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The purpose of this systematic review was to describe the characteristics of clinical trials that focused on COVID-19 patients with cytokine release syndrome (CRS) and the variability in CRS definitions. Two authors independently searched three clinical trial registries and included interventional clinical trials on COVID-19 hospitalized patients that required at least one elevated inflammatory biomarker. Relevant data, including the type and cutoff of the measured biomarker, oxygen/respiratory criteria, fever, radiologic criteria, and medications, were summarized. A total of 47 clinical trials were included. The included studies considered the following criteria: oxygen/respiratory criteria in 42 trials (89%), radiologic criteria in 29 trials (62%), and fever in 6 trials (18%). Serum ferritin was measured in 35 trials (74%), CRP in 34 trials (72%), D-dimer in 26 trials (55%), LDH in 24 trials (51%), lymphocyte count in 14 trials (30%), and IL-6 in 8 trials (17%). The cutoff values were variable for the included biomarkers. The most commonly used medications were tocilizumab, in 15 trials (32%), and anakinra in 10 trials (24.4%). This systematic review found high variability in CRS definitions and associated biomarker cutoff values in COVID-19 clinical trials. We call for a standardized definition of CRS, especially in COVID-19 patients.

Background The COVID-19 global pandemic caused by severe acute respiratory syndrome coronavirus 2 infection, warranted attention for whether it has unique manifestations in children. Children tend to develop less severe disease with a small percentage present with clinical manifestations of paediatric multisystem inflammatory syndrome and have poor prognosis. We studied the characteristics of COVID-19 in children requiring hospitalisation in the Kingdom of Saudi Arabia and assessed the clinical presentation and the risk factors for mortality, morbidity, and paediatric intensive care (PICU) admission. Methods We conducted a retrospective analysis of COVID-19 patients under 15 years hospitalised at three tertiary academic hospitals between 1 March and 30 June 2020. Results Eighty-eight children were enrolled (>20% were infants). Seven (8%) were in critical condition and required PICU admission, and 4 (4.5%) died of which 3 met the full diagnostic criteria of multi-system inflammatory syndrome and had a high Paediatric Risk of Mortality (PRISM) score at the time of admission. The initial polymerase chain reaction (PCR) test result was positive for COVID-19 in most patients (97.7%), and the remaining two patients had positive result in the repeated confirmatory test. In a subset of patients (20 subjects), repeated PCR testing was performed until conversion to negative result, and the average duration for conversion was 8 (95% CI: 5.2–10.5) days Children requiring PICU admission presented with signs of respiratory distress, dehydration, and heart failure. Most had fever (71.4%) and tonsillitis; 61.4% were discharged within 7 days of hospitalisation. Risk factors for mortality included skin rash, hypotension, hypoxia, signs of heart failure, chest radiograph suggestive of acute respiratory distress syndrome, anaemia, leucocytosis, hypernatraemia, abnormal liver enzymes, and high troponin I, and risk factors for prolonged hospitalisation (>7 days) included the presence of comorbidities, leucopaenia, hyponatraemia, and elevated C-reactive protein. Conclusions The majority of hospitalised children had a brief febrile illness and made a full recovery, but a minority had severe disease.

Background Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), is associated with significant morbidity and mortality. The clinical features of COVID-19 were mentioned in previous studies. However, risk factors for COVID-19 are not fully recognized. The aim of this study is to characterize risk factors and clinical features of COVID-19 disease in Jeddah, Saudi Arabia. Methods A retrospective, chart-review, case-control study was conducted at King Abdulaziz University, Jeddah, Saudi Arabia. Demographic, clinical, radiological, and laboratory data on patients diagnosed between March 18 and May 18, 2020 were collected and analyzed. Results We reviewed medical records on 297 suspected cases of COVID-19. Of these, 175 (59%) tested positive for COVID-19 by polymerase chain reaction (PCR) and considered as cases, while 122 (41%) tested negative and considered as control. COVID-19 positive cases were more likely to be males, and non-health care providers. Hypertension (15%), diabetes (10%) and two or more concurrent comorbidities (54.4%) were more prevalent among COVID-19 patients. Patients presented with fever, cough, and loss of taste/smell were more likely to test positive for COVID-19 (P = 0.001, 0.008, 0.008; respectively). Radiological evidence of pneumonia was associated with confirmed COVID-19 disease (P = 0.001). Shortness of breath and gastrointestinal symptoms were not associated with the risk of COVID-19 at presentation. On admission, white blood cells, neutrophils, lymphocytes, eosinophils, basophils, and platelets were significantly lower among COVID-19 patients compared with controls. Surprisingly, D-Dimer levels were lower among COVID-19 positive patients when compared with controls. Conclusion Male gender, hypertension, and diabetes are the most commonly observed risk factors associated with COVID-19 disease in Jeddah, Saudi Arabia. COVID-19 patient had significantly lower lymphocyte and neutrophil counts.

Background: Effective treatment for Coronavirus Disease-2019 (COVID-19) is under intensive research. Nigella sativa oil (NSO) is a herbal medicine with antiviral and immunomodulatory activities, and has been recommended for the treatment of COVID-19. This study aimed to evaluate the efficacy of NSO treatment in patients with COVID-19. Methods: All adult patients with mild COVID-19 symptoms presented to King Abdulaziz University Hospital, Jeddah, Saudi Arabia, were recruited for an open label randomized clinical trial (RCT). They were randomly divided into control or treatment groups, with the latter receiving 500 mg NSO (MARNYS® Cuminmar) twice daily for 10 days. Symptoms were daily monitored via telecommunication. The primary outcome focused on the percentage of patients who recovered (symptom-free for 3 days) within 14-days. The trial was registered at clinicaltrials.gov (NCT04401202). Results: A total of 173 patients were enrolled for RCT. The average age was 36(±11) years, and 53 % of patients were males. The control and NSO groups included 87 and 86 patients respectively. The percentage of recovered patients in NSO group (54[62 %]) was significantly higher than that in the control group (31[36 %]; p = 0.001). The mean duration to recovery was also shorter for patients receiving NSO (10.7 ± 3.2 days) compared with the control group (12.3 ± 2.8 days); p = 0.001. Conclusions: NSO supplementation was associated with faster recovery of symptoms than usual care alone for patients with mild COVID-19 infection. These potential therapeutic benefits require further exploration with placebo-controlled, double-blinded studies.

Background: Coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS2), is associated with significant morbidity and mortality. The aim of this study is to characterize risk factors and clinical features of COVID-19 disease in an adult cohort in Jeddah, Saudi Arabia. Methods: A retrospective case control study was conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia. Clinical and demographic data on patients presenting at KAUH with concern for COVID-19 disease between March 18 and May 18, 2020 were collected and analyzed. Results: Electronic medical records on 297 patients presenting at KAUH were reviewed. Of these, 175 (59%) tested positive for COVID-19 by polymerase chain reaction (PCR) and 122 (41%) tested negative. COVID-19 positive patients were more likely to be males (OR=1.59; 95% CI=1.22-2.07), and non-health care workers (OR=1.53; 95% CI=1.13-2.08). Hypertension (10%), diabetes (10%), and two or more concurrent co-morbid conditions (54.4%), were more prevalent among COVID-19 positive patients. Patients presenting with fever, cough, and loss of sense of taste or smell were more likely to test positive for COVID-19 (p=0.001, 0.008, 0.008, respectively. Radiological evidence of pneumonia was associated with confirmed COVID-19 disease. Dyspnea, cough and gastrointestinal symptoms were not associated with risk of COVID-19 at presentation. On admission, white blood cells, neutrophils, lymphocytes, eosinophils, basophils, and platelets were significantly lower among COVID-19 positive patients compared to controls. Surprisingly, D-dimer levels were lower among COVID-19 positive patients. Furthermore, only two patients developed thrombosis; one with pulmonary embolism and one with coronary artery thrombosis. Conclusion: Male gender, hypertension and diabetes were associated with risk of COVID-19 disease in this study population. D-dimer levels were not elevated in COVID-19 patients, and venous thromboembolism was not prevalent in cases, compared to controls. This is in contrast to previous reports on the association of COVID-19 disease with venous thromboembolism in other populations. Thus, individual and environmental risk factors may play an important role in the pathophysiology of thrombosis in COVID-19 disease. Disclosures No relevant conflicts of interest to declare.

Objectives To investigate the potential efficacy of Nigella sativa (NS) oil supplementation on the outcomes of patients with mild Coronavirus Disease 2019 (COVID-19). Trial design Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio), open-label, controlled, exploratory phase II clinical trial of oral NS oil in patients with mild COVID-19. Participants Inclusion Criteria: - Patients with mild COVID19 (defined as upper respiratory tract infection symptoms in the absence of clinical or radiological signs of pneumonia). - Adult (18 - 65 years old). - Written informed consent by the patient (or legally authorized representative) prior to initiation of any study procedures. - All patients should understand and agree to comply with planned study procedures. - Polymerase chain reaction (PCR)-confirmed infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from throat swab. Exclusion Criteria: - Patients with pneumonia or severe illness requiring admission to intensive care unit. - Severe chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR] < 30 mL/min) or end stage renal disease requiring dialysis - Severe chronic liver disease (Alanine transaminase [AlT] or Aspartate transaminase [AST] > 5 times the upper limit of normal). - Pregnancy or breast feeding. - Anticipated transfer within 72 hours to another hospital that is not a study site. - Allergy to the study medication The trial is currently conducted on patients recruited from King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Intervention and comparator Intervention group: Nigella sativa oil (MARNYS® Cuminmar) 500 mg softgel capsules, one capsule orally twice daily for 10 days plus standard of care treatment (antipyretic, antitussive). Comparator group: standard of care treatment. Main outcomes Proportion of patients who clinically recovered (defined as 3 days of no symptoms) within 14 days after randomisation. Randomisation Patients will be randomly assigned to treatment or control groups in a 1:1 ratio using a computer-generated randomization scheme (Random permuted blocks of 10) developed using the web-based program: http://www.randomization.com. Blinding (masking) No blinding. Numbers to be randomised (sample size) Up to 200 eligible patients will be randomly assigned to either treatment or control groups. Trial Status Protocol version 1, as of July 14, 2020. Recruitment was started on May 21, 2020. The intended completion date is December 31, 2020. Trial registration ClinicalTrials.gov Identifier: NCT04401202. Date of trial registration: May 26, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Background: Brucellosis is a zoonotic disease caused by Brucella spp. It can be either uncomplicated or complicated when it disseminates to other organs. Treatment for brucellosis involves a combination of at least two antibiotics, or more in complicated brucellosis. Limited data exist on the use of ceftriaxone in the clinical setting. Therefore, we present patient cases in which ceftriaxone was used in brucellosis treatment regimen. Methods: Patients with documented brucellosis from January 2008 to December 2018 were evaluated for the use of ceftriaxone for treatment in King Abdulaziz Univeristy Hospital, Jeddah, Saudi Arabia. Patients’ data were evaluated retrospectively and are described. Results: Out of 94 treated brucellosis patients, six patients received ceftriaxone 2 g IV every 12 h for therapy for varied durations. Four had neurobrucellosis, one had Brucella epididymo-orchitis and one had uncomplicated brucellosis. All six patients experienced clinical cure, though one neurobrucellosis patient had complications and one had ceftriaxone stopped after one week of therapy due to presumed antibiotic-induced fever. Conclusion: Ceftriaxone represents a reasonable option for the treatment of complicated brucellosis when added to the initial regimen at a dose of 2 g IV every 12 h. Keywords: Brucella, Brucellosis, Ceftriaxone, Cases, Zoonotic infection, Saudi Arabia

To the Editor: Melioidosis refers to infection caused by the facultative intracellular gram-negative bacterium Burkholderia pseudomallei. The clinical manifestations of melioidosis span a wide spectrum, from asymptomatic exposure or localized cutaneous infection to septic shock with multiorgan failure. Melioidosis usually occurs in residents of or travelers to disease-endemic areas in northern Australia and Southeast Asia; however, an increasing number of confirmed melioidosis cases are being reported from the Caribbean. We report a case of melioidosis acquired in Trinidad and Tobago. In February 2014, a 17-year-old male student was admitted to a tertiary care hospital in Vancouver, British Columbia, Canada, with catecholaminergic polymorphic ventricular tachycardia and electrical storm. He had a 9-month history of dry cough that was unresponsive to multiple and prolonged courses of treatment for community-acquired pneumonia. During the 6 months before his admission, the patient had hemoptysis and radiologic evidence of pneumonia that were treated with courses of cephalosporins without resolution of symptoms. Bronchoscopy and culture of lavage samples had revealed infection with Staphylococcus aureus and an organism most closely related to Actinomyces graevenitzii . The patient had no history indicative of risk factors for recurrent sinusitis or pneumonia (e.g., cystic fibrosis, chronic granulatomous disease, Job syndrome), and no risk factors for tuberculosis or infection with dimorphic fungi. He was up to date on his vaccinations and had no pets. He was born in Jamaica, had moved to Canada at age 4, and had not traveled anywhere other than Trinidad and Tobago, Canada, and England. He had traveled to visit family in Trinidad for 2 months during the rainy season in 2012, at which time he also visited Tobago. On day 5 of hospital admission, the patient became febrile (39.6°C), and an infectious diseases specialist was consulted. Examination revealed that the patient was clinically stable but emaciated at 45 kg. His oxygen saturation while breathing room air was 98%. Physical examination, including cardiorespiratory examination, was unremarkable. Laboratory results showed a normal hemoglobin concentration of 133 g/L; elevated leukocyte count of 22.8 × 109 cells/L; neutrophils 19.4 × 109 cells/L; normal platelet count of 295 × 109/L; and normal creatinine of 54 μmol/L. Test results for HIV-1 and blood cultures were negative. Computed tomography scan showed dilated bronchi and dense consolidation of the right and left lower lobes. Piperacillin/tazobactam was started for presumed hospital-acquired pneumonia. The patient underwent diagnostic bronchoscopy with bronchoalveolar lavage. Gram staining of specimens showed occasional gram-negative bacilli, and aerobic cultures grew gram-negative bacilli. Further testing with the Vitek 2 (bioMerieux, Laval, Quebec, Canada) (96%) and RapID NF (Oxoid, Nepean, Ontario, Canada) (99.9%) systems identified B. pseudomallei, but matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Vitek MS, bioMerieux) did not. Phenotypic confirmation was performed at the provincial public health and reference laboratory. Antimicrobial drug susceptibility testing performed by broth microdilution according to Clinical and Laboratory Standards Institute recommendations (1) and by Etest (bioMerieux) showed susceptibility to amoxicillin/clavulanic acid, ceftazidime, imipenem, doxycycline, and trimethoprim/sulfamethoxazole. The patient’s condition improved after 2 weeks of intravenous meropenem, and antimicrobial therapy was changed to oral trimethoprim/sulfamethoxazole. The B. pseudomallei isolate was sent to the Public Health Agency of Canada’s National Microbiology Laboratory for molecular typing. Query of 7 standard multilocus sequence typing loci (http://bpseudomallei.mlst.net/) identified the isolate as a novel multilocus sequence type. The sequence type (1,1,2,1,5,6,1) closely resembled that of B. pseudomallei previously isolated from the Caribbean (2). Although melioidosis was first described in the Caribbean in 1947 (3), most case reports of the disease in the area are from the past 2 decades. This case report suggests progression of the range of melioidosis to include Trinidad and Tobago. A recent study documented the presence of B. pseudomallei in soil samples and high seroprevalence rates among contacts of persons with melioidosis in Puerto Rico (4). If examined, this pattern of regional melioidosis endemicity may also be found on other Caribbean islands. Increased clinical awareness of and improved surveillance for B. pseudomallei infection may partly explain emergence. Nonetheless, underascertainment probably occurs in rural areas with limited access to advanced diagnostic support and in urban areas when B. pseudomallei infection is not suspected because of lack of travel to classic disease-endemic areas. Because B. pseudomallei is a Biosafety Level 3 agent, when infectious disease specialists consider melioidosis in their differential diagnoses, they should alert the microbiology laboratory to confirm species identification and ensure that staff use proper biosafety measures. A total of 19 cases of melioidosis acquired in the Caribbean have been reported (Table). Nine of these were travel related, suggesting that melioidoisis may be emerging as a travel health issue. Travelers with known risk factors for melioidosis, such as diabetes mellitus and chronic lung disease, should be informed of their increased infection risk. Physicians should include B. pseudomallei in the differential diagnosis of travelers with pneumonia or sepsis who are returning from the Caribbean, particularly when they have a history of travel during the rainy season, soil-contaminated wounds, or known risk factors for melioidosis. Table Published case reports of melioidosis from the Caribbean*

Methemoglobinemia is an uncommon cause of cyanosis that may present at any age. Although acquired methemoglobinemia secondary to exposure to oxidative stressors is the most common cause of methemoglobinemia in adults, hereditary methemoglobinemia has to be considered in patients presenting with cyanosis during infancy and childhood. We report the case of a patient who was investigated for cyanosis that was only noted at the age of 15 years. Despite the negative family history, he was diagnosed with hereditary autosomal recessive methemoglobinemia with no other factors that can be identified to cause such an elevation of methemoglobin level. This case illustrates that hereditary methemoglobinemia has to be considered in such patients even if they were completely asymptomatic for many years of their lives.

Introduction: Respiratory viruses are common causes of outbreaks in residential care. Multiplex PCR assays for respiratory viruses enable the detection of multiple viruses, though the clinical significance of dual infections is unclear. We describe an outbreak of 2 respiratory viruses cocirculating in a residential care facility in Vancouver, Canada. Methods: Outbreak investigation was conducted in a facility with 216 residents distributed among 3 separate units in January 2014. Cases were defined as any resident or staff with acute onset respiratory illness [fever (>38.0°C) and cough], and with at least one of the following: sore throat, nasal congestion, malaise, chills, muscle aches, headache or change in mental status. Affected patients were placed on contact and droplet precautions. Nasopharyngeal swabs were collected on symptomatic residents and tested using an in-house multiplex PCR assay (influenza A/B, respiratory syncytial virus, parainfluenza 1/2/3, adenovirus and human metapneumovirus). An epidemic curve of the outbreak was created. Results: The outbreak persisted for 13 days. Twelve patients were infected, including 7 with parainfluenza 1, 2 with influenza A and 3 with parainfluenza 1/influenza A co-infection (Figure 1). All patients manifesting respiratory symptoms were tested (12/28, 43%), rather than empirically treating subsequent patients meeting case definition. Treatment with oseltamivir was provided for 5 patients positive for influenza A, with all others receiving prophylaxis. Two staff developed upper respiratory tract symptoms and were considered cases. Outbreak management also included cessation of group activities, closure to admissions and enhanced unit cleaning. Influenza vaccination rates were 94% for residents and 83% for healthcare workers. Conclusion: Routine testing using a multiplex PCR assay detected a respiratory outbreak involving single and co-infections. Two circulating viruses can affect outbreak management. In this outbreak, all symptomatic residents were tested and confirmed rather than empirically treated. In addition to accurate classification and management of cases, overall consumption of oseltamivir prophylaxis can be reduced by monitoring for the persistence of both viruses.