Anakinra for COVID-19 associated secondary haemophagocytic lymphohistiocytosis - Evidence review - NICE
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Evidence review Anakinra for COVID-19 associated secondary haemophagocytic lymphohistiocytosis Publication date: May 2020
This evidence review sets out the best available evidence for anakinra for COVID-19 associated secondary haemophagocytic lymphohistiocytosis. It should be read in conjunction with the evidence summary, which gives the key messages. Commissioned by NHS England Disclaimer The content of this evidence review was up-to-date on 13 May 2020. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. For details on the date the searches for evidence were conducted see the search strategy. Copyright © NICE 2020. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3800-1 Evidence review: COVID-19: Anakinra for sHLH (May 2020) 2 of 23
Contents
Contents ...................................................................................................... 3
Background ................................................................................................. 4
Intervention .................................................................................................. 5
Clinical problem ........................................................................................... 6
Objective...................................................................................................... 7
Methodology ................................................................................................ 7
Summary of included studies....................................................................... 8
Effectiveness and safety .............................................................................. 8
Discussion and limitations of the evidence .................................................. 9
Conclusion ................................................................................................. 12
References ................................................................................................ 13
Appendices ................................................................................................ 16
Appendix A: Research questions ........................................................... 16
Appendix B: Search strategy .................................................................. 19
Appendix C: Evidence selection ............................................................. 23
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 3 of 23Anakinra for COVID-19 associated secondary
haemophagocytic lymphohistiocytosis
Background
As of 13 May 2020, the COVID-19 interactive web-based dashboard developed at
Johns Hopkins University (Dong et al. 2020) stated that there have been over
4,291,000 confirmed cases of COVID-19 globally. Around 293,000 people had
reportedly died by that date and 1,507,000 have recovered. COVID-19 is a disease
caused by a novel coronavirus (SARS-CoV-2), which emerged in Wuhan, China in
December 2019. Other diseases caused by coronaviruses include severe acute
respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and the
common cold.
The clinical presentation of COVID-19 is that of a respiratory infection with a
symptom severity ranging from a mild common cold-like illness, to a severe viral
pneumonia leading to acute respiratory distress syndrome (ARDS) that is potentially
fatal. Hyperinflammation has been reported in people with COVID-19, which likely
represents a type of virus-induced secondary haemophagocytic lymphohistiocytosis
(sHLH) that may be fatal (BMJ Best Practice: Coronavirus disease 2019). Patients
with COVID-19 are currently offered best supportive care, with no known effective
medication to treat it (WHO 2020).
Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome,
which can lead to a cytokine storm, tissue damage and multi-organ failure. It has a
high mortality rate. Primary HLH is an inherited condition, which presents mainly in
childhood and may be associated with immunodeficiency. Secondary HLH (sHLH)
usually occurs in previously immunocompetent people and may be triggered by
autoimmune or autoinflammatory disease (when it is called macrophage activation
syndrome [MAS]), malignancy (especially haematological malignancy) or, most
often, infection (when it may be indistinguishable from sepsis). Viral infections are
the most common cause of secondary sHLH; for example, Epstein Barr virus,
cytomegalovirus, herpes simplex virus, varicella zoster, HIV, influenza, Dengue and
Ebola (Carter et al. 2019). Recently, UK clinicians have seen an increased incidence
of sHLH during the COVID-19 pandemic (reported through the national network of
interested specialists (the HLH across-specialty collaboration [HASC]).
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 4 of 23Diagnosis of primary HLH is according to the HLH-2004 criteria (Henter et al. 2007), which requires at least 5 out of 8 parameters to be positive (fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinaemia, haemophagocytosis, low or no NK cell activity and raised soluble interleukin-2 receptor [sIL-2r]). Modified HLH-2004 criteria are used for diagnosing sHLH in conjunction with clinical judgment and patient history (La Rosee et al. 2019). Treatment of sHLH is with immunosuppressive therapy (including corticosteroids, intravenous immunoglobulin [IVIG], anakinra and etoposide) combined with treatment of the triggering illness (Carter et al. 2019). There remains uncertainty about whether corticosteroids are beneficial to people with severe forms of COVID-19 ARDS or not (Villar et al. 2020 and Wu et al. 2020). Both corticosteroids and etoposide may also increase the risk of secondary infection in COVID-19. IVIG is scarce and expensive and supplies are being requisitioned to ensure patients on chronic replacement have their treatment protected (Updated Commissioning Guidance for the use of therapeutic immunoglobulin in immunology, haematology, neurology and infectious diseases in England December 2018). There is currently no validated treatment for the triggering virus (SARS-CoV-2) in COVID-19. Intervention Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist that blocks the biologic activity of natural IL-1 by competitively inhibiting the binding of IL-1 to the interleukin-1 type receptor (Kineret summary of product characteristics). IL-1 is a proinflammatory mediator produced in response to infection and is central to the hyperinflammation seen in cytokine storm syndromes such as sHLH (Mehta et al 2020). Anakinra is licensed as a subcutaneous injection for treating adults with rheumatoid arthritis, and people aged at least 8 months with Still’s disease or cryopyrin- associated periodic syndromes (Kineret summary of product characteristics). Anakinra was associated with reduced mortality in patients with sepsis and features of MAS (a type of sHLH) in a post-hoc analysis (n=43) of a phase 3 trial (Shakoory et al 2016). It is recommended in treatment algorithms for sHLH (Carter et al. 2019 and La Rosee et al. 2019) as part of a multi-disciplinary team decision-making process. Evidence review: COVID-19: Anakinra for sHLH (May 2020) 5 of 23
The recommended starting dose of anakinra for sHLH is usually 1–2 mg/kg/day subcutaneously, increasing to a maximum of 8 mg/kg/day (Carter et al. 2019). Anakinra is not licensed for sHLH or for intravenous administration. However, in critical illness subcutaneous absorption can be unreliable and intravenous dosing is sometimes used in clinical practice to achieve a higher and faster maximal plasma concentration. If the therapeutic response is inadequate, dose escalation is sometimes considered up to 8 mg/kg/day (as continuous intravenous infusion or in divided doses). If intravenous dosing is used, the subcutaneous route should be restarted as soon as possible once the person’s condition is stable (Mehta et al 2020. Anakinra has been used to treat a range of cytokine storm syndromes and appears to be well tolerated (Mehta et al 2020). Reported adverse effects of subcutaneous anakinra include headache, injection site reactions, neutropenia, thrombocytopenia, serious infections, allergic reactions and hepatitis (Kineret summary of product characteristics). Anakinra can cross the blood-brain barrier when given intravenously and therefore may be favoured in patients with cytokine storm syndromes and neurological manifestations (Mehta et al 2020). Clinical problem COVID-19 is a rapidly evolving global pandemic, with countries tackling different stages of the disease spread. Therefore, there is limited published information about the disease course, vulnerable populations and mortality rate. Studies on COVID-19 are limited mainly to observational studies from China, particularly Wuhan, where the disease first emerged. Data from this region suggest that older age and presence of comorbidities are the main risk factors for dying in hospital (Zhou et al. 2020). UK data from 16,749 patients showed that increasing age over 50 years was a strong predictor of mortality in hospital (hazard ratio 4.02 for 50–69 years, 9.6 for 70– 79 years and 13.6 for 80 years or over: Docherty et al. 2020). Children and young people appear to be less affected by the virus, with low numbers of deaths and critical care admissions in this age group (Lu et al. 2020). SARS-CoV-2 infection can produce a profound cytokine response in the host, with raised levels of many inflammatory mediators. Observational studies have shown an Evidence review: COVID-19: Anakinra for sHLH (May 2020) 6 of 23
association between systemic inflammation, severity and adverse outcomes in COVID-19 (Huang et al. 2020, Ruan et al. 2020, Zhou et al. 2020). A hyperinflammatory response develops in some people with COVID-19, which may be localised to the lungs or lead to widespread systemic illness and sHLH (McGonagle et al. 2020). When sHLH is triggered by SARS-CoV-2 infection in COVID-19, immunomodulatory treatment with corticosteroids, etoposide and IVIG may not be appropriate or available. Anakinra is recommended in standard sHLH treatment algorithms and may be an option but is not currently licensed for this indication. As of 30 April 2020, the Intensive Care National Audit Research Centre (ICNARC) had been notified of 9,801 admissions for critical care with confirmed COVID-19 in England, Wales and Northern Ireland (ICNARC 2020). To date, data on the incidence of sHLH in COVID-19 are lacking. An alert from NHS England issued on 26 April 2020 reported a small rise in the number of cases of critically ill children presenting with a novel presentation of multisystem inflammatory disease. Some of these children had tested positive for COVID-19, but some had not. It remains unclear whether there could be another, as yet unidentified, infectious pathogen associated with some of the cases (PICSUK 2020). Objective This evidence review considers the clinical effectiveness, safety and cost effectiveness of anakinra for treating sHLH triggered by SARS-CoV-2 in people of all ages. Methodology A description of the relevant Population, Intervention, Comparison and Outcomes (PICO) for this review was provided by NHS England for the topic (see the search strategy section for more information). The research questions for this evidence review are: Evidence review: COVID-19: Anakinra for sHLH (May 2020) 7 of 23
1. In adults and children with sHLH triggered by SARS-CoV-2 or a similar
coronavirus, what is the clinical effectiveness of anakinra compared with
supportive treatment?
Supportive care may involve treatment with corticosteroids, IVIG, etoposide,
organ support (ventilation, renal replacement therapy, transfusions etc) and
antimicrobials.
2. In adults and children with sHLH triggered by SARS-CoV-2 or a similar
coronavirus, what is the safety of anakinra compared with supportive
treatment?
3. In adults and children with sHLH triggered by SARS-CoV-2 or a similar
coronavirus, what is the cost effectiveness of anakinra compared with
supportive treatment?
4. From the evidence selected, are there any subgroups of patients that may
benefit from anakinra more than the wider population of interest?
The searches for evidence to support using anakinra for COVID-19 associated sHLH
were undertaken by NICE Guidance Information Services. Results from the literature
searches were screened using their titles and abstracts for relevance against the
criteria from the PICO. Full text references of potentially relevant evidence were
obtained and reviewed to determine whether they met the PICO inclusion criteria for
this evidence review. More information can be found in the sections on search
strategy and evidence selection.
The evidence review was undertaken following a modified version of the NHS
England process for developing evidence reviews.
Summary of included studies
No relevant papers were identified in the searches undertaken for this evidence
review.
Effectiveness and safety
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 8 of 23No studies were found considering the effectiveness, safety or cost effectiveness of anakinra in adults and children with sHLH triggered by SARS-CoV-2 or a similar coronavirus. Discussion and limitations of the evidence No published evidence was found to support using anakinra for COVID-19 associated sHLH. Two preprints were identified. Preprints are preliminary reports of work that have not yet undergone peer review and should be considered unpublished. Preprints are usually submitted to a preprint server before or at the same time they are submitted for publication to a peer-reviewed journal. Therefore, the findings reported in the preprint need to be interpreted with caution and should not be reported as established information. The first preprint was the PROSPERO systemic review (Khan et al. 2020). This systematic review did not identify any published studies of anakinra (search conducted on 08/04/2020), although 5 studies of tocilizumab or siltuximab were identified. The second preprint was a small study (Dimopoulos et al. 2020) that included 8 people with severe COVID-19 pneumonia and sHLH who were treated with anakinra. At the end of treatment with anakinra, the authors report that laboratory outcomes were improved, as was the patients’ respiratory function. Two patients died. The authors conclude that anakinra may be a viable treatment for severe COVID-19 associated sHLH and note that larger clinical studies are needed to validate this concept. A further paper was published after the searches were undertaken, which looked at the effects of anakinra in people with COVID-19, moderate to severe ARDS and hyperinflammation (Cavalli et al. 2020). It looked at the effects of anakinra in people with COVID-19, moderate to severe ARDS and hyperinflammation but hyperinflammation in the study population was not defined in the same way as sHLH (La Rosee et al. 2019). Evidence review: COVID-19: Anakinra for sHLH (May 2020) 9 of 23
The study by Cavalli et al. was a retrospective cohort study in Italy. It compared
clinical outcomes in adults with COVID-19, ARDS, and hyperinflammation who
received anakinra (off label) in addition to non-invasive ventilation and standard
treatment (hydroxychloroquine, lopinavir and ritonavir) outside of intensive care with
outcomes in a similar population of adults who did not receive anakinra. Seven
patients received low-dose anakinra (100 mg twice daily subcutaneously),
29 patients received high-dose anakinra (5 mg/kg twice daily, intravenously over
1 hour) and 16 patients received standard treatment only.
At 7 days, low-dose anakinra was not associated with reductions in serum C-reactive
protein or improvements in clinical status. Therefore, anakinra was stopped in these
patients. At 21 days, treatment with high-dose anakinra (median treatment duration
9 days) was associated with improvements in respiratory function in 72% (21/29) of
patients compared with 50% (8/16) of patients in the standard treatment group
(p value not reported). At 21 days, survival was 90% (26/29) in the high-dose
anakinra group and 56% (9/16) in the standard treatment group (p=0.009). There
was no statistically significant difference between the groups in mechanical
ventilation-free survival (p=0.15).
High-dose anakinra was discontinued because of adverse effects in 24% (7/29) of
patients. Bacteraemia occurred in 14% (4/29) of patients receiving anakinra and 13%
(2/16) of patients receiving standard treatment (p value not reported). The authors
report that discontinuation of anakinra was not followed by inflammatory relapses.
The study by Cavalli et al. has many limitations that affect its application to clinical
practice, including its small size, retrospective nature, short follow up and lack of an
active control arm. It should be considered hypothesis-generating only.
Many trials are planned or underway to assess anakinra for treating symptoms
associated with SARS-CoV-2, including several for cytokine storm syndromes and
hyperinflammation, including sHLH. The most relevant to this evidence review are:
• A phase 2/3 randomised open-label trial in Italy comparing emapalumab,
anakinra and usual care for reducing hyperinflammation and respiratory
distress in people with SARS-CoV-2 infection (Sobi.IMMUNO-101,
NCT04324021, primary completion date July 2020).
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 10 of 23• A phase 3 randomised, double-blind trial in Belgium comparing various
regimens using anakinra, siltuximab, tocilizumab and usual care in people with
SARS-CoV-2 infection, acute hypoxic respiratory failure and systemic cytokine
release syndrome (COV-AID, NCT04330638, primary completion date
September 2020).
• A phase 2 non-randomised, open-label trial in Greece comparing anakinra and
tocilizumab in people with SARS-CoV-2 associated with organ dysfunction and
laboratory findings of MAS or immune dysregulation (ESCAPE, NCT04339712,
primary completion date April 2022).
• A phase 3 randomised, part blinded trial in the USA comparing anakinra and
placebo in people with cytokine storm syndrome (Chatham-Cytokine Covid-19,
NCT04362111, primary completion date July 2020).
• A phase 2 randomised, open-label trial in France comparing anakinra with
anakinra plus ruxolitinib with usual care in people with SARS-Cov2, serious
respiratory symptoms and hyperinflammation (JAKINCOV, NCT04366232,
primary completion date August 2020).
Anakinra has been used (off label) for cytokine storm syndromes triggered by other
viruses (such as herpes viruses), including sHLH, and is reported to be relatively well
tolerated, with a favourable safety profile. Caution is advised when using
immunomodulating therapies in critically ill people with known or suspected
infections because they can increase the risk of infectious complications. However, it
has been proposed that anakinra may be an option if such a treatment is considered
necessary because it has a relatively short half-life and can be discontinued quickly if
an adverse effect or concern for worsening infection arises (Wampler Muskardin et
al. 2020). Anakinra can be given intravenously (off label) or subcutaneously and has
a large therapeutic window. When anakinra is effective for cytokine storm
syndromes, it reportedly works within 2 or 3 days (Cron et al. 2020).
Although some data are available for children, there is little published information on
using intravenous anakinra in adults with non-coronavirus sHLH. A recent
retrospective chart review (Monteagudo et al. 2020) identified in the searches for this
evidence review found that continuous intravenous anakinra infusions (usually the
equivalent of 1–2 mg/kg/hour, up to 2400 mg/day) resulted in improvement in
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 11 of 23laboratory values, then clinical response in 4 out of 5 severely ill adults with MAS who were refractory to all other therapies, including subcutaneous anakinra. Cytopenias occurred in all 5 patients and renal injury occurred in 3 patients. It is unclear whether these were caused by the disease or the treatment. The study by Monteagudo et al. was a small single centre, retrospective observational study and, therefore, has many limitations. It also included people with MAS rather than virus-induced sHLH and is not directly relevant to this evidence review. Nevertheless, the authors conclude that using intravenous anakinra may have relevance to the current COVID-19 pandemic because a subgroup of patients with severe COVID-19 may have a cytokine storm syndrome (sHLH) and treatment with agents used for cytokine storm may be indicated. Other studies may also provide indirect evidence for using anakinra for non- coronavirus sHLH. However, formal searches and critical appraisal were not conducted because this is outside of the scope for this evidence review. Conclusion No evidence was found to determine whether anakinra is effective, safe or cost effective for treating adults and children with sHLH triggered by SARS-CoV-2 or a similar coronavirus. Some new studies have considered intravenous anakinra for related conditions including hyperinflammation in people with COVID-19 and ARDS. However, administering anakinra intravenously is off label, which raises safety concerns. Also, these studies do not compare anakinra with other treatments such as tocilizumab. At this time, policy decisions on whether anakinra should be used for treating COVID-19 associated sHLH will need to consider data extrapolated from studies assessing anakinra for related conditions, such as MAS, non-coronavirus sHLH and hyperinflammation in people with COVID-19 and ARDS. Evidence review: COVID-19: Anakinra for sHLH (May 2020) 12 of 23
References BMJ Best Practice 2020 Coronavirus disease 2019 (COVID-19) Carter SJ, Tattersall RS, Ramanan AV et al. (2019) Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology 58(1): 5–17 Cavalli G, De Luca G, Campochiaro C et al. (2020) Interleukin-1 blockade with high- dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study Lancet Rheumatology doi.org/10.1016/S2665-9913(20)30127-2 Cron RQ and Chatham WW (2020) The Rheumatologist's Role in COVID-19. Journal of Rheumatology 47(5): 639–42 Dimopoulos G, de Mast Q, Markou N et al (2020) Responses in COVID-19 Patients with Severe Respiratory Failure. Accessed online on 6 May 2020 Docherty AM, Harrison EM, Green CA et al. (2020) Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol. Accessed online on 5 May 2020 Dong E, Du H, Gardner L (2020) An interactive web-based dashboard to track COVID-19 in real time. Lancet Infectious Diseases doi.org/10.1016/S1473- 3099(20)30120-1 Henter JI, Horne A, Arico M et al. (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer 48: 124–31 Huang C, Wang Y, Li X et al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223): 497–506 ICNARC (2020) ICNARC report on COVID-19 in critical care. Accessed online on 5 May 2020 Evidence review: COVID-19: Anakinra for sHLH (May 2020) 13 of 23
Khan F, Fabbri L, Stewart I et al. (2020) A systematic review of anakinra, tocilizumab, sarilumab and siltuximab for coronavirus-related infections. doi.org/10.1101/2020.04.23.20076612 La Rosee P, Horne A, Hines M et al. (2019) Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 133(23): 2465–77 Lu X, Zhang L, Du H et al. (2020) SARS-CoV-2 infection in children. New England Journal of Medicine DOI: 10.1056/NEJMc2005073. McGonagle D, Sharif K, O’Regan A et al. (2020) The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmunity Reviews doi: 10.1016/j.autrev.2020.102537 Mehta P, Cron RQ, Hartwell J et al. (2020) Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistocytosis or macrophage activation syndrome. Lancet Rheumatology doi.org/10.1016/S2665-9913(20)30096-5 Monteagudo LA, Boothby A and Gertner E (2020) Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome. ACR open rheumatology doi.org/10.1002/acr2.11135 PICSUK (2020). PICS Statement: Increased number of reported cases of novel presentation of multisystem inflammatory disease. Accessed online on 5 May 2020 Ruan Q, Yang K, Wang W et al. (2020) Clinical predictors of mortality due to COVID- 19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine doi.org/10.1007/s00134-020-05991-x Shakoory B, Carcillo JA, Chatham WW et al. (2016) Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Critical Care Medicine. 44(2): 275–81 Villar J, Ferrando C, Martinez D et al. (2020) Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respiratory Medicine 8(3): 267–76 Evidence review: COVID-19: Anakinra for sHLH (May 2020) 14 of 23
Wampler Muskardin TL (2020) IV anakinra for macrophage activation syndrome may hold lessons for treatment of cytokine storm in the setting of COVID19. ACR open rheumatology doi.org/10.1002/acr2.11140 World Health Organization (2020) Q&A on coronaviruses (COVID-19). Accessed online on 4 May 2020 Wu C, Chen X, Cai Y et al. (2020) Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Internal Medicine doi:10.1001/jamainternmed.2020.0994 Zhou F, Yu T, Du R et al. (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395: 1054–62 Evidence review: COVID-19: Anakinra for sHLH (May 2020) 15 of 23
Appendices
Appendix A: Research questions
Research questions
1. In adults and children with sHLH triggered by SARS-CoV-2 or a similar coronavirus, what is the clinical effectiveness of
anakinra compared with supportive treatment?
Supportive care may involve treatment with corticosteroids, IVIG, etoposide, organ support (ventilation, renal replacement
therapy, transfusions etc) and antimicrobials.
2. In adults and children with sHLH triggered by SARS-CoV-2 or a similar coronavirus, what is the safety of anakinra compared
with supportive treatment?
3. In adults and children with sHLH triggered by SARS-CoV-2 or a similar coronavirus, what is the cost effectiveness of
anakinra compared with supportive treatment?
4. From the evidence selected, are there any subgroups of patients that may benefit from anakinra more than the wider
population of interest?
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 16 of 23Population, Intervention, Comparator and Outcomes (PICO) table
P – Population and Indication Adults and children with suspected or confirmed COVID-19 with features of secondary haemophagocytic
lymphohistiocytosis (sHLH) triggered by SARS-CoV-2 or similar coronaviruses1.
Subgroups:
• Adults > 50 years
• Children• C-reactive protein (CRP) elevation – reduction in serum CRP levels by greater 50% or to less than
50
Cost effectiveness
Inclusion criteria
Study design Systematic reviews, randomised controlled trials, controlled clinical trials, observational studies including
case series. If no higher-level quality evidence is found, case reports can be considered.
Language Any
Patients Human studies only in the review. Evidence from in vitro and animal studies can be considered for the
background (rationale for theories).
Age All ages
Date limits 2000–2020
Publication type None
Study design None
Notes
1 There may be limited evidence related to COVID-19. Evidence related to other coronaviruses (such as
severe acute respiratory syndrome [SARS-CoV-1] or Middle East respiratory syndrome [MERS-CoV])
should also be considered.
2 Supportive care may involve treatment with corticosteroids, IVIG, etoposide, organ support (ventilation,
renal replacement therapy, transfusions etc) and antimicrobials.
3 Diagnosis of HLH is based on either A, B, C or D: A) Criteria of HLH-2004 protocol for primary HLH (5 of
eight of 1. Fever, 2. Splenomegaly, 3. Cytopenias affecting at least 2 of 3 lineages in the peripheral blood,
4. Hypertriglyceridemia and/or hypofibrinogenemia, 5. Hemophagocytosis in bone marrow, spleen, or
lymph nodes, 6. Low or absent NK cell activity, 7.Hyperferritinaemia, and 8. High levels of sIL-2r. Patients
with a molecular diagnosis consistent with HLH do not necessarily need to fulfil the diagnostic criteria). B) H
score/ferritin >10000/tissue diagnosis in sHLH http://saintantoine.aphp.fr/score/. C) Advice from a multi-
disciplinary team (MDT) D) Criteria for MAS in Systemic JIA
https://www.rheumatology.org/Portals/0/Files/A-and-R-Classification-Criteria-Macrophage-Activation-
Syndrome-2016.pdf.
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 18 of 23Appendix B: Search strategy
Cochrane Central Register of Controlled Trials (CENTRAL)
#1 MeSH descriptor: [Interleukin 1 Receptor Antagonist Protein] explode all trees 297
#2 (anakinra* or kineret* or IL-1ra or IL1ra or Il-a):ti,ab 901
#3 ((interleukin-1 or interleukin1) near/3 (blocker* or blocking* or antagonis* or inhibit* or
agonist* or agent*)).ti,ab 3889
#4 {or #1-#3} 4839
#5 MeSH descriptor: [Coronavirus] explode all trees 13
#6 MeSH descriptor: [Coronavirus Infections] explode all trees 131
#7 ((corona* or corono*) near/1 (virus* or viral* or virinae*)):ti,ab,kw 28
#8 (coronavirus* or coronovirus* or coronavirinae* or CoV or HCoV*):ti,ab,kw 336
#9 ("COV-HI" or COVHI or "2019-nCoV" or 2019nCoV or nCoV2019 or "nCoV-2019" or
nCoV19 or "nCoV-19" or "COVID-19" or COVID19 or "CORVID-19" or CORVID19 or "WN-
CoV" or WNCoV or "HCoV-19" or HCoV19 or "HCoV-2019" or HCoV2019 or "2019 novel*"
or Ncov or "n-cov" or "SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-CoV2" or
SARSCov19 or "SARS-Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona*
or Ncorono* or NcovWuhan* or NcovHubei* or NcovChina* or NcovChinese* or SARS2 or
"SARS-2" or SARScoronavirus2 or "SARS-coronavirus-2" or "SARScoronavirus 2" or "SARS
coronavirus2" or SARScoronovirus2 or "SARS-coronovirus-2" or "SARScoronovirus 2" or
"SARS coronovirus2"):ti,ab,kw 72
#10 (respiratory* near/2 (symptom* or disease* or illness* or condition*) near/10 (Wuhan*
or Hubei* or China* or Chinese* or Huanan*)):ti,ab,kw 30
#11 (("seafood market" or "seafood markets" or "food market" or "food markets" or
pneumonia*) near/10 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)):ti,ab,kw 120
#12 ((outbreak* or wildlife* or pandemic* or epidemic*) near/1 (Wuhan* or Hubei* or
China* or Chinese* or Huanan*)):ti,ab,kw 2
#13 MeSH descriptor: [Middle East Respiratory Syndrome Coronavirus] explode all trees
1
#14 ("middle east respiratory syndrome" or "middle eastern respiratory syndrome" or
"middle east respiratory syndromes" or "middle eastern respiratory syndromes" or
MERSCoV or "MERS-CoV" or MERS):ti,ab,kw 53
#15 ("severe acute respiratory syndrome" or "severe acute respiratory
syndromes"):ti,ab,kw 161
#16 ("SARS-CoV-1" or "SARSCoV-1" or "SARSCoV1" or "SARS-CoV1" or SARSCoV or
SARS-CoV or SARS1 or "SARS-1" or SARScoronavirus1 or "SARS-coronavirus-1" or
"SARScoronavirus 1" or "SARS coronavirus1" or SARScoronovirus1 or "SARS-coronovirus-
1" or "SARScoronovirus 1" or "SARS coronovirus1"):ti,ab,kw 119
#17 {or #5-#16} 589
#18 #4 and #17 5
#19 #4 and #17 in Trials 1
Embase
# Searches Results
1 interleukin 1 receptor blocking agent/ 13386
2 anakinra/ 2146
3 (anakinra* or kineret* or IL-1ra or IL1ra or Il-a).af. 13480
((interleukin-1 or interleukin1) adj3 (blocker* or blocking* or antagonis* or inhibit* or agonist* or
4 21591
agent*)).af.
5 or/1-4 25285
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 19 of 236 exp Coronavirinae/ 14019
7 exp Coronavirus infection/ 12644
8 ((corona* or corono*) adj1 (virus* or viral* or virinae*)).ti,ab,kw. 683
9 (coronavirus* or coronovirus* or coronavirinae* or CoV or HCoV*).ti,ab,kw. 18294
("COV-HI" or COVHI or "2019-nCoV" or 2019nCoV or nCoV2019 or "nCoV-2019" or nCoV19 or
"nCoV-19" or "COVID-19" or COVID19 or "CORVID-19" or CORVID19 or "WN-CoV" or WNCoV
or "HCoV-19" or HCoV19 or "HCoV-2019" or HCoV2019 or "2019 novel*" or Ncov or "n-cov" or
"SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-CoV2" or SARSCov19 or "SARS-
10 Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona* or Ncorono* or 6243
NcovWuhan* or NcovHubei* or NcovChina* or NcovChinese* or SARS2 or "SARS-2" or
SARScoronavirus2 or "SARS-coronavirus-2" or "SARScoronavirus 2" or "SARS coronavirus2" or
SARScoronovirus2 or "SARS-coronovirus-2" or "SARScoronovirus 2" or "SARS
coronovirus2").ti,ab,kw.
(respiratory* adj2 (symptom* or disease* or illness* or condition*) adj10 (Wuhan* or Hubei* or
11 538
China* or Chinese* or Huanan*)).ti,ab,kw.
(("seafood market*" or "food market*" or pneumonia*) adj10 (Wuhan* or Hubei* or China* or
12 1295
Chinese* or Huanan*)).ti,ab,kw.
((outbreak* or wildlife* or pandemic* or epidemic*) adj1 (Wuhan* or Hubei* or China* or
13 96
Chinese* or Huanan*)).ti,ab,kw.
14 Middle East respiratory syndrome/ 918
("middle east respiratory syndrome*" or "middle eastern respiratory syndrome*" or MERSCoV or
15 5157
"MERS-CoV" or MERS).ti,ab,kw.
16 ("severe acute respiratory syndrome*" or SARS).ti,ab,kw. 12495
("SARS-CoV-1" or "SARSCoV-1" or "SARSCoV1" or "SARS-CoV1" or SARSCoV or SARS-CoV
or SARS1 or "SARS-1" or SARScoronavirus1 or "SARS-coronavirus-1" or "SARScoronavirus 1"
17 4315
or "SARS coronavirus1" or SARScoronovirus1 or "SARS-coronovirus-1" or "SARScoronovirus 1"
or "SARS coronovirus1").ti,ab,kw.
18 or/6-17 38277
19 5 and 18 14
MEDLINE ALL
# Searches Results
1 interleukin 1 receptor blocking agent/ 13386
2 anakinra/ 2146
3 (anakinra* or kineret* or IL-1ra or IL1ra or Il-a).af. 13480
4 ((interleukin-1 or interleukin1) adj3 (blocker* or blocking* or antagonis* or inhibit* or agonist* or 21591
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 20 of 23agent*)).af.
5 or/1-4 25285
6 exp Coronavirinae/ 14019
7 exp Coronavirus infection/ 12644
8 ((corona* or corono*) adj1 (virus* or viral* or virinae*)).ti,ab,kw. 683
9 (coronavirus* or coronovirus* or coronavirinae* or CoV or HCoV*).ti,ab,kw. 18294
("COV-HI" or COVHI or "2019-nCoV" or 2019nCoV or nCoV2019 or "nCoV-2019" or nCoV19 or
"nCoV-19" or "COVID-19" or COVID19 or "CORVID-19" or CORVID19 or "WN-CoV" or WNCoV
or "HCoV-19" or HCoV19 or "HCoV-2019" or HCoV2019 or "2019 novel*" or Ncov or "n-cov" or
"SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-CoV2" or SARSCov19 or "SARS-
10 Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona* or Ncorono* or 6243
NcovWuhan* or NcovHubei* or NcovChina* or NcovChinese* or SARS2 or "SARS-2" or
SARScoronavirus2 or "SARS-coronavirus-2" or "SARScoronavirus 2" or "SARS coronavirus2" or
SARScoronovirus2 or "SARS-coronovirus-2" or "SARScoronovirus 2" or "SARS
coronovirus2").ti,ab,kw.
(respiratory* adj2 (symptom* or disease* or illness* or condition*) adj10 (Wuhan* or Hubei* or
11 538
China* or Chinese* or Huanan*)).ti,ab,kw.
(("seafood market*" or "food market*" or pneumonia*) adj10 (Wuhan* or Hubei* or China* or
12 1295
Chinese* or Huanan*)).ti,ab,kw.
((outbreak* or wildlife* or pandemic* or epidemic*) adj1 (Wuhan* or Hubei* or China* or
13 96
Chinese* or Huanan*)).ti,ab,kw.
14 Middle East respiratory syndrome/ 918
("middle east respiratory syndrome*" or "middle eastern respiratory syndrome*" or MERSCoV or
15 5157
"MERS-CoV" or MERS).ti,ab,kw.
16 ("severe acute respiratory syndrome*" or SARS).ti,ab,kw. 12495
("SARS-CoV-1" or "SARSCoV-1" or "SARSCoV1" or "SARS-CoV1" or SARSCoV or SARS-CoV
or SARS1 or "SARS-1" or SARScoronavirus1 or "SARS-coronavirus-1" or "SARScoronavirus 1"
17 4315
or "SARS coronavirus1" or SARScoronovirus1 or "SARS-coronovirus-1" or "SARScoronovirus 1"
or "SARS coronovirus1").ti,ab,kw.
18 or/6-17 38277
19 5 and 18 14
All sources
Source No. of Total Total after
results results deduplication
MEDLINE ALL 6
Embase 14 53 42
Cochrane CENTRAL 1
Evidence review: COVID-19: Anakinra for sHLH (May 2020) 21 of 23WHO COVID-19 3 CEBM 0 BMJ Best Practice 1 Cochrane COVID-19 Study 19 Register WHO – Pharmacological 0 treatments for COVID-19 Brigham and Women's 2 Hospital First Affiliated Hospital, 0 Zhejiang AI HTA 0 ACE 0 CADTH 0 EUnetHTA 0 HSE Ireland 0 INAHTA 0 IQWIG 0 NCP 0 NIH 1 NICE Evidence 0 TRIP database 2 Google Scholar 4 Evidence review: COVID-19: Anakinra for sHLH (May 2020) 22 of 23
Appendix C: Evidence selection A literature search was conducted which identified 42 references (see search strategy for full details). These references were screened using their titles and abstracts and no references were obtained and assessed for relevance. Evidence review: COVID-19: Anakinra for sHLH (May 2020) 23 of 23
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