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 Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 8  |  Issue : 4  |  Page : 145-151

Secondary hemophagocytic lymphohistiocytosis syndrome in adults: A case series and review of the literature


1 Department of Medicine, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia
2 Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
3 Department of Medicine, Dr. Soliman Fakeeh Hospital, Jeddah; Department of Medicine, Faculty of Medicine, Umm Al-Qura University, Makkah; Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

Date of Web Publication12-Jan-2018

Correspondence Address:
Dr. Hani Almoallim
Associate Professor, Medical College, Umm Al-Qura University (UQU), Makkah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_42_17

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  Abstract 


Hemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening condition characterized by immune dysregulation and benign proliferation of phagocytic cells, macrophages, and histiocytes. Lymphocytes (CD8 T-cells and natural killer cells) also play a major role in HLH. The ensuing cytokine storm and blood cells phagocytosis can lead to fatal multiple organ failure. So any diseases that can lead to activation of these cytokines can lead to hemophagocytic syndrome. 5 adult patients presented to Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia during 2014–2016 and fulfill the diagnostic criteria of HLH according to HLH-2004 diagnostic and therapeutic guidelines for HLH , have been included in this case series. Two out of five had viral infection, one patient was diagnosed with tuberculosis, and one patient developed secondary HLH in due to malignancy. The fifth patient did not have an identiable etiology. All of our patients presented with different symptoms and were diagnosed based on the standard approved criteria. Only two Out of five patients survived and remained disease free for a follow-up period of 24 months. As a conclusion, HLH syndrome is a rare condition with a high mortality rate. Aggressive treatment approach and early Intensive Care Unit admission is strongly recommended in patients with the cardinal diagnostic features of this condition.

Keywords: Hemophagocytic lymphohistiocytosis syndrome, hemophagocytic syndrome, lymphohistiocytosis


How to cite this article:
Taha R, Al-Dhaheri F, Dwid N, Almowarey MR, Al-Ammari M, Abbas H, Alamoudi A, Fathaldin O, Mohamed T, Almoallim H. Secondary hemophagocytic lymphohistiocytosis syndrome in adults: A case series and review of the literature. J Appl Hematol 2017;8:145-51

How to cite this URL:
Taha R, Al-Dhaheri F, Dwid N, Almowarey MR, Al-Ammari M, Abbas H, Alamoudi A, Fathaldin O, Mohamed T, Almoallim H. Secondary hemophagocytic lymphohistiocytosis syndrome in adults: A case series and review of the literature. J Appl Hematol [serial online] 2017 [cited 2019 Sep 18];8:145-51. Available from: http://www.jahjournal.org/text.asp?2017/8/4/145/223176




  Introduction Top


Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening condition characterized by defective apoptosis and cytotoxic activity and cytolytic defects in natural killer (NK) and CD8 T-cells leading to immune dysregulation and benign proliferation of phagocytic cells and histiocytes. Hyperactivation of macrophages results in the release of cytokines and phagocytosis of blood cells and their precursors in the bone marrow and other tissues such as the liver, spleen, skin, and lymph nodes.[1]

HLH syndromes can be classified into primary (genetic) or secondary (acquired) HLH.[2],[3] Primary HLH, otherwise known as familial HLH, is an autosomal recessive disease that presents during infancy or early childhood with a progressive course and fatal outcome, there are x-linked disorders as well. Secondary HLH (sHLH) can be triggered by infection, malignancy, or the presence of an underlying autoimmune disease. sHLH may also manifest without a specific identifiable trigger (i.e., sporadic).[4],[5],[6] HLH due to infection in infancy is difficult to distinguish from the familial type as both conditions have the same presentation and generally the same lethal course. Viral infection has been identified as a common causative agent for viral-associated HLH, in particular, infections resulting from Epstein–Barr virus (EBV), herpes virus, and adenovirus.[7],[8],[9] However, many other viral, bacterial, or fungal infectious agents have been implicated in triggering the disease. Malignancy-associated HLH can present either during the malignancy or treatment. Irrespective of the etiology, the clinical course of HLH typically includes fever, pancytopenia, abnormal liver function tests, hypofibrinogenemia, elevated ferritin, and triglycerides (TGs) levels and can be complicated by end-organ damage, neurologic manifestations, and coagulopathy. Tissue biopsy typically reveals low NK cell activity and hemophagocytosis, particularly in the bone marrow. The diagnosis of HLH usually rests upon a combination of clinical, laboratory, genetic, and histopathological criteria. In the absence of familial disease or molecular identification of an HLH-associated gene mutation, at least 5 out of the 8 criteria [Table 1] must be present to establish a diagnosis of HLH.[2]
Table 1: Hemophagocytic lymphohistiocytosis diagnostic criteria

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Several treatment protocols have been shown to improve the survival of patients with HLH. In general, treatment regimens combine both chemotherapy and immunotherapy (e.g., etoposide, steroids, and cyclosporine) and in familial cases, are followed by bone marrow transplantation. Intrathecal methotrexate is considered when there is neurological involvement. Other sHLH therapies include intravenous immunoglobulin (IVIg), rituximab, Actemra, anakinra, pheresis, Campath.[10]

Rapid diagnosis and initiation of treatment significantly improve survival of patients with HLH.[2],[10] The 3-year survival after proper therapy with the HLH-94 protocol for both familial and sHLH is approximately 50%. In familial cases, this increases to 62% after bone marrow transplantation.[10],[11] The wide range of clinical presentations often contributes to a delay in diagnosing HLH. In many cases, the diagnosis is not made until there is evidence of end-organ failure.

Although the incidence of HLH in the adult population is unknown, the number of cases reported in the literature has dramatically increased over the past 10 years. Given the rarity of this condition, we present a series of cases of sHLH in adult patients with a variety of presentations and associated comorbidities.


  Case Reports Top


We identified 5 cases of HLH in adults diagnosed at Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia. The ethics committee and the hospital research committee approvals were obtained. The diagnosis was made on the basis of clinical and laboratory criteria put forth in the guidelines of the Histiocyte Society in the revised diagnostic criteria for HLH.[2] [Table 2] summarizes the comorbidities and the key clinical characteristics of each case while [Table 3] presents the laboratory investigations and outcomes.
Table 2: Case specific clinical characteristics

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Table 3: Case-specific morbidity and outcomes

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Case 1

A 20-year-old female with a known diagnosis of tuberculosis (TB) 2 months before admission presented with persistent fever and headache for the previous 10 days. On examination, her vital signs were stable except for pyrexia (38.5°C). Physical examination revealed hepatomegaly and a rash on her lower limbs. Diagnostic workup revealed a high ferritin 4393 (12–300 ng/mL), pancytopenia: White blood cell (WBC) 1.2 × 103/uL (4–10 × 103/uL), Hb 6.7 g/dL (12–14 g/dL), platelets 92 × 103/uL (150–450 × 103/uL), normal C-reactive protein (CRP), and elevated lactate dehydrogenase (LDH) at 390 U/L (140–280 U/L). The liver enzymes were also elevated with aspartate aminotransferase (AST) at 396 U/L (8–48U/L) and alanine aminotransferase (ALT) at 196 U/L (7–55 U/L) [Table 3]. To avoid further liver injury, anti-TB medications were held and then switched to second-line medications. Sputum and blood cultures were negative for acid-fast bacilli. Infective endocarditis was ruled out. An autoimmune workup was initiated based on the persistent pancytopenia and fever. Serologic tests for autoimmunity were negative. Fundus examination showed bilateral papilledema. A brain magnetic resonance imaging (MRI) and lumbar puncture showed no evidence of mass lesions or infection, respectively. Bone marrow biopsy showed hematopoietic hyperplasia and hemophagocytosis. A diagnosis of HLH was made, and the patient was started on the HLH 1994 (HLH-94) protocol with pneumocystis prophylaxis and antifungals. She showed dramatic improvement but was subsequently readmitted for complaints of agitation, irritability, and headache. There was no clinical or laboratory evidence of infection or metabolic abnormality. An MRI was unremarkable. A lumbar puncture suggested high intracranial tension without evidence of infection on gram stain, culture, polymerase chain reaction (PCR), or cytology. Diuresis with acetazolamide and symptomatic treatment with the antiepileptic topiramate were initiated without improvement. The treatment with HLH-94 protocol was reinitiated, and the patient showed marked improvement with full recovery. She had no evidence of relapse during the follow-up period of 18 months.

Case 2

A 56-year-old male with a known history of diabetes mellitus and hypertension presented with fever for 8 days associated with watery diarrhea, repeated vomiting, abdominal pain, and cough. He was admitted to another hospital for 5 days for evaluation of similar complaints, and then transferred to our hospital. On examination, his vital signs were stable except for pyrexia (38°C). Hepatosplenomegaly was noted on physical examination. Diagnostic workup revealed pancytopenia: WBC 2.6 × 103/uL (4–10 × 103/uL), Hb 9.8 g/dL (12–14 g/dL), and platelets of 92 × 103/uL (150–450 × 103/uL). The liver enzymes were raised with AST being markedly raised at 359 U/L (8–48 U/L) and ALT at 105 U/L (7–55 U/L) [Table 3]. Marked elevation of CRP at 312 mg/L (0–6 mg/L) and LDH was 593 U/L (140–280 U/L) A sepsis workup was negative except for positive IgM (negative IgG) for dengue fever. Stool analysis, Clostridium difficile toxin and culture were both negative. Abdominal ultrasound showed mild hepatosplenomegaly. A chest X-ray showed an increase in bronchovascular markings but no signs of pneumonia. A diagnosis of dengue fever was suspected because of the low platelets and WBC count, and the patient received supportive therapy. The fever continued for more than 10 days. Autoimmune disorders, acute human immunodeficiency virus (HIV), malaria, and infective endocarditis were all ruled out. A computed tomography (CT) with the contrast of the chest, abdomen, and pelvis were unremarkable. The patient underwent bone marrow biopsy which showed an increase in histiocytic activity with scattered hemophagocytosis. A diagnosis of HLH most likely secondary to dengue fever was made. He was started on the HLH-94 protocol with pneumocystis carinii and antifungal prophylaxis. Five days after starting the HLH protocol, the patient showed signs of end organ damage and developed a supraventricular arrhythmia followed by rapid atrial fibrillation. His heart rate was 170/min. He converted to sinus rhythm following the administration of amiodarone bolus and an infusion. The patient had cardiac arrest and died 5 days after his admission to the Intensive Care Unit (ICU).

Case 3

A 22-year-old male with an unremarkable medical history presented with fever and chills of 2-week duration. His family history was significant for a sibling who died from a viral infection. The patient had a positive Widal test as part of a diagnostic workup in another health-care facility and was given a course of antibiotic treatment with ciprofloxacin and amoxicillin-clavulanate. Clinical examination was unremarkable except for pyrexia 38°C. Initial diagnostic workup revealed a normal complete blood count WBC 9.2 × 103/uL (4–10 × 103/uL), Hb 12 g/dL (12–14 g/dL), platelets 188 × 103/uL (150–450 × 103/uL), and elevated liver enzymes AST 135 U/L (8–48U/L) and ALT 106 U/L (7–55 U/L) and a high CRP 193 mg/L (0–6 mg/L). Other laboratory workup for autoimmune diseases, viral infections, malaria, and  Brucella More Details was negative.

Seven days after his first visit, he presented to the clinic with cellulitis of the lower limb associated with a persistent high-grade fever of 39.5°C. Repeated laboratory workup showed pancytopenia: WBC of 2 × 103/uL (4–10 × 103/uL), Hb of 8 g/dL (12–14 g/dL), and platelets of 121 × 103/uL (150–450 × 103/uL). Other investigations showed hypertriglyceridemia, a ferritin level of 15,482 ng/mL (12–300 ng/mL), positive direct antiglobulin test, LDH of 2,571 U/L (140–280 U/L), and ALT/AST levels that had increased from his initial presentation [Table 3]. CT scan of the chest, abdomen, and pelvis were unremarkable. A bone marrow confirmed the diagnosis of HLH. IVIg was started, and the patient showed improvement. His fever subsided and hematologic parameters improved (WBCs 3.2 × 103/uL, Hb 8.5 g/dL, and platelets 155 × 103/uL). The ferritin level decreased to 13,000 ng/mL. The patient was discharged on oral steroids. Four days after his discharge, he developed panniculitis in his lower limbs and was advised to continue the steroids.

A week later, the patient presented again with fever, personality changes, and agitation. Laboratory results showed recurrent pancytopenia (WBC 2 × 103/uL, Hb 7.8 g/dL, and platelets 119 × 103/uL) and a ferritin level of 9,500 ng/mL. A brain MRI was unremarkable. A lumbar puncture revealed a WBC of 7.5 × 103/uL with normal protein and glucose levels. He was admitted and his hospital course was complicated by a seizure which was treated successfully with antiepileptic medications. Before initiation of the HLH-94 management protocol, the patient transferred to another medical center.

Case 4

A 44-year-old male with a known history of rheumatoid arthritis who was nonadherent to his treatment, presented to our hospital with dizziness and a high-grade fever 39°C for 1 week followed by severe headaches, nausea, and vomiting for 5 days. He had self-administered over-the-counter antipyretics with no clinical improvement. On examination, his vital signs were stable except for fever. Diagnostic workup revealed pancytopenia: WBC 1.7 × 103/uL (4–10 × 103/uL), Hb 7.5 g/dL (12–14 g/dL), platelets 34 × 103/uL (150–450 × 103/uL). AST was markedly elevated at 879 U/L (8–48U/L), ALT 315 U/L (7–55 U/L), and ferritin level of 67,073 ng/mL (12–300 ng/mL) [Table 3]. During his hospital course, his condition deteriorated clinically, and he developed confusion, respiratory distress and bleeding per rectum. EBV PCR was positive at 8,678,536 copies/ml. Proton pump inhibitors and octreotide were initiated. A chest X-ray showed bilateral infiltrates. Teicoplanin and Meropenem were added to his medications. His condition continued to deteriorate with the development of hypotension and respiratory failure requiring intubation, mechanical ventilation and inotropes. Then, he received circulatory supportive care with packed red blood cells, fresh frozen plasma, platelets, furosemide, and hemodialysis. Plasmapheresis was also initiated with suspension of catastrophic antiphospholipid syndrome. A bone marrow biopsy confirmed the diagnosis of HLH [Figure 1] and [Figure 2]. The patient was started on steroids, IVIg, and etoposide, but he continued to be hypotensive and died soon after.
Figure 1: Hemophagocytosis in a bone marrow biopsy of Case 4. (Histiocyte engulfing red blood cell in black arrows)

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Figure 2: Bone marrow biopsy of the Case 4 with immunohistochemistry study showing CD68+ve histiocytes “brown color”

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Case 5

A 54-year-old male with a known history of classic Hodgkin's disease developed signs of relapse after treatment. He was diagnosed in 2011 with stage IV a mixed cellularity Hodgkin's disease with bone marrow involvement. He received 6 cycles of ABVD regimen (adriamycin, bleomycin, vinblastine, and dacarbazine) with an initial response, but relapsed with general constitutional B-symptoms including abdominal pain and bone pain. He did not tolerate a salvage DHAP regimen (dexamethasone, high-dose cytarabine, and cisplatin) due to nephrotoxicity, renal tubular acidosis, and febrile neutropenia after the second dose. On admission, he complained of 5 days of fever, nausea, and vomiting associated with anorexia. On examination, his vital signs were stable except for fever 38°C. He was pale and jaundiced. Cervical lymphadenopathy and hepatomegaly were also present. Diagnostic workup revealed pancytopenia: WBC 0.12 × 103/uL (4–10 × 103/uL), Hb 6.1 g/dL (12–14 g/dL), and platelets 6 × 103/uL (150–450 × 103/uL). The serum ferritin was 95,953 ng/mL [Table 3]. No abnormal cells were noted on the blood smear. Ultrasound of the abdomen and pelvis showed mild hepatomegaly, bilateral grade I medial nephropathy, mild pelvic ascites, and mild pelvic bowel wall thickening. Blood cultures, HIV serology, hepatitis B surface antigen, hepatitis C virus serology, and antinuclear antibody were negative. Bone marrow biopsy showed many reticulum cells with hemophagocytosis. A diagnosis of HLH was made. Unfortunately, the patient's condition deteriorated, and he died within 7 days of admission before starting the HLH protocol.


  Discussion Top


We present a case series of five patients, four males and one female with HLH with a mean age of 40.4 years, median age is 41 with 20-year-old being the youngest and 56-year-old being the eldest. Four of the five cases were associated with a triggering agent: Two cases were associated with a viral infection (EBV and dengue fever), one patient had TB, and one patient had a malignancy. No trigger was identified for the last patient [Table 2]. All of our patients fulfilled the criteria for a diagnosis of HLH, which showed features of hemophagocytosis on bone marrow biopsy. They all presented with fever, elevated liver enzymes, pancytopenia, and high ferritin levels. Four out of five patients had hepatomegaly. Two patients had neurological manifestations; also same number of patients was for both rash and splenomegaly. Only one patient had lymphadenopathy [Figure 3]. None of our patients had primary HLH due to familial disease. The patients were admitted to the ICU due to either end-organ damage, acute respiratory distress syndrome, or neurological manifestations. [Figure 3] summarizes the most common presenting symptoms and the patients' hospital course.
Figure 3: Clinical presentation of hemophagocytic lymphohistiocytosis in our case series

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Recently, there have been several published reports of clinical outcomes of patients with HLH who were treated with different management plans, including the HLH-94 protocol.

In 2009, three cases of HLH were reported from India.[12] One case was familial and the others were associated with TB and T-cell lymphoma. All patients presented with fever, hepatosplenomegaly, and pancytopenia. One of the three patients was a 7-year-old child and all had the diagnosis of HLH confirmed by the presence of hemophagocytosis and NK cell hypoactivity in bone marrow biopsies. The mortality rate was 66.6%.

In 2012, ten patients were included in a 2-year retrospective study from India.[13] HLH was secondary to infection in 80% of patients. There was one case each of leishmania, parvovirus B19, Leptospira, TB,  Salmonella More Details, and 3 cases due to EBV. About 10% of the cases were secondary to systemic lupus erythematous, and in 10% no etiology could be determined. All patients presented with fever, while 90% had neurological symptoms including delirium, seizure, or coma. Skin manifestations were found in 80% of patients, including petechial rash, purpura, and malar rash. Hepatomegaly was found in 90% of patients, splenomegaly in 60% of patients, while lymphadenopathy was found only in 30% of the patients. Serum ferritin and TGs levels were only measured in six patients. Serum ferritin levels were >500 ng/ml in all of the cases, while the TG levels were >265 mg/dl in only four patients. Fibrinogen was measured in seven patients, but only four patients had a level <1.5 g/L. Bicytopenia was found in 40% of patients. The mortality rate was 80%.

Five patients with HLH, two adults and three children, were included in another report from India in November 2013.[14] The adult cases were secondary to a bacterial infection, leptospirosis, and to viral encephalitis. Fever, elevated serum ferritin, elevated LDH and TG levels were observed in both cases. The mortality rate among adult cases was 100%.

In the United States, four adult cases were included in a case series in 2016.[15] Two of the cases were secondary to malignancy, one resulted from EBV infection, and one was primary HLH. All patients were cytopenic and had a fever. Splenomegaly was detected in 2 cases, and all patients had a ferritin level above 500 μg/L. The mortality rate was 25%.

In March 2016, a review of three patients, aged 50–69 years, with HLH in the United States was reported.[16] The first patient had primary HLH, and the other 2 cases were secondary to cytomegalovirus infection and diffuse large B-cell lymphoma. All of the patients presented with fever, cytopenia, elevated ferritin levels, hyponatremia, and elevated CD25. Two of them had splenomegaly. The mortality rate was 33.3%.

In 2016, five additional patients were reported in the United States.[17] The cases were diagnosed with HLH secondary to Still's disease, dengue virus, severe pneumonia with acute respiratory distress syndrome (suspicion of viral associated HLH), acute lymphoblastic leukemia, and metastatic breast cancer. All patients presented with fever and elevated ferritin levels. The mortality rate was 60%.

Several studies have reported that elevated ferritin levels and fever are the most common findings in patients with HLH.[12],[13],[14],[15],[16],[17] In our study, these findings were present in all of the cases.

Ferritin levels have been evaluated in adults and children with HLH. In a retrospective study of 330 patients with ferritin levels >500 μg/L, ten patients had HLH. The authors found that a ferritin level of more than 10,000 was 90% sensitive and 96% specific for HLH.[18] Another study showed that 19% of patients with ferritin levels >50,000 μg/L with coexisting infections, renal failure, hepatocellular injury, and hematologic malignancies had HLH.[19] Ferritin levels also appear to be clinically significant in children. In a study of 48 patients with HLH in which 50% were <2-year-old, the serum ferritin level was found to be an important prognostic factor for determining the outcome of the disease.[20]

Taken together, these observations suggest that ferritin levels can be a useful screening tool that, when combined with a high clinical suspicion for HLH, should prompt early treatment.

We also found that a rapid decrease in ferritin levels after treatment is a good prognostic sign. Patients with high ferritin levels who did not respond to treatment had a poor prognosis and high mortality rate, while patients with low ferritin levels after treatment had a better prognosis. Arca et al. identified several poor prognostic markers for patients with HLH.[21]

Neurological involvement has been reported in nearly half of the patients with HLH and can present as seizures, facial palsy, delirium, or an abnormal cerebrospinal fluid sample. The onset of the symptoms can vary during the disease. Although some studies have reported that neurological manifestations are associated with a poor prognosis,[22] our patients with neurological symptoms and normal findings on MRI had a high rate of remission without residual complications.

Age also appears to influence prognosis. A cohort study of 162 patients[21] found that a poor prognosis is associated with extremes in age (<6 months or older than 50 years), a high ferritin level, low platelets, and neurological manifestations. The above predictors of prognosis were noted in our cohort except for the neurological manifestations. The number of cases in our series is however small and therefore does not allow for effectively defining the predictors of prognosis.

All of our patients received either the 1994 or 2004 HLH protocol treatments. However, patients with neurological manifestations did not receive intrathecal methotrexate or intrathecal steroids. Patients with viral illnesses (EBV and dengue fever) and malignancy had a poorer prognosis compared with the patient with TB. The mean survival time was 20 days for the viral illness group and 4 days for the malignancy group. The patient with a malignancy passed away before the bone marrow results were available. In a case series of 6 patients with HLH associated with EBV, all of the cases died within 3 months of diagnosis.[7] Our patients with HLH secondary to TB and an unknown trigger were successfully treated according to the HLH protocol 2004 and 1994, with no evidence of relapse after a 24-month follow-up.


  Conclusion Top


HLH syndrome is a rare condition with a high mortality rate. Given the nonspecificity of the diagnostic features of the disease and its aggressive nature, it is important to have a low index of suspicion. Patients with the cardinal diagnostic features (fever, pancytopenia, elevated ferritin, and hypofibrinogenemia) should be promptly treated appropriately and considered for an early transfer to ICU.

Acknowledgment

We would like to thank Research-Medics for their editorial assistance in the preparation of this manuscript. This work was funded and supported by Alzaidi Chair of Research in Rheumatic Diseases, Umm Alqura University, Makkah, Saudi Arabia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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