
86
28 53a
49
65
95
147
Ferritin (15-400 ng/mL) Fibrinogen (134-351 mg/dL)
1826 257 11.9
10.0/30.3 10.1/30.6 9.3/27.2 0.59 0.51 0.49 32 32 32 12 596 119
8.4/24.6
0.98
9.3/27.0 9.5/27.3 9.4/27.3 0.49 0.50 0.43 33 34 31
8.6/25.1 7.9/23.6
WBC (4.5-11.0 × 103/μL)
11.6/33.9 10.0/29.0 10.1/29.7 0.91 0.71 0.68 60 54 40 4836
(b0.50 μg/mL) AST (10-35 U/L)/ALT (6-45 U/L) Total bilirubin (0.0-1.2 mg/dL)/direct bilirubin (0.0-0.3 mg/dL) LDH (110-230 U/L) Triglycerides (b50.0 mg/dL) Sodium (135-145 mmol/L)
D-Dimer
75/39 2.9/0.7
106/38 2.1/0.8
466
732
134
123 134
135
135
Bicarbonate (23-30 mmol/L)
21
20
21
22
Creatinine (0.6-1.2 mg/dL)
1.53
1.54
1.36
1.21
a
14 995
134 135 23 23 1.30 1.34
136
135
138
139
24
23
24
24
1.35
1.26
1.09
1.04
Transfused 2 units of platelets before interventional radiology-guided BMA and biopsy.
having the 6 of 8 positive. Fardet et al [5] published criteria specifically for diagnosing adult sHLH, available online at http://saintantoine.aphp. fr/score/. Our patient's H-score was 224 (HLH probability of 97%). Different criteria may apply to diagnosing HLH with acute flares of rheumatic diseases such as systemic juvenile idiopathic arthritis [6]. In these instances, baselines levels of leukocytes, platelets, and fibrinogen may be significantly elevated so that the thresholds of HLH-2004 may
be too stringent. Relative decreases with higher cutoffs may be more appropriate, with published criteria specifically for systemic juvenile idiopathic arthritis available (Table 2). Emergency medicine physicians should be aware of these nuances of diagnosis to most effectively recognize potential cases presenting to the ED. Equally important to establishing a diagnosis of HLH is defining any potentially triggering agent(s). The most common triggers in adult HLH
Table 2 Diagnostic and classification criteria for HLH HLH2004 diagnostic criteriaa
H-score diagnostic criteriab
Macrophage activation syndromec
The diagnosis of HLH can be established by a molecular diagnosis consistent with HLH or by meeting ≥5 of the following 8 clinical and laboratory diagnostic criteria:
A higher score is associated with a higher risk for HLH, as calculated based on the following criteria and scoring system
A patient with known or suspected systemic juvenile idiopathic arthritis is classified as having macrophage activation syndrome if the following criteria are met: Fever
1. Fever 2. Ferritin ≥500 ng/mL
3. Cytopenias (affecting ≥2 of 3 lineages in peripheral blood): Hemoglobin b90 g/L Platelets b100 × 109/L Neutrophils b1.0 × 109/L 4. Splenomegaly
5. Hypertriglyceridemia and/or hypofibrinogenemia: Fasting triglycerides ≥265 mg/dL Fibrinogen ≤150 mg/dL 6. Soluble CD25 ≥ 2400 U/mL 7. Low or absent NK-cell activity
8. Hemophagocytosis in bone marrow or spleen or lymph nodes
Temperature (°C): 0 (b38.4), 33 (38.4-39.4), or 49 (N39.4) Ferritin (ng/mL): 0 (b2000), 35 (2000-6000), or 50 (N6000) No. of cytopenias (hemoglobin ≤ 9.2 g/dL and/or leukocytes ≤5000/mm3 and/or platelets ≤110 000/mm3): 0 (1 lineage), 24 (2 lineages), or 34 (3 lineages) Organomegaly: 0 (no), 23 (hepatomegaly or splenomegaly), or 38 (hepatomegaly and splenomegaly) Triglyceride (mg/dL): 0 (b132), 44 (132-353), or 64 (N353) Fibrinogen (mg/dL): 0 (N250) or 30 (≤250) Serum glutamic oxaloacetic transaminase (IU/L): 0 (b30) or 19 (≥30) Known underlying immunosuppression due to human immunodeficiency virus or long-term immunosuppressive therapy: 0 (no) or 18 (yes) Hemophagocytosis features on bone marrow aspirate: 0 (no) or 35 (yes)
Ferritin N684 ng/mL Plus any 2 of the following: Platelets ≤181 × 109/L
Triglycerides N156 mg/dL Fibrinogen ≤360 mg/dL Aspartate aminotransferase N48 U/L
a
Henter J-E, Horne A, Aricó M, et al. Pediatr Blood Cancer. 2007;48:124–31. In a development and validation study, the probability of having reactive hemophagocytic syndrome was less than 1% with an H-score less than 90% to greater than 99% with an H-score greater than 250; the median H-score for a positive diagnosis was 230 (interquartile range, 203-257), and the median H-score for a negative diagnosis was 125 (interquartile range, 91-150) [5]. c Cron RQ, Davi S, Minoia F, Ravelli A. Expert Rev Clin Immunol. 2015;11:1043–53. b
Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034
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are infections and malignancy (usually lymphomas or leukemia) with flares of rheumatic disease found in about 10%. Multiple triggers may exist in up to one third [3]. Almost any infection can trigger HLH, but viruses are most notable [7]. The single most common virus is EBV, but other herpes viruses are also prominent, including cytomegalovirus, herpes simplex, HHV-6, and HHV-8. Other viruses to consider testing for include parvovirus B19, hepatitis (A, B, and C), dengue, adenovirus, measles, mumps, and rubella. Importantly, HLH had a prominent role in mortality from 2009 influenza A (H1N1). The most common bacterial infections triggering HLH include intracellular bacteria such as tuberculosis and Rickettsia, but pyogenic bacteria such as Staphylococcus and Escherichia coli have been reported. The most common parasite is leishmania, and diagnosis may require PCR of BMA fungi such as histoplasmosis have also been reported. Malignancy underlies up to half of adult cases of sHLH and becomes especially prominent in the elderly [8]. Active malignancy can trigger HLH, or it can occur during chemotherapy-induced remission typically associated with infection. The most common malignancies involve lymphocytes, including T- and natural killer (NK) cell lymphomas or leukemias, diffuse large B-cell lymphoma, or Hodgkin's. Immunosuppression is a significant risk factor, secondary to HIV [9] or following either solid organ or hematopoietic stem cell transplantations (HSCTs) [10]. In these cases, infections are the usual triggers, but malignancy can be as well. The pathogenesis of HLH is incompletely understood. In FHL, defective cytotoxic degranulation or reduced perforin synthesis impairs the ability of CTLs and NK cells to lyse target cells [11]. Infected or malignant cells cannot be effectively killed initially. Similarly, antigen presenting cells cannot be appropriately eliminated upon resolution of the initial challenge. In sHLH, acquired transient defects occur. In either case, CTLs release large quantities of interferon γ, which then results in macrophage activation and proliferation. Overproduction of inflammatory cytokines (interleukin [IL] 1, IL-6, IL-18, tumor necrosis factor α, among others) occurs, with the resulting “cytokine storm” driving the syndrome. Hemophagocytes may actually be reactionary, as these alternatively activated M-2 macrophages release the anti-inflammatory IL-10, and by catabolizing heme produce further anti-inflammatory factors (carbon monoxide, biliverdin, and ferritin) [12]. Our patient illustrates the dilemma with treating a potentially infected or immunosuppressed patient with further chemoimmunotherapy. Fortunately, he recovered without specific therapy. No published randomized controlled trials exist. Recommended therapy for FHL (the HLH-2004 protocol) includes dexamethasone, etoposide, and cyclosporine with the intent of HSCT when a suitable donor becomes available [4]. Etoposide has special benefit given its activity against CD8+ CTLs. Utilization of an earlier version of HLH-2004 changed 5-year survival of FHL from less than 5% without therapy to more than 50% [13]. The approach to treatment of the adult with sHLH depends on the particular circumstances given its heterogeneity and the variability in mortality [3]. Our patient recovered with only supportive therapy, and no specific trigger was identified. In the critically ill patient with multiorgan dysfunction syndrome, some form of immunosuppression is usually administered to quell the hyperinflammation as hospital mortality exceeds 50% [14]. High-dose steroids (methylprednisolone or dexamethasone if central nervous system involvement) may be combined with additional agents, such as cyclosporine, anakinra, or intravenous immunoglobulin [15]. Plasmapheresis has also been used. The mortality of HLH complicating rheumatic disease is much lower than FHL or other causes of sHLH such as malignancy or infection, perhaps around 10% [16]. Steroids and cyclosporine are typically used, but cytokine inhibitors such as anakinra or tocilizumab may be tried. Etoposide is usually reserved for severe or refractory cases [16]. Epstein-Barr virus requires special consideration. It is the most common infectious trigger, and it may occur with primary infection or
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reactivation of latent disease. Mortality is substantial. Etoposide is indicated as EBV may predominantly infect T cells in this circumstance, and it should be started within 4 weeks of onset [17]. Hematopoietic stem cell transplantation has been used for refractory cases, and rituximab may be considered. Because hypomorphic mutations in the genes responsible for FHL can be found in a significant minority of adult sHLH cases, screening by flow cytometry for intracellular perforin and surface expression of CD107 (indicating normal T-cell degranulation) should be performed in all cases of sHLH [18]. If abnormal, genetic testing can follow. An underlying genetic defect would signify possible recurrence if the patient survives, and hence, the possible need for HSCT. Such testing is indicated in our patient. Hemophagocytic lymphohistiocytosis is a severe, potentially fatal hyperinflammatory syndrome that may present unsuspectedly to the ED. Physicians should be aware of its features to both ensure timely ordering of confirmatory tests for diagnosis as well as to initiate appropriate evaluation of triggering agents. Hemophagocytic lymphohistiocytosis should be in the differential diagnosis of a febrile patient with unexplained bicytopenia/pancytopenia or abnormal neurologic function. Ferritin, fibrinogen, LDH, and liver function tests should be immediately obtained, along with evaluation for splenomegaly. Bone marrow aspiration should not be delayed if features are consistent. Our patient serves to illustrate these issues. Joseph Cesarine MD Lisa M. Filippone MD Department of Emergency Medicine Cooper Medical School of Rowan University, Camden, NJ Edward J. Filippone MD Division of Nephrology, Department of Medicine Sydney Kimmel Medical College at Thomas Jefferson University Philadelphia, PA 19107 ⁎Corresponding author. 2228 south Broad St, Philadelphia, PA 19145 Tel.: +1 215 467 8955; fax: +1 215 467 8955 E-mail address: [email protected]
http://dx.doi.org/10.1016/j.ajem.2016.03.034
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Please cite this article as: Cesarine J, et al, Hemophagocytic lymphohistiocytosis in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.03.034