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Ribavirin and interferon therapy in patients infected with the middle east respiratory syndrome coronavirus: an observational study
Contents lists available at International Journal of Infectious Diseases Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study Jaffar A. Al-Tawﬁq , Hisham Momattin Jean Dib , Ziad A. Memish , a Internal Medicine, Saudi Aramco Medical Services Organization, PO Box 76, Room A-428-2, Building 61, Dhahran Health Center, Dhahran 31311, b Indiana University School of Medicine, Indiana, USA c Pharmacy Services Division, Saudi Aramco Medical Services Organization, Dhahran, Saudi Arabia d WHO Collaborating Center for Mass Gathering Medicine, Ministry of Health, Riyadh, Saudi Arabia e Al-Faisal University, Riyadh, Saudi Arabia Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) has been reported to have a Received 9 December 2013 high case-fatality rate. Currently, there is no speciﬁc therapy or vaccine with proven effectiveness for Accepted 9 December 2013 Corresponding Editor: Eskild Petersen, Methods: A combination of ribavirin and interferon therapy was used for the treatment of ﬁve MERS- CoV-positive patients. We reviewed the therapeutic schedule and the outcome of these patients.
Results: All patients were critically ill with acute respiratory distress syndrome treated with adjunctive corticosteroids and were on mechanical ventilation at the time of initiation of therapy. The median time from admission to therapy with ribavirin and interferon was 19 (range 10–22) days. None of the patients responded to the supportive or therapeutic interventions and all died of their illness.
Conclusions: While ribavirin and interferon may be effective in some patients, our practical experience Pegylated interferon suggests that critically ill patients with multiple comorbidities who are diagnosed late in the course of their illness may not beneﬁt from combination antiviral therapy as preclinical data suggest. There is clearly an urgent need for a novel effective antiviral therapy for this emerging global threat.
ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. Open access under outcome of the use of a combination of interferon-a2b and ribavirin in the management of ﬁve patients with MERS-CoV Since the discovery of Middle East respiratory syndrome coronavirus (MERS-CoV), the virus has caused 163 cases of disease, with a fatality rate of The disease was initially described 2. Materials and methods in a patient from Saudi Arabia in June 2012.MERS-CoV has caused sporadic cases and clusters in families and healthcare settings.
This was a retrospective observational study of ﬁve MERS-CoV- The best treatment option for the virus is not known. In view of the positive patients who received a combination therapy of interfer- high case-fatality rate and the potential global spread of the virus, on-a2b and ribavirin. We describe the therapeutic schedule, the there is an urgent need to develop effective therapies for this clinical course, clinical and laboratory parameters, and outcomes.
infection. In a recent review, based on therapies used for the related severe acute respiratory syndrome (SARS) coronavirus, the 2.1. MERS-CoV testing possible use of interferon and ribavirin was considered as a therapeutic option.The purpose of this study was to describe the Either Dacron ﬂocked nasopharyngeal swabs or tracheal aspirates were obtained from the patients, and these were submitted to the Ministry of Health MERS-CoV laboratory for MERS-CoV diagnosis. The clinical samples were screened at the Ministry of Health laboratory using a real-time reverse transcrip- tase PCR.Ampliﬁcation targeted both the upstream E protein (upE gene) and open reading frame 1a (ORF1a) for MERS-CoV * Corresponding author. Tel.: +966 13 877 3524; fax: +966 13 877 3790.
testing, and a case was considered positive if both assays were E-mail addresses: , (J.A. Al-Tawﬁq).
positive, as described previously ( 1201-9712 ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. Open access under
J.A. Al-Tawﬁq et al. / International Journal of Infectious Diseases 20 (2014) 42–46 intravenous (IV) every 2 days for 15 days. Imipenem was added on day 5 for 3 days. On day 21 after admission, she was started on ribavirin for 5 days with a loading dose of 2000 mg via nasogastric tube, followed by 400 mg per os (PO) every 8 h, one dose of interferon-a2b 130 mg subcutaneously, and methylprednisolone 40 mg IV every 8 h for 1 day, then twice daily for 1 day, then daily for 2 days. She had a mild rise in amylase and lipase (from 61 to 126 U/l and from 274 to 348 U/l, respectively). The patient remained critically ill on mechanical ventilation requiring inotropic support.
She died 34 days after admission from respiratory and multi-organ A 58-year-old man with diabetes, hypertension, and ESRD on hemodialysis was admitted with cough, fever, and hypoxemic respiratory failure of 2-day duration. He tested positive for MERS- CoV by PCR. Baseline laboratory data are shown in On admission, the patient was started on oseltamivir 75 mg once daily for 5 days, levoﬂoxacin 500 mg IV every 2 days for 6 days, and imipenem 250 mg IV twice daily for 7 days. On day 6, he was prescribed methylprednisolone 60 mg IV every 6 h for 6 days, then every 8 h for 1 day, then 40 mg every 12 h for 1 day, followed by a prednisolone tapered dose for another 10 days. On day 13 after admission, he was started on ribavirin for 5 days with a loading dose of 2000 mg PO, followed by 400 mg every 8 h and two doses of interferon-a2b 100 mg subcutaneously once per week. Two weeks after the initiation of the therapy, platelets dropped from 408 to 43 109/l ). The patient remained on the ventilator for more than 30 days. He died 35 days after admission from multi- organ failure.
A 63-year-old woman with a history of severe bronchial asthma and obstructive sleep apnea (on continuous positive airway pressure (CPAP)), with coronary artery disease, diabetes, hyper- tension, and chronic kidney disease (estimated glomerular ﬁltration rate 15.7 ml/min), was admitted with fever, cough, and dyspnea of 3-day duration and a diagnosis of pneumonia. She tested positive for MERS-CoV by PCR. Baseline laboratory data are shown in On admission, the patient was also started on oseltamivir 75 mg once daily for 5 days, levoﬂoxacin 750 mg IV every 2 days for 7 days, and imipenem 500 mg IV every 6 h for 8 days. On day 11, she was started on ribavirin for 5 days, with a loading dose of 2000 mg via nasogastric tube followed by 600 mg PO every 8 h, one dose of interferon-a2b 144 mg subcutaneously, and prednisone 40 mg PO daily, tapered to 10 mg PO daily for 10 days. One week after initiation of the antiviral and steroid therapy, serum creatinine, aspartate aminotransferase (AST) , and amylase increased (from 0.6 to 2.9 mg/dl, from 6.3 to 20 109/ l, from 25 to 126 IU/l, and from 35 to 255 U/l, respectively). The Figure 1. Median, minimum, and maximum values for amylase, lipase, and lactate patient was diagnosed with pancreatitis and thus further interferon and ribavirin was not given. The patient remained critically ill on mechanical ventilation. She died 45 days after admission from multi-organ failure.
An 81-year-old man with a history of atrial ﬁbrillation, diabetes A 62-year-old woman with diabetes, hypertension, and end- mellitus, and hypertension was admitted with progressive stage renal disease (ESRD) on hemodialysis was admitted with respiratory distress and hypoxemia with fever for 2 days. He fever, cough, and respiratory failure of 3-day duration (). She tested positive for MERS-CoV by PCR. Baseline laboratory data are tested positive for MERS-CoV by PCR. Baseline laboratory data are shown in On the ﬁrst day of hospitalization, the shown in On admission, the patient was started on patient was started on oseltamivir 75 mg once daily for 6 days, oseltamivir 75 mg once daily for 5 days and levoﬂoxacin 500 mg levoﬂoxacin 750 mg every 48 h for 5 days, and imipenem 250 mg J.A. Al-Tawﬁq et al. / International Journal of Infectious Diseases 20 (2014) 42–46 Patient demographics and underlying conditions Other chronic conditions Asthma, obstructive sleep apnea, coronary Atrial ﬁbrillation End-stage renal disease ClCr, creatinine clearance; F, female; M, male; HD, hemodialysis.
Laboratory results of patients at baseline and at 1 and 2 weeks after the initiation of interferon and ribavirin therapy Serum creatinine, mg/dl Platelet count, 109/l WBC count, 109/l IV every 6 h for 6 days. On day 20 after admission, he was started on ribavirin for 9 days, with a loading dose of 2000 mg via nasogastric tube followed by 800 mg via nasogastric tube every We reviewed the cases of ﬁve patients with MERS-CoV 8 h, two doses of interferon-a2b 100 mg subcutaneously once per (). Their median age was 62 (range 24–81) years. The week on hospital days 20 and 27, and methylprednisolone 40 mg patients had chronic kidney disease and four were on maintenance IV every 8 h for 4 days, then 40 mg IV twice daily for 2 days, then hemodialysis. There were three men and two women. All patients 40 mg daily for 2 days (started on hospital day 22). Three weeks tested negative for inﬂuenza. The median number of days from after the initiation of therapy, his hemoglobin dropped (from 11.7 admission to therapy with ribavirin and interferon was 19 (range to 8.7 g/dl) ), while bilirubin increased (from 0.7 to 7.4 mg/ 10–22) All patients received adjunctive corticosteroid dl), suggestive of hemolysis. The patient died 52 days after therapy for acute respiratory distress syndrome. Two patients admission from multi-organ failure.
developed increased lipase after the initiation of therapy, but both of them were given corticosteroids at the same time as antiviral therapy. One patient (case 2) developed thrombocytopenia, with a platelet count that dropped from 408 to 49 109/l () A 24-year-old man with a history of ESRD on hemodialysis was and one patient had possible hemolysis (case 3). All patients had admitted with a febrile illness, a cough for 10 days, and respiratory severe disease with progressive respiratory failure, developed failure requiring mechanical ventilation. He tested positive for multi-organ failure, and died a mean 39.6 (standard deviation 8.5) MERS-CoV by PCR. Baseline laboratory data are shown in days after admission. None of the patients had bacteremia or On the ﬁrst day of hospitalization, the patient was started on fungemia during their hospital stay. shows the median, oseltamivir 75 mg once daily for 2 days and imipenem 250 mg IV minimum, and maximum values for amylase, lipase, and lactate twice daily for 11 days. On day 19 of admission, he was started on dehydrogenase (LDH) for all the patients before initiation of ribavirin for 11 days, with a loading dose of 2000 mg via therapy and at week1 and 2 after therapy initiation.
nasogastric tube, followed by 400 mg via nasogastric tube every 8 h, and two doses of interferon-a2b 100 mg subcutaneously once per week on hospital days 19 and 26. On the same day he started ribavirin, he was also started on methylprednisolone 40 mg IV Since the emergence of MERS-CoV in 2012, the virus has caused every 8 h for 4 days, then 40 mg IV twice daily for 2 days, and then a total of 163 cases of disease, with a high case-fatality rate of 40 mg daily for 2 days. Two weeks after the initiation of therapy, There is an urgent need for effective therapeutic agents. To date, lipase increased (from 561 to 612 U/l). The patient died 32 days no data are available on the use of any agents for the therapy of after admission from multi-organ failure.
MERS-CoV-positive patients. In this report we have described the J.A. Al-Tawﬁq et al. / International Journal of Infectious Diseases 20 (2014) 42–46 Hepatic and pancreatic enzymes of patients at baseline and at 1 and 2 weeks after the initiation of interferon and ribavirin therapy Liver function test Pancreatic enzymes ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase.
a ALP, U/L; ALT, IU/L; AST, IU/L; LDH, IU/L; bilirubin, mg/dl.
b Amylase, U/L; lipase, U/L in very mild radiographic evidence of pneumoniThe treatment Days from admission to initiation of therapy or death was given within 8 h after inoculation of the rhesus macaques.
Days to antiviral therapy Days to steroid therapy Treated animals had lower levels of systemic and local proin- ﬂammatory markers and fewer viral genome copieAlthough these preclinical data are promising, our report illustrates some of the real world issues of dealing with a novel emerging viral infection.
Our patients were not diagnosed until a week into their illnesses, by which time all ﬁve were on mechanical ventilation. They had multiple comorbidities, which most likely adversely affected their therapy of ﬁve MERS-CoV patients who received interferon and clinical outcomes. In addition, we had no serial virologic determi- nation of MERS-CoV levels in airway secretions to shed light on the The patients were treated during the initial phase of the Al-Hasa possibility of virological clearance, virological failure, or clinical outbreak in April and May 2013, a time at which the disease failure of therapy.
epidemiology and clinical characteristics were not known. Hence, In our small series, adverse effects from combination ribavirin there was an inevitable time lapse from admission to the initiation and interferon therapy were observed in three cases. These side of therapy. All patients were already on mechanical ventilation by effects have been noted Two patients had pancreatic the time interferon and ribavirin therapy was instituted and all had enzyme elevation and one had signiﬁcant hemolysis. These a fatal outcome. The patients received the therapy late in the ﬁndings were complicated by the presence of abnormal laboratory course of the disease, at a median of 19 (range 10–22) days after ﬁndings even before the initiation of combination therapy, so it is admission. Late therapy may have contributed to the poor difﬁcult to determine which side effects were due to disease outcome, in addition to the severity of the disease and the progression and which were due to the therapeutic drugs.
multiple comorbidities of the patients.
There is an urgent need for large-scale clinical trials to The timing of initiation of antiviral therapy is critical in the determine the safest and most effective regime for the treatment treatment of most viral infections. In the treatment of SARS-CoV, no of this novel highly fatal emerging infection. While ribavirin and effect of oseltamivir or ribavirin was observed when these agents interferon may show promise, their use needs to be prompt and were started 6–14 days after symptom onset.Early therapy adverse effects monitored closely. This therapeutic approach with ribavirin, within 48 h of hospitalization or after the diagnosis of should be tested in careful clinical studies.
SARS, has been shown to be associated with better outcomes, although the numbers of patients enrolled in these studies has been smalIn the treatment of inﬂuenza, oseltamivir therapy early in the disease resulted in reduced mortality when this was started The authors (JAT, HM, and JD) wish to acknowledge the use of not later than 8 days after the onset of symptomsEarly in vitro the Saudi Aramco Medical Services Organization (SAMSO) facilities studies showed that ribavirin and interferon have anti-MERS-CoV for the data and study, which resulted in this paper. Opinions activity.The in vitro activity of interferon was augmented by expressed in this article are those of the authors and not the concomitant use of ribavirin.In a rhesus macaque model of necessarily of SAMSO. The authors thank Dr Paul Anantharajah MERS-CoV infection, the combination of interferon-a2b and Tambyah of the National University of Singapore Department of ribavirin therapy was effective in limiting the disease and resulted Medicine for his critical review of the manuscript.
J.A. Al-Tawﬁq et al. / International Journal of Infectious Diseases 20 (2014) 42–46 Financial support: All authors have no funding.
Conﬂict of interest: All authors have no conﬂict of interest to 2. World Health Orzination. Middle East respiratory syndrome coronavirus (MERS-CoV)—update. Geneva: WHO; 2013, Available at: last (accessed December 3).
18. Adisasmito W, Chan PK, Lee N, Oner AF, Gasimov V, Aghayev F, et al. Effective- ness of antiviral treatment in human inﬂuenza A(H5N1) infections: analysis of a global patient registry. J Infect Dis 2010;202 19. Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013 Oct 3. pii: S0163-4453(13)00298-3.
Handerwärmungstraining bei Morbus Raynaud-Syndrom Das Raynaud-Syndrom (Morbus Raynaud) ist eindie durch anfallsweises Erblassen der Hände oder Füße aufgrund von gekennzeichnet ist. Unter Umständen können auch Nase und Ohren betroffen sein. Etwa 3% der Bevölkerung leiden an einem primären M. Raynaud (siehe weiter unten). Frauen sind fünfmal häufiger betroffen als Männer. Bei stillenden Frauen können auch die Brustwarzen betroffen sein, während des Stillens verfärbt sich die jeweilige Brustwarze weiß. Manifestationsalter des primären M. Raynaud meist zwischen dem 20-40 Lj. Die Erkrankung ist nach ihrem Entdecker – dem französischen Arzt(1834–1881) – benannt. Umgangssprachlich wird sie auch als Weißfingerkrankheit oder Leichenfinger bezeichnet, andere Bezeichnungen hinsichtlich der Symptome sind Digitus mortuus (Totenfinger) oder Reilscher Finger.