Severe "blood phagocytosis" - a rare group of critically ill patients, where is the diagnosis and treatment broken?

Only for medical professionals to read and refer to the latest interpretation of the diagnosis and treatment of severe hemophagocytic syndrome! Hemophagocytic lymphohistiocytosis (HLH, also known as "hemophagocytic syndrome") is a rare, immune-mediated, life-threatening disorder with diverse symptoms involving multiple tissues and organs, consisting of primary or Acquired immune abnormalities caused by [1]
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The medical community specially invited Professor Miao Hongjun from the Department of Acute and Critical Care Medicine, Children's Hospital Affiliated to Nanjing Medical University, to interpret the new progress in the diagnosis and treatment of severe hemophagocytic syndrome
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Approval number: NP-20092, Valid until: 1/5/2023 The pathogenesis of HLH is a decrease in the function of perforin or its ability to release cytolytic antigen-presenting cells and T lymphocytes [2]
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Nonspecific "cytokine storm" of pro-inflammatory cytokines such as interferon-gamma, interleukin-1, and interleukin-6, and compensatory downregulation of activated macrophages, natural killer cells, and cytotoxic T lymphocytes The cytokine interleukin-10, which mediates damage to multiple tissues and organs
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The main clinical manifestations are persistent fever in bone marrow, liver, spleen and lymph node tissues, hepatomegaly, splenomegaly, pancytopenia, coagulation disorders and the discovery of "hemophagocytic" cells [1]
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 HLH is divided into primary and secondary types, can occur at any age [3]
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Although the majority of cases are children, more than 40% of HLH cases have been demonstrated in adults [4]
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 Severe HLH progresses rapidly, and the mortality rate caused by multiple organ failure is high.
HLH patients rapidly deteriorated liver function in a short period of time, and appeared crises such as jaundice, abdominal distension, "three blood lines" significantly reduced, severe abnormal coagulation function, and systemic bleeding tendency [3]
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The main causes of severe HLH are sepsis, intracellular infection, and malignant tumor [5]
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Critically ill patients with fever, splenomegaly, low hemoglobin and low platelet count may be HLH.
H Score (H Score) is helpful for rapid diagnosis of HLH, and lactate dehydrogenase level is significantly associated with HLH death [1]
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Severe neutropenia and liver damage are prognostic factors for early death in children with HLH [6], and age, presence of bone marrow hemophagocytic cells, and organ failure are prognostic factors for adult HLH death in the ICU [5]
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 Mortality due to multiple organ failure in patients is high
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A total of 34 patients with multiple organ failure were rescued from April 2010 to March 2011, including 26 males and 8 females, aged 32 to 88 years, including 30 patients over 65 years old
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The mortality rate of 4 or more organ failure patients was significantly higher than that of 2 or 3 organ failure patients, P<0.
05.
The mortality rate of multiple organ failure was proportional to the number of organ failures [7]
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Figure 1 The relationship between the number of patients with organ failure and mortality [n(%)] How should the diagnosis and treatment of severe HLH be carried out? The current international authoritative guidelines and norms for the diagnosis and treatment of HLH are the HLH-2004 program formulated by the International Association of Histology and Cells
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The treatment of primary HLH mostly follows this standard, and the treatment of secondary HLH may not be carried out completely according to this plan, focusing on the treatment according to the cause
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The specific HLH-2004 scheme is as follows [3]: Table 1 Diagnostic criteria for HLH (HLH-2004) Figure 2 Treatment methods for HLH Severe HLH diagnosis requires attention to the following aspects [8-11]: Distinguishing symptoms, rapid diagnosis, ICU physician support for severe HLH diagnosis can rely on H score and HLH-2004 criteria [12]
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Other markers that identify HLH have been investigated
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Among them, a Chinese study used the diagnostic criteria of IFNγ>75 pg/ml and IL-10>60 pg/ml to diagnose HLH with a sensitivity of 98.
9% and a specificity of 93% [8]
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Other markers are soluble CD163, monocyte human leukocyte antigen (HLA)-DR, bilirubin, transaminases, liver, lactate dehydrogenase and D-dimer levels, interferon-gamma, IL-10 and IL- 6 et al [10]
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Treatment of severe HLH needs to focus on the following aspects [2,8,10]: Timely emergency treatment and antimicrobial therapy based on etiological treatment Data to guide the management of adult HLH by summarizing findings from clinical trials targeting HLH, including There are few data on the treatment of HLH in adults with induction and maintenance regimens or the use of established or new drugs, and only NCT01547143 was designed to study the treatment of HLH in adults, and additional studies targeting this patient population are urgently needed
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The current status of HLH treatment is a combination of immunosuppressive and cytotoxic therapy [19]
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In conclusion, the flow chart of diagnosis and treatment of critically ill patients with HLH/MAS-HLH and (multi) organ failure is shown in the figure below [13]
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 Figure 3 Flow chart of diagnosis and treatment of critically ill patients with HLH/MAS-HLH and (multi) organ failure Future of severe HLH treatment? Mortality remains high in patients with HLH under conventional regimens.
Corticosteroids and/or cyclosporine are the most commonly used regimens
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In a retrospective study of 18 adult patients with HLH, 14 received high-dose steroids and/or cyclosporine for initial treatment, and 3 patients received etoposide in combination with cyclosporine and corticosteroids.
, Under the conventional program, the mortality rate of adult HLH patients was 72% [14]
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 The anti-IFNγ monoclonal antibody Emapalumab can be used for refractory HLH The treatment of patients with refractory HLH has been difficult, and there are limited data on the success of different rescue regimens
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The anti-IFNγ monoclonal antibody Emapalumab is currently the only targeted drug approved for primary HLH in the world
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The clinical efficacy of Emapalumab has been demonstrated in pediatric patients with primary HLH who are refractory to or intolerable to conventional HLH therapy
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Emapalumab pivotal study results: Overall objective response rate (primary endpoint) 63%; median time to response 8 days; median cumulative duration of response to preconditioning 31 days; percentage of patients surviving to hematopoietic stem cell transplantation (HSCT) 82 %; the rate of patients undergoing HSCT is 70%; the estimated survival rate at 12 months after HSCT is 89.
5% [8,15]
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Figure 4.
Key study results of Emapalumab: Prospects for diagnosis and treatment of severe HLH The multi-disciplinary treatment (MDT) model is particularly suitable for the diagnosis of complex diseases
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For critically ill children with rare diseases, ICU treatment is the key, and ICU is the key discipline for initiating MDT.
Through multidisciplinary collaboration, efforts are made to achieve the goals of early detection, early diagnosis, treatment, and management of critically ill rare diseases.
It is recommended to take MDT management as some Practical strategies for the clinical situation of HLH
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 It is believed that in the future, the future of HLH patients will be even brighter with the deepening of the following research [8]: The advent of high-throughput sequencing and other novel mutation discovery technologies will greatly improve the understanding of HLH pathophysiology, especially in " Acquired” case group; great progress in understanding the genetic basis and pathogenesis of familial HLH is expected to translate into more effective targeted therapy for patients; current uncertainty about the diagnosis of HLH severely impacts prognostic assessment and Treatment decisions
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Accelerate the development of diagnostic markers, enable more targeted treatment of critically ill patient populations, and increase research in adult HLH patients and the role of MDT in HLH
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Expert Profile Professor Hongjun Miao Director of the Department of Emergency and Critical Care Medicine, Children's Hospital Affiliated to Nanjing Medical University Doctor, Chief Physician, Master's Supervisor Branch Standing Committee Member of the Chinese Medical Doctor Association Children's Respiratory Critical Care and Mechanical Ventilation Special Committee Vice Chairman Group leader, chairman of the Children's Critical Care Branch of Jiangsu Medical Association, member of the Emergency Medicine Branch of the Jiangsu Medical Association, member of the Critical Care Medicine Branch of the Jiangsu Medical Association, etc.
References: [1] Zhang FJ, et al.
Int J Gen Med.
2021 Aug 20 ;14:4687-4694.
[2]Lachmann G, et al.
Anaesthesist.
2016 Oct;65(10):776-786.
German.
[3]Hematology Group, Pediatric Society of Chinese Medical Association.
Chinese Journal of Pediatrics, 2012 , 050(011):821-825.
[4]Ishii E, et al.
Int J Hematol.
2007 Jul;86(1):58-65.
[5]Bichon A, et al.
Front Med (Lausanne).
2021 Oct 6;8: 735-796.
[6]Bin Q, et al.
Ann Hematol.
2016 Sep;95(9):1411-8.
[7]Huang Mou.
Modern Chinese Physicians, 2011, 49(33) :2.
[8]Tothova Z, Berliner N.
J Intensive Care Med.
2015 Oct;30(7):401-12.
[9]Zhang et al.
Int J Gen Med.
2021 Aug 20;14:4687-4694 .
[10]Athale J.
Crit Care Med.
2020 Apr;48(4):599-600.
[11]Eichenauer DA, et al.
Wien Klin Mag.
2021 Oct 21:1-6.
German.
[12]Valade S,et al.
Crit Care Med.
2021 Sep 1;49(9): e874-e879.
[13]Knaak C, et al.
Shock.
2020 Jun;53(6):701-709.
[14]Shabbir M, et al.
al.
Hematol Oncol.
2011 Jun;29(2):100-6.
[15]Locatelli F, et al.
N Engl J Med.
2020 May 7;382(19):1811-1822.
Approval number: NP-20092 , Valid until: 1/5/2023 This information is for medical and scientific reference only, it is not recommended to use this product in any way that is inconsistent with the prescribing information approved in your country,