Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial.

Background: Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto-Abs) to type I IFNs were reported as a risk factor for life-threatening COVID-19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS). Methods: We evaluated the prevalence of type I IFN auto-Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo-controlled clinical trial for treatment with IFN-ß1b and lopinavir-ritonavir (MIRACLE trial). Samples were tested for type I IFN auto-Abs using a multiplex particle-based assay. Results: Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto-Abs for at least one subtype of type I IFNs. Auto-Abs positive patients were not different from auto-Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto-Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto-Abs negative patients. The effect of treatment with IFN-ß1b and lopinavir-ritonavir did not significantly differ between the two groups. Conclusion: This study demonstrates the presence of type I IFN auto-Abs in hospitalized patients with MERS.

Heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels.

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).

Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).

Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-ß1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial.

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-ß1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-ß1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

Diabetes Mellitus, Hypertension, and Death among 32 Patients with MERS-CoV Infection, Saudi Arabia.

Diabetes mellitus and hypertension are recognized risk factors for severe clinical outcomes, including death, associated with Middle East respiratory syndrome coronavirus infection. Among 32 virus-infected patients in Saudi Arabia, severity of illness and frequency of death corresponded closely with presence of multiple and more severe underlying conditions.

Middle East Respiratory Syndrome Coronavirus Infection Dynamics and Antibody Responses among Clinically Diverse Patients, Saudi Arabia.

Middle East respiratory syndrome coronavirus (MERS-CoV) shedding and antibody responses are not fully understood, particularly in relation to underlying medical conditions, clinical manifestations, and mortality. We enrolled MERS-CoV-positive patients at a hospital in Saudi Arabia and periodically collected specimens from multiple sites for real-time reverse transcription PCR and serologic testing. We conducted interviews and chart abstractions to collect clinical, epidemiologic, and laboratory information. We found that diabetes mellitus among survivors was associated with prolonged MERS-CoV RNA detection in the respiratory tract. Among case-patients who died, development of robust neutralizing serum antibody responses during the second and third week of illness was not sufficient for patient recovery or virus clearance. Fever and cough among mildly ill patients typically aligned with RNA detection in the upper respiratory tract; RNA levels peaked during the first week of illness. These findings should be considered in the development of infection control policies, vaccines, and antibody therapeutics.

Infectious MERS-CoV Isolated From a Mildly Ill Patient, Saudi Arabia.

Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with a wide range of clinical presentations, from asymptomatic or mildly ill to severe respiratory illness including death. We describe isolation of infectious MERS-CoV from the upper respiratory tract of a mildly ill 27-year-old female in Saudi Arabia 15 days after illness onset.

Predictors of MERS-CoV infection: A large case control study of patients presenting with ILI at a MERS-CoV referral hospital in Saudi Arabia.

BACKGROUND: A case control study to better characterize the clinical features, laboratory, and radiological abnormalities associated with MERS-CoV infection in order to help with early identification of this syndrome from other respiratory infections. METHODS: Eighty patients admitted to a hospital in Riyadh, diagnosed with MERS-CoV infection based on RT-PCR were matched on age, sex, and the presence of a co-morbid condition on a basis of 1:2 to other patients admitted with respiratory symptoms and tested negative for MERS-CoV on RT-PCR. RESULTS: None of the reported MERS-CoV presenting symptoms was significantly associated with being infected with MERS-CoV. On the other hand, WBC count was significantly lower in patients with confirmed MERS-CoV infection (median 5.7 vs 9.3, P: 0.0004). Neutrophil count was as well significantly lower in MERS-CoV patients (median 3.7 vs 6.7, P: 0.0001). Both AST, and ALT values were significantly higher in MERS-CoV infected group (AST median 42 vs 36, P: 0.03, and ALT median 33 vs 28, P: 0.003). Overall our MERS-CoV mortality rate was (10%) below the national figure of (40%). CONCLUSIONS: None of the presenting symptoms are specific for MERS-CoV infection. And out of all the investigations WBC, neutrophil counts, AST and ALT values have some predictive utility.

Utility of surveillance blood cultures in patients undergoing hematopoietic stem cell transplantation.

BACKGROUND: Surveillance blood cultures are often obtained in hematopoietic stem cell transplant (HSCT) patients for detection of bloodstream infection. The major aims of this retrospective cohort study were to determine the utility of the practice of obtaining surveillance blood cultures from asymptomatic patients during the first 100 post-transplant days and to determine if obtaining more than one positive blood culture helps in the diagnosis of bloodstream infection. METHODS: We conducted a 17-month retrospective analysis of all blood cultures obtained for patients admitted to the hospital for HSCT from January 2010 to June 2011. Each patient's clinical course, vital signs, diagnostic testing, treatment, and response to treatment were reviewed. The association between number of positive blood cultures and the final diagnosis was analyzed. RESULTS: Blood culture results for 205 patients were reviewed. Cultures obtained when symptoms of infection were present (clinical cultures) accounted for 1,033 culture sets, whereas 2,474 culture sets were classified as surveillance cultures (no symptoms of infection were present). The total number of positive blood cultures was 185 sets (5.3% of cultures obtained) and accounted for 84 positive culture episodes. Incidence of infection in autologous, related allogeneic and unrelated allogeneic transplants was 8.3%, 20.0%, and 28.6% respectively. Coagulase-negative staphylococci were the most common organisms isolated. Based on our application of predefined criteria there were 29 infections and 55 episodes of positive blood cultures that were not infections. None of the patients who developed infection were diagnosed by surveillance blood cultures. None of the uninfected patients with positive blood cultures showed any clinical changes after receiving antibiotics. There was a significant difference between the incidence of BSI in the first and second 50-day periods post-HSCT. There was no association between the number of positive blood cultures and the final diagnosis. CONCLUSION: Surveillance blood cultures in patients who have undergone HSCT do not identify bloodstream infections. The number of positive blood cultures was not helpful in determining which patients had infection. Patients are at higher risk of infection in the first 50 days post-transplant period.

Surgical site infections, International Nosocomial Infection Control Consortium (INICC) report, data summary of 30 countries, 2005-2010.

OBJECTIVE: To report the results of a surveillance study on surgical site infections (SSIs) conducted by the International Nosocomial Infection Control Consortium (INICC). DESIGN: Cohort prospective multinational multicenter surveillance study. SETTING: Eighty-two hospitals of 66 cities in 30 countries (Argentina, Brazil, Colombia, Cuba, Dominican Republic, Egypt, Greece, India, Kosovo, Lebanon, Lithuania, Macedonia, Malaysia, Mexico, Morocco, Pakistan, Panama, Peru, Philippines, Poland, Salvador, Saudi Arabia, Serbia, Singapore, Slovakia, Sudan, Thailand, Turkey, Uruguay, and Vietnam) from 4 continents (America, Asia, Africa, and Europe). PATIENTS: Patients undergoing surgical procedures (SPs) from January 2005 to December 2010. METHODS: Data were gathered and recorded from patients hospitalized in INICC member hospitals by using the methods and definitions of the Centers for Disease Control and Prevention National Healthcare Safety Network (CDC-NHSN) for SSI. SPs were classified into 31 types according to International Classification of Diseases, Ninth Revision, criteria. RESULTS: We gathered data from 7,523 SSIs associated with 260,973 SPs. SSI rates were significantly higher for most SPs in INICC hospitals compared with CDC-NHSN data, including the rates of SSI after hip prosthesis (2.6% vs. 1.3%; relative risk [RR], 2.06 [95% confidence interval (CI), 1.8-2.4]; P < .001), coronary bypass with chest and donor incision (4.5% vs. 2.9%; RR, 1.52 [95% CI, 1.4-1.6]; [P < .001); abdominal hysterectomy (2.7% vs. 1.6%; RR, 1.66 [95% CI, 1.4-2.0]; P < .001); exploratory abdominal surgery (4.1% vs. 2.0%; RR, 2.05 [95% CI, 1.6-2.6]; P < .001); ventricular shunt, 12.9% vs. 5.6% (RR, 2.3 [95% CI, 1.9-2.6]; P < .001, and others. CONCLUSIONS: SSI rates were higher for most SPs in INICC hospitals compared with CDC-NHSN data.

Characterisation of MRSA strains isolated from patients in a hospital in Riyadh, Kingdom of Saudi Arabia.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is spreading worldwide and poses a serious public health problem, being present in hospital settings and communities. However, from the Middle East and the Arabian Peninsula few molecular typing data on MRSA strains are currently available. In order to obtain data on the population structure of MRSA in Riyadh, Saudi Arabia, 107 clinical and environmental MRSA isolates were genotyped using a microarray-based assay. RESULTS: Five major MRSA strains from four clonal complexes were identified CC8/ST239-III (20.75%), PVL-positive as well as -negative CC22-IV (18.87% and 9.43%, respectively), PVL-positive CC30-IV (12.26%) and PVL-positive CC80-IV (17.92%). Minor strains, which accounted for less than 3% each, included CC1-IV/SCCfus, PVL-positive CC1/ST772-V, PVL-positive as well as- negative CC5-IV, CC5-IV/SCCfus, CC5-V, CC6-IV, CC45-IV, PVL-negative CC80-IV, PVL-positive CC88-IV, CC97-V and a CC9/ST834-MRSA strain. CONCLUSIONS: Typing of MRSA strains from Riyadh revealed a high diversity of clonal complexes. The prevalence of the genes encoding the Panton-Valentine leukocidin was surprisingly high (54.21%), and a significant rate of resistance markers was detected also in strains considered as community-associated.

International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004-2009.

The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium's ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries' ICUs was remarkably similar to that reported in US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia).

Outbreak of Burkholderia cepacia bacteremia in immunocompetent children caused by contaminated nebulized sulbutamol in Saudi Arabia.

BACKGROUND: An outbreak of 5 inpatient and otherwise healthy children admitted for respiratory problems developed dry fever and cough after a few days of hospitalization. Burkhuldaria cepacia was isolated from their blood culture. The Infection Control Department (ICD) in the King Fahad Medical City (KFMC) detected and investigated the outbreak to identify the source of the organism and mode of transmission. METHODS: After the initial review of all the existing records in the KFMC, log book of the laboratory, and direct questioning of all physicians and revising the method of B cepacia identification in our laboratory, an observational study to identify any violation of infection control policy and a case-control study were designed to identify possible risk factors associated with the occurrence and transmission of the disease. RESULTS: A total of 7 healthy patients were reported to have B cepacia-positive blood culture, with 5 patients infected in the KFMC and 2 patients in their referring hospitals. We could isolate the same organism from sulbutamol solution 0.5% manufactured locally (Vintec). Among the risk factors studied, concomitant use of nebulized budesonide with sulbutamol (OR, 26; 95% CI: 1.31-1,187) was found to be 26 times more likely to be associated with infection and to be statistically significant; concomitant use of systemic hydrocortisone increased the risk of infection 4 times but, statistically, was not significant. No significant association was found with concomitant syncitial respiratory virus (RSV) infections or having chronic diseases. None of the affected patients were found to be immunocompromised. CONCLUSION: B cepacia can affect healthy children. Contaminated nebulized sulbutamol with B cepacia was the source of infection, and inhalation was the mode of transmission. Concomitant use of nebulized budesonide solution is a significant risk factor. The KFMC was the first health institution to diagnose this national outbreak.

Staphylococcal toxic shock syndrome in a small infant.

Non menstrual staphylococcal toxic shock syndrome is rare in small infants. This is a 4-month-old infant presented to us with a picture of bronchiolitis and few postuler skin lesions, treated with antistapylococcal antibiotics in addition to other supportive medications. On the 4th day of therapy the patient developed sunburn like erythroderma, hypotension, and high grade fever. The dose of antibiotics was increased to the maximum possible dose, in addition to other supportive medications. The patient improved and developed extensive desquamation in both hands and feet on the 14th day of hospitalization, which confirms the diagnosis.

Ceftriaxone treatment failure of meningitis due to penicillin and ceftriaxone resistant streptococcus pneumonia.

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