Middle East respiratory syndrome coronavirus infection medical therapy: Difference between revisions

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==Overview==
==Overview==
[[MERS|Middle East Respiratory Syndrome]] ([[MERS]]) is a [[viral]] [[respiratory disease|respiratory illness]]. It is caused by an emerging [[coronavirus]], specifically a ''betacoronavirus'' called [[Middle east respiratory syndrome coronavirus|MERS-CoV]] (Middle East Respiratory Syndrome Coronavirus), first discovered in 2012. Being a relatively novel [[virus]], treatment options are very limited, with no [[antiviral]] therapy approved for treating patients yet. Outbreaks of [[MERS-CoV]] represent a great challenge since there is very limited time to develop and test new pharmaceutical [[drugs]]. Up until now, supportive medical care, along with untested convalescent [[plasma]], have been the only treatment options. However, reuse of [[drugs]] for other [[viruses]] is presenting as an attractive alternative for [[MERS-CoV]].<ref name="pmid24841273">{{cite journal| author=Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J et al.| title=Repurposing of clinically developed drugs for treatment of Middle East Respiratory Coronavirus Infection. | journal=Antimicrob Agents Chemother | year= 2014 | volume=  | issue=  | pages=  | pmid=24841273 | doi=10.1128/AAC.03036-14 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24841273  }} </ref>
Antiviral therapy against MERS-CoV is not yet recommended. Supportive care is the mainstay of management of MERS-CoV. Monitoring for and early management of MERS-CoV-associated complications is also important.


==Medical Therapy==
==Medical Therapy==
[[MERS]] represents a great challenge in terms of treatment because it is caused by a relatively novel [[virus]] to which there is no approved therapy yet. According to
According to the ''International Severe Acute Respiratory & Emerging Infection Consortium'' from the ISARIC and the ''Interim Guidance Document'' from the [[WHO]], supportive medical care is the mainstay of management of [[MERS-CoV]].<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref><ref name=ISARIC>{{cite web | title =  
the ''International Severe Acute Respiratory & Emerging Infection Consortium'' (ISARIC), supportive medical care continues to be the approved treatment for [[MERS]]. The search for broad-spectrum inhibitors aiming to minimize the impact of [[coronaviruses]] [[infections]] remains the major goal. Recent studies are showing the potential use of other [[drugs]] and therapies to treat the [[MERS-CoV]], which are based on the experience in treating other [[coronaviruses]] like the [[SARS virus]]. This repurposing of [[drugs]] has advantages such as: better availability, lower cost and known safety and tolerability profiles. However, lack of evidence makes these new therapies uncertain.<ref name="pmid24841273">{{cite journal| author=Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J et al.| title=Repurposing of clinically developed drugs for treatment of Middle East Respiratory Coronavirus Infection. | journal=Antimicrob Agents Chemother | year= 2014 | volume=  | issue=  | pages=  | pmid=24841273 | doi=10.1128/AAC.03036-14 | pmc= | url=http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416 }} </ref>
Treatment of MERS-CoV: Decision Support Tool | url = http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416 }}</ref>


Cell and animal studies have shown conflicting results: the combination of [[ribavirin]] with [[Interferon-α|interferon α]]-2b in a cell study reduced [[viral replication]]<ref name="pmid23594967">{{cite journal| author=Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H| title=Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. | journal=Sci Rep | year= 2013 | volume= 3 | issue=  | pages= 1686 | pmid=23594967 | doi=10.1038/srep01686 | pmc=PMC3629412 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23594967  }} </ref>; in another study with rhesus monkeys, the combination of [[intramuscular]] [[ribavirin]] with [[Interferon-α|interferon α-2b]], the group that received the treatment did not develop [[breathing]] abnormalities nor [[radiographic]] evidence of [[pneumonia]]<ref name="pmid24013700">{{cite journal| author=Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP et al.| title=Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. | journal=Nat Med | year= 2013 | volume= 19 | issue= 10 | pages= 1313-7 | pmid=24013700 | doi=10.1038/nm.3362 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24013700  }} </ref>; however, when tried in 5 critically ill patients in Saudi Arabia, this combination was inefficient in all patients, leading to a fatal outcome.<ref name="pmid24406736">{{cite journal| author=Al-Tawfiq JA, Momattin H, Dib J, Memish ZA| title=Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. | journal=Int J Infect Dis | year= 2014 | volume= 20 | issue=  | pages= 42-6 | pmid=24406736 | doi=10.1016/j.ijid.2013.12.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24406736  }} </ref>
===Supportive Care===


ISARIC recommends, additionally to routine investigations, that some approaches are more worth of consideration for experiment. These include:<ref name=ISARIC>{{cite web | title = Treatment of MERS-CoV: Decision Support Tool | url = http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416 }}</ref><ref name="pmid23782860">{{cite journal| author=Guery B, van der Werf S| title=Coronavirus: need for a therapeutic approach. | journal=Lancet Infect Dis | year= 2013 | volume= 13 | issue= 9 | pages= 726-7 | pmid=23782860 | doi=10.1016/S1473-3099(13)70153-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23782860 }} </ref><ref name="pmid23549610">{{cite journal| author=Ren Z, Yan L, Zhang N, Guo Y, Yang C, Lou Z et al.| title=The newly emerged SARS-like coronavirus HCoV-EMC also has an "Achilles' heel": current effective inhibitor targeting a 3C-like protease. | journal=Protein Cell | year= 2013 | volume= 4 | issue= 4 | pages= 248-50 | pmid=23549610 | doi=10.1007/s13238-013-2841-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23549610 }} </ref><ref name=WHO>{{cite web | title = WHO-ISARIC joint MERS-CoV Outbreak Readiness Workshop: Clinical management and potential use of convalescent plasma | url = http://www.who.int/csr/disease/coronavirus_infections/MERS_outbreak_readiness_workshop.pdf }}</ref>
The supportive medical care aims to minimize as much as possible the damages caused by [[MERS]]. It is divided into 4 categories, according to the clinical status of the patient. These categories include:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*'''Convalescent [[plasma]]''' - this therapy, along with others that involve [[antibodies]] for the [[MERS-CoV]] has the strongest evidence for intervention. [[Plasma]] from patients who recovered from [[MERS-CoV]] [[infection]] contains neutralizing [[antibodies]], which represents the best therapy to neutralize the [[extracellular]] [[virus]].
 
*'''[[Intravenous immunoglobulin]]''' -
====Supportive Management of Primary Infection====
*'''[[Interferon]]''' -  
*Provide [[oxygen]] therapy to patients with severe acute [[respiratory infections]], presenting with [[hypoxemia]] or [[shock]]
*'''[[HIV]] [[Protease inhibitors|Protease Inhibitors]]''' -
*Administer empiric [[antibiotics]] until the diagnosis of MERS-CoV is confirmed
*'''[[Ribavirin]]''' -
*Administer fluids carefully in patients with severe acute [[respiratory infections]], even in the absence of [[shock]], since volume overload may jeopardize [[oxygenation]]
*'''[[Corticosteroids]]''' -  
*Monitor forpossible clinical deterioration of patients with severe acute [[respiratory infections]]
*'''[[Nitazoxanide]]''' -
*Avoid high-dose systemic [[corticosteroids]] to prevent side-effects such as opportunistic [[infections]] and [[avascular necrosis]]
 
====Management of Acute Respiratory Distress Syndrome====
 
{{Details|Acute respiratory distress syndrome medical therapy|the management of ARDS}}
 
This section focuses on management of patients who deteriorate and develop [[ARDS]]. Management includes the following:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*Recognition of severe cases where [[oxygen]] therapy may not be enough and a higher flow system may be required
*[[Mechanical ventilation]] in patients with [[respiratory distress]] or [[hypoxemia]] that does not resolve with high-flow [[oxygen]] therapy
*Non-invasive [[ventilation]] (NIV) in cases of [[immunosuppression]] or  in [[ARDS]] that does not present with lack of [[consciousness]] or [[cardiac failure]], under constant monitoring in an [[ICU]] environment. It is important not to delay [[endotracheal intubation]] if NIV is unsuccessful.
*[[Endotracheal intubation]] for [[mechanical ventilation]]
*In patients with [[ARDS]], use of a lung-protective [[ventilation]] with a low pressure ventilation protocol, has shown to reduce mortality in ARDS patients<ref name=ARDSnet>{{cite web | title = NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary | url = http://www.ardsnet.org/system/files/Ventilator%20Protocol%20Card.pdf }}</ref><ref name="pmid23353941">{{cite journal| author=Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al.| title=Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. | journal=Crit Care Med | year= 2013 | volume= 41 | issue= 2 | pages= 580-637 | pmid=23353941 | doi=10.1097/CCM.0b013e31827e83af | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23353941 }} </ref>
*Adjunctive therapeutics in patients with severe [[ARDS]] particularly if [[ventilation]] targets are not achieved, such as neuromuscular blockage or repositioning the patient to a [[prone]] position<ref name="PapazianForel2010">{{cite journal|last1=Papazian|first1=Laurent|last2=Forel|first2=Jean-Marie|last3=Gacouin|first3=Arnaud|last4=Penot-Ragon|first4=Christine|last5=Perrin|first5=Gilles|last6=Loundou|first6=Anderson|last7=Jaber|first7=Samir|last8=Arnal|first8=Jean-Michel|last9=Perez|first9=Didier|last10=Seghboyan|first10=Jean-Marie|last11=Constantin|first11=Jean-Michel|last12=Courant|first12=Pierre|last13=Lefrant|first13=Jean-Yves|last14=Guérin|first14=Claude|last15=Prat|first15=Gwenaël|last16=Morange|first16=Sophie|last17=Roch|first17=Antoine|title=Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome|journal=New England Journal of Medicine|volume=363|issue=12|year=2010|pages=1107–1116|issn=0028-4793|doi=10.1056/NEJMoa1005372}}</ref><ref name="pmid12016096">{{cite journal| author=Messerole E, Peine P, Wittkopp S, Marini JJ, Albert RK| title=The pragmatics of prone positioning. | journal=Am J Respir Crit Care Med | year= 2002 | volume= 165 | issue= 10 | pages= 1359-63 | pmid=12016096 | doi=10.1164/rccm.2107005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12016096 }} </ref>
*Fluid management in [[ARDS]] patients, in the absence of [[shock]], in order to decrease duration of [[mechanical ventilation]]
 
====Management of Septic Shock====
 
{{Details|Sepsis medical therapy|the management of septic shock}}
 
This section targets the adequate management of [[septic shock]]. Management includes the following:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
 
*Recognition of [[septic shock]] in the presence of persistent [[hypotension]] after fluid administration or signs of peripheral [[hypoperfusion]], followed by [[resuscitation]]
*Administration of [[intravenous]] crystalloids in [[septic shock]]
*In persistent [[shock]] it is recommended the use of:
:*[[vasopressors]], such as [[norepinephrine]], [[epinephrine]] and [[dopamine]], preferably through a [[central venous catheter]] and at minimal [[dosage]] to insure an [[SBP]] >90 mmHg
:*need for concomitant [[IV]] [[hydrocortisone]] (<200 mg/day) or [[prednisolone]] (<75 mg/day) administration should be assessed
 
====Prevention of Complications====
This section is mainly based on preventing possible [[complications]]. It includes:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*Reduction of the period under invasive [[ventilation]], by daily evaluation of spontaneous [[breathing]] and [[titration]] of [[sedation]] to a specific target
*Prevent ventilator-related pneumonia by:
:*preferring oral [[intubation]]
:*performing frequent [[antiseptic]] oral care
:*adjusting the patient to a reclined position
:*preferring a closed suctioning system
:*changing the [[ventilator]] circuit for every patient
:*monitoring the status of heat moisture exchanger
:*reducing intermittent mandatory [[ventilation]]
*Prevention of [[venous thromboembolism]] with [[pharmacological]] [[prophylaxis]], in the absence of [[contraindications]]. If [[contraindications]] are present, it is suggested the [[prophylactic]] use of a mechanical device for pneumatic compression
*Prevention of [[infection]] through [[catheter]] manipulation<ref name="pmid17192537">{{cite journal| author=Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S et al.| title=An intervention to decrease catheter-related bloodstream infections in the ICU. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 26 | pages= 2725-32 | pmid=17192537 | doi=10.1056/NEJMoa061115 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17192537  }} </ref>
*Avoid prolonged immobilization by turning the patient every 2 hours
*Reduce formation of [[gastric ulcer]]s by administration of early [[enteric]] nutrition along with an [[Histamine H2 receptor]] blocker or a [[PPI]]
*Reduce [[weakness]] by immobilization
 
==Antimicrobial regimen==
*'''Middle East Respiratory Syndrome treatment'''<ref>http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf?ua=1</ref>
 
:* Preferred regimen: supportive care.
:* Note: There is no antiviral recommended for this infection at this moment, even though experimental therapies are at research (IFNs, [[Ribavirin]], [[Lopinavir]], [[Mycophenolic acid]], [[Cyclosporine]], [[Chloroquine]], [[Chlorpromazine]], [[Loperamide]], [[6-mercaptopurine]] and [[6-thioguanine]]). Supportive care include: administer oxygen to patients with severe acute pulmonary infection with signs of respiratory distress, hypoxaemia or shock; use conservative fluids management, avoid administering high-dose systemic glucocorticoids, use non-invasive ventilation, but, if its nor effective, do not delay endotracheal intubation; use lung-protective strategy for intubated patients, recognize sepsis as early as possible and treat it accordingly.


==References==
==References==
{{Reflist|2}}
{{reflist|2}}
 
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Antiviral therapy against MERS-CoV is not yet recommended. Supportive care is the mainstay of management of MERS-CoV. Monitoring for and early management of MERS-CoV-associated complications is also important.

Medical Therapy

According to the International Severe Acute Respiratory & Emerging Infection Consortium from the ISARIC and the Interim Guidance Document from the WHO, supportive medical care is the mainstay of management of MERS-CoV.[1][2]

Supportive Care

The supportive medical care aims to minimize as much as possible the damages caused by MERS. It is divided into 4 categories, according to the clinical status of the patient. These categories include:[1]

Supportive Management of Primary Infection

Management of Acute Respiratory Distress Syndrome

This section focuses on management of patients who deteriorate and develop ARDS. Management includes the following:[1]

Management of Septic Shock

This section targets the adequate management of septic shock. Management includes the following:[1]

Prevention of Complications

This section is mainly based on preventing possible complications. It includes:[1]

  • preferring oral intubation
  • performing frequent antiseptic oral care
  • adjusting the patient to a reclined position
  • preferring a closed suctioning system
  • changing the ventilator circuit for every patient
  • monitoring the status of heat moisture exchanger
  • reducing intermittent mandatory ventilation

Antimicrobial regimen

  • Middle East Respiratory Syndrome treatment[8]
  • Preferred regimen: supportive care.
  • Note: There is no antiviral recommended for this infection at this moment, even though experimental therapies are at research (IFNs, Ribavirin, Lopinavir, Mycophenolic acid, Cyclosporine, Chloroquine, Chlorpromazine, Loperamide, 6-mercaptopurine and 6-thioguanine). Supportive care include: administer oxygen to patients with severe acute pulmonary infection with signs of respiratory distress, hypoxaemia or shock; use conservative fluids management, avoid administering high-dose systemic glucocorticoids, use non-invasive ventilation, but, if its nor effective, do not delay endotracheal intubation; use lung-protective strategy for intubated patients, recognize sepsis as early as possible and treat it accordingly.

References

  1. 1.0 1.1 1.2 1.3 1.4 "Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do" (PDF).
  2. "Treatment of MERS-CoV: Decision Support Tool".
  3. "NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary" (PDF).
  4. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM; et al. (2013). "Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012". Crit Care Med. 41 (2): 580–637. doi:10.1097/CCM.0b013e31827e83af. PMID 23353941.
  5. Papazian, Laurent; Forel, Jean-Marie; Gacouin, Arnaud; Penot-Ragon, Christine; Perrin, Gilles; Loundou, Anderson; Jaber, Samir; Arnal, Jean-Michel; Perez, Didier; Seghboyan, Jean-Marie; Constantin, Jean-Michel; Courant, Pierre; Lefrant, Jean-Yves; Guérin, Claude; Prat, Gwenaël; Morange, Sophie; Roch, Antoine (2010). "Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome". New England Journal of Medicine. 363 (12): 1107–1116. doi:10.1056/NEJMoa1005372. ISSN 0028-4793.
  6. Messerole E, Peine P, Wittkopp S, Marini JJ, Albert RK (2002). "The pragmatics of prone positioning". Am J Respir Crit Care Med. 165 (10): 1359–63. doi:10.1164/rccm.2107005. PMID 12016096.
  7. Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S; et al. (2006). "An intervention to decrease catheter-related bloodstream infections in the ICU". N Engl J Med. 355 (26): 2725–32. doi:10.1056/NEJMoa061115. PMID 17192537.
  8. http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf?ua=1