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|Haemophagocytic lymphohistiocytosis and the challenge of early diagnosis
Hoda Mohamed Hammoda1, Mahmoud Mohamed Marashi2, Hesham Abdalla Mohamed Abdalla1, Mahmod El Shahat Awad Makhlof3, Manal Sayed Rezzek1
1 Department of Internal Medicine, Hatta Hospital, Dubai, UAE
2 Department of Haematology, Dubai Hospital, Dubai, UAE
3 Department of Intensive Care, Hatta Hospital, Dubai, UAE
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Haemophagocytic lymphohistiocytosis (HLH) is an uncommon, life-threatening hyperinflammatory syndrome in which abnormal, ineffective energising of the immune system causes excessive activation of lymphocytes and macrophages, which can lead to hypercytokinaemia and massive tissue destruction. A high index of suspicion is necessary for early diagnosis. We report a case of HLH in a 66-year-old woman who presented with fever, pancytopenia and hepatosplenomegaly.
Keywords: Hypercytokinaemia, hyperinflammatory syndrome, lymphohistiocytosis
|How to cite this URL:|
Hammoda HM, Marashi MM, Mohamed Abdalla HA, Awad Makhlof ME, Rezzek MS. Haemophagocytic lymphohistiocytosis and the challenge of early diagnosis. Hamdan Med J [Epub ahead of print] [cited 2019 Mar 20]. Available from: http://www.hamdanjournal.org/preprintarticle.asp?id=237849
| Introduction|| |
Haemophagocytic lymphohistiocytosis (HLH) is an uncommon, life-threatening hyperinflammatory syndrome in which abnormal, ineffective energizing of the immune system causes excessive activation of lymphocytes and macrophages, which can lead to hypercytokinaemia and massive tissue destruction. A high index of suspicion is necessary for early diagnosis. We report a case of HLH in a 66-year-old woman who presented with fever, pancytopenia and hepatosplenomegaly.
| Case Report|| |
A 66-year-old Syrian woman with a long-standing history of hypertension and diabetes mellitus, who was taking oral hypoglycaemic medication, presented to the emergency department of Hatta Hospital with symptoms of anaemia and intermittent fever for 3 months. She claimed to have lost around 10 kg in the preceding 6 months. She had neither loss of appetite nor night sweats and no history of bleeding from any site. The patient had been previously examined in Syria to exclude malignancy; upper and lower gastrointestinal endoscopy results were unremarkable. The patient was anxious about her recurrent symptoms of anaemia despite treatment.
The patient was conscious, alert and oriented, with a Glasgow Coma Scale score of 15/15. Her heart rate was 120 bpm, blood pressure was 140/90 mmHg, respiration rate was 18 breaths/min and oxygen saturation was 98% (on room air). She was pale and febrile with a temperature of 39°C. There was no jaundice, meningeal irritation, sign of cyanosis, tender or swollen joints, or skin rashes. There were no palpable lymph nodes. Her chest was clear on auscultation and heart sounds were normal.
Abdominal examination revealed an enlarged liver (three fingers below costal margin) and splenomegaly.
Results revealed pancytopenia: haemoglobin 6.8 g/dl (normal range 11–15 g/dl); white blood cell count 3000 cells/mm3 (normal range 4000–10,000 cells/mm3); platelet count 84 000 cells/mm3 (normal range 150,000–450,000 cells/mm3); mean corpuscular volume 81.9 fl (normal range 77–92 fl); mean corpuscular haemoglobin (MCH) 27.9 pg (normal range 26–34 pg); MCH concentration (MCHC) 34.9 g/dl (normal range 32–36 g/dl); erythrocyte sedimentation rate (ESR) 128 mm/h; ferritin 1850 ng/ml; creatinine 0.9 mg/dl; HbA1C 6.6%; glucose 247 mg/dl; lactate dehydrogenase 434 u/L; reticulocyte count 0.62%; and triglyceride count 292 mg/dl. Collagen work-up was negative. Blood film was inconclusive. No infection could be clinically detected to explain the fever. Septic work-up, tuberculosis screen and viral isolation tests were negative.
Computerised tomography of the abdomen and pelvis, with contrast enhancement, showed marked hepatomegaly (span ≈ 25 cm) and marked splenomegaly (span ≈ 19 cm) with a ring-like hilar calcification shadow that was likely to be vascular.
The patient was admitted to a medical ward at Hatta Hospital and received several units of packed red blood cells for her anaemia. However, haemoglobin levels rapidly declined and fever was persistent.
On detailed work-up, her bone marrow aspirate showed hypercellular bone marrow with focal fibrosis. There were multiple nodular infiltrates of small lymphocytes. Bone marrow culture showed no growth after 9 days. Lymphoma and leukaemia were excluded by immunohistochemistry.
Thorough physical examination did not reveal any neurological deficit.
Our challenge was the early diagnosis of haemophagocytic lymphohistiocytosis (HLH) based on the diagnostic criteria outlined in the Histiocyte Society's diagnostic and therapeutic guidelines. Diagnosis of HLH can be established if either of the below (1 or 2) is fulfilled.
- A molecular diagnosis consistent with HLH is made
- Diagnostic criteria for HLH are fulfilled (five or more of the eight criteria below):
- Temperature ≤38.5°C
- Peripheral blood cytopenia, with at least two of the following– haemoglobin <9 g/dl; platelet count <100,000 cells/mm3; absolute neutrophil count <1000 cells/mm3
- Hypertriglyceridaemia (fasting triglycerides >265 mg/dl) and/or hypofibrinogenaemia (fibrinogen <150 mg/dl)
- Haemophagocytosis in bone marrow, spleen, lymph node or liver
- Low or absent natural killer (NK) cell activity
- Ferritin >500 ng/ml
- Elevated soluble CD25 (interleukin-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms.
Our patient fulfilled five of these criteria (i.e., fever, with a temperature ≤38.5°C; splenomegaly; pancytopenia; hypertriglyceridaemia; and ferritin >1123.5 pmol/L).
The patient received steroid induction therapy followed by high-dose prednisolone. She was monitored closely for signs of improvement as well as potential complications. She showed excellent response to therapy, with a resolution of her symptoms, normalisation of her counts, progressive decline in ferritin and triglyceride levels and a return to normal ESR levels. She was discharged on ciclosporin.
Follow-up test results are presented in [Table 1].
| Discussion|| |
HLH is a disease with major diagnostic and therapeutic difficulties. HLH comprises two conditions: a primary (genetic) and secondary (acquired) form. The primary form, familial HLH (FHL, is an autosomal recessive form and has an estimated incidence of around 1 in 50,000 live-born children.
Familial HLH was first described as familial haemophagocytic reticulosis and reported by Farquhar and Claireaux in a 1952 study in which various organs of two infant siblings were infiltrated by histiocytes showing active phagocytosis of blood cells. FHL is rapidly fatal, with a median survival of 1–2 months, unless treated with haematopoietic cell transplantation.
Secondary HLH (sHLH) may develop as a result of progressive organ dysfunction caused by massive activation of the immune system. Infections (41.1%), malignancies (28.8%), idiopathic disorders (17.8%), autoimmune disorders (6.8%), primary immunodeficiency (1.4%) and postsolid organ transplantation disorders (2.7%) are all commonly found in patients with this syndrome.
Proliferation, migration and infiltration of hyperactivated CD8+ T lymphocytes and macrophages into various organs, including bone marrow, liver, spleen and lymph nodes, leads to hypercytokinaemia and subsequently progressive multiorgan dysfunction.
Patients who fulfil the criteria for HLH should be screened thoroughly for infection, including viral, bacterial and fungal infections. Neurological findings and deterioration in liver functions are common features of HLH though they are not included in diagnostic criteria.
Diagnosis of sHLH is difficult if no trigger factor can be localised, as was the case for our patient, in whom bone marrow aspiration (BMA) was not conclusive.
In 2008, Gupta et al. reported that the failure of BMA to reveal haemophagocytosis does not rule out a diagnosis of HLH, and a negative initial BMA should not delay therapy, as haemophagocytosis may appear later in the disease course, thus requiring serial BMA examination for detection.
Unfortunately, tests for NK cell cytotoxicity and flow cytometry were not performed because they are expensive and time-consuming.
Chemotherapy and immunotherapy are the recommended treatments for HLH to downregulate the inflammatory process; 8 weeks of therapy is recommended for sHLH. For genetic disease, therapy should be continued after week 8 until stem cell transplantation. Chemotherapy with etoposide, anti-thymocyte globulin, dexamethasone and ciclosporin is recommended, with the use of intrathecal methotrexate in patients with neurological symptoms or persistent cerebrospinal fluid abnormalities. Treating the underlying triggers of HLH is also highly recommended.
Many patients suffer dramatic deterioration necessitating admission to intensive care, which is a particular risk if there is any delay in diagnosis or there are complications. Although individual findings in HLH may mimic features of sepsis and multiorgan dysfunction, close follow-up is needed to define the diagnostic criteria for HLH, and the degree of abnormality of inflammatory markers may help to distinguish these disorders.
| Conclusion|| |
We aimed in this article to draw attention to and give a brief overview of HLH diagnostic criteria and emphasise the importance of early diagnosis. Physicians should suspect HLH if their patient fulfils the diagnostic criteria regardless of bone marrow test results. According to HLH protocol, treatment should preferably be started in a qualified immunology centre, which is likely to improve outcomes.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
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.
Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991;80:428-35.
Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519-25.
Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2015;90:220-4.
Weitzman S. Approach to hemophagocytic syndromes. Hematology Am Soc Hematol Educ Program 2011;2011:178-83.
Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601-8.
Gupta A, Tyrrell P, Valani R, Benseler S, Weitzman S, Abdelhaleem M, et al
. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;51:402-4.
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.
Hoda Mohamed Hammoda,
Department of Internal Medicine, Hatta Hospital, Dubai
Source of Support: None, Conflict of Interest: None
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