Adult hemophagocytic lymphohistiocytosis triggered by disseminated tuberculosis and Klebsiella pneumoniaeco-infection in an immunocompetent individual-a diagnostic challenge

Here in we report a diagnostically challenging case of adult hemophagocytic lymphohistiocytosis (HLH) triggered by disseminated tuberculosis and Klebsiella pneumoniaeco-infection in an immunocompetent Individual. She was a young female presented with complaints of fever, abdominal pain and jaundice. Her evaluation showed cytopenias, hyperbilirubinemia, transaminitis, and hepatosplenomegaly. She progressed to have multi-organ involvement in the form of myocarditis, pleural effusion. Provisional diagnosis of fever with unknown origin and sepsis with multiple-organ dysfunction was made and evaluated for the same. Rapid clinical deterioration with evaluation for sepsis being normal prompted for considering HLH in the differential diagnoses, bone marrow and other criteria have been met resulting in confirmation of the same. Without prior past or family history of HLH, secondary HLH was suspected and substantial evaluation for possible triggers was made, and concomitantly immune suppression was started with corticosteroids. Disseminated tuberculosis was diagnosed and concomitantly Klebsiella pneumoniaewas isolated from the bronchioalveolar lavage cultures. As there was no significant immune response culmination, intravenous immunoglobulins were added along with the treatment for possible triggers-tuberculosis and Klebsiellasimultaneously. Patient showed significant improvement with this approach. In conclusion management of HLH is different from conventional sepsis and the treatment for each cause of HLH also varies. Furthermore, this case report stresses on the importance for initiating treatment rapidly and tailored approach of management therapy for each case.

Adult hemophagocytic syndrome in emergency department setting: the implications of hormone therapy on diagnosis and prognosis / 中华急诊医学杂志

Objective:To assess the implications of hormone therapy on confirmation of clinical diagnosis and prognosis of adult hemophagocytic syndrome (HPS) in the emergency department setting.Methods:The eligible 34 patients admitted with suspected HPS in the Emergency Department of Peking University People's Hospital from September 2019 to August 2021 were respectively collected. The patients were divided into the death group and survival group according to the prognosis and divided into early hormone therapy group and standard hormone therapy group according to the timing of hormone application. Patients in the early hormone therapy group were divided into the routine 4 criteria group and non-routine 4 criteria group according to the conditions of meeting the four HLH-2004 diagnostic criteria. Medical records of the following were collected and statistically analyzed: complete blood count, blood biochemical index, coagulation function, serum ferritin, NK cell activity, sCD25 level, peripheral blood smear, bone marrow biopsy, abdominal ultrasound scan, and abdominal CT on admission, and recheck the clinical indicators such as blood count, blood biochemical index and blood coagulation dunction 5-7 days later.Results:①Patients from the death group were older, with higher APACHEⅡ scores and SOFA scores, higher total bilirubin, and lower serum albumin. ② Univariate Logistic analysis showed age ( OR=1.098, CI: 1.019-1.183, P=0.014), APACHE Ⅱ score ( OR=1.144, CI: 1.017-1.285, P=0.024), SOFA score ( OR=1.441, CI: 1.079-1.925, P=0.013) were associated with the risk of death. Multivariate Logistic analysis showed that age ( OR=1.099, CI: 1.014-1.190, P=0.021) was associated with the risk of death. There was no significant correlation between early hormone therapy and clinical prognosis. Kaplan-Meier survival curves showed that there was no difference in the 60-day survival rate between the early hormone therapy group and the standard hormone therapy group. ③ The level of triglyceride still increased after early hormone therapy, and the number of indexes meeting the diagnostic criteria of HLH-2004 increased significantly. All patients met the criteria of Hscore>169, and 3 patients did not meet at least 5 diagnostic criteria of HLH-2004, accounting for 16.7% of the total cases of early hormone therapy. ④ Starting hormone therapy when the four HLH-2004 diagnostic criteria were met could reduce the length of hospital stay. Prothrombin time and activited partial thomboplastin time were closer to normal levels in patients 5-7 days after treatment. Early hormone therapy had no significant effect on treatment response and in-hospital death risk. There were no significant differences in APACHE Ⅱ score, SOFA score, confirmation of diagnosis, treatment response, clinical prognosis, and related clinical indicators after hormone therapy between the routine 4 criteria and non-routine 4 criteria groups. Conclusions:Initiation of early hormone therapy has no significant effect on the confirmation of clinical diagnosis, treatment response, in-hospital mortality, and 60-day survival rate of patients with HPS, and can quickly correct coagulation dysfunction and effectively reduce the length of hospital stay. An earlier start of hormonal therapy (meeting the four HLH-2004 diagnostic criteria) may be considered by the emergency physician when a patient is highly suspected of HPS diagnosis

Clinical characteristics of 111 patients with chronic active Epstein-Barr virus infection / 中华传染病杂志

Objective:To analyze the clinical features of chronic active Epstein-Barr virus infection (CAEBV) in order to reduce the rates of underdiagnosis and misdiagnosis of this disease.Methods:The CAEBV related literatures of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, WanFang Database and Chongqing VIP since the first literature published (May 1987) until August 29, 2020 were searched. The clinical characteristics, laboratory examinations, outcome and causes of death of CAEBV patients were retrospectively analyzed. Statistical analysis was performed by Mann-Whitney U test, chi-square test or Fisher′s exact probability test. Results:A total of 111 patients aged 22.0 (10.0, 39.0) years were included from 46 articles. There were 64 cases (57.7%) in the age ≥18 years group and 47 cases (42.3%) in the age <18 years group. Fever, splenomegaly, hepatomegaly, and lymph node enlargement were common clinical manifestations, with incidences of 95.5%(106/111), 84.7%(94/111), 57.7%(64/111) and 56.8%(63/111), respectively. The incidences of rash and hepatomegaly in the age ≥18 years group were 3.1%(2/64) and 45.3%(29/64), respectively, which were both lower than those in patients aged <18 years group (27.7%(13/47) and 74.5%(35/47), respectively), while the incidence of abnormal liver biochemical indexes was higher (45.3%(29/64) vs 23.4%(11/47)). The differences were all statistically significant ( χ2=13.957, 9.436 and 5.643, respectively, all P<0.05). Of the 70 patients with follow-up outcomes, 38(54.3%) died and 32(45.7%) survived. The causes of death included gastrointestinal bleeding, severe infection, respiratory failure, liver failure, etc. The incidences of splenomegaly in the death and survival groups were 92.1%(35/38) and 68.8%(22/32), respectively. The difference was statistically significant ( χ2=6.266, P<0.05). Of 21 death and 17 survival cases in the age <18 years group, 15(71.4%) and two cases were combined hemophagocytic lymphohistiocytosis (HLH), respectively, with statistical significance ( χ2=13.527, P<0.01). Of the 90 patients whose HLH-related information was available, 38(42.2%) combined HLH and 52(57.8%) without HLH, with 36.8%(14/38) and 65.4% (34/52) of males, respectively. The difference of gender distribution was statistically significant ( χ2=7.187, P=0.007). The treatment regimens of the 111 CAEBV patients during the course of disease were various, but the detailed information was lacking. Conclusions:The clinical manifestations of CAEBV are diverse. CAEBV can be complicated with fatal complications, lacks of effective treatment, and shows poor prognosis. It is necessary to actively carry out related research to improve the understanding of the disease, and explore effective treatment and reduce mortality.

Hemophagocytic lymphohistiocytosis: a rare and fatal manifestation of dengue fever

Authors describe a rare case of dengue fever manifesting as hemophagocytic lymphohistiocytosis. A 26-year-old man presented with acute gastroenteritis along with high grade fever, leukopenia, thrombocytopenia, acute kidney injury, liver dysfunction. Further work-up revealed elevated serum ferritin and LDH levels, and bone marrow biopsy showed hemophagocytes. As dengue fever is in rising trend all over the world, especially in Asian countries, clinicians should look out for this rare but potentially fatal complication of dengue fever.

Predictors and Outcome of Severe Dengue Illness in Children.

Dengue fever has become a major public health concern during the last few years with an alarming increase in the incidence in 2017. The state of Kerala was one among the top of the list in India reported to have severe dengue infection. The two main districts in Kerala with high prevalence were Thiruvananthapuram and Palakkad, of which latter is the main referring area to our institution. This study was conducted to evaluate the clinical and demographic profile of children affected with dengue fever and determine the predictors of severity.METHODSThis is a hospital based prospective study done at the Department of Paediatrics, Government Medical College, Trissur, during the Monsoon season in 2017. Children diagnosed to have Dengue fever and confirmed by NS1 Ag test or IgM Elisa were included. Children were classified into 3 clinical groups and compared. Comparison was also made in 2 groups as dengue with warning signs and severe dengue as per WHO 2015 clinical guidelines, to find out the predictors of severity. Qualitative data was analysed and expressed in proportions and quantitative data in mean and standard deviation. Chi-square (χ2) test was used to evaluate the association between qualitative variables and ANOVA for quantitative variables. p value less than 0.05 was considered significant. SPSS 16.0 software was used for statistical analysis.RESULTSA total of 235 children were included. 77 children (32.9%) had mild dengue fever, 106 (45.29%) had DWS and 52 (22.22%) were having DSS). Mean age was 6.61± 3.497 years. 19 cases (8.2 %) were Infants below 1 year of age. Majority of children had normal nutritional status. Myalgia, tiredness, vomiting, diarrhoea, abdominal pain, flushing, bleeding, oedema, hypotension, were found to be the common clinical manifestations. Thrombocytopenia, elevated serum hepatic enzymes both SGOT and SGPT, abnormal renal function tests, low sodium, hypoalbuminemia, hypoglycaemia, abnormal radiological findings were found to be the predictors of severity. We had many cases of expanded dengue syndrome including 3 cases of Hemophagocytic lymphohistiocytosis (HLH). The mortality was 0.6%.CONCLUSIONSDengue fever can affect children irrespective of their age or nutritional status. Older children and male sex were found to be more affected. There are definite clinical and lab parameters which can predict the severity in Dengue fever. Though severe illness is associated with high morbidity early diagnosis and timely appropriate clinical management, correction of dehydration along with proper referral system can save the children. The mortality can be reduced to zero even in patients having expanded dengue syndrome and Dengue shock syndrome. None of the comorbidities had affected the outcome.

Secondary hemophagocytic lymphohistiocytosis: a rare case report

Haemophagocytic lymphohistiocytosis (HLH) is a clinicopathologic syndrome, characterised by hyperinflammation due to inherited or acquired defects in the immune function, leading to unchecked proliferation of histiocytes and lymphocytes resulting in multiorgan dysfunction. HLH can be primary (familial) occurring in young children caused by underlying genetic defects in natural killer cells/cytotoxic T cells or secondary HLH occurring in older children or adults following infections, rheumatological disorders or malignancies.  HLH is a medical emergency, having varied clinical presentations and lacks a pathognomonic clinical or laboratory abnormality. Clinical presentations include unexplained fever, hepatomegaly, splenomegaly, skin rash, cytopenias, liver dysfunction, coagulation abnormality and neurological manifestations. It carries a poor prognosis. Early diagnosis based on HLH 2004 criteria and initiation of treatment is crucial in the management strategy, which is likely to improve the outcome of this life-threatening disease. The treatment strategies include immunosuppressive drugs, immunomodulatory therapy and autologous hematopoietic stem cell transplant in selected cases. Here with authors report a case of young adult, presenting with fever, thrombocytopenia, splenomegaly, and multi organ dysfunction, diagnosed as a case of secondary HLH based on the HLH 2004 guidelines.

Higher Fatality for Severe Fever with Thrombocytopenia Syndrome Complicated by Hemophagocytic Lymphohistiocytosis

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious zoonosis caused by the SFTS virus. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome associated with excessive immune activation. Cytokine storms are often seen in both SFTS and HLH, resulting in rapid disease progression and poor prognosis. The aim of this study was to identify whether SFTS cases complicated by HLH are related to higher rates of mortality. Descriptive analysis of the frequency of clinical and laboratory data, complications, treatment outcomes, and HLH-2004 criteria was performed. Cases presenting with five or more clinical or laboratory findings corresponding to the HLH-2004 diagnostic criteria were defined as SFTS cases complicated by HLH. Eighteen cases of SFTS were identified during a 2-year study period, with a case-fatality proportion of 22.2% (4 among 18 cases, 95% confidence interval 9%–45.2%). SFTS cases complicated by HLH were identified in 33.3% (6 among 18 cases). A mortality rate of 75% (3 among 4 cases) was recorded among SFTS cases complicated by HLH. Although there were no statistically significant differences in outcomes, fatal cases exhibited more frequent correlation with HLH-2004 criteria than non-fatal cases [3/14 (21.4%) vs. 3/4 (75%), p=0.083]. In conclusion, the present study suggests the possibility that SFTS cases complicated by HLH are at higher risk of poor prognosis.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: response to HLH-04 treatment protocol / Linfohistiocitosis hemofagocítica asociada con el virus de Epstein-Barr: respuesta al tratamiento con el protocolo HLH-04

Abstract Introduction: Hemophagocytic syndrome, macrophage activation syndrome, reactive histiocytosis or hemophagocytic lymphohistiocytosis (HLH) represent a group of diseases whose common thread is reactive or neoplastic mononuclear phagocytic system cells and dendritic cell proliferation. Clinical case: We present a case of an HLH probably associated with Epstein-Barr virus (EBV) in a 4-year-old male patient treated with HLH-04 protocol. Viral etiology in HLH is well accepted. In this case, clinical picture of HLH was assumed secondary to EBV infection because IgM serology at the time of clinical presentation was the only positive factor in the viral panel. Conclusions: Diagnosis of HLH is the critical first step to successful treatment. The earlier it is identified, the less the tissue damage and reduced risk of multiple organ failure, which favors treatment response.

Resumen Introducción: El síndrome hemofagocítico, síndrome de activación de macrófagos, histiocitosis reactiva o linfohistiocitosis hemofagocítica (HLH) representan un grupo de enfermedades cuyo factor común es la proliferación reactiva o neoplásica de las células mononucleares fagocíticas y del sistema de células dendríticas. Caso clínico: Se presenta un caso de HLH sugestivo de tener una asociación con el virus del Epstein Barr (VEB) de un paciente masculino de 4 años de edad, tratado con el protocolo HLH-04. La etiología viral en HLH es reconocida. En este caso se asumió un cuadro de HLH secundario a una infección por VEB, ya que la serología de IgM en el momento de la presentación clínica fue la única positiva en el panel viral. Conclusiones: El diagnóstico de la HLH es el primer paso crítico para el éxito del tratamiento. Entre más temprano se identifique, existe menor daño tisular y menor riesgo de falla orgánica múltiple, lo que favorece la respuesta al tratamiento.

Síndrome de ativação macrofágica em paciente com artrite idiopática juvenil sistêmica / Macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis

A síndrome de ativação macrofágica (SAM) é uma doença rara e potencialmente fatal, normalmente associada às doenças reumáticas crônicas, em especial a artrite idiopática juvenil. É incluída no grupo das formas secundárias de síndrome hemofagocítica, cujas outras causas podem ser as doenças linfoproliferativas e infecções. As manifestações clínicas e laboratoriais mais importantes são a febre não remitente, esplenomegalia, hemorragias, disfunção hepática, citopenias, hipoalbuminemia, hipertrigliceridemia e hiperferritinemia. O tratamento deve ser iniciado rapidamente, e a maioria dos casos responde bem aos corticosteroides e à ciclosporina (CSA). O vírus Epstein-Barr (EBV) é descrito como possível gatilho para muitos casos de SAM, especialmente naqueles em tratamento com bloqueadores do fator de necrose tumoral (TNF). Nos casos refratários ao tratamento convencional, etoposide (VP16) deve ser administrado, em associação com corticosteroides e CSA. Nosso objetivo foi descrever um caso raro de síndrome hematofagocítica provavelmente secundária à infecção pelo vírus Epstein-Barr (EBV), em paciente com artrite idiopática juvenil sistêmica, confirmada pelas manifestações clínicas e laboratoriais típicas, mielograma e sorologia positiva contra o EBV, que atingiu remissão completa após inclusão no protocolo de tratamento HLH-04.

Machrophage activation syndrome (MAS) is a rare and potentially fatal disease, commonly associated with chronic rheumatic diseases, mainly juvenile idiopathic arthritis. It is included in the group of secondary forms of haemophagocytic syndrome, and other causes are lymphoproliferative diseases and infections. Its most important clinical and laboratorial manifestations are non-remitting fever, splenomegaly, bleeding, impairment of liver function, cytopenias, hypoalbuminemia, hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia. The treatment needs to be started quickly, and the majority of cases have a good response with corticosteroids and cyclosporine. The Epstein–Barr virus is described as a possible trigger for many cases of MAS, especially in these patients in treatment with tumor necrosis factor (TNF) blockers. In these refractory cases, etoposide (VP16) should be administered, associated with corticosteroids and cyclosporine. Our objective is to describe a rare case of MAS probably due to EBV infection in a subject with systemiconset juvenile idiopathic arthritis, which achieved complete remission of the disease after therapy guided by 2004-HLH protocol.

Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: recent advances and controversies

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory clinical syndrome of uncontrolled immune response which results in hypercytokinemia due to underlying primary or secondary immune defect. A number of genetic defects in transport, processing and function of cytotoxic granules which result in defective granule exocytosis and cytotoxicity of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have been well identified at the cellular and molecular level. Important advances have been made during the last 20 years in the diagnosis and treatment of HLH. The Histiocyte Society has proposed diagnostic guideline using both clinical and laboratory findings in HLH-2004 protocol, and this has been modified partly in 2009. HLH used to be a fatal disease, but the survival of HLH patients has improved to more than 60% with the use of chemoimmunotherapy combined with hematopoietic cell transplantation (HCT) over the past 2 decades. However, HCT is still the only curative option of treatment for primary HLH and refractory/relapsed HLH after proper chemoimmunotherapy. The outcome of HCT for HLH patients was also improved steadily during last decades, but HCT for HLH still carries significant mortality and morbidity. Moreover, there remain ongoing controversies in various aspects of HCT including indication of HCT, donor selection, timing of HCT, conditioning regimen, and mixed chimerism after HCT. This review summarized the important practical issues which were proven by previous studies on HCT for HLH, and tried to delineate the controversies among them.

Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare multiorgan disease of toxic immune activation caused by the interaction of cytotoxic T cells and innate immune cells and frequently involves the central nervous system (CNS). Posterior reversible encephalopathy syndrome (PRES) might develop during treatment with the HLH-2004 protocol from the Histiocyte Society. The aims of this study were to evaluate clinical outcomes and putative risk factors for prediction of PRES related to HLH. METHODS: We reviewed the medical records of 28 patients with HLH who were treated between April 2005 and April 2012. We compared various clinical and laboratory parameters in patients without or with PRES to evaluate putative risk factors related to development of PRES. RESULTS: Six (21.4%) of the patients experienced PRES during treatment with the HLH-2004 protocol. Clinical and laboratory manifestations were not different compared with other conditions causing PRES. The main mechanism of PRES may be related to the HLH-2004 protocol and a high pro-inflammatory state. Most patients recovered quickly from neurologic manifestations without significant long-term sequelae. Preceding hypertension, an increase in ferritin level >50% compared with 1 week before development of PRES and hyponatremia were statistically significant factors. CONCLUSION: PRES is clinically reversible and has a favorable outcome in patients with HLH. Awareness of PRES and a differential diagnosis of other causes of neurologic complications, including CNS involvement of HLH, can help avoid unnecessary treatment or delayed management. Patients with preceding hypertension, hyponatremia, and rising ferritin levels during HLH treatment should be closely monitored for PRES.

Histiocytosis Syndromes of Childhood: A report of four cases.

Histiocytosis Syndromes of Childhood (HSC) are a group of rare and diverse disorders characterized by aggressive proliferation or accumulation of cells of monocyte - macrophage system of bone marrow. The clinical spectrum of this syndrome is distinctly varied. The exact pathophysiology of HSC is yet to be determined; however, evidence suggests that one of the subtypes, Hemophagocytic Lymphohistiocytosis, is due to decreased Natural Killer cell activity, resulting in increased activation of other T cell subtypes and production of cytokines. We present four cases of HSC managed at our center between October 2008 & February 2010.

Successful Treatment of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis with HLH-94 Protocol

Hemophagocytic lymphohistiocytosis (HLH) is a rare, fatal disorder of children, affecting predominantly the mononuclear phagocytic system. Previous reports indicate that Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) can also be fatal in many cases, although the prognosis for EBV-HLH is better than for the familial form of hemophagocytic lymphohistiocytosis. We treated four patients with EBV-HLH using immunochemotherapy including steroid, etoposide (VP-16), and cyclosporin, according to the HLH-94 protocol. All patients experienced persistent fever, cytopenia, and hypertriglyceridemia. Serological testing for EBV showed reactivated EBV infections in all patients. EBV DNA detected by PCR and EBV-encoded small RNA measured by in situ hybridization were confirmed in the patients' bone marrow specimens. Hemophagocytosis was shown in bone marrow aspirates and liver biopsy specimen. Complete remission was achieved in all patients after induction and continuation therapy for 4-10 months (median, 7 months) and was maintained for 15-27 months (median, 19 months) without the need for bone marrow transplantation. These results suggest that EBV-HLH can be effectively controlled by immunochemotherapy using the HLH-94 protocol.