|Year : 2015 | Volume
| 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 Publication||15-Apr-2015|
Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital and Research Center, MBC 53, P. O. Box: 3354, Riyadh 11211
Source of Support: None, Conflict of Interest: None
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 2021 Oct 21];6:1-5. Available from: https://www.jahjournal.org/text.asp?2015/6/1/1/155168
| Introduction|| |
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.  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.  Since then, there have been many reports of infection-associated hemophagocytic syndrome (IAHS).  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%.  Pulmonary involvement in HLH has been reported in some severe cases.  The occurrence of pulmonary involvement is quite frequent, especially in HLH triggered by viral infections. , Thus, an associated HLH may explain the rapid deterioration of pulmonary, hepatic and renal functions observed in severe MERS-CoV infections.
| Hemophagocytic lymphohistiocytosis|| |
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.  The HLH patients are usually ill with fever, hepatosplenomegaly, cytopenia and bone marrow hemophagocytosis. , 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.  The HLH Study Group of the Histiocyte Society published useful guidelines for the diagnosis of HLH in 1991, which were revised in 2004  [Table 1].
Hemophagocytic lymphohistiocytosis could be primary (Familial HLH)  or secondary;  however, this classification may not be possible as the distinction requires molecular techniques that are not widely available. ,,,, The untreated primary autosomal recessive form of HLH is a fatal disease with a median survival of <2 months after diagnosis.  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). 
| VIRAL INFECTION-ASSOCIATED HEMOPHAGOCYTIC SYNDROME|| |
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. ,,,,,,,,,,,,
| EPSTEIN-BARR VIRUS-RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS|| |
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. ,,,, The EBV is the most commonly reported trigger of HLH.  The epidemiology of EBV-related HLH is not well-known although a higher incidence has been observed in Asian countries.  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. 
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%.  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.  Lee et al.  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.  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. 
| INFLUENZA-RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS|| |
Influenza-related HLH has been rarely reported in immunocompromised and otherwise healthy children. ,,, One fatal case of HLH was observed among 32 children hospitalized with seasonal influenza in a prospective pediatric study,  but reactive HLH has also been associated with avian and swine (nonpandemic) influenza. , 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.  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.  HLH has also been found in fatal cases of H1N1 infection during the pandemic that emerged in April 2009. 
| CORONAVIRUS-RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS|| |
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.  Thus, virus-associated HLH was considered in the differential diagnosis of life-threatening atypical pneumonia and SARS-CoV infection.  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|| |
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.  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. 
Since EBV-associated HLH can be successfully treated with HLH-directed therapy, including pro-apoptotic cytotoxic therapy (Etoposide) and corticosteroids, ,, Henter et al. hypothesized that cytotoxic therapy might be beneficial for severe avian influenza A (H5N1) infection.  A 31-year-old with a novel swine-origin influenza A (H1N1) virus and a secondary HLH has been treated successfully with cytotoxic therapy. 
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. , 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|| |
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.
| References|| |
Ministry of Health, Saudi Arabia. Middle East respiratory syndrome coronavirus (MERS-CoV). Available from: http://www.moh.gov.sa/en/CCC/PressReleases/Pages/default.aspx. [Last updated on 2014 Nov 07].
Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH Jr, Simmons RL, et al.
Virus-associated hemophagocytic syndrome: A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993-1002.
Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7:814-22.
Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection - and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:435-44.
Heydari AA, Ahmadi F, Sarvghad MR, Safari H, Bajouri A, Saeidpour M. Hemophagocytosis and pulmonary involvement in brucellosis. Int J Infect Dis 2007;11:89-90.
To KF, Chan PK, Chan KF, Lee WK, Lam WY, Wong KF, et al.
Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 2001;63:242-6.
Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, et al.
Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003;361:1773-8.
Aricò M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol 2001;114:761-9.
Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007;166:95-109.
Aricò M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al.
Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996;10:197-203.
Jabado N, McCusker C, Basile Gde S. Pediatric hemophagocytic syndromes: A diagnostic and therapeutic challenge. Allergy Asthma Clin Immunol 2005;1:142-60.
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, Aricò M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:417-33.
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al.
Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957-9.
Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al.
Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;115:461-73.
zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al.
Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 2005;14:827-34.
zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al.
Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 2009;85:482-92.
Côte M, Ménager MM, Burgess A, Mahlaoui N, Picard C, Schaffner C, et al.
Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest 2009;119:3765-73.
Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983;140:221-30.
Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr 1993;82:369-72.
Dilber E, Cakir M, Erduran E, Koksal I, Bahat E, Mutlu M, et al.
High-dose methylprednisolone in children with Crimean-Congo haemorrhagic fever. Trop Doct 2010;40:27-30.
Erduran E, Cakir M. Reactive hemophagocytic lymphohistiocytosis and Crimean-Congo hemorrhagic fever. Int J Infect Dis 2010;14 Suppl 3:e349.
Barut S, Dincer F, Sahin I, Ozyurt H, Akkus M, Erkorkmaz U. Increased serum ferritin levels in patients with Crimean-Congo hemorrhagic fever: Can it be a new severity criterion? Int J Infect Dis 2010;14:e50-4.
Kamihira T, Yano K, Tamada Y, Matsumoto T, Miyazato M, Nagaoka S, et al.
Case of domestically infected hepatitis E with marked thrombocytopenia. Nihon Shokakibyo Gakkai Zasshi 2008;105:841-6.
Zhang Z, Zhang J, Huang K, Li KS, Yuen KY, Guan Y, et al.
Systemic infection of avian influenza A virus H5N1 subtype in humans. Hum Pathol 2009;40:735-9.
Lu M, Xie ZG, Gao ZC, Wang C, Li N, Li M, et al.
Histopathologic study of avian influenza H5N1 infection in humans. Zhonghua Bing Li Xue Za Zhi 2008;37:145-9.
Zhang W, Wen LY, Lu M, Xiong Y, Qian KJ, Deng AH, et al.
Clinical characteristic analysis of the first human case infected by influenza A (H5N1) in Jiangxi Province. Zhonghua Jie He He Hu Xi Za Zhi 2006;29:300-6.
Kimura K, Adlakha A, Simon PM. Fatal case of swine influenza virus in an immunocompetent host. Mayo Clin Proc 1998;73:243-5.
Hsueh PR, Chen PJ, Hsiao CH, Yeh SH, Cheng WC, Wang JL, et al.
Patient data, early SARS epidemic, Taiwan. Emerg Infect Dis 2004;10:489-93.
Zajkowska JM, Hermanowska-Szpakowicz T, Pancewicz S, Kondrusik M, Grygorczuk S. Severe acute respiratory syndrome (SARS) - New, unknown disease? Pol Merkur Lekarski 2004;16:183-7.
Pei F, Zheng J, Gao ZF, Zhong YF, Fang WG, Gong EC, et al.
Lung pathology and pathogenesis of severe acute respiratory syndrome: A report of six full autopsies. Zhonghua Bing Li Xue Za Zhi 2005;34:656-60.
Watanabe T, Okazaki E, Shibuya H. Influenza A virus-associated encephalopathy with haemophagocytic syndrome. Eur J Pediatr 2003;162:799-800.
Imashuku S, Hlbi S, Todo S. Hemophagocytic lymphohistiocytosis in infancy and childhood. J Pediatr 1997;130:352-7.
Broxmeyer HE, Williams DE, Lu L, Cooper S, Anderson SL, Beyer GS, et al.
The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: Synergism of tumor necrosis factor and interferon-gamma. J Immunol 1986;136:4487-95.
Mamus SW, Beck-Schroeder S, Zanjani ED. Suppression of normal human erythropoiesis by gamma interferon in vitro
. Role of monocytes and T lymphocytes. J Clin Invest 1985;75:1496-503.
Chen CJ, Huang YC, Jaing TH, Hung IJ, Yang CP, Chang LY, et al.
Hemophagocytic syndrome: A review of 18 pediatric cases. J Microbiol Immunol Infect 2004;37:157-63.
Tabata YHibi S, Teramura T, Kuriyama K, Yagi T, Todo S, Sawada T, et al.
Molecular analysis of latent membrane protein 1 in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan. Leuk Lymphoma 2000;38:373-80.
Imashuku S, Hibi S, Tabata Y, Sako M, Sekine Y, Hirayama K, et al.
Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 1998;31:131-7.
Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et al.
Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007;86:58-65.
Imashuku S, Teramura T, Tauchi H, Ishida Y, Otoh Y, Sawada M, et al.
Longitudinal follow-up of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Haematologica 2004;89:183-8.
Lee JS, Kang JH, Lee GK, Park HJ. Successful treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol. J Korean Med Sci 2005;20:209-14.
Lu G, Xie ZD, Shen KL, Wu RH, Jin YK, Yang S, et al.
Clinical analysis and follow-up study of Epstein-Barr virus associated-hemophagocytic lymphohistiocytosis in childhood. Zhonghua Er Ke Za Zhi 2010;48:121-6.
Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother 2001;2:1437-48.
Potter MN, Foot AB, Oakhill A. Influenza A and the virus associated haemophagocytic syndrome: Cluster of three cases in children with acute leukaemia. J Clin Pathol 1991;44:297-9.
Ando M, Miyazaki E, Hiroshige S, Ashihara Y, Okubo T, Ueo M, et al.
Virus associated hemophagocytic syndrome accompanied by acute respiratory failure caused by influenza A (H3N2). Intern Med 2006;45:1183-6.
Mou SS, Nakagawa TA, Riemer EC, McLean TW, Hines MH, Shetty AK. Hemophagocytic lymphohistiocytosis complicating influenza A infection. Pediatrics 2006;118:e216-9.
Samransamruajkit R, Hiranrat T, Chieochansin T, Sritippayawan S, Deerojanawong J, Prapphal N, et al.
Prevalence, clinical presentations and complications among hospitalized children with influenza pneumonia. Jpn J Infect Dis 2008;61:446-9.
Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al.
Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: A mechanism for the unusual severity of human disease? Lancet 2002;360:1831-7.
Ng WF, To KF, Lam WW, Ng TK, Lee KC. The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1 - A review. Hum Pathol 2006;37:381-90.
Harms PW, Schmidt LA, Smith LB, Newton DW, Pletneva MA, Walters LL, et al.
Autopsy findings in eight patients with fatal H1N1 influenza. Am J Clin Pathol 2010;134:27-35.
Ishii H, Asai S, Suzuki T, Eguchi K, Miyachi H. Virus-associated hemophagocytic syndrome in an international traveler as a differential diagnosis of SARS. Intern Med 2005;44:342-5.
Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al.
Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: A preliminary study. JAMA 2003;290:3222-8.
Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA. Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV) - Possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis 2013;17:e792-8.
Imashuku S, Kuriyama K, Teramura T, Ishii E, Kinugawa N, Kato M, et al.
Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol 2001;19:2665-73.
Imashuku S, Hibi S, Ohara T, Iwai A, Sako M, Kato M, et al.
Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood 1999;93:1869-74.
Henter JI, Chow CB, Leung CW, Lau YL. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet 2006;367:870-3.
Henter JI, Palmkvist-Kaijser K, Holzgraefe B, Bryceson YT, Palmér K. Cytotoxic therapy for severe swine flu A/H1N1. Lancet 2010;376:2116.
Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, et al.
Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002;100:2367-73.
|This article has been cited by|
||Hemophagocytic Lymphohistiocytosis in the Emergency Department: Recognizing and Evaluating a Hidden Threat
| ||Katelin Morrissette,Rachel Bridwell,Skyler Lentz,Elizabeth Brem,Karla Olmedo Gutierrez,Manpreet Singh,Alex Koyfman,Brit Long |
| ||The Journal of Emergency Medicine. 2021; |
|[Pubmed] | [DOI]|
||Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology
| ||Jose Gómez-Rial,Maria José Currás-Tuala,Irene Rivero-Calle,Alberto Gómez-Carballa,Miriam Cebey-López,Carmen Rodríguez-Tenreiro,Ana Dacosta-Urbieta,Carmen Rivero-Velasco,Nuria Rodríguez-Núñez,Rocio Trastoy-Pena,Javier Rodríguez-García,Antonio Salas,Federico Martinón-Torres |
| ||Frontiers in Immunology. 2020; 11 |
|[Pubmed] | [DOI]|
||The amount of cytokine-release defines different shades of Sars-Cov2 infection
| ||S Bindoli,M Felicetti,P Sfriso,A Doria |
| ||Experimental Biology and Medicine. 2020; 245(11): 970 |
|[Pubmed] | [DOI]|
||Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy
| ||Paola Toniati,Simone Piva,Marco Cattalini,Emirena Garrafa,Francesca Regola,Francesco Castelli,Franco Franceschini,Emanuele Focà,Laura Andreoli,Nicola Latronico |
| ||Autoimmunity Reviews. 2020; : 102568 |
|[Pubmed] | [DOI]|
||COVID-19: Infection or Autoimmunity
| ||Timothy Icenogle |
| ||Frontiers in Immunology. 2020; 11 |
|[Pubmed] | [DOI]|