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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 6  |  Issue : 1  |  Page : 1-5

Is secondary hemophagocytic lymphohistiocytosis behind the high fatality rate in Middle East respiratory syndrome corona virus?


Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center; King Fahad Center for Children with Cancer; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

Date of Web Publication15-Apr-2015

Correspondence Address:
Ali Al-Ahmari
Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital and Research Center, MBC 53, P. O. Box: 3354, Riyadh 11211
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1658-5127.155168

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  Abstract 

Middle East respiratory syndrome corona virus (MERS-CoV) is becoming a major health concern in Saudi Arabia resulting in an associated high case fatality. The rapid deterioration of vital organs functions and high mortality rate seen in MERS-CoV has been observed previously in Epstein-Barr virus (EBV), severe acute respiratory syndrome caused by a coronavirus (SARS-CoV) and avian and bird flu-related hemophagocytic lymphohistiocytosis (HLH). There are many reports of successful treatments for severe cases of EBV-HLH using HLH-94/2004-type immunochemotherapy with etoposide as a pro-apoptotic agent. The use of immunochemotherapy in severe MERS-CoV-related HLH merits an urgent investigation in a well-designed clinical trial.

Keywords: Hemophagocytic lymphohistiocytosis, high fatality rate, Middle East respiratory syndrome coronavirus


How to cite this article:
Al-Ahmari A. Is secondary hemophagocytic lymphohistiocytosis behind the high fatality rate in Middle East respiratory syndrome corona virus?. J Appl Hematol 2015;6:1-5

How to cite this URL:
Al-Ahmari A. Is secondary hemophagocytic lymphohistiocytosis behind the high fatality rate in Middle East respiratory syndrome corona virus?. J Appl Hematol [serial online] 2015 [cited 2020 Apr 1];6:1-5. Available from: http://www.jahjournal.org/text.asp?2015/6/1/1/155168


  Introduction Top


Since the initial description of Middle East respiratory syndrome corona virus (MERS-CoV) infection, the disease has been associated with a high case-fatality rate. Globally, froam September 2012 to the present, the Ministry of Health in Saudi Arabia has been informed of a total of 798 laboratory-confirmed cases of infection with MERS-CoV, including 338 deaths leading to 42% fatality rate. [1] Treatment is primarily supportive, and there are no convincing data that the use of potent antiviral agents, such as ribavirin and interferon, brings any benefit.

The widely observed association of hemophagocytic lymphohistiocytosis (HLH) with viral infection was first report by Risdall et al., who described several patients, mostly adults after organ transplantation, of whom the majority had evidence of a viral infection and presented with clinical signs and symptoms of HLH. [2] Since then, there have been many reports of infection-associated hemophagocytic syndrome (IAHS). [3] IAHS proved to be a dangerous disease: A review of the published cases in children diagnosed with IAHS before 1996 reported a mortality rate of 50%. [4] Pulmonary involvement in HLH has been reported in some severe cases. [5] The occurrence of pulmonary involvement is quite frequent, especially in HLH triggered by viral infections. [6],[7] Thus, an associated HLH may explain the rapid deterioration of pulmonary, hepatic and renal functions observed in severe MERS-CoV infections.


  Hemophagocytic lymphohistiocytosis Top


Hemophagocytic lymphohistiocytosis is a life - threatening immune disorder that is associated with a wide spread lymphocytic and hemophagocytic infiltration of vital organs and the overwhelming activation of T-lymphocytes and macrophages. [8] The HLH patients are usually ill with fever, hepatosplenomegaly, cytopenia and bone marrow hemophagocytosis. [9],[10] The constellation of signs and symptoms of HLH is not specific, and none of the biochemical abnormalities are distinctive. The dramatic presentation of the syndrome includes unremitting fever, visceromegaly, thrombocytopenia, lethargy, seizures, skin rash, pulmonary failure and cardiac and/or renal involvement, and the mortality rate without treatment is high. [11] The HLH Study Group of the Histiocyte Society published useful guidelines for the diagnosis of HLH in 1991, which were revised in 2004 [12] [Table 1].
Table 1: Revised diagnostic guidelines for HLH (HLH-2004)


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Hemophagocytic lymphohistiocytosis could be primary (Familial HLH) [13] or secondary; [4] however, this classification may not be possible as the distinction requires molecular techniques that are not widely available. [14],[15],[16],[17],[18] The untreated primary autosomal recessive form of HLH is a fatal disease with a median survival of <2 months after diagnosis. [19] Secondary HLH can develop as a result of intense immunological activation of the immune system. It has been described in both immunocompromised and immunocompetent patients in association with viral infections, and is referred to as viral infection-associated hemophagocytic syndrome (VAHS). [20]


  VIRAL INFECTION-ASSOCIATED HEMOPHAGOCYTIC SYNDROME Top


Viruses, especially Epstein-Barr virus (EBV), human parainfluenza and influenza viruses, coronaviruses (CoV) cytomegalovirus, hepatitis A virus, human immunodeficiency virus, parvovirus, nairovirus adenovirus, paramyxovirus (leading to measles and mumps), rubella virus, flavivirus (leading to dengue fever) and hantavirus (leading to hemorrhagic fever and severe acute respiratory syndrome [SARS]) have been associated with HLH. [6],[7],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31]


  EPSTEIN-BARR VIRUS-RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Top


The pathogenesis of VAHS is still unclear, but the condition is hypothesized to be caused by abnormal immune regulation resulting in a cytokine storm and massive lymphohistiocytic infiltration of vital organs. [6],[32],[33],[34],[35] The EBV is the most commonly reported trigger of HLH. [36] The epidemiology of EBV-related HLH is not well-known although a higher incidence has been observed in Asian countries. [37] Furthermore, the inflammatory cytokine overproduction seen in patients with EBV-related HLH tends to be much more pronounced than that observed in patients with other forms of HLH. [38]

There are many reports of successful treatments for severe cases of EBV-HLH using HLH-94/2004-type immunochemotherapy with etoposide as pro-apoptotic agent. A nationwide study of 163 EBV-HLH cases in Japan, including all cases treated variously, showed a better outcome in that the overall survival at 5 years was 82.7%. [39] In the treatment of EBV-HLH with HLH-94 treatment, 59 out of 78 patients (75.6%) were alive and well after a median follow-up of 43 months. [40] Lee et al. [41] also obtained a complete remission in four out of four patients using a similar treatment. The most challenging issue, however, is how to manage early life-threatening events resulting in death.

In China, Lu et al. [42] recently reported that 15 out of 62 (24.2%) pediatric EBV-HLH patients died within 2 months of hospitalization. Of all of the infections associated with HLH, EBV infection has the worst prognosis. [43]


  INFLUENZA-RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Top


Influenza-related HLH has been rarely reported in immunocompromised and otherwise healthy children. [32],[44],[45],[46] One fatal case of HLH was observed among 32 children hospitalized with seasonal influenza in a prospective pediatric study, [47] but reactive HLH has also been associated with avian and swine (nonpandemic) influenza. [25],[28] In particular, patients with severe H5N1 (avian) influenza infection have symptoms and laboratory findings that are similar to those observed in patients with HLH, mainly encephalitis, organ dysfunction with hemophagocytosis, bone marrow failure, and pro-inflammatory cytokine overproduction. [48] Avian influenza A (H5N1) infection and SARS due to CoV share similar pathologic features. Systemic cytokine activation results in hemophagocytic syndrome, lymphoid depletion, and skeletal muscle fiber necrosis. [49] HLH has also been found in fatal cases of H1N1 infection during the pandemic that emerged in April 2009. [50]


  CORONAVIRUS-RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Top


Coronaviruses are a large family of viruses that include viruses that may cause a range of illnesses in humans, from the common cold to SARS. In the epidemic of SARS in Taiwan, HLH and high serum levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-α associated with lung lesions were found in 10 patients. [51] Thus, virus-associated HLH was considered in the differential diagnosis of life-threatening atypical pneumonia and SARS-CoV infection. [29] MERS-CoV has not been previously identified in humans. There is very limited information on transmission, severity and clinical impact with only a small number of cases reported thus far. The occurrence of MERS-CoV-associated HLH has not been investigated so far. The author believes that the high mortality rate associated with MERS-CoV is secondary to the intense stimulation of the immune system and development of HLH. Since immunochemotherapy is an established treatment modality of severe viral-related HLH, investigating the severe cases of MERS-CoV infection for HLH should be considered.


  Therapeutic approach for the severe middle east respiratory syndrome coronavirus infections Top


There is a lack of proven effective medications for therapy of MERS-CoV. The current knowledge of therapeutic options for MERS-CoV is based on the experience from SARS-CoV and from in vitro studies. From the SARS experience, 22 patients with probable SARS were treated with corticosteroids or corticosteroids plus subcutaneous interferon alfacon-1. The interferon alfacon-1 treatment group had a shorter time to resolution of lung radiographic abnormalities, had better oxygen saturation, resolved their need for supplemental oxygen more rapidly, had less of an increase in creatine kinase levels and showed a trend toward more rapid resolution of lactate dehydrogenase levels compared with the group receiving corticosteroids alone. [52] Thus, interfering with the host immune response is a way that should be explored in developing therapeutic agents for MERS-CoV infection. The efficacy of interferon therapy for MERS-CoV remains to be demonstrated in clinical settings. [53]

Since EBV-associated HLH can be successfully treated with HLH-directed therapy, including pro-apoptotic cytotoxic therapy (Etoposide) and corticosteroids, [54],[55],[56] Henter et al. hypothesized that cytotoxic therapy might be beneficial for severe avian influenza A (H5N1) infection. [57] A 31-year-old with a novel swine-origin influenza A (H1N1) virus and a secondary HLH has been treated successfully with cytotoxic therapy. [58]

Considering the current high mortality of MERS-CoV infections, searching for an associated HLH in the severe cases is critically needed. MRES-Cov patients who fulfill the HLH clinical and biochemical criteria may benefit from the use of HLH-1994/2004 immuno-chemotherapeutic agents. [12],[39] Since the multi-organ failure is a common feature in such patients; the therapeutic agents should be adjusted according to renal and liver functions. Furthermore, the age should be considered in calculating the Etoposide doses as children usually tolerate higher doses than adults.


  Conclusion Top


The diagnosis of secondary HLH should be considered in patients with severe MERS-CoV infection as it may be a contributing factor to the high death rate observed in young patients. Thus, the author believes that the use of modified HLH-1994/2004 therapy might benefit such severe MERS-CoV cases. Due to the limited experience of immune-chemotherapy in viral-associated HLH other than EBV-related, it should be used in a context of a well-designed clinical trial.

 
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Abstract
Introduction
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