Middle East respiratory syndrome coronavirus infection medical therapy
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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
Middle East Respiratory Syndrome (MERS) is a viral respiratory illness. It is caused by an emerging coronavirus, specifically a betacoronavirus called MERS-CoV (Middle East Respiratory Syndrome Coronavirus), first discovered in 2012. Being a relatively novel virus, there is no virus-specific prevention or treatment options for MERS patients. Attending to the fact that a vaccine hasn't been developed yet, enhancing infection prevention and control measures is critical to prevent the possible spread of MERS-CoV in hospitals and communities. Health‐care facilities that provide care for patients suspected or confirmed to be infected with MERS-CoV, should take appropriate measures to decrease the risk of transmission of the virus from an infected patient to others. It is not always possible to identify patients with MERS-CoV early in time due to the fact that some have mild or unusual symptoms. For this reason, it is mandatory that health‐care providers apply precaution measures consistently with all patients, regardless of their diagnosis, in all work practices.[1][2][3]
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 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 coronavirus infection 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 of treatment of 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.[1]
Cell and animal studies have shown conflicting results: the combination of ribavirin with interferon α-2b in a cell study reduced viral replication[4]; another study in rhesus monkeys with combination of intramuscular ribavirin and interferon α-2b, the group that received the treatment did not develop breathing abnormalities nor radiographic evidence of pneumonia[5]; however, when tried in 5 critically ill patients in Saudi Arabia, this combination was inefficient in all cases, leading to a fatal outcome.[6]
Despite the absence of a specific therapy, some approaches are considered to be more worth of experimentation than others. These include:[7][8][9][2][10]
- 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.
- Interferon - there is supporting evidence from in vitro (SARS virus and MERS-CoV) and in vivo (SARS virus) studies that interferon inhibits viral replication, especially when administered in the early course of the disease. Additionally it is commonly more available than plasma.
- Corticosteroids - there is no evidence of the benefit in the mortality rate and their use is only recommended in a planned treatment regimen or when the benefits of the drug outweigh the potential harms. When used, constant monitoring is mandatory and the ideal timing is the early course of the disease, during the period of maximal inflammatory response.
- Ribavirin - the most commonly used drug in the treatment of SARS. Due to the controversial results of clinical trials relating to the use of ribavirin for MERS and its high level of toxicity in humans, some experts recommend the withhold of the drug.
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:[2]
Early recognition
This section focuses on the early recognition of symptoms and management of patients with severe acute respiratory infections. This includes:[2]
- Recognition of severe manifestations of acute respiratory infections, such as pneumonia or sepsis
- Prevention of infection by implementing measures like droplet or airborne precautions
- Providing oxygen therapy to patients with severe acute respiratory infections, presenting with hypoxemia or shock
- Specimen collection for laboratory testing, from upper and lower respiratory tracts
- Empiric antibiotics until diagnosis of is confirmed
- Careful fluid administration in patients with severe acute respiratory infections, even in the absence of shock, since volume overload may jeopardize oxygenation
- Monitoring of possible clinical deterioration of patients with severe acute respiratory infections
- Avoidance of high-dose systemic corticosteroids to prevent side-effects such as opportunistic infections and avascular necrosis
ARDS
This section focuses on management of patients who deteriorate and develop ARDS. It includes:[2]
- 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[11][12]
- 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[13][14]
- Fluid management in ARDS patients, in the absence of shock, in order to decrease duration of mechanical ventilation
Septic Shock
This section targets the adequate management of septic shock. It includes:[2]
- 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:[2]
- 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[15]
- Avoid prolonged immobilization by turning the patient every 2 hours
- Reduce formation of gastric ulcers by administration of early enteric nutrition along with an Histamine H2 receptor blocker or a PPI
- Reduce weakness by immobilization
In Vitro Studies
The development of an antiviral drug is a long-winded process that may not be compatible with the need of a drug to treat coronaviruses, specifically MERS-CoV. Therefore, some studies using existing therapies are being developed in order to find a drug that will likely inhibit the infection by MERS-CoV.[16][17] One of these studies was performed on cell cultures, in the hope of finding a previously approved FDA compounds that would inhibit the replication of the virus in vitro. It was able to find four molecule inhibitors of the replication of MERS-CoV:[16][17]
Although the selectivity index of some compounds was limited, the researchers were able to determine a concentration of drug that inhibited the replication of the virus by more than 80%, preserving the viability of the cell. These drugs were also found to be able to inhibit the replication of other coronaviruses, namely the HCoV-229E and the SARS-CoV. The off-label use of these drugs, particularly when used in combination, might be able to reduce the viral load of the host, therefore halting the course of infection and allowing the building of a proper immune response by the host's immune system.[16]
Further studies will evaluate the potential benefit of the combination of 2+ of these drugs, along with interferon as well. Of the above mentioned, the two presenting as better options for more animal studies and/or off-label use, are the chloroquine and lopinavir. This potential use is due to the fact that these drugs were able to inhibit replication of the virus, in the tested cell cultures, in concentrations that are possible to be achieved in the human plasma.[16]
References
- ↑ 1.0 1.1 Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J; et al. (2014). "Repurposing of clinically developed drugs for treatment of Middle East Respiratory Coronavirus Infection". Antimicrob Agents Chemother. doi:10.1128/AAC.03036-14. PMID 24841273.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do" (PDF).
- ↑ "MERS Prevention and Treatment".
- ↑ Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H (2013). "Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin". Sci Rep. 3: 1686. doi:10.1038/srep01686. PMC 3629412. PMID 23594967.
- ↑ Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP; et al. (2013). "Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques". Nat Med. 19 (10): 1313–7. doi:10.1038/nm.3362. PMID 24013700.
- ↑ Al-Tawfiq JA, Momattin H, Dib J, Memish ZA (2014). "Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study". Int J Infect Dis. 20: 42–6. doi:10.1016/j.ijid.2013.12.003. PMID 24406736.
- ↑ "Treatment of MERS-CoV: Decision Support Tool".
- ↑ Guery B, van der Werf S (2013). "Coronavirus: need for a therapeutic approach". Lancet Infect Dis. 13 (9): 726–7. doi:10.1016/S1473-3099(13)70153-1. PMID 23782860.
- ↑ Ren Z, Yan L, Zhang N, Guo Y, Yang C, Lou Z; et al. (2013). "The newly emerged SARS-like coronavirus HCoV-EMC also has an "Achilles' heel": current effective inhibitor targeting a 3C-like protease". Protein Cell. 4 (4): 248–50. doi:10.1007/s13238-013-2841-3. PMID 23549610.
- ↑ Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA (2013). "Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)--possible lessons from a systematic review of SARS-CoV therapy". Int J Infect Dis. 17 (10): e792–8. doi:10.1016/j.ijid.2013.07.002. PMID 23993766.
- ↑ "NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary" (PDF).
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 16.0 16.1 16.2 16.3 de Wilde, A. H.; Jochmans, D.; Posthuma, C. C.; Zevenhoven-Dobbe, J. C.; van Nieuwkoop, S.; Bestebroer, T. M.; van den Hoogen, B. G.; Neyts, J.; Snijder, E. J. (2014). "Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture". Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.03011-14. ISSN 0066-4804.
- ↑ 17.0 17.1 de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW; et al. (2013). "MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment". J Gen Virol. 94 (Pt 8): 1749–60. doi:10.1099/vir.0.052910-0. PMC 3749523. PMID 23620378.