Inflammatory Response and Phenotyping in Severe Acute Respiratory Infection From the Middle East Respiratory Syndrome Coronavirus and Other Etiologies.

OBJECTIVES: In this study, we evaluated the inflammatory response in patients with severe acute respiratory infection due to the Middle East respiratory syndrome and non-Middle East respiratory syndrome and assessed the presence of distinct inflammatory subphenotypes using latent class analysis. DESIGN: Prospective cohort study. SETTING: A tertiary care ICU in Riyadh, Saudi Arabia. PATIENTS: Consecutive critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We measured cytokines on days 1, 3, 7, and 14 of ICU stay. We included 116 patients (40 with Middle East respiratory syndrome severe acute respiratory infection and 76 with non-Middle East respiratory syndrome severe acute respiratory infection). On ICU day 1, both patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection had higher levels of interleukin-3, interleukin-4, interleukin-6, interleukin-8, interleukin-17A, eotaxin, and epidermal growth factor compared with healthy controls. There were no differences in cytokines over time between patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection. Using day 1 cytokine levels, latent class analysis categorized patients into two subphenotypes: subphenotype 1 (n = 74 [64%]) and subphenotype 2 (n = 42 [36%]); the latter had significantly higher levels of interleukin-1ß, interleukin-1ra, interleukin-2, interleukin-6, interleukin-7, interleukin-8, interleukin-10, interleukin-12p70, interleukin-15, interleukin-17A, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-1ß, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, granulocyte-colony stimulating factor, interferon-α, and interferon-γ. Although baseline characteristics were not different between the two subphenotypes, patients in the subphenotype 2 had higher ICU mortality compared with the subphenotype 1 (18/42 [43%] vs 17/74 [23%]; p = 0.03). CONCLUSIONS: One third of critically ill patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection demonstrated a subphenotype characterized by increased proinflammatory cytokines, consistent with cytokine storm. Further research is needed to examine whether immunomodulators have differential effects based on inflammatory subphenotypes.

Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study.

AIMS: The pathogenesis, viral localization and histopathological features of Middle East respiratory syndrome - coronavirus (MERS-CoV) in humans are not described sufficiently. The aims of this study were to explore and define the spectrum of histological and ultrastructural pathological changes affecting various organs in a patient with MERS-CoV infection and represent a base of MERS-CoV histopathology. METHODS AND RESULTS: We analysed the post-mortem histopathological findings and investigated localisation of viral particles in the pulmonary and extrapulmonary tissue by transmission electron microscopic examination in a 33-year-old male patient of T cell lymphoma, who acquired MERS-CoV infection. Tissue needle biopsies were obtained from brain, heart, lung, liver, kidney and skeletal muscle. All samples were collected within 45 min from death to reduce tissue decomposition and artefact. Histopathological examination showed necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. The brain and heart were histologically unremarkable. Ultrastructurally, viral particles were localised in the pneumocytes, pulmonary macrophages, renal proximal tubular epithelial cells and macrophages infiltrating the skeletal muscles. CONCLUSION: The results highlight the pulmonary and extrapulmonary pathological changes of MERS-CoV infection and provide the first evidence of the viral presence in human renal tissue, which suggests tissue trophism for MERS-CoV in kidney.

Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia.

We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.

Improving cord blood unit quantity and quality at King Abdullah International Medical Research Center Cord Blood Bank.

BACKGROUND: Public cord blood banks (CBBs) store cord blood unit (CBU) donations for anyone in need. However, strict regulations need to be followed to build up high-quality bank products that can be used worldwide. We established a public CBB at a tertiary hospital in Saudi Arabia. Here, we investigated the reasons behind rejecting or not collecting CBUs over 2 years (2011-2012) and which steps were implemented to improve the number and quality of storable units. STUDY DESIGN AND METHODS: A total of 2891 mothers were evaluated. Reasons for rejecting donors, not collecting, and rejecting units before or after collection were analyzed and compared for the years 2011 and 2012. RESULTS: A total of 1157 (40%) CBUs were not collected, mainly due to staff availability, and 564 (20%) CBUs were rejected. The main reason for rejecting donations was the mother's or neonate's health. Rejecting CBUs after collection was due to low volume. A total of 1170 (40%) CBUs were successfully collected for potential banking and sent for processing; however, 58% were rejected in the laboratory due to low total nucleated cell counts. Several changes were implemented during the 2 years including physician education and awareness, in utero collection, cesarean collection, and staff recruitment. These changes positively affected the numbers of our collected units. Out of the initially eligible mothers in 2011, only 17% were banked; this was increased to 33% in 2012. CONCLUSIONS: We identified the problems with collecting CBUs for banking and will keep improving our selection process of recruiting more CBUs of high quality.

Screening panel-reactive antibody negative, single-antigen positive: a case report.

Sensitized patients remain a challenge for successful transplant. Virtual crossmatch is used to determine the presence or absence of donor-specific antibodies. A 60-year-old woman with a negative screening for panel-reactive antibodies (PRA) received an A*11, A*68 type kidney with a negative anti-human globulin/complement-dependent cytotoxicity (AHG-CDC) crossmatch. Her transplant course was complicated by delayed graft function, and she required hemodialysis. On day 8 after receiving the transplant, she had a kidney biopsy that showed features of antibody-mediated rejection/severe acute tubular necrosis, which was treated by plasmapheresis for 5 sessions and intravenous immunoglobulin (2 g/kg). Her serum level of creatinine decreased from 6.7 to 3.6 mg/dL (600-320 µmol/L). Panel-reactive antibody by Luminex was repeated and again was negative. Single-antigen detection was tried next. Surprisingly, A*11:02 came up positive with a mean fluorescence intensity of 9500. High-resolution donor HLA type was A*68:01 and A*11:01. A*11:02 is not part of the screening Luminex PRA whereas the 11:01 allele is. Serologically, HLA-A11 has 2 defined splits, A11.1 and A11.2, which encode A*11:01 and A*11:02, respectively. In this case, the A*11:02 antibody does not seem to be responsible for the increasing creatinine level. However, if the donor had been A*11:02, a humeral rejection would have occurred and been missed by a virtual crossmatch. Thus virtual crossmatch may not work at all times. Screening for PRA by single antigens is suggested even in PRA-negative cases, if only virtual crossmatch is to be used.

A need to adopt new strategies for organ donation in Saudi Arabia.

BACKGROUND: HLA matching in kidney transplantation is a major factor in long-term survival of the graft. In Saudi Arabia, most deceased donors are non-Saudi, making it difficult to achieve minimal HLA mismatches between donor and recipient. OBJECTIVE: To analyze HLA types of 200 deceased donors and compare them with the Saudi population's HLA types. MATERIALS AND METHODS: In a retrospective study analyzing HLA types of the last 398 deceased donors processed in a tertiary hospital in Riyadh, Saudi Arabia, HLA types of all donors were compared with HLA types from a control group of healthy Saudi persons. RESULTS: HLA types were significantly different between the deceased donor group and the Saudi population. In all deceased donors, zero mismatches was never achieved. The major differences in HLA types were in HLA-A*02, HLA-B*15, B*40, B*50, HLA-DRB1*14, DRB1*15, and DRB1*04. CONCLUSIONS: As most of our deceased donors are non-Saudis, it is difficult to match for HLA-A, HLA-B, and HLA-DR. HLA matching should be attempted nationwide by adopting different strategies, including typing donors centrally and distributing results to all centers, agreeing on a national point system for allocating organs from deceased donors, and making HLA matching a priority, especially for highly sensitized patients.

Identification of the novel HLA-C*04:495 allele by sequencing-based typing.

The HLA-C*04:495 allele differs from HLA-C*04:01:01:31 by two nucleotide changes in the 5'UTR and exon 5.

Combined effect of age and body mass index on postoperative mortality and morbidity in laparoscopic cholecystectomy patients.

Background: Previous studies have assessed the impact of age and body mass index (BMI) on surgery outcomes separately. This retrospective cohort study aimed to investigate the combined effect of age and BMI on postoperative mortality and morbidity in patients undergoing laparoscopic cholecystectomy. Methods: Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for laparoscopic cholecystectomy patients between 2008 and 2020 were analyzed. Patient demographics, functional status, admission sources, preoperative risk factors, laboratory data, perioperative variables, and 30-day postoperative outcomes were included in the dataset. Logistic regression was used to determine the association of age, BMI, and age/BMI with mortality and morbidity. Patients were stratified into different subcategories based on their age and BMI, and the age/BMI score was calculated. The chi-square test, independent sample t-test, and ANOVA were used as appropriate for each category. Results: The study included 435,052 laparoscopic cholecystectomy patients. Logistic regression analysis revealed that a higher age/BMI score was associated with an increased risk of mortality (adj OR 13.13 95% CI, 9.19-18.77, p < 0.0001) and composite morbidity (adj OR 2.57, 95% CI 2.23-2.95, p < 0.0001). Conclusion: Older age, especially accompanied by a low BMI, appears to increase the post-operative mortality and morbidity risks in laparoscopic cholecystectomy patients, while paradoxically, a higher BMI seems to be protective. Our hypothesis is that a lower BMI, perhaps secondary to malnutrition, can carry a greater risk of surgery complications for the elderly. Age/BMI is strongly and positively associated with mortality and morbidity and could be used as a new scoring system for predicting outcomes in patients undergoing surgery. Nevertheless, laparoscopic cholecystectomy remains a very safe procedure with relatively low complication rates.

Identification of the novel HLA-DQB1*03:483 allele by sequencing-based typing.

A single nucleotide change in exon 1 of HLA-DQB1*03:01:01:03 results in the novel HLA-DQB1*03:483 allele.

Identification of the novel HLA-A*74:03:03 allele by sequencing-based typing.

HLA-A*74:03:03 differs from A*74:03:01 by a synonymous mutation at nucleotide 1948 in exon 4.

Age/BMI is a Stronger Predictor of Death in COVID-19 Patients than Age Alone: A Pilot Study.

The objective of this study was to investigate the effect of age and BMI on the risk of death in patients with coronavirus disease 2019 (COVID-19). A cohort of 206 Saudi COVID-19 patients was included in this study. Data on age, BMI, hospitalization, comorbidities, and death were collected and analyzed. Descriptive, univariate, and multivariate logistic regression analyses were carried out. Out of the 206 studied patients, 28 died. Hypertension, cardiac disease, and hospital admission were predictors of death in univariate and multivariate logistic regression analysis. Moreover, age was a significant predictor of death, while increased BMI seemed to be protective at an older age. Therefore, a new score was suggested taking into consideration both factors, namely age/BMI score. Although older age was associated with death in univariate (OR, 1.09 [95% CI 1.05-1.12], p < 0.001) and multivariate analysis (OR, 1.05 [95% CI 1.02-1.09], p = 0.004), a higher age/BMI score was a stronger predictor of death than age alone, in both univariate (OR 4.42 [95% CI 2.50-7.80], p < 0.001) and multivariate analysis (OR 3.11 [95% CI 1.66-5.82], p < 0.001). Several factors appear to contribute to the risk of COVID-19 death. Interestingly, our new age/BMI score seems to carry a higher risk of death than age alone. This new score will be designated as the Hajeer score. Since this is a small cohort study, we recommend investigating this score in a larger cohort.

Characterization of the novel HLA-A*31:199 allele by sequencing-based typing.

A single nucleotide change in exon 4 of HLA-A*31:01:02:31 results in the novel HLA-A*31:199 allele.

Identification of a novel HLA-A*31 variant, HLA-A*31:01:02:31, in a Saudi individual.

A single nucleotide change in the 5' UTR of A*31:01:02:01 results in the novel HLA-A*31:01:02:31 allele.

Identification of a novel HLA-B*18 variant, HLA-B*18:01:01:52, in a Saudi individual.

A single nucleotide change in the 3' UTR of HLA-B*18:01:01:01 results in the novel HLA-B*18:01:01:52 allele.

Characterization of the novel HLA-A*68:277 allele by sequencing-based typing.

A single nucleotide change in exon 1 of HLA-A*68:01:01:02 results in the novel HLA-A*68:277 allele.

Characterization of the novel HLA-B*57:02:01:03 allele by sequencing-based typing.

Two-nucleotide changes in the 3' UTR of HLA-B*57:02:01:01 result in the novel HLA-B*57:02:01:03 allele.

Kinetics of antibody response in critically ill patients with Middle East respiratory syndrome and association with mortality and viral clearance.

The objective of this study is to examine the IgG antibody response in critically ill patients with the Middle East respiratory syndrome (MERS) and to examine the association of early antibody response with mortality and viral clearance. We collected blood samples from 40 consecutive real-time reverse transcription-polymerase chain reaction (rRT-PCR) confirmed critically ill MERS patients on ICU days 1, 3, 7, 14 and 28. MERS-CoV antibodies were detected by enzyme-linked immunosorbent assay (ELISA), using wells coated with MERS-CoV S1 antigen. Patients were admitted to ICU after a median (Q1, Q3) of 9 (4, 13) days from onset of symptoms with an admission Sequential Organ Failure Assessment (SOFA) score of 11 (6.5, 12). Among the study cohort, 38 patients (95%) received invasive ventilation, 35 (88%) vasopressors, 21 (53%) renal replacement therapy and 17 (43%) corticosteroids. Median (Q1,Q3) ELISA optical density (OD) ratio significantly increased with time (p < 0.001) from 0.11 (0.07, 1.43) on day 1; to 0.69 (0.11, 2.08) on day 3, 2.72 (1.84, 3.54) on day 7, 2.51 (0.35, 3.35) on day 14 and 3.77 (3.70, 3.84) on day 28. Early antibody response (day 1-3) was observed in 13/39 patients (33%) and was associated with lower mortality (hazard ratio: 0.31, 95% CI 0.10, 0.96, p = 0.04) but was not associated with faster clearance of MERS-CoV RNA. In conclusion, among critically ill patients with MERS, early antibody response was associated with lower mortality but not with faster clearance of MERS-CoV RNA. These findings have important implications for understanding pathogenesis and potential immunotherapy.

Association between antibiotic use and risk of prostate cancer.

The association between antibiotics and risk of cancer has been addressed in different studies, most of which were addressing breast cancer. The objective of this study was to assess the association between antibiotics use and risk of prostate cancer. We carried out a population-based case-control study using data from Saskatchewan Health administrative databases (Canada) between the years 1981 and 2000. Cases identified by the Saskatchewan Cancer Agency were matched to 4 controls, using incidence density sampling. The effect of dosage and timing of antibiotic use, over a minimum of 15 years before diagnosis, on prostate cancer risk was assessed. Number of prescriptions and number of tablets were used as exposure definitions. Moreover, the effect of different classes of antibiotics on prostate cancer was also studied. A total of 4,052 prostate cancer cases and 16,208 matched controls were included in this study. Antibiotics exposure (number of prescriptions) during the period of 1-15 years in the past was significantly associated with an increased risk of prostate cancer; RR = 1.69, 2.61, 2.71, and 2.83 for the 4 quartiles, respectively, p-trend = 0.0001. When number of units was taken as the exposure definition, similar results were found. We did not find any effect of the timing or class of antibiotic exposure on prostate cancer risk. We found a dose-dependent association between antibiotics exposure up to 15 years in the past and risk of prostate cancer. However, the lack of temporal trends and the absence of class specific effects suggest a noncausal relationship.

Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial.

BACKGROUND: Recent studies have reported a high prevalence of relative adrenal insufficiency in patients with liver cirrhosis. However, the effect of corticosteroid replacement on mortality in this high-risk group remains unclear. We examined the effect of low-dose hydrocortisone in patients with cirrhosis who presented with septic shock. METHODS: We enrolled patients with cirrhosis and septic shock aged 18 years or older in a randomized double-blind placebo-controlled trial. Relative adrenal insufficiency was defined as a serum cortisol increase of less than 250 nmol/L or 9 µg/dL from baseline after stimulation with 250 µg of intravenous corticotropin. Patients were assigned to receive 50 mg of intravenous hydrocortisone or placebo every six hours until hemodynamic stability was achieved, followed by steroid tapering over eight days. The primary outcome was 28-day all-cause mortality. RESULTS: The trial was stopped for futility at interim analysis after 75 patients were enrolled. Relative adrenal insufficiency was diagnosed in 76% of patients. Compared with the placebo group (n = 36), patients in the hydrocortisone group (n = 39) had a significant reduction in vasopressor doses and higher rates of shock reversal (relative risk [RR] 1.58, 95% confidence interval [CI] 0.98-2.55, p = 0.05). Hydrocortisone use was not associated with a reduction in 28-day mortality (RR 1.17, 95% CI 0.92-1.49, p = 0.19) but was associated with an increase in shock relapse (RR 2.58, 95% CI 1.04-6.45, p = 0.03) and gastrointestinal bleeding (RR 3.00, 95% CI 1.08-8.36, p = 0.02). INTERPRETATION: Relative adrenal insufficiency was very common in patients with cirrhosis presenting with septic shock. Despite initial favourable effects on hemodynamic parameters, hydrocortisone therapy did not reduce mortality and was associated with an increase in adverse effects. (Current Controlled Trials registry no. ISRCTN99675218.).