KAIMRC Innovations Issue 8 by Nature Research Custom Media

DECEMBER 2020 - Issue No.8

ISSN 7901-2398 innovations.kaimrc.med.sa

REDUCING MERS MORTALIT Y A combination drug regimen reduces Middle East Respiratory Syndrome deaths by a third

P. 44

CHE APER, BE T TER SCREENING OF T Y PE 1 DIABE TES IN HIGH-RISK CHILDREN A low-cost model could help predict type 1 diabetes

P. 21

FACE MASKS

PROVE TO BE OUR FIRST LINE OF DEFENCE AGAINST COVID-19 P. 60

INFECTIOUS DISEASES RESEARCH

Is dedicated to enhancing prevention and treatment of infectious diseases through diversified basic, translational, and clinical research activities, surveillance programs and reference laboratory services. It aims to become the underpinning of the infectious disease public health research for the Kingdom of Saudi Arabia.

THE LABORATORY IS DIVIDED INTO • Microbial Genomics and AMR Unit, • Virology and Vaccine Development unit, and • Biosafety Level 3 laboratory (BSL3).

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COVE R I M AG E : A L E S _ U TOVKO/ I S TOCK / G E T T Y I M AG E S P LU S

TABLE OF CONTENTS

P.8 MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE FOUND IN SAUDI PATIENT

P.10 FINDING THE CORRECT WARFARIN DOSE FOR SAUDI PATIENTS

Cases of a worrying form of multidrug resistant bacterial infection have been detected in Saudi Arabia

A study involving a cohort of Saudi recipients warfarin provides valuable insights into dosing and effectiveness

P.12 PROFILING A RARE GENETIC DISORDER

P.14 A NOVEL IMMUNE DISORDER

P.16 FINDING THE SWEET SPOT FOR CLINICAL GENOMICS

A deep dive into data about a rare amino acid deficiency points the way towards early diagnosis and drug discovery

Mutation of a gene related to cell structure leads to immunodeficiency and hyperinflammation

Assessing genome sequencing strategies for cost-effective approach for diagnosing hereditary disorders

P.18 RAMADAN GUIDANCE FOR MUSLIMS WITH DIABETES

P.20 SAUDI DIABETES RISK SCORE IDENTIFIES INDIVIDUALS AT RISK

P.21 CHEAPER, BETTER SCREENING OF

Researchers publish first comprehensive guidelines for the clinical management of type 1 diabetes during Ramadan

Saudi researchers have developed a tool to identify adults at risk of developing type 2 diabetes

A low-cost model combining genetic, clinical, and immunological risk factors could help predict type 1 diabetes

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TYPE 1 DIABETES IN HIGH-RISK CHILDREN

Issue No.8

TABLE OF CONTENTS

P.22 IMPROVED DELIVERY OF CANCER DRUGS

P.24 PROTEINS PROVIDE AN EARLY WARNING OF BLADDER CANCER

Nanoparticles made of two materials improve the safety of a common cancer drug

Blood-based protein test could help with diagnosis and treatment

P.26 PREVALENCE OF BLOOD CLOTTING AFTER HIP PROCEDURES

P.28 IVF CONCEPTION DOES NOT AFFECT EDUCATIONAL OUTCOMES OF PREMATURE CHILDREN

Venous thromboembolism after hip procedures is not abnormally common in Saudi Arabia

IVF has no impact on whether children born very prematurely will go on to need extra help at school

P.30 A CLOSE LOOK AT PERITONITIS IN SAUDI ARABIA

P.31 NEW GENE DATABASE TO INFORM BESPOKE TREATMENTS

Identifying high rates of peritonitis in children undergoing dialysis at a Saudi hospital will stimulate a strategy for improvement

A global reference showing the variation of immune system genes improves personalized medicine and transplant outcomes

December 2020

TABLE OF CONTENTS

P.32 KNOWLEDGE GAPS OVER TREATING SEVERE RESPIRATORY INFECTIONS

P.34 GUT MICROBE TRANSPLANT TREATS GRAFT VERSUS HOST DISEASE

Researchers call for trials to investigate the efficacy of treatments for severe respiratory viral infections

Faecal bacteria from healthy donors can save the lives of blood stem cell transplant recipients

P.36 MEASURES NEEDED TO REDUCE ROAD CASUALTIES

P.37 REDUCING THE STING OF CANCER THERAPY

Study highlights global disparities in improving traffic safety

Packaging cancer therapy within injectable microcubes mitigates the need for multiple invasive treatments

P.38 HAIR-GROWING SKIN PRODUCED FROM HUMAN STEM CELLS

P.39 UNCOVERING TRENDS IN ANTIBIOTIC CONSUMPTION

Complete skin-in-a-dish tissue offers new options for wound healing, genetic skin conditions and baldness

Study assesses global antibiotic consumption patterns over a 15-year period

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Issue No.8

TABLE OF CONTENTS

P.40 MEASURING THE RISK OF CONTRACTING LATENT TUBERCULOSIS IN CLINICAL TRAINING

P.42 UPTICK IN LAB-CONFIRMED SEROPREVALENCE OF MERS INFECTIONS

Medical students face a greater risk of being infected with TB bacteria than trainees in other specializations

A trend of increasing MERS prevalence has been detected in a West Saudi Arabian population after testing over 7,000 samples

FEATURE

P.44 REDUCING MERS MORTALITY

P.48 HIGH POST-SURGICAL INFECTION LEVELS IN SAUDI ARABIA

Clinicians test a combination drug regimen that reduces the number of MERS deaths by a third

Antibiotic resistant bacteria are widespread in surgical-site infections in Saudi Arabian hospitals

COVID-19

P.52 INVESTIGATING COVID-19 IMMUNE RESPONSES

P.54 AI ALGORITHMS FOR RAPID CORONAVIRUS DIAGNOSIS

An in-depth analysis of the COVID-19 immune response offers new tools to clinicians

Researchers use advanced deep learning models to create an AI system that can help identify COVID-19 in minutes

December 2020

TABLE OF CONTENTS

COVID-19

P.56 BUILDING ON EXPERIENCE: SAUDI ARABIA’S COVID-19 RESPONSE

P.57 T CELLS RECOGNIZE COVID-19 BEFORE AND AFTER INFECTION

P.58 FINDING GENETIC LEADS FOR SEVERE CORONAVIRUS CASES

The knowledge gained from the MERSCoV epidemic helps Saudi Arabia roll out an early response footing for COVID-19

SARS-CoV-2 triggers a strong T cell-based immune response, but many people already have some cross-reactive immune memory

Respiratory failure in some COVID-19 patients could be associated with their genetic profile

FEATURE

P.60 THE CASE FOR MASKS IN COMBATTING COVID-19

P.64 HIDDEN IMMUNE FAILURE IN SEVERE CASES OF COVID-19

Specific studies assessing face masks and COVID-19 transmission are limited, but related scientific evidence suggests that even simple fabric masks can make a difference

Two studies find that genetic anomalies and autoimmune antibodies dampen the immune response in severely ill COVID-19 patients

KAIMRC Innovations is published for the King Abdullah International Medical Research Center (KAIMRC) by Nature Research Custom Media. King Abdullah International Medical Research Center (KAIMRC) P.O. Box 3660 Riyadh 11481 Mail Code 1515, Saudi Arabia Email: kaimrc@ngha.med.sa Web: kaimrc.med.sa

KAIMRC Innovations Phone: +966 11 429 4516 Email: innovations@ngha.med.sa Web: innovations.kaimrc.med.sa

Springer Nature The Campus – 4 Crinan Street – London, N1 9XY, UK Email: nature@nature.com Web: www.nature.com

The Researcher Newsletter Phone: +966 11 429 4516 Email: theresearcher@ngha.med.sa Web: innovations.kaimrc.med.sa/en/newsletter

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Issue No.8

Multidrug resistant Klebsiella pneumoniae found in Saudi patient Cases of a worrying form of multidrug resistant bacterial infection have been detected in Saudi Arabia

acteria that are resistant to antibiotics are among the world’s greatest healthcare threats. Researchers at KAIMRC are taking a lead in assessing the threat from multidrug resistance (MDR) in gram negative bacteria in Saudi Arabia and have carried out a detailed genetic analysis of a particularly concerning MDR infection in a patient in the Kingdom. They describe the bacteria, a strain of Klebsiella pneumoniae, as a serious new public health concern. “A couple of years ago we started a nationwide genome-based surveillance programme focused on characterising clinically important MDR gram negative bacteria,” says Michel Doumith of the Infectious Diseases Research Department at KAIMRC. Doumith explains that a major concern is bacteria that produce enzymes called beta lactamases. These enzymes are able to break down the ‘beta lactam’ molecules that are the most widely used types of antibiotics. In 2018, clinicians identified a multidrug resistant Klebsiella pneumoniae infection in a Saudi patient who had recently returned after undergoing surgery in Egypt. The KAIMRC researchers isolated the bacterium and analysed its genome to gain a better understanding of the mechanisms underlying the drug resistance. The bacteria produced a particularly problematic beta lactamase enzyme called a carbapenamase. This is the first instance of a Klebsiella pneumoniae producing carbapenamase (known as a KPC) found in Saudi Arabia.

December 2020

One finding of significant concern is that the gene that produces the carbapenamase enzyme is located on a small mobile DNA element called a plasmid. “This gives it the potential to jump into other bacteria that could be more able to thrive in hospital settings,” says Doumith. The researchers were able to determine the precise strain of KPC bacteria infecting the Saudi patient, attributing its origin to a strain first observed in Greece. The investigation also identified the genes for a variety of molecules, called virulence factors, that help the bacterium to thrive. The ongoing KAIMRC survey has not detected a significant increase in KPC infections, but researchers have detected a few cases and are currently analysing them in the local and global context. “Our colleagues in the infection prevention and control teams are putting in place measures to isolate patients with carbapenamase-producing bacteria very early to prevent further transmission in hospitals,” says Doumith. He emphasises the importance of prevention because once these infections take hold, it has been proven at hospitals elsewhere around the world that they are very difficult to eliminate. Alghoribi, M.F., Binkhamis, K., Alswaji, A.A., Alhijji, A., Alsharidi, A. et al.

Genomic analysis of the first KPC-producing Klebsiella pneumoniae isolated from a patient in Riyadh: A new public health concern in Saudi Arabia. Journal of Infection and Public Health 13 647‎–‎650 (2020).

K AT E RYN A KO N / S H UT T ER S TOC K .C OM

Klebsiella pneumoniae

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Issue No.8

December 2020

Finding the correct warfarin dose for Saudi patients

A cohort of patients has contributed to the first in-depth pharmacogenetic study of responses to the blood-thinner warfarin in the Saudi population. The findings will inform a novel drug dosing algorithm to better treat Saudi patients.

innovations.kaimrc.med.sa

ome Saudi patients could require higher doses of the blood-thinning drug warfarin because of genetic variance, according to a KAIMRC study. Other factors also affect the correct dosage, highlighting the need for an algorithm to aid clinicians determine dosage. Warfarin is used around the world to prevent dangerous blood clots. However, patient response to warfarin varies widely, and scientists believe that individual genetic variations influence the way the drug works in the body. “Dosing and effectiveness of warfarin have been widely tested in patients, but most pharmacogenetic studies have been conducted in European-centred populations, not on Middle Eastern patients,” says Jahad Alghamdi of KAIMRC’s Saudi Biobank. “There are several genotype-guided dosing algorithms available to determine the correct dose to offer, but their applicability to our population is questionable.” Indeed, there may even be genotypic differences within the Arab population that affect warfarin effectiveness. Alghamdi, together with collaborators across Saudi Arabia, collated and studied the largest cohort of Saudi warfarin users to date—936 patients—to begin identifying the genetic factors that contribute to warfarin effectiveness in the Saudi population. The Saudi WArfarin Pharmacogenetic (SWAP) cohort will also form the basis for future warfarin studies in the Kingdom. Warfarin works by blocking the production of vitamin K to make blood clot more slowly. Its target is a product of

the VKORC1 gene, the VKORC1 enzyme, which is a key enzyme in the vitamin K cycle. People with a mutation in this gene might have reduced VKORC1 activity, meaning the required dose of warfarin will be lower, while in other patients the opposite might be the case. Genetic variations in VKORC1 explain between 40 and 50 % of dose variability. “We sought to determine the effect of one particular VKORC1 variant on warfarin responsiveness in our population. We found that patients with this variant required a higher warfarin dose and took a longer time to achieve a stable blood clotting ratio than other patients,” says Alghamdi. The team also found that patient age, weight, and certain metrics of liver function were important factors to be considered when prescribing warfarin in the Saudi population. “Our target goal is to translate these findings into clinical practice by developing a genotype-guided dosing algorithm that is specifically suited to the Saudi population,” says Alghamdi. “We are now working to identify further prevalent and rare variants that may explain more of the observed differences in warfarin responsiveness in the Saudi population to help us refine the algorithm and maximize its accuracy.” Al Ammari, M., AlBalwi, M., Sultana, K., Alabdulka-

reem, I.B., Almuzzaini, B., Almakhalifa, N.S., Aldrees, M., & Alghamdi, J. The effect of VKORC1 promoter

variant on warfarin responsiveness in the Saudi Warfarin Pharmacogenetic (SWAP) cohort. Nature Scien-

tific Reports 10 (2020)

Issue No.8

S TOC K T R EK I M AG ES , I N C . / A L A M Y S TOC K P H OTO

A pharmacogenetics study involving a cohort of Saudi recipients of the drug warfarin provides valuable insights into dosing and effectiveness

“ASNSD diagnosis is challenging because tests based on asparagine levels in plasma or cerebrospinal fluid (CSF) have proven unreliable.“ Mutations that interfere with the function of the enzyme asparagine synthetase lead to a metabolic deficiency with severe neurological and developmental consequences.

Profiling a rare genetic disorder A deep dive into data about a rare amino acid deficiency points the way towards early diagnosis and drug discovery

esearchers from across Saudi Arabia have analysed clinical data from patients with the often fatal metabolic disorder asparagine synthetase deficiency (ASNSD), revealing new criteria for diagnosis and potential treatment. ASNSD can be treated if detected early, but clinicians struggle to promptly diagnose the condition. Our bodies naturally manufacture the amino acid asparagine, and asparagine synthetase is a critical enzyme in this process. ASNSD diagnosis is challenging

December 2020

because tests based on biochemical analysis of asparagine levels in plasma or cerebrospinal fluid (CSF) have proven unreliable. Naif Almontashiri at Taibah University in Saudi Arabia sought to get a deeper understanding of this disorder, and approached Majid Alfadhel at KAIMRC, an established expert on ASNSD. “We collaborated with him and submitted our unpublished cases, collecting the largest cohort in the world for this disorder,” says Alfadhel. The researchers examined clinical reports about 31 ASNSD patients from

Their analysis also confirmed that many patients retained modest levels of asparagine in their plasma and CSF, and the team showed that this diagnostic test has a false-negative rate of 17%. But the authors also identified potentially useful alternative indicators. “We delineated clinical phenotypes and radiological findings which could help diagnosis before molecular genetic testing,” says Alfadhel. This is important, because the progression of the disease can be halted in some patients by prompt supplementation of asparagine. This study uncovered a range of different mutations in the asparagine synthetase gene, and Alfadhel is now looking to understand how these contribute to the severity and manifestation of the disease. “Understanding the molecular genetic mechanisms will help us with treatment discovery,” he says. The insights could also assist in efforts to develop a robust test for this condition as part of the national premarital screening program (Healthy Marriage Program) in Saudi Arabia for rare genetic disorders. Alharby, E., Faqeih, E.A., Saleh, M., Alameer, S., Almuntashri, M. et al. Clinical, molecular, and biochemical delin-

eation of asparagine synthetase deficiency in Saudi cohort. Genet. Med. Published online 3 August 2020.

JA NI E CBR OS / E + / G E T T Y I M AG E S

13 Saudi families and identified some consistent patterns. Seizures and spasticity were particularly common neurological manifestations, and all affected children also presented with malformation of the brain, skull and facial features. They also identified a range of other symptoms that only occurred in a subset of families, including manifestations affecting the bones, lungs, skin, or hearing.

BIOSTATISTICS & BIOINFORMATICS

It focuses on conducting state of the art biomedical research SERVICES • Novel statistical and bioinformatics methods/tools • Biostatistics, mathematical modeling, protein modeling, next generation OMICS analysis, and artificial intelligence • Large collaborative initiatives that cover several disease areas • Independent research projects

• Outreach program for general technical advice as well as systematic educational activities

KAIMRC-DBB@NGHA.MED.SA

B L AC KJ AC K3 D / I S TO C K / GE T T Y I MAG ES P LU S

• Collaborations with mega projects that align with KAIMRC strategic initiatives

A homozygous mutation has been identified as the cause of a novel immune disorder in children.

December 2020

A novel immune disorder

enetic analysis of two Middle Eastern patients lymphohistiocytosis (HLH), a rare life-threatening congenital has revealed that mutation of a gene involved in condition that is also characterized by symptoms of hypermaintaining cellular structure has cascading coninflammation, lymphoproliferation and immunodeficiency. sequences, leading to impaired immune activity However, the researchers noted that the patients also displayed and hyperinflammation. symptoms inconsistent with HLH, such as an absence of cytoMutations that cause cellular processes to go awry can lead to penia (reduction of mature blood cells), and the boy did not a malfunctioning immune system. When the immune system is improve when given an HLH treatment. working properly, lymphocytes and macrophages target infecTo get to the root of this, the researchers performed whole-extions so that healthy tissues are not harmed. However, when ome sequencing and found that both patients, as well as their it malfunctions, the adaptive immune system may overreact, parents and several siblings in family 2, had a mutation in causing severe inflammation, NCKAP1L, a gene involved uncontrolled lymphocyte in the reorganization of “NCKAP1L deficiency is a novel proliferation and weakening actin cytoskeleton. The of the immune system. cytoskeleton plays a vital disease in humans that leads to An international team led role in enabling cells to immunodeficiency, lymphoproliferation by Seiamak Bahram from the migrate, contract and keep University of Strasbourg has their shapes. As a result, the and hyperinflammation with features of now reported the discovery of patients’ T cells displayed a two unrelated patients whose wide range of abnormalities, hemophagocytic lymphohistiocytosis.“ immunity problems were including impaired early caused by a homozygous activation, immune synapse mutation. The research team included Saudi researchers Amjad morphology and defective edge formation. Khan, Wafaa Eyaid, and Fayhan Alroqi from the King Abdullah The researchers concluded by classifying the syndrome as a International Medical Research Center. new entity that is similar to yet distinct from HLH and is caused The two patients, a 15-month-old baby girl of Iranian origin by recessive mutations in NCKAP1L. “NCKAP1L deficiency is a and an 11-year-old boy from Saudi Arabia, presented symptoms novel disease in humans that leads to immunodeficiency, lymof hyperinflammation, lymphoproliferation and immunodefiphoproliferation and hyperinflammation with features of hemociency. Specifically, the girl had fever, mild anaemia, as well as phagocytic lymphohistiocytosis,” says Alroqi. a hugely enlarged spleen, while the boy had fever, recurrent ear infection, sinopulmonary infections, bronchiectasis (widening Castro, C.N., Rosenzwajg, M., Carapito, R., Shahrooei, M., Konantz, M. et al. NCKAP1L of airways) and oligemia (reduction of total blood volume). defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, Both patients were originally diagnosed with hemophagocytic and hyperinflammation. Journal of Experimental Medicine 217, e20192275 (2020). innovations.kaimrc.med.sa

Issue No.8

K E V I N C U R T I S/ SC I EN C E P H OTO LI B R A RY / B R A N DX P I C T UR ES / G ET T Y I M AG ES

Mutation of a gene related to cell structure leads to immunodeficiency and hyperinflammation

Finding the sweet spot for clinical genomics An assessment of genome sequencing strategies reveals the most cost-effective approach for diagnosing hereditary disorders

December 2020

Modern DNA sequencing instruments can deliver comprehensive information about genetic mutations, but clinicians are still learning how to use this technology to make diagnoses in the most efficient manner.

harmless and potentially harmful mutations. A subset of the cases were ‘trio plus’ analyses, which also includes siblings. Though each additional family member adds cost and delay to the analysis, the extra data should increase the ‘hit rate’ for identifying disease-related mutations, particularly with WGS. “But surprisingly, there was no difference in the hit rate between WES and WGS-solo, WGS-trio, or WGS-trio plus,” says Alfadhel. Indeed, every single hit found with WGS could also be detected in the WES data, suggesting that more thorough reanalysis might be better than additional sequencing.

This work indicates that broader genome coverage generally does not deliver extra clinical value—in fact, it yields numerous enigmatic mutations that are impossible to interpret with current genetics knowledge. As a consequence, Alfadhel says that Saudi Arabia’s clinical genetics teams “will do more WES- or WGS-solo than trio or trio-plus to conserve the budgets of our hospitals.” Alfares, A., Alsubaie, L., Aloraini, T., Alaskar, A., Althagafi,

A. et al. What is the right sequencing approach? Solo VS extended family analysis in consanguineous populations. BMC Med. Genomics 13, 103 (2020).

AS HR AF HA B I B 2 02 0

linicians now have the capacity to comb through entire genomes in search of mutations underlying hereditary disorders, but a narrower approach may be a more efficient diagnostic strategy, according to new research. Some children exhibit complex combinations of birth defects and symptoms that are difficult to diagnose. Whole-genome sequencing (WGS) allows clinicians to home in on the causative mutations by scanning through the complete nucleotide sequences of genes and the regulatory sequences that control them. But this is relatively expensive, and a strategy known as whole-exome sequencing (WES) offers a simpler alternative. In WES, only the sequences of protein-coding genes are analyzed. This cuts the cost of sequencing and analysis in half, making it a good first step. “Most hospitals in Saudi Arabia go with WES first, and if that proves negative, they proceed with WGS,” explains KAIMRC’s Majid Alfadhel, who led a team to investigate whether this is the best strategy, or if starting with the broader dragnet of WGS might offer a more cost-effective road to a diagnosis. To address this, they reviewed four years of WES and WGS data from King Abdulaziz Medical City in Riyadh. This center has produced a plethora of genetic diagnostics data, and Alfadhel and colleagues have already published 17 studies based on these data in 2020. Some of these were from ‘solo’ patients who were sequenced individually, but in most cases the clinicians performed ‘trio’ sequencing, which includes the patient’s parents to more easily distinguish between

MEDICAL GENOMICS RESEARCH

Is equipped with the latest technologies and poised to carry out cutting-edge research aimed at addressing medical problems with an emphasis on the people of Saudi Arabia. The major areas of research are in the fields of human genetics, medical and cancer genomics, hepatology besides cellular/gene therapy.

SERVICES • Next generation sequencing • Microarray • Sanger sequencing • Prevention genetics technology • Functional studies & real-time PCR

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Ramadan guidance for Muslims with diabetes Researchers have published the first comprehensive guidelines for the clinical management of type 1 diabetes during Ramadan

pproximately 1.9 billion Muslims celebrate Ramadan, a time to reflect on the suffering of the less fortunate and foster one’s spirituality and self-restraint. For younger followers with type 1 diabetes, Ramadan also brings uncertainty due to the lack of research and clinical consensus on how the condition should be managed during the month of fasting. A global research group has taken steps to rectify this gap by publishing the first set of comprehensive recommendations for the clinical management of type 1 diabetes in children and adolescents during Ramadan fasting. Fasting during Ramadan is only mandatory for those to whose health it wouldn’t jeopardise. Even though people with type 1 diabetes can therefore be exempted on medical grounds, researchers note that many young people with diabetes are driven to fulfil their religious obligations, often without approval from a doctor. The group’s new recommendations shed light on the best practices for pre-Ramadan counselling, the importance of regular glucose monitoring, and specific information on insulin therapies, nutrition, and physical activity. The guidelines also give criteria as to when patients should break fasting to protect their health. The group stress the importance of pre-Ramadan counselling as an essential opportunity to ensure that patients (and caregivers) recognize the symptoms of

December 2020

hypoglycemia, that their diabetes is well controlled, and that they are aware of the risks involved with fasting, and taught how to fast safely. A survey quoted in the paper highlights that many patients are not aware of the extent to which their metabolic control can deteriorate over a month of fasting. Despite a host of publications on Ramadan fasting and diabetes, there is a lack of original research and data specifically involving younger patients. Ibrahim Al Alwan, Vice-President of Postgraduate Education and Academic Affairs at King Saud Bin Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia, and a co-author of the new guidelines, says that he’d like to see new studies, particularly into the epidemiology of type 1 diabetes and its complications. In addition, he hopes to bring attention to the lack of research on “the effect of Ramadan on the management of chronic illness” and on “proper medication adjustment during fasting.” Al Alwan wants the team’s recommendations to be made available to physicians via endorsement by national paediatric societies. In the meantime, the group’s guidelines offer much-needed consensus and direction for the clinical management of the many young diabetes patients during Ramadan. Deeb, A., Elbarbary, N., Smart, C. E., Beshyah, S. A., Habeb, A. et al. ISPAD Clinical Practice Consensus Guidelines: Fasting during Ramadan by young people with diabetes.

Pediatric Diabetes 21, 5‎–‎17 (2020).

New guidance offers some much-needed consensus on how to best manage young people’s diabetes during Ramadan fasting, while also highlighting an ongoing dearth of quality data.

JAS M I N M ER DA N / M OM EN T / G ET T Y I M AG ES

innovations.kaimrc.med.sa

Issue No.8

The Saudi Diabetes Risk Score is set to help improve diabetes prevention programmes in Saudi Arabia and reduce the economic burden of the disease.

Saudi Diabetes Risk Score identifies individuals at risk Saudi researchers have developed a tool to identify adults at risk of developing type 2 diabetes

audi Arabia has one of the highest prevalence rates of type 2 diabetes in the world, with one in five people living with the disease. It represents a major clinical and public health problem, as an uncontrolled blood glucose level can lead to serious complications, including blindness, kidney failure and cardiovascular disease. Over the past two decades, healthcare expenditure and treatment for diabetes in Saudi Arabia increased more than 500%, straining the healthcare system. This prompted Rajaa Al-Raddadi at King Abdulaziz University (KAU), Jeddah, and colleagues from KAU and KAIMRC to

December 2020

develop a tool that identifies individuals at high risk of developing type 2 diabetes. By recruiting 1,403 Saudis with diabetes or prediabetes, they developed the Saudi Diabetes Risk Score (SADRISC), which they hope will help improve diabetes prevention programmes in Saudi Arabia and reduce the economic burden of the disease. The major risk factors for type 2 diabetes are well established. Some are genetic, but many others can be reduced by lifestyle changes. Low-carbohydrate diets and exercise, for example, have been shown to help reduce insulin levels and prevent the development of type 2 diabetes. Abnormalities in blood sugar levels,

Bahijri, S., Al-Raddadi, R., Ajabnoor, G. et al. Dysglycemia risk score in Saudi Arabia: A tool to identify

people at high future risk of developing type 2 diabetes [published online ahead of print, 2020 Jan 19]. J Diabetes Investig. (2020).

BS I P / U NI VE R SA L I M AG E S G R OU P VI A G E T T Y I M AG E S

known as dysglycemia, are one of the first telltale signs of type 2 diabetes. In most cases, however, slightly higher than normal blood sugar levels can go unnoticed for several years, leading to further deterioration in metabolic regulation and progression to diabetes. Detecting dysglycemia requires specific laboratory tests that are impractical for assessing the risk of diabetes in large population screening programmes. However, participant-completed questionnaires can help determine a Diabetes Risk Score that can be used to identify individuals with prediabetes or asymptomatic type 2 diabetes, who are likely to benefit from early intervention. Because of differences in genetics and lifestyle, these questionnaires need to be adapted to different populations. Al-Raddadi and colleagues collected demographic and clinical data to select the most relevant variables for a non-invasive, easy screening questionnaire that identifies adults with undiagnosed diabetes in Saudi Arabia. To make their tool more inclusive than previous attempts, the researchers recruited participants from five areas in Jeddah to ensure a spread of socioeconomic sectors and ethnicities living in Saudi Arabia was represented. In addition, data collection was carried out by well-trained medical students using standardized instruments to improve the accuracy of the results. The SADRISC comprises only five variables: sex, age, waist circumference, history of hyperglycemia and family history of diabetes, and score values range from 0 to 15. If someone scores 5 or 6 on the scale, then it would suggest with a 75% accuracy that this individual is at high risk of developing diabetes. The researchers are now working with health professionals and the Ministry of Health to introduce SADRISC into national diabetes prevention programmes aimed at reducing the incidence of the condition.

Type 1 diabetes will be easier to detect in high-risk children thanks to a new model.

A low-cost model combining genetic, clinical, and immunological risk factors could help predict type 1 diabetes

he onset of type 1 diabetes could become easier to detect early, thanks to a recent study. An international team led by William Hagopian, from the Pacific Northwest Research Institute in Seattle, has developed a cost-effective model to screen and predict type 1 diabetes onset in high-risk children. Type 1 diabetes is a serious and longterm disease in which the body’s immune system destroys the pancreatic beta cells that produce insulin, disrupting sugar uptake. The resulting insulin deficiency can initiate diabetic ketoacidosis, a life-threatening illness with symptoms including nausea, dehydration, excessive urine production, and severe abdominal pain. innovations.kaimrc.med.sa

Current screening approaches rely on monitoring a set of immune response markers known as beta-cell specific autoantibodies. These approaches are effective but require frequent measurement, which is costly. The onset of type 1 diabetes, which can occur in infants, is also linked to metabolic status, genetic risk, family history, and environmental factors, but these have been ignored in screening and prediction approaches. Therefore, the elements that trigger this onset are unclear, making who will develop T1D and at what age difficult to predict. Using data from The Environmental Determinants of Diabetes in the Young (TEDDY) cohort, which screened newborns at six centres in the US and Europe, the researchers devised a simple model

Ferrat, L.A., Vehik, K., Sharp, S.A., Lernmark, Å, Rewers, M.J. et al. A combined risk score enhances prediction of type 1 diabetes among susceptible children. Nature

Medicine 26, 1247–1255. (2020).

Issue No.8

AG EN C E P H OTOG R A P H I Q UE B S I P / C OR B I S DOC UM EN TA RY / G ET T Y I M AG E S P LUS

Cheaper, better screening of type 1 diabetes in high-risk children

that can assess the susceptibility of highrisk children to diabetes onset during their first ten years of life. They combined autoantibody monitoring with other aspects known to increase disease risk. The team produced a three-variable model incorporating autoantibody testing, genetic risk, and family history using TEDDY data from 7,798 high-risk children who were closely followed from birth to 9.3 years of age. They found that combining genetic risk factors with early and frequent autoantibody monitoring enhanced the efficiency of newborn screening to prevent ketoacidosis. The model best predicted diabetes in children older than two years over an eight-year period, outperforming conventional autoantibody-based screening. The researchers make the case that their model could reduce testing frequency and costs by facilitating adaptive strategies, allowing children to opt out of close follow-up, despite having a high genetic risk, if they maintain low onset probabilities throughout the screening period. The team plans to expand its assessment to other populations with distinct genetic backgrounds and environments to further validate its model.

Improved delivery of cancer drugs

Nanoparticles made of two materials improve the safety of a common cancer drug

A new potent and less toxic hybrid nanocarrier provides targeted delivery to cancer cells.

December 2020

innovations.kaimrc.med.sa

“It’s more potent, less toxic, and offers targeted delivery to the cancer cells, demonstrating the power of nanotechnology to improve existing therapies and create a new generation of drugs.“ solubility and helps ensure the drug is fully absorbed into the bloodstream, leading to more stable dosage levels in the body. This not only protects against debilitating side effects such as thrombocytosis, a blood clotting disorder that can result from variable drug concentrations in the body, but also means that patients will need less frequent doses. The researchers showed that the hybrid nanoparticles had a consistent spherical shape measuring around 200 nanometers in diameter and that around 80% of the nanodrug carriers were successfully filled with anastrozole. The team treated breast cancer cells with their nanotherapeutic and saw a similar level of cell death as in treatments using standard anastrozole. The KAIMRC team next plans to test the anastrozole-loaded nanoparticles in mice. If the therapy proves safe and effective, trials with patients could follow. Massadeh, S., Omer, M.E., Alterawi, A., Ali, R., Alanazi, F.H. et al. Optimized polyethylene glycolylated polymer–lipid hybrid nanoparticles as a potential breast cancer treatment. Pharmaceutics 12, 666 (2020).

Issue No.8

K AT ERY N A KON /S C I EN C E P H OTO LI B R A RY / G ET T Y I M AG E S

new drug delivery platform developed by Saudi scientists could enhance the safety and efficacy of a common therapeutic for breast cancer. The technology is based on hybrid nanoparticles composed of a biodegradable polymer coated with a layer of fatty molecules known as lipids. This mixed design combines the biological compatibility and cell penetrability of lipids with the enhanced stability and prolonged drug release of polymers. When loaded with the anti-estrogen drug anastrozole, the hybrid nanocarrier proved stable and effective against breast cancer cells. “This is a novel formulation that provides better safety and biocompatibility than the free-form drug,” says Salam Massadeh, leader of the Therapy Development Lab at KAIMRC. “It’s more potent, less toxic, and offers targeted delivery to the cancer cells, demonstrating the power of nanotechnology to improve existing therapies and create a new generation of drugs.” Massadeh co-led the study with KAIMRC’s Manal Alaamery in collaboration with researchers at King Saud bin Abdulaziz University for Health Sciences. Both Massadeh and Alaamery have a track record of developing nanotechnology-based treatments for breast cancer, having received patents for innovations related to nanoparticle delivery of various drugs over the past few years. However, the earlier advances were built around nanoparticles consisting entirely of polymers. The incorporation of lipids on the outer surface improves

S CI E NCE P HOTO L I BR A RY / A L A M Y S TOCK P HOTO

Proteins provide an early warning of bladder cancer

Blood-based protein test could help with diagnosis and treatment

A new blood-based protein signature could detect bladder cancer in its earliest stages.

roteins in the bloodstream could help doctors detect bladder cancer at its earliest stages, according to a KAIMRC-led study. These findings lay the groundwork for a cheap and simple test to diagnose bladder cancer before it spreads and becomes harder to treat. “Several biomarkers have been proposed for the detection and surveillance of bladder cancer, but unfortunately none of them warrant replacing the old system,” says Taoufik Nedjadi, a tumour biologist who led the study. The current test involves inserting a thin instrument with a camera at its tip into the bladder to visually examine the inside of the organ. Urine samples are also inspected under the microscope to see if they contain cancerous cells. Both techniques have drawbacks— the former is invasive, while the latter often lacks accuracy. In contrast, the new blood-based protein signature holds immense promise as a reliable, 24

December 2020

non-invasive alternative. To identify the proteins involved in cancer formation and progression, Nedjadi and his colleagues analysed blood taken from a small group of Saudi patients diagnosed with low-grade non muscle invasive bladder cancer (NMIBC). They compared the protein levels with those in blood from healthy individuals and discovered a total of 15 proteins with significantly different expression patterns. Of these, 12 were more abundant in the patients, and three were less abundant. The researchers focused on the three proteins with the starkest expression differences and validated their findings in an independent cohort of patients. All three proteins could be used to successfully diagnose cancer, but one in particular —a liver protein called haptoglobin— proved especially useful, with high sensitivity and specificity for discriminating between patients with early-stage bladder cancer and healthy individuals. Ha p to globi n i s k now n to bi nd

iron-carrying molecules in the bloodstream and prevent their loss through urine. The link between haptoglobin and bladder cancer remains a mystery, but Nedjadi’s team is working to clarify it through further experiments. His group is also studying other putative protein biomarkers that seem to be involved in regulating inflammatory responses, DNA replication, and other biological processes implicated in cancer development. Nedjadi notes that these findings are only preliminary, based on analyses from only a few dozen patient samples. “To make this diagnostic tool a clinical reality, there is an urgent need to validate the recently discovered biomarkers in well-designed, multicentre clinical studies,” he says. Nedjadi, T., Benabdelkamal, H., Albarakati, N., Masood, A., Al-Sayyad, A. et al. Circulating proteomic signature

for detection of biomarkers in bladder cancer patients.

Scientific Reports 10, 10999 (2020).

SAUDI BIOBANK

Is a national project; shepherded by (KAIMRC) and one of the important medical research projects in the Kingdom of Saudi Arabia that aims to:

SERVICES • Support a wide range of genetic and epidemiological research studies with focusing on improving preventive, diagnostic, and treatment of common and rare diseases • Increase the quality of patient care with implementing the highest standards of biological banking to provide outstanding clinical, medical, demographic and analytic data.

KAIMRC-BIOBANK@NGHA.MED.SA

Venous thromboembolism involves the formation of blood clots and is a common complication after knee and hip surgery.

December 2020

Prevalence of blood clotting after hip procedures

he risk of blood clots for people with acetabular fractures was 5% and the prevalence hip fractures in Saudi Arabia has been among those with hip fractures was 3%. Comparassessed by KAIMRC researchers. The ison with studies conducted in Europe, the US and study establishes how common venous Southeast Asia indicated that the identified rate of thromboembolism (VTE) is among these patients, VTE among patients with hip fractures was similar an important step towards preventing this but the rate among patients with acetabular fracture life-threatening complication. was lower. “Our findings provide a baseline prevaVTE involves the formation of blood clots in the lence of VTE in acetabular and hip fracture in Saudi deep venous system. These clots can cause local pain, Arabia, and our prevalence is the same as in develswelling, and skin changes and can travel to the lungs oped countries,” concludes Althuwaykh. to cause potentially fatal pulmonary embolism (PE). On the basis of previous work suggesting a link VTE is common after orthopaedic surgery, particu- between blood haemoglobin concentration and larly after hip and knee procedures, though the rea- the risk of VTE, Althuwaykh and colleagues invessons for this are unclear. tigated this relationship in Salem Althuwaykh from their data. They found that “Our findings provide a KAIMRC and his colleagues haemoglobin concentrabaseline prevalence of VTE in tions at admission did not investigated the prevalence of VTE among patients in differ between patients acetabular and hip fracture Saudi Arabia with fracwho d id a nd d id no t in Saudi Arabia, and our tures of the hip or the acedevelop VTE, suggesting no tabulum, the socket of the effect of haemoglobin conprevalence is the same as hip joint. “No study in our centration in this context. in developed countries.“ country or the Gulf region “Our next step is to find has been published on the associations between VTE in prevalence of VTE with acetabular and hip fracture,” these patients and other risk factors, such as comorexplains Althuwaykh. “We wanted to find the prev- bidities, BMI, length of surgical procedure and length alence to assess how good we are at preventing VTE of hospital stay,” explains Althuwaykh. “We aim to compared with other countries.” establish a score to measure the risk of VTE in order The researchers analysed the records of 995 peo- to reduce or prevent this complication.” ple with hip or acetabular fractures at the level 1 trauma centre at the King Abdulaziz Medical City in Althuwaykh, S.H., Alnasser, A.M., Khubrani, A.M., Alamari, Z.S. & Saudi Arabia between 2009 and 2015. Patients were Aljuhani, W.S. Prevalence of venous thromboembolism in patients grouped according to whether they developed deep with acetabular or hip fractures and their association with hemovein thrombosis (DVT), PE, both, or neither. globin concentration. Journal of Musculoskeletal Surgery and The prevalence of VTE among patients with Research 4, 21–24 (2020).

innovations.kaimrc.med.sa

Issue No.8

I LEX X / I S TOC K / G ET T Y I M AG ES P LUS

Venous thromboembolism after hip procedures is not abnormally common in Saudi Arabia

IVF conception does not affect educational outcomes of premature children In vitro fertilization (IVF) has no impact on whether children born very prematurely will go on to need extra help at school, according to researchers at KAIMRC

remature babies are known to face an born after natural conception. The children were increased risk of neurodevelopmental 8 to 16 years old when the study was carried out problems. Studies on whether children conand had all received care in the neonatal intensive ceived through IVF are more likely to have care unit at King Abdulaziz Medical City between developmental problems and longer-term health 2001 and 2009. issues have had conflicting results. While these Al-Hathlol’s team found that being conceived via two factors have been studied independently, little IVF treatment did not affect the proportion of chilresearch has been pubdren who required extra lished on the long-term lessons or had to repeat Among very low birth weight developmental outcomes a grade. It also did not of preterm children born affect their chance of premature babies, those born following IVF. having learning diffiIn previous research culties or special educafollowing IVF were at no greater published in 2018, tional needs. risk of major birth defects, neonatologist Khalid Using both quesAl-Hathlol of KAIMRC tionnaires and medical short-term disease or death. found that among very records, the researchers low birth weight prealso found that levels of mature babies, those born following IVF were at no ADHD, autism, visual impairment, hearing problems, greater risk of major birth defects, short-term disease and difficulties with whole-body and large muscle or death than those born as a result of spontaneous movements were similar in both groups. The results conception. were adjusted to take into account other differences He and his colleagues then turned to the quesbetween the groups, such as parental education level. tion of educational performance. They compared the school performance of 79 IVF children born Al-Hathlol, K. School performance and long-term outcomes of very prevery prematurely (at 32 weeks or earlier) with that term children conceived via in vitro fertilization. JBRA Assisted Reproof the same number of very premature children duction 24(1) 61‎–‎65 (2020).

December 2020

NE NOV/ M OM E NT / G E T T Y I M AG E S

Very premature babies born following IVF are at no greater risk.

innovations.kaimrc.med.sa

Issue No.8

A close look at peritonitis in Saudi Arabia

Identifying high rates of peritonitis in children undergoing dialysis at a Saudi hospital will stimulate a strategy for improvement

study of Saudi children receiving peritoneal dialysis to treat kidney disease reveals a worryingly high rate of peritonitis—an infection in the lining of the abdominal cavity. Peritonitis is a key factor leading to treatment failure for peritoneal dialysis and poor outcomes for patients, including other diseases and death. Peritoneal dialysis uses a tube inserted through the wall of the peritoneum to flush out the toxins that accumulate in a patient’s abdomen when their kidneys are failing. It is often used as an alternative to hemodialysis, which directly extracts and cleanses the blood, as it can bring better outcomes for patients in many circumstances. “Peritonitis is a frequent complication among children, [but its incidence] has not been widely reported in Saudi Arabia,” say

December 2020

the KAIMRC-based authors of the research report. To fill this gap, they turned to the medical records of children at King Abdullah Specialist Children’s Hospital-Riyadh (KASCH-R), in Saudi Arabia. The researchers looked at the medical history of 27 children who received peritoneal dialysis between September 2007 and December 2017. They identified 86 diagnoses of peritonitis, with around two-thirds of the children experiencing at least two episodes of the condition. This rate of peritonitis is high when compared with data from other countries and above the acceptable levels set out in the recommendations of the International Society for Peritoneal Dialysis. This KAIMRC study supports similar, albeit limited, findings from some previous studies of Saudi patients.

The key challenge for the researchers was to try to identify the reasons for the higher rates of peritonitis in the Saudi hospital, and to come up with interventions to tackle the problem. “We tested the hypothesis that certain demographic and clinical factors may be associated with the high frequency of peritonitis,” the authors report. They managed to determine several variables that could increase the likelihood of developing peritonitis, such as being female and older. Coming from a low socioeconomic background, and being shorter and lighter than average could also increase the probability. The team also found that having the kidney condition called congenital nephrosis, some specific biochemical indicators of disease, and having undergone long-term treatment with antibiotics were also risk factors that increased the odds of children developing peritonitis. Armed with these insights, the research team now plan to develop “an optimal peritonitis prevention strategy or best-practice guideline” in order to try to reduce and prevent peritonitis occurrence at their centre. Their strategy could also be applied more widely throughout Saudi Arabia and elsewhere. Al Mokali, K., Al Sannaa, Z., Al Mutairi, F., Ahmed, A.E. Factors influencing occurrence of peritonitis in Saudi children on peritoneal dialysis. BMC Pediatrics 20:42 (2020)

A LEKSA N DR I VAS EN KO/ S H UT T ER S TOC K .C OM

Peritonitis is a frequent complication among children receiving dialysis.

New gene database to inform bespoke treatments

A global reference showing the variation of immune system genes across populations will improve personalised medicine and transplant outcomes

innovations.kaimrc.med.sa

Understanding genetic variations can prevent adverse drug reactions and ensure successful transplants.

ambiguity about which parts of genes were analyzed, and to what resolution. Hurley and co-workers “addressed these challenges by collecting data from blood stem cell registries that have very large numbers of individuals tested by powerful DNA sequencing methods.” The new HLA database is named the CIWD catalog because it categorizes alleles based on their frequency of occurrence as ‘Common,’ ‘Intermediate’ or ‘Well Documented.’ The latter refers to alleles that were observed in at least five unrelated individuals. So, while they may be rare, their existence is not in question. The catalog also places individuals into geographical, ancestral and ethnic

groups, enabling researchers to identify which variations are most prevalent in certain populations. Hurley’s paper, published in the journal HLA, includes four co-authors affiliated with the Saudi Stem Cell Donor Registry at KAIMRC. “Their contribution helped us understand the HLA profile of individuals in the Middle East,” says Hurley. “The data from the publication will help the registry itself to find the best donor for a Saudi patient requiring a transplant.” Hurley C.K., Kempenich J., Wadsworth K., Sauter J., Hofmann JA. et al. Common, intermediate and well-docu-

mented HLA alleles in world populations: CIWD version 3.0.0. HLA 95, 516‎–‎531 (2020).

Issue No.8

S YA HR I R M AUL A N A / AL A MY S TO C K P H O TO

ncreased access to next-generation DNA sequencing is enabling researchers to compile huge databases, revealing human genetic variation around the world. Now, a global collaboration between researchers at 20 blood stem cell donor registries has compiled data on important immune system genes called human leukocyte antigens (HLAs) in more than eight million individuals. HLA genes produce cell surface proteins that bind to pathogens including bacteria, viruses and cancer cells, leading to their destruction. However, there are many variants of these genes, called alleles, which have evolved in the human population through mutations and natural selection. “The different HLA variants interact with different pieces of a pathogen,” explains Carolyn Hurley from Georgetown University, USA, who led the work to compile the database. “This results in variation among individuals in our ability to respond to infection, and our susceptibility to specific autoimmune diseases.” Understanding these individual variations can help prevent adverse drug reactions, inform immunotherapy approaches, and ensure successful blood stem cell, tissue or organ transplants. “The presence of different HLA proteins on a graft, compared to the patient’s, may result in graft rejection or a destructive immune response,” says Hurley. “Finding a graft donor who shares HLA protein variants with the patient reduces or prevents this.” Previous efforts to compile HLA allele data have been limited by the variety of methods used to collect them, leaving

“The global pandemic has demonstrated the threat posed by RVIs and how devastating such viral infections can be.“ A review of current knowledge about the treatment and management of severe respiratory viral infections in the ICU highlights that data is lacking and urgent research is required.

Knowledge gaps over treating severe respiratory infections Researchers call for trials to investigate the efficacy of treatments for severe respiratory viral infections

here is a growing need to understand the scale of community-acquired severe respiratory viral infections (RVIs) in patients admitted to the ICU with respiratory failure, and to improve RVI therapies and associated care management plans. Together with scientists in Canada and the US, KAIMRC’s Yaseen Arabi has reviewed existing knowledge about RVI clinical care management around the world, highlighting pressing issues that require immediate attention. “The global pandemic has demonstrated the threat posed by RVIs and how devastating such viral infections can be,” says Arabi.

December 2020

“However, the diagnosis of RVIs depends on specialised molecular techniques, which are relatively new and not widely available. This means that on a global scale, the success of treatments and management of critically ill patients with RVIs is under-researched and poorly understood.” Recent technological advances mean that RVIs are increasingly being identified in adult patients who are hospitalised with respiratory tract problems such as pneumonia. Studies suggest that between 17 and 53 % of such patients have an RVI. Linking patient symptoms directly to the viral infection can be challenging, although there is considerable evidence

The most widely used drug is oseltamivir, a neuraminidase inhibitor that blocks the reproduction of the influenza virus inside host cells. When oseltamivir is used early in patients with severe influenza, it reduces mortality rates. However, there are no clinically proven antivirals for treatment of other RVIs, and while immunomodulatory therapies have been trialled to improve the body’s immune response, none are currently recommended for RVI care in ICUs. Supportive care therefore remains the main response to RVIs in the ICU – patients receive ventilation aid, for example. The review highlights uncertainty regarding the comparative effectiveness of different modalities of respiratory support, such as high-flow nasal oxygen, non-invasive ventilation, and invasive mechanical ventilation. “Data regarding supportive care, clinical outcomes and therapies is severely lacking for RVIs,” notes Arabi. “Across the world, we urgently need more randomised controlled trials to assess this efficiently and effectively.” Arabi, Y.M., Fowler, R. & Hayden, F.G. Critical care

management of adults with community-acquired severe respiratory viral infection. Intensive Care

Medicine 46 (2020).

M AG I CM I NE / A L A M Y S TOCK P HOTO

that many RVIs directly cause severe illness, particularly in the elderly and in immunosuppressed patients. “RVIs commonly affect the upper and lower respiratory tracts, reducing oxygen in the bloodstream and disturbing the function of other organs,” says Arabi. “But every RVI is different and affects individuals in different ways. It may be that treatments should change at varying stages of these illnesses. Unfortunately, effective antiviral therapeutics for severe RVIs are limited.”

KAIMRC EXPERIMENTAL MEDICINE

Three state of the art vivarium facilities are located in Riyadh, Jeddah and Al Hasa. The vivariums are planned and designed according to international standards. They aim to assist biomedical research by providing animals and veterinary expertise. Moreover, they offer training and education in animal use for research. The facilities also work on the development and implementation of institutional policy, animal care and use policy including animal husbandry and veterinary care.

EMD@NGHA.MED.SA

The bacteria in human faecal matter can help deal with graft versus host disease.

December 2020

Gut microbe transplant treats graft versus host disease esearchers in the Netherlands have found a potential role in mediating our immune system. Recipients of blood stem treatment for graft rejection in an unlikely place, the cell transplants are known to have disrupted populations of gut gut bacteria found in faeces. bacteria, which seem to predispose them to GvHD. Patients with blood diseases such as leukaemia are “To give these patients trillions of bacteria from an unrelated often treated with transplants of blood stem cells from donors, person was quite nerve-wracking, as they already had suppressed which sometimes stimulate devastating graft versus host disease immune systems,” says Hazenberg. But the patients’ desperate (GvHD)—an immune attack initiated by donor cells against those situation made it worthwhile to try, and they readily agreed. of the patient. Now, research shows that transplanting faecal In patients who responded well, a single transplant of donor matter from healthy donors directly into a patient’s gut can lead faecal matter was sufficient to cure the GvHD. Ten of the 15 to a successful transplant. patients exhibited a good “We were able to cure some initial response, and six of patients who had a really them were apparently cured “To give these patients trillions of grim outlook,” says Mette long-term. bacteria from an unrelated person was Hazenberg of the Amsterdam All of the patients who did University Medical Centre, not respond died from GvHD quite nerve-wracking, as they already who led the research team. within six months of the trial. had suppressed immune systems.“ Using stem cells to treat These initial results suggest blood diseases such as leuthe treatment could offer a kaemia relies on balancing dramatic benefit to a signifthe benefits and risks of the donor cells. The diseased stem cells icant proportion of patients, but Hazenberg cautions that the in the patient are mostly destroyed by drug treatment prior to team has only completed a single, small-scale pilot study. This the transplant, but some can remain. The donor cells can help will need to be followed up with larger randomised and coneradicate any residual malignant host cells. However, the benefit trolled clinical trials to see if the initial promise is borne out of this attack on diseased cells can be negated if the donated cells sufficiently to establish this as a new routine treatment. also stimulate an immune attack against the patient’s healthy cells. Resistance to drug therapies used to treat GvHD can leave van Lier, Y. F., Davids, M., Haverkate, N. J. E., de Groot, P. F., Donker, M. L., et al. Donor some patients with no treatment options. fecal microbiota transplantation ameliorates intestinal graft-versus-host disease The researchers turned to the microbes in the gut because in allogeneic hematopoietic cell transplant recipients. Science Translational Mediresearch is steadily revealing that these microbes play a significant cine 12, eaaz8926 (2020). innovations.kaimrc.med.sa

Issue No.8

SC I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

Faecal bacteria from healthy donors can save the lives of blood stem cell transplant recipients

There were 1,045 agestandardised road injuries per 100,000 people in 2017. This compares with a global rate of 692 per 100,000 people

Saudi Arabia has one of the highest mortality rates from traffic accidents in the world.

Measures needed to reduce road casualties Study highlights global disparities in improving traffic safety

nternational action is needed to help countries with high rates of traffic injuries and deaths to reduce the number of accidents, and save lives, a KAIMRC researcher says. Data from the Global Burden of Disease (GBD) study shows that there were more than 54 million injuries and around 1.25 million deaths on roads around the world in 2017. Although injuries have become more frequent among pedestrians, cyclists, drivers and passengers since 1990, the number of resulting deaths has fallen. However, only the wealthiest states have

December 2020

managed to reduce the numbers of people hurt on roads in the last 30 years. People in the least developed countries are, on average, about three times more likely to die in traffic than those in the most developed territories. There was an average of 7.5 road deaths per 100,000 people, standardised by age, in countries in the most developed fifth of the world in 2017, down 56% since 1990. This compared with 20.6 per 100,000 in the least developed fifth of countries, where the rate fell by only 19%. Suliman Alghnam, head of the Population Health Research department at

means prevention programmes in countries with the highest rates, including increased seat belt enforcement, improving patient transfer to hospitals and more trauma centres.” In Saudi Arabia, there were 1,045 age-standardised road injuries per 100,000 people in 2017. This compares with a global rate of 692 per 100,000 people and was the third highest rate in the North Africa and Middle East region, where the average was 603 per 100,000. The age-standardised death rate from road injuries in the Kingdom was 36.7 per 100,000 people, compared to a global average of 15.8 per 100,000. Only nine other countries in the world had higher mortality rates. Researchers say that speeding, failure to wear seat belts, and cell phone use while driving are key reasons for Saudi Arabia’s higher rates of road injuries and related deaths. In a 2018 study, Alghnam concluded that the installation of cameras and a system of automatic penalties around Riyadh more than doubled compliance with seat belt laws and significantly cut mobile phone use while driving. James, S.L., Lucchesi, L.R. , Bisignano, C., Castle, C.D.,

Dingels, Z. V. et al. Morbidity and mortality from road injuries: results from the Global Burden of Disease Study 2017. Injury Prevention 0, 1–11 (2020).

E R I C L A FFOR G U E / A R T I N A L L OF U S / COR BI S NE WS VI A G E T T Y I M AG E S

KAIMRC, and a co-author of the study, called for the United Nations and World Health Organization to help developing countries introduce measures that have been shown to work in developed countries. “Overall, things are improving, however in some countries we have seen an increase in accidents and mortality,” said Alghnam. “We need efforts on a global scale to reduce the disparities. That

Reducing the STING of cancer therapy

Packaging cancer therapy within injectable microcubes mitigates the need for multiple invasive treatments

early half of cancer patients don’t complete their full course of treatment. Multiple hospital trips, invasive procedures, and repeated physical and psychological distress all affect the ability of patients to persist with life-saving therapies. A US-developed drug delivery system looks to alleviate some of this burden by packaging a cancer therapy within micro-sized cubes that are able to deliver a weeks-long course of cancer treatments from a single injection. Led by researchers at the Massachusetts Institute of Technology (MIT), the team behind the new development constructed hollow microcubes of a material called polylactic-co-glycolic acid (PLGA), measuring less than half a millimeter per side. In contrast to existing slow-release drug delivery systems, these microparticles innovations.kaimrc.med.sa

release their payloads in a way “similar to how an egg cracks,” says MIT’s Ana Jaklenec, one of the research team’s leaders. The team designed the PLGA microparticles to be used with the experimental stimulator of interferon genes (STING) agonist cancer therapy, which is being tested in multiple US clinical trials. Currently, the therapy depends on multiple injections directly into a tumour. The team’s system offers a preferable alternative. By incorporating differently tuned PLGA cubes into a single injectable solution, the system provides multiple doses over a course of time as the cubes break down sequentially. The researchers tested the efficacy of their system on mouse models of multiple cancers, including breast cancer, melanoma, and pancreatic cancer. The results showed that a single injection of STING

agonist-loaded cubes was able to induce a strong anti-tumour response and effectively inhibit tumour growth both locally and systemically. The treatment was as effective as multiple injections given over time. When injected after the removal of a tumour, the encapsulated STING agonist lowered the chances of recurrence from 100% to 25%. A critical advantage of a one-shot treatment course is that the tumour and its blood vessels are not repeatedly physically disturbed, reducing the chances of metastasis, an effect observed by the team in their own study. The team’s research is set to make STING agonist therapy more bearable and effective, as well as expanding its scope to more difficult-to-reach tumours. Jaklenec says that her team overcame “several technical challenges” that required them to develop new fabrication methods, in vivo assays, and injection methods. After optimising their microparticles and scaling up production, the team hopes to collaborate with pharmaceutical companies to bring their platform to clinical trial. Lu, X., Miao, L., Gao, W., Chen, Z., McHugh, K. J. et al. Engineered PLGA microparticles for long-term, pulsatile

release of STING agonist for cancer immunotherapy. Sci-

ence Translational Medicine 12, eaaz6606 (2020).

Issue No.8

X UEG UA N G LU, ZAC H A RY TOC H K A , ET A L . 20 20

PLGA microparticles offer a way to non-invasively administer a cancer drug directly to a tumour, with a huge potential for minimising patient suffering.

Hairgrowing skin produced from human stem cells Complete skin-in-adish tissue offers new options for wound healing, genetic skin conditions and baldness

December 2020

A stem cell-derived human skin organoid with sprouting hair follicles (red) with dermal papilla cells (cyan) after three months in culture.

After the cells grew for 70 days as spherical aggregates, the first hair follicles were observed on the surface along with some associated tissues such as sebaceous glands, nerves, muscles and fat. “We were truly astounded to see hair growing in our culture dish,” says Koehler. “As we repeated the experiments we learned how the process closely mimics the sequence of human fetal skin development.” To further investigate the cellular composition of the skin organoids, the team performed single-cell RNA sequencing at various time points. They identified four main cell subtypes, but found them in slightly different proportions between organoids. Despite this variability, the gene expression signatures indicate that the organoids mimic facial skin. Tweaking the protocol could generate skin with the characteristics of other body parts and could shed new light on the mechanisms involved in skin growth.

To explore the therapeutic potential of these skin organoids, the authors transplanted them on to immunodeficient mice. Just over half of the grafts sprouted hair, highlighting the exciting possibility of using skin organoids for healing wounds or producing hair in bald scalps. The authors also point out that skin organoids generated from patients with genetic skin disorders or skin cancers could be used to screen for drug efficacy and toxicity, accelerating the discovery of new treatments. “The next steps will be to better understand how skin organoids might react with a patient’s immune system,” says Koehler. “The path to the clinic is going to be challenging, but these early results are quite promising.” Lee, J., Rabbani, C.C., Gao, H. et al. Hair-bearing human skin generated entirely from pluripotent stem cells.

Nature 582, 399–404 (2020).

DR . JIYOON LEE AND DR . KARL KOEHLER, BOSTON CHILDREN’S HOSPITAL/HARVARD MEDICAL SCHOOL

n ew p ro c e d u re e n a b l e s researchers to generate skin from undifferentiated cells. As well as a tool for studying how skin develops, these skin organoids could be used as a source for grafts as well as for screen and testing drug treatments. Skin is the body’s largest organ. It is also multi-layered and multi-functional, acting as a protective barrier, helping to control body temperature and mediating sensation. Although outer-layer skin cells have been grown in laboratories for decades, scientists had previously not been able to recreate this organ, with its follicles and glands, in a dish. Now, Karl Koehler at Boston Children’s Hospital, United States, and his colleagues, have managed to generate skin organoids by directing the differentiation of human pluripotent stem cells in a 3D culture system. Because the cells that form the main layers of skin (epidermis and dermis) are derived from different cell types in the early embryo, the authors first had to optimise the growth conditions. The sequential addition of growth factors triggered the differentiation of human pluripotent stem cells into non-neural ectoderm. This gave rise to epidermal cells, and cranial neural crest cells, which gave rise to cells of the dermis in the face.

Uncovering trends in antibiotic consumption Study assesses global antibiotic consumption patterns over a 15-year period

innovations.kaimrc.med.sa

countries in 2000 to 42 of 76 countries in 2015. Nearly all LMICs showed a decline in the consumption of Access antibiotics compared with Watch antibiotics. The total global increase in the consumption of Watch antibiotics was found to be mainly driven by India and China. A number of factors have likely driven the increase in consumption of Watch antibiotics in LMICs, says corresponding author Eili Klein of the CDDEP. “Economic growth has led to increased consumption of Access and Watch antibiotics in LMICs —however, policies and programmes to regulate the use of Watch antibiotics have not developed at an adequate rate.” He notes that several LMICs, including Algeria and Tunisia, have relatively high

Klein, E.Y., Milkowska-Shibata, M., Tseng, K.K., Sharland,

M. Gandra, S. et al. Assessment of WHO antibiotic con-

sumption and access targets in 76 countries, 2000–15: an analysis of pharmaceutical sales data. Lancet Infec-

tious Diseases (2020).

FA H RO N I / A L A M Y S TOC K P H OTO

here is increasing global use of antibiotics marked by the World Health Organization (WHO) for monitoring because of the likelihood of resistance to them. This trend will make it harder to meet the 2023 antibiotic consumption targets set by the WHO, raising concerns about the spread of antibiotic resistance. Measures to support antibiotic monitoring and optimal use are essential for curbing the emergence and spread of antimicrobial resistance. In 2017 the WHO introduced the Access, Watch, Reserve (AWaRe) classification of antibiotics on its Essential Medicines List. Antibiotics in the Access category are first- or second-line therapies for common infections. Those in the Watch category have higher resistance potential. The Reserve group consists of last-resort antibiotics for targeted use in multidrug resistant infections. An international team led by researchers at the Center for Disease Dynamics, Economics & Policy (CDDEP) in Washington, DC, USA used antibiotic sales data obtained from the healthcare information company IQVIA to study patterns of antibiotic consumption in 76 countries between 2000 and 2015. They found that growth in consumption of Watch antibiotics was nearly four times greater (90.9%) than that of Access antibiotics (26.2%). The increase in Watch antibiotic consumption was much greater in low- and middle-income countries (LMICs, 165%) than in high-income countries (27.9%). The number of countries in which Access antibiotics constituted at least 60% of total antibiotic consumption fell from 50 of 66

consumption of Access antibiotics, comparable to high-income countries with substantial stewardship programmes. This suggests improvements in the Access-toWatch ratio are possible regardless of a country’s GDP. The study is not without limitations, as the researchers point out that some regions such as sub-Saharan Africa were excluded from the analysis due to lack of data, and continuous data for all years up to 2015 were not available for some countries. Nevertheless, the study rings a warning bell that without policy changes, the WHO’s national-level target of 60% of total antibiotic consumption being in the Access category by 2023 will be difficult to achieve. “Ultimately, greater investment in infrastructure, regulations and leadership is needed to improve prescribing practices,” says Klein. “Limiting the spread of antimicrobial resistance is not often prioritized at the same level as higher profile diseases in low-resource healthcare systems.”

The consumption of Watch antibiotics has increased much faster than Access antibiotics, particularly in low- and middle-income countries.

Issue No.8

An artist’s rendition of Mycobacterium tuberculosis, the rod-shaped bacteria which causes the disease tuberculosis.

Measuring the risk of contracting latent tuberculosis in clinical training

Medical students face a greater risk of being infected with TB bacteria than trainees in other specializations

n average 1 in 10 health science students at King Abdulaziz University Hospital develop an asymptomatic and non-contagious form of tuberculosis known as latent tuberculosis infection (LTBI) during

December 2020

their clinical training. Tuberculosis (TB) is a public health concern in the Kingdom of Saudi Arabia, where approximately 10 in 100,000 people contracted the disease in 2018, according to the World Health Organization. A larger

proportion of the population, around 9%, is estimated to harbour an inactive form of the TB bacterium Mycobacterium tuberculosis. The dormant bacteria can reactivate after a period of years if the immune system is weakened immune or if other

innovations.kaimrc.med.sa

Students were tested for M. tuberculosis infection before and after their hospital training, and those with an active TB were excluded at the beginning of the study. Among 1997 students, the initial test detected TB in 6% of the students across the different disciplines, and 10% of the remaining students had a positive test after their clinical training. The researchers observed a significant difference between trainees in different specialities, with medical students having the highest risk of developing LTBI (14.6%). The least at risk were those who specialised in nutrition (4.6%) and laboratory science (5.4%). The length of the training or internship, which was 25 months on average, did not affect the likelihood of infection.

The researchers also noted that less than 50% of the students who tested positive for LTBI were prescribed isoniazid, an antibiotic prophylactic therapy recommended by the WHO to prevent the progression from LTBI to active TB. “Our study shows that medical students are a vulnerable group and should have adequate training to learn how protect themselves from TB. During hospital practice, I recommend an annual TB screening and prophylactic treatment for those who develop latent tuberculosis infection,” says Albanna. Alsharif, M. H., Alsulami, A. A., Alsharef, M., Albanna, A. S., & Wali, S. O. Incidence of latent tuberculosis infection

among health science students during clinical training.

Annals of Thoracic Medicine 15(1), 33 (2020).

Issue No.8

KAT ERY N A KO N / SC IE N C E P HO TO L IB RA RY / G ET T Y I MAG ES

risk factors are present. Healthcare workers and medical students are at risk of acquiring TB in its active or latent form while working in hospitals. “This research was proposed by a recent medical college graduate, Mada Alsharif, who noticed a rise in positive turberculin skin tests (TST) in medical students who completed their clinical training,” explains Amr S. Albanna of the King Saud Bin Abdulaziz University for Health Sciences, who led the research team. The researchers analysed TB screenings of 2,000 undergraduate students who were enrolled in a degree in medicine, dentistry, nursing, pharmacy, radiology, physiotherapy, laboratory science or nutrition between 2010 and 2017.

Uptick in lab-confirmed seroprevalence of MERS infections A trend of increasing MERS prevalence has been detected in a West Saudi Arabian population after testing more than 7,000 samples

December 2020

large study tracing levels of the MERS-CoV virus in the blood serum of a population in Western Saudi Arabia over five years has revealed that asymptomatic or mild infections are still lurking and possibly being silently exported. Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the virus behind MERS, was first identified in a pneumonic patient in Saudi Arabia in 2012. In 2015, the Kingdom experienced a major MERS outbreak of 2,077 infections

The dromedary camel is the only known reservoir animal of MERS-CoV and handlers are at risk of infection.

and 773 deaths, a toll that was reported by the World Health Organization to be the worst worldwide. The outbreak resulted in hospital shutdowns and an eventual increase in research into the then-novel coronavirus and its only proven reservoir animal, the dromedary camel, to trace its epidemiology and explore therapeutic paths. Since then, scientists have been trying to get to the root of how sporadic community cases crop up and spread. In this new study, researchers at innovations.kaimrc.med.sa

KAIMRC sifted through thousands of archived human blood sera collected between 2011 and 2016 from healthy adult donors of 50 nationalities inhabiting the Western part of Saudi Arabia. Their goal was to “search for traces of positivity,” according to Mohammad Bosaeed, a coronavirus researcher at KAIMRC and an infectious diseases consultant at the Ministry of National Guard Health Affairs, who was not involved in the study. “The researchers tried to see if there are camel handlers, for instance, who had

zero positivity, comparing them with other people in the population who didn’t have any camel exposure,” he explains. The scientists examined the blood samples for MERS-CoV S1-specific antibodies, using ELISA, an immunological assay designed to detect and quantify antibody content in response to an antigen. They also confirmed the results by testing for neutralising antibodies using neutralisation tests on both live viruses and pseudotypes, which are clinical surrogates of the live virus. The ELISA test was positive in about 2.3% of the 7,461 samples, spanning 18 nationalities, while neutralising antibodies were confirmed in 17 samples. Seroprevalence—the level of the virus as detected in blood samples—was greatest in people aged 15–44 from Saudi Arabia, Egypt, Yemen, Pakistan, Palestine, Sudan, and India without significant preference. Seroprevalence was greater in males than females, despite slightly increasing prevalence in both sexes over time. “There’s a big difference between males and females, which is related to exposure and contact with proxies, like husbands who might be camel handlers and deal with the animals,” says Bosaeed. “Risks increase when the person is dealing with the meat of the animals as well.” Bosaeed says the slight increase in serum positives, including in females, is not a cause for worry. “After 2016, we’re doing well in terms of knowing how to deal with the virus and taking measures against it,” he adds. Nevertheless, the study authors recommend “enhanced and continuous surveillance” to monitor the transfer of potentially positive MERS-CoV cases inside and outside the Kingdom through general travel or camel trade. Degnah, A.A. et al . Seroprevalence of MERS-CoV in healthy adults in western Saudi Arabia, 2011–

2016. Journal of Infection and Public Health 13, 697‎–‎7 03 (2020).

Issue No.8

FAYE Z N U R EL D I N E/A F P VI A G ET T Y I M AG ES

“Risks increase when the person is dealing with the meat of the animals as well.“

FEATURE

December 2020

Reducing MERS mortality

Standfirst clinicians have tested a combination drug regimen that reduces the number of deaths from Middle East Respiratory Syndrome by a third.

Although MERS in humans is declining, it is still prevalent in dromedaries.

innovations.kaimrc.med.sa

N I A ID / N AT I O N AL IN S T I T U T ES O F H EA L T H / S C I E NC E P H OTO LI B R A RY

team of researchers from the Saudi Critical Care Trials Group (SCCTG) has shown that a drug combination regimen reduced mortality by a third in a group of hospitalized patients with the Middle East Respiratory Syndrome (MERS). Caused by the MERS-CoV virus, MERS is fatal in over a third of infections , with 2,519 confirmed cases and 866 deaths reported as of January 2020 . The disease, which reportedly first spread from dromedary camels to humans in 2012, typically presents with severe respiratory symptoms including fever, cough, and shortness of breath . As with COVID-19, pre-existing conditions predispose patients to severe illness, and some individuals are mildly symptomatic or asymptomatic. Although MERS cases in humans are declining, the virus is still widespread in dromedaries, posing a potentially grave risk. “MERS, at present, is not easily transmissible between humans, unlike COVID-19,” says Yaseen Arabi, chairman of the Intensive Care Department at King Abdulaziz Medical City and professor at the College of Medicine at King Saud Bin Abdulaziz University for Health Sciences, who was the principal investigator of the new research. “The worry is always that maybe a mutation makes the virus more transmissible.”

Issue No.8

FEATURE

The team found that after 90 days, 44% of the placebo group had died from the disease, whereas the mortality rate was only 28% in the experimental treatment group.

December 2020

A new trial for a stubborn disease

The team enrolled 95 patients from nine clinical sites in Saudi Arabia in a MERS clinical trial. Of the cohort, 43 were given a 14-day course of experimental therapy that combined interferon Beta-1b and lopinavir-ritonavir, and a second group of 52 patients received a course of placebo therapy. The team found that after 90 days, 44% of the placebo group had died from the disease, whereas the mortality rate was only 28% in the experimental treatment group. This represents a significant reduction in mortality for a disease that has so far been untreatable. The team found that to receive the clinical benefit, patients needed to start the regimen within seven days

of symptom onset. “Early treatment makes a big difference. I think early recognition and treatment might help bring mortality down even lower,” says Arabi. The drugs used in the trial were chosen based on their efficacy in preclinical studies, which showed that lopinavir inhibited the replication of MERS-CoV and SARS-CoV (the causative virus of the SARS epidemic) in vitro, and lopinavir-ritonavir/interferon beta-1b was previously shown to improve the condition of infected marmosets. By using a therapy of two medications, one of which (lopinavir-ritonavir) is a twodrug combination, the team was able to target MERS-CoV at different levels, providing both immunomodulatory and antiviral effects.

One of the challenges in conducting the recent trials was that MERS is an uncommon virus with episodic infection flares.

One of the challenges in conducting the trial was that MERS is an uncommon virus with episodic infection flares. “We started recruiting patients in 2016, and the last one was recruited in early 2020,” says Arabi, highlighting the time needed to get a useful number of cases. While randomised controlled trials are typically based on pilot studies, Arabi and his team recognized that the low rate of new cases meant they would need to design an adaptive trial that incorporated multiple stages with interim assessments to guide the trial to research-validated findings. To ensure the design was robust, the team included a longer-term 90-day follow-up. The study found that the survival of the two groups “continued to diverge well beyond day 28.” innovations.kaimrc.med.sa

A focus on intensive care research

The SCCTG represents a concerted effort by clinical academia within the Kingdom of Saudi Arabia to boost the country’s clinical trials portfolio and expertise in intensive care medicine. KAIMRC researchers are part of the SCCTG, and the institution also hosts Saudi Arabia’s National Command Center for Clinical Trials. Active for several years, the SCCTG has published multiple papers in high-impact journals, including a series of publications on MERS therapies. “All of these questions turned out to be really critical when COVID struck,” says Arabi. “People asked the same questions.” Despite the horrors of MERS, it primed Saudi society for the onslaught of COVID19. “Exposure to MERS over the last several

https://www.who.int/health-topics/mid-

https://applications.emro.who.int/docs/

https://www.cdc.gov/coronavirus/mers/about/

dle-east-respiratory-syndrome-coronavirus-mers#tab=tab_1 EMCSR254E.pdf symptoms.html

Arabi, Y.M., Asiri, A.Y., Assiri, A.M., Balkhy, H.H., Al Bshabshe, A., et al. Interferon Beta-1b and Lopina-

vir–Ritonavir for Middle East Respiratory Syndrome.

The New England Journal of Medicine 383, 1645‎–

‎1656 (2020).

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S CI E NCE P HOTO L I BR A RY / A L A M Y S TOCK P HOTO

years has helped a lot in building our prescience, advising the culture to the threat of viral infections. So, when COVID-19 came, people knew what the risks were and that we should take precautions,” says Arabi. And perhaps more importantly, the Saudi healthcare system was primed to respond, already having prepared response plans for viral infections and pandemics. Just as the fight against MERS prepared society for the fight against COVID, the ongoing pandemic may in turn offer insights that help researchers combat MERS. While Arabi believes some COVID treatments may warrant testing as MERS therapies, he and other MERS researchers will have to cope with the difficulty of evaluating multiple potential therapies with only a small group of patients. Even with the experimental therapy, mortality from MERS remained at 28% in the trial. This is a significant reduction from the generally reported mortality rate of 35%, but it simultaneously highlights the need for more work to reduce mortality further. The SCCTG is now looking at questions raised by the COVID-19 pandemic, and they have two clinical trials in the works. One investigates whether prone positioning in awake patients helps their oxygenation and clinical outcomes, as has been shown for patients on ventilators, while the other looks at the benefits of non-invasive helmet-based ventilation in COVID-19. Arabi and the SCCTG are also involved in the international REMAP-CAP trial, designed to simultaneously and efficiently evaluate a number of treatment options for COVID-19.

“As many as 30% of patients in low- and middle-income countries who underwent surgeries experienced surgical-site infections.“ Surgical-site infections are an economic burden to the public health system.

High postsurgical infection levels in Saudi Arabia Antibiotic resistant bacteria are widespread in surgical-site infections in Saudi Arabian hospitals

December 2020

ccording to the WHO, surgical-site infections (SSIs) are the most common healthcare-associated infections. In low- and middle-income countries, as many as 30% of patients who underwent surgeries had experienced surgical-site infections. Even in high-income countries, surgical-site infections account for more than one fifth of all healthcare-associated infections. Surgical-site infections increase treatment costs, prolong hospitalisation, and can lead to septic complications. To see how Saudi Arabia fares compared to other countries, Hanan Balkhy at the Infection Prevention and Control Department of King Abdulaziz Medical City in Riyadh and co-workers conducted a prevalence survey on surgical-site infections in four hospitals run by the Ministry of National Guard -Health Affairs (MNG-HA). These four hospitals perform approximately 30,000 surgical procedures every year. The researchers’ survey targeted surgical procedures conducted between 2007 and 2016, with a focus on finding the causative pathogens of surgical-site infections and their antimicrobial resistance patterns. Balkhy and her team recorded a total of 492 pathogens in 403 surgical-site infection

Remarkably, all bacteria exhibited varying degrees of antimicrobial resistance. Some bacteria, such as Staphylococcus aureus, were found to be methicillin-resistant, while other bacteria such as Klebsiella and Escherichia coli displayed multi-drug resistance. Overall, Gram-negative bacteria with antimicrobial resistance were the most widespread pathogen, making up around 60% of all surgical site infections in the four hospitals. Even more worrying is that, in comparison with US National Healthcare Safety Network hospitals, multi-drug resistant Klebsiella and Escherichia coli were significantly more common in Saudi Arabian hospitals. The finding suggests that the current guidelines on the use of antibiotics before surgery might not be sufficient to tackle surgical-site infections. The researchers urge clinicians and health authorities in the Kingdom to secure resources and ensure support in implementing interventions, such as antimicrobial stewardship programmes and evidence-based preventive practices, to limit the number of surgical-site infection cases. El-Saed, A., Balkhy, H.H., Alshamrani, M.M., Aljohani, S., Alsaedi, A., et al. High contribution and impact of resistant gram negative pathogens causing surgical

site infections at a multi-hospital healthcare system in Saudi Arabia, 2007–2016. BMC Infectious Diseases

20, 275 (2020).

DAVI D HE R R A E Z / A L A M Y S TOCK P HOTO

cases. The most frequent pathogens found were Staphylococcus aureus (a Gram-positive bacterium frequently found on the skin), Pseudomonas aeruginosa (a Gram-negative bacterium found in soil, skin, as well as man-made environments), Klebsiella (a Gram-negative bacterium commonly found in the digestive tract), and Escherichia coli (a Gram-negative bacterium commonly found in the lower intestine).

MEDICAL BIOTECHNOLOGYPARK

The Medical Biotechnology Park is a strategic project of KAIMRC/ MNG-HA to contribute to the Saudi Vision 2030 through: • The development and commercialization of biomedical R&D products, technologies and services • The contribution to economic and health improvement through science and innovations in medical and health sectors

WEBSITE: KAIMRC-BIOTECH.ORG.SA E-MAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH

COVID-19

Combatting

COVID As we race to understand the novel coronavirus, studies show that respiratory failure in some COVID-19 patients could be associated with their genetic profile, that genetic anomalies and autoimmune antibodies dull the immune response in severely ill patients, and that face masks can effectively protect against infection

December 2020

N I A I D/ N I H

innovations.kaimrc.med.sa

Issue No.8

COVID-19

Through a greater understanding of how our bodies respond to SARS-CoV-2, researchers and clinicians can develop more effective therapeutics, and predict and improve clinical outcomes.

December 2020

Investigating COVID-19 immune responses

nvestigations into the immune response against antibodies from convalescent patients and use SARS-CoV-2 have yielded a host of clinical- them to treat others. Understanding the profile of ly-relevant findings, including ‘signatures’ of a successful immune response also offers guidance immune cell receptors that are associated with to teams working on prophylactics. clinical severity. This data could offer clinicians The team’s study is one of the first to report a prognostic indicator for new cases and inform that the B cell response to the new coronavirus efforts to create effective therapeutics. differs from the norm. “In the majority of viral Mascha Binder at the Martin Luther Univer- or bacterial infections, B cell genes accumulate sity of Halle Wittenberg, Germany, and her team, mutations that adapt their antibody molecules to compared the immune responses of two cohorts of the infecting pathogen,” explains Binder. Howpatients. The first comprised 20 hospitalized patients ever, in COVID-19, unspecialized antibodies are with an active SARS-CoV-2 also able to recognize the infection, including 12 critvirus. “There is a concern “There is a concern ically ill patients. The secthat certain antibodies ond group consisted of 19 could possibly have an that certain antibodies patients who had recovered unfavorable influence on could possibly have an from the pathogen. the course of the disease.” Binder and her team Analyses also found unfavourable influence on found signatures of T cell “striking abnormalities” the course of the disease.“ surface receptors that in cytokine levels, even were present exclusively after patients had recovin patients who had recovered from COVID-19. ered. Increased levels of the clotting-associated “Patients with severe disease had lower T cell diver- protein sCD40L were also discovered several weeks sity and very different T cell receptor clusters than post-infection, which may be indicative of propatients with milder courses,” says Binder. longed cardiovascular risk to those infected. This research led to the creation of an online Two additional research papers by the team are repository of more than 14 million T and B cell currently in the works, including one showing that receptor sequences, and the team are continually certain B cell receptor configurations are also assoadding more. The data is freely available and could ciated with disease severity. prove invaluable as scientists look to create new therapeutics to fight the pandemic. Schultheiß, C., Paschold, L., Simnica, D., Mohme, M., Willscher, E. et Armed with knowledge of how specific immune al. Next-Generation Sequencing of T and B Cell Receptor Repertoires cell signatures influence clinical outcomes, from COVID-19 Patients Showed Signatures Associated with Severresearchers could feasibly clone the most potent ity of Disease. Immunity 53, 442–455 (2020).

innovations.kaimrc.med.sa

Issue No.8

S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

An in-depth analysis of the COVID-19 immune response offers new tools to clinicians

COVID-19

AI algorithms for rapid coronavirus diagnosis Researchers use advanced deep learning models to create an AI system that can help identify COVID-19 in minutes.

December 2020

n i nter nat iona l te a m o f researchers trained an artificial intelligence (AI) model to sort and combine radiology data and clinical information to rapidly and accurately diagnose patients with COVID-19. “The AI system could rapidly flag suspected cases so radiologists can review those with a higher priority,” says Zahi Fayad, study co-author and professor of radiology and medicine at the Mount Sinai School of Medicine, New York, USA. “If radiologists also diagnose these AI-identified patients as COVID, these patients can be isolated before they get their RT-PCR test results.” The researchers trained their system using datasets from 905 patients from different medical centres and hospitals across China between January and March 2020. The trained model was tested on a set of 279

patients and performed well, with a confidence rate of 84%. The model improved detection by correctly identifying COVID-19 infection in 17 out of 25 patients who presented with normal CT scans and who had previously been classified as COVID-19 negative by radiologists. The algorithms integrate chest CT scans with information such as a patient’s age and sex, symptoms, and exposure history to identify a SARS-CoV-2 infection in the early stages. The model can work alongside routine tests, such as reverse transcriptase polymerase chain reaction (RT–PCR), to reduce the frequency of false negatives and decrease the risk of viral transmission. Fayad explains that they created three models for testing: a deep convolutional neural network (CNN) that only used CT scans; a model that used support vector innovations.kaimrc.med.sa

machine (SVM) and random forest and multilayer perceptron (MLP) to classify clinical data; and a joint one that integrated CT scans with clinical data. Patient data were entered into the AI system as numeric values of 1 and 0—with 1 representing the presence of symptoms, confirmed travel to Wuhan or close contact with positive cases, and 0 representing no symptoms or link to Wuhan or anyone carrying the virus. Chest CTs were input into the system as pixel values. The data are then converted into vectors that are combined and used for making predictions. The proposed AI system is fast compared to conventional diagnostic methods, yielding results in a minute or less using GPU-powered computers, and in a few minutes with CPU-based machines. RT-PCR tests typically take two days to complete.

For the system to be reliable, however, researchers say that they would need to collect more scans and data from multiple countries. The proposed model also carries a few limitations, such as a bias in the training data towards patients with COVID-19, as opposed to other infections and pneumonias that exhibit similar symptoms. The researchers plan to improve predictions by updating their model architecture to a three-dimensional mesh that incorporates more frames from CT imaging. Fayad explains that “the current model was developed at slice level. Only key suspected frames were used from CT scans due to the trade-off between efficiency and turnaround time.” Mei, X. et al. Artificial intelligence-enabled rapid diagnosis of patients with COVID-19. Nature Medicine 26 1224‎–‎1228 (2020).

Issue No.8

DA- KUK / E + / G ET T Y I M AG ES

Researchers are using machine learning algorithms to help diagnose COVID-19 in a few minutes or less.

Saudi Arabia’s experiences of the MERS-CoV epidemic led to the implementation of early and strict precautionary measures against SARS-CoV-2.

Building on experience: Saudi Arabia’s COVID-19 response The knowledge gained from the MERS-CoV epidemic in Saudi Arabia put the country on a strong early response footing for COVID-19

n 2012, Saudi Arabia was the first country to report human cases of Middle East respiratory syndrome (MERS). The disease spread to humans from camels, causing 2,538 infections and 871 deaths in 27 countries by February 2020. The majority of cases were in Saudi Arabia, and the country’s government invested considerable resources and took rapid steps to help stem the spread of the disease. When SARS-CoV-2, the virus that causes COVID-19, emerged in China in late 2019, countries around the world

December 2020

were placed on high alert as the possibility of a worldwide pandemic grew. Recognising the threat early, the Saudi Arabian government was among the first to implement precautionary measures and set up a national response committee to oversee the situation as it unfolded. The Saudi government suspended all direct flights to and from China in early February 2020, a month before the first case of COVID-19 was confirmed in the Kingdom. By March 17, the government had taken the unprecedented decision to close the country’s mosques, except the

two holy mosques in Mecca and Medina, and ask all Muslims to pray at home. A major concern for the government remains the regular influxes of Muslim pilgrims to key religious sites in the two cities; all social and religious gatherings such as these remain vastly limited, even after easing constraints in June. In a recent paper published in the Journal of Infection and Public Health, Anwar Hashem at King Abdulaziz University in Jeddah and co-workers including Naif Khalaf Alharbi at KAIMRC, attribute the rapid response of the Saudi government to lessons of the MERS-CoV outbreak. The infrastructure put in place for MERS has played a key role. “After the discovery of MERS-CoV,” state the authors in their paper, “the Saudi Ministry of Health promptly established a command and control center and accelerated the establishment of the Saudi Center for Disease Control and Prevention.” Specialised diagnostic laboratories and strict biosafety in all hospitals are critical to disease control, and more than 25 hospitals that had isolation wards for the treatment of MERS patients are now treating those with COVID-19. Hashem’s team stresses that the country must remain vigilant, though. The government must maintain stringent measures to control infection and continue investing in vaccine research in the Kingdom. Through cooperation with global partners, KAIMRC has developed a new vaccine that has been tested successfully in camels and is now being tested on humans, marking the first phase I clinical trial to be conducted in Saudi Arabia. A similar focus is now needed for SARS-CoV-2. The researchers hope to see more high containment laboratories set up in the Kingdom, and call for “more advanced industrial-scale development grants, networking between academia and industry, and better governance of research and development.” Algaissi, A.A., Alharbi, N.K., Hassanain, M., & Hashem, A.M. Preparedness and response to COVID-19 in Saudi Arabia: Building on MERS experience. Journal of Infec-

tion and Public Health 13 834‎–‎838 (2020)

R E U T E R S / A L A M Y S TOCK P HOTO

COVID-19

T cells recognise the COVID-19 virus before and after infection

SARS-CoV-2 triggers a strong T cell-based immune response, but many people already have some cross-reactive immune memory

innovations.kaimrc.med.sa

“We saw a robust T cell response against the spike protein of the virus, the target of most vaccines.“ virus, the target of most vaccines,” Sette says. However, they also found T cells that recognised other parts of the virus, revealing some aspects of the complexity of the anti-viral T-cell response.

Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M. et al. Targets of T Cell Responses to SARS-CoV-2

Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489–1501 (2020).

JUA N G AE R T N E R /S C I E N CE PH O TO L I B R A RY / G ET T Y I M AG ES

mmune cells known as T cells are a significant part of the immune response to SARS-CoV-2, the virus that causes COVID-19, according to new research from the US. The study also revealed that a substantial proportion of people who have not been infected with SARS-CoV-2 nevertheless have T cells that can recognise the virus. “Our study was the first to show that COVID-19 triggers a strong immune response in most people,” says Alessandro Sette of the La Jolla Institute of Immunology in California, who led the research team. Much of the discussion of the immune response to COVID-19 has focused on antibodies, protein molecules that bind to specific parts of a virus and thus stimulate activities that neutralize the virus. However, another major aspect of immunity is mediated by circulating T cells. One category of T cells, known as killer T cells, can bind to and destroy virus-infected cells. Another category, helper T cells, can assist in generating the antibody-based response. Sette and his colleagues examined blood from 20 patients who had recovered from COVID-19. They found helper T cells that could recognise and act against the SARS-CoV-2 virus in all of the samples. They also found killer T cells that could target SARS-CoV-2 in 14 of the samples. “Importantly, we saw a robust T-cell response against the spike protein of the

Perhaps equally significant is their discovery of T cell activity against the SARS-CoV-2 virus in around 50 % of blood samples taken from people who could not have been exposed to this virus, since the samples dated from 2015–2018, before SARS-CoV-2 emerged. The researchers believe that this recognition may be due to previous infection with less harmful coronaviruses that cause common colds. They say it is possible that this ‘cross-reactivity’ of immune response against coronaviruses may help explain the relatively mild illness experienced by some people with COVID-19. At present, however, there is no firm evidence for or against this speculation. By learning more about the immune response to SARS-CoV-2 the researchers hope to contribute to the development of effective vaccines and treatments. “Hopefully we can learn how to push the immune response in the right direction,” says Sette.

A graphical depiction of a T cell.

Issue No.8

those connected to severe COVID-19. Karlsen explains that the COVID-19-related respiratory infection appears atypical and is associated with aggravated inflammation, which could also often point to a genetic predisposition. “We felt obliged to do something in the serious situation of the pandemic,” Karlsen says.

“We will try to contribute to the bigger effort of the scientific community to understand and deal with COVID-19.“

Gene mutations could determine the severity of symptoms in COVID-19 patients.

Finding genetic leads for severe coronavirus cases Respiratory failure in some COVID-19 patients could be associated with their genetic profile

December 2020

illions of people around the world have been infected with the novel coronavirus that causes COVID-19, but there is considerable disparity in how serious their symptoms can be. A European team has now analysed the genetic profiles of COVID-19 patients from Spain and Italy who showed severe symptoms and found gene mutations that may be responsible for the severity of the disease. Since its appearance in Wuhan, China in late 2019, COVID-19 has quickly spread to become a global pandemic. Although most infected people display mild symptoms or none, some patients develop serious lung diseases that could trigger life-threatening respiratory failure. These patients need early and prolonged oxygen support, or to be put on a mechanical ventilator. Although pre-existing conditions, such as hypertension and diabetes, can worsen the risks from COVID-19, the underlying mechanism leading to these severe symptoms remains unclear. There are several genetic risk factors that link patient susceptibility to viral disease symptoms. This prompted Tom Karlsen from the University of Oslo in Norway and Andre Franke from Christian-Albrechts-University in Germany to investigate

The team enrolled 1,980 confirmed patients with severe COVID-19 symptoms from seven hospitals in four cities of the Spanish and Italian pandemic epicentres. For comparison, they also recruited 2,205 control participants—mostly healthy volunteers and a few COVID-19 infected individuals presenting mild or no symptoms. The researchers evaluated the DNA sequence genomes of all patients and control participants to determine variations between their genetic profiles and identified certain mutations that appear related to COVID-19-induced respiratory failure on two distinct chromosomes in the patients. These mutations involved a gene cluster on chromosome 3, and the ABO blood type gene on chromosome 9. “The chromosome 3 mutation is the most interesting finding,” Karlsen says. It provides the strongest signal, becomes stronger when corrected for age and gender, and seems to be more pronounced in the most severe patients, he adds. The team is planning to expand their assessment to more patients to find other genetic risk factors to specific COVID-19 symptoms. “We will try to contribute to the bigger effort of the scientific community to understand and deal with COVID19,” Karlsen says. Ellinghaus, D., Degenhardt, F., Bujanda, L., Buti, M., Albil-

los, A. et al. Genomewide association study of severe

COVID-19 with respiratory failure. The New England

Journal of Medicine, Published online on June 17, 2020.

P I YA M AS DU L M U NS U M P HU N / A L A M Y S TOCK P HOTO

COVID-19

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FEATURE

There is now consensus among the scientific community that masks can help stop the transmission of the novel coronavirus that causes COVID-19.

December 2020

The case for masks in combatting COVID-19

he COVID-19 pandemic took the world by surprise, leading to frenzied debates about how governments should respond. Perhaps the most confusing and divisive of these debates surrounds the use of face masks, with both scientists and politicians presenting mixed messages. The World Health Organization (WHO) initially recommended that medical masks should only be used by healthcare workers and COVID-19 patients – advice that was welcomed by governments concerned that personal protective equipment (PPE) might run out. Meanwhile, public-led movements promoted the use of simple fabric masks, even home-made ones using handkerchiefs or T-shirts, as effective barriers to block SARS-CoV-2, the virus that causes COVID-19. Eventually, on 5 June the WHO issued new advice that the general public should wear non-medical, fabric masks where physical distancing of at least one metre is not possible, for example in shops1.

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This guidance has been applied in most countries as an extra protective measure while communities emerge from lockdown restrictions. In early July, the Ministry of Industry in Saudi Arabia announced plans to increase their production of masks from 2.5 million up to 10 million masks every day2. This strongly indicates the intention that masks will play a major role in the country’s ‘return to normality’, allowing people to attend weddings, funerals and beauty salons. However, many scientific questions remain unanswered. How effective are fabric masks compared to bespoke PPE medical masks? Can masks be sterilized and re-used? Will they protect the wearer, or just people around them? A major sticking point is that there has not been enough time to gather the gold standard of scientific evidence – fully peer-reviewed, replicable randomized control trials specifically testing masks against SARS-CoV-2 ref. 3. Some research Issue No.8

Y UL I A S HA I HU D I N OVA/ M OM EN T / G ET T Y I M AG ES

Specific studies assessing face masks and COVID-19 transmission are limited, but related scientific evidence suggests that even simple fabric masks can make a difference

FEATURE such as influenza, which is of very similar size to SARS-CoV-2. Lab and modelling studies had found that masks could be effective tools in managing an epidemic by blocking a large percentage of the influenza viral load from escaping a wearer’s mouth7, though there is less evidence that they protect the wearer themselves8. Home-made fabric masks blocked fewer influenza viruses than commercial masks, but were certainly better than no protection9. Another hazard that masks can protect against is air pollution, especially tiny PM2.5 – particles smaller than 2.5 micrometres in diameter which stay in the air for long periods and can penetrate deep into the lungs. When 239 scientists wrote a commentary in early July urging the WHO to recognize mounting evidence that many microscopic droplets containing viable SARS-CoV-2 viruses can be classified as aerosols, protection from these tiny particles became particularly important10. They are light enough to stay aloft in the air over tens of meters, complicating social distancing efforts considerably.

Growing support

Lab experiments include pumping polluted air through masks of different types. These have shown that some professional-standard masks can block up to 99%

Masks protect against tiny particles lingering in the air and complicating social distancing.

December 2020

of PM2.5 ref. 10,11,12. Tests on fabric masks are limited, but one study12 showed that a thin cotton handkerchief could block over 28% of PM2.5.

“All studies were conclusive to the fact that wearing high-quality masks aids in preventing infection, especially alongside eye protection.“ This might seem poor, but these tests greatly underestimate the effectiveness of masks, for several reasons. Firstly, the detectors used in such studies measure particles ten times smaller than even SARS-CoV-2 itself. Secondly, most cotton masks are a lot thicker than a single handkerchief. Moreover, most droplets emerging from people’s mouths are larger than PM2.5, and the problematic aerosols arise from larger droplets evaporating once they are well away from the mouth. Perhaps the strongest evidence in favour of using masks in the current pandemic arises from epidemiological studies of state-13 or country-wide14 COVID-19 data. A statistical analysis published in August reports the extraordinary finding that “in countries with cultural norms or government policies supporting public mask-wearing, per-capita coronavirus mortality increased on average by just 15.8% each week, as compared with 62.1% each week in remaining countries.” Given these findings, many governments have made masks mandatory in different situations, and started looking for ways to sterilize and reuse masks so that they do not run out or create a waste problem. A recent review paper states that the most promising methods for sterilizing masks against SARS-CoV-2 are those using hydrogen peroxide vapor, ultraviolet radiation, moist heat, dry heat or ozone gas, while other methods such as washing with soapy water or alcohol are not recommended15. Perhaps the burden of proof in the masks debate actually lies with those

RE U T E R S/ A L A M Y S TOC K P H OTO

groups have reported data for small numbers of patients, showing that a large percentage of the viral load is blocked by masks, but those results are inconclusive until they are fully checked. “It is scientifically proven that wearing good quality masks by the population at risk will significantly decrease the spread of any respiratory virus spreading via droplets,” says pharmacoepidemiologist Islam Anan, the chief executive officer of Accsight (Healthcare Integrated Solutions) and a lecturer in the Faculty of Pharmacy at Ain Shams University in Cairo. “The top evidence that wearing masks can be a pandemic stopper is a systematic review published in The Lancet4, analysing 216 general studies over 25,000 cases of COVID-19, SARS and MERS. All studies were conclusive to the fact that wearing high quality masks aids in preventing infection, especially alongside eye protection.” Anan also points to powerful epidemiological modelling studies5,6 that examine the impact of different scenarios, varying mask quality and the percentage of the population wearing masks. “These very comprehensive studies clearly demonstrate that masks will decrease [the infection rate],” he says. For now, our best shot is to look to established work on masks with other viruses

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Methods such as steam, microwave treatment or high temperature are not recommended for mask sterilization.

1. World Health Organization. Advice on the use of masks

in the context of COVID-19. (5 June 2020) https://www. who.int/publications/i/item/advice-on-the-use-ofmasks-in-the-community-during-home-care-and-

in-healthcare-settings-in-the-context-of-the-novelcoronavirus-(2019-ncov)-outbreak

2. https://english.alarabiya.net/en/coronavi-

rus/2020/07/02/Coronavirus-Saudi-Arabia-plansto-produce-10-million-face-masks-daily-

3. Howard, J. et al. Face masks against COVID-19: An evidence review. PNAS (April 2020) 10.20944/preprints202004.0203.v1

4. Chu, D.K et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic

review and meta-analysis. The Lancet 395 (10242), 1973-1987 (2020).

5. Eikenberry et al. To mask or not to mask: Modeling the potential for face mask use by the general public to

curtail the COVID-19 pandemic. Infectious Disease

Modelling 5, 293-308 (2020).

6. De Kai et al. Universal Masking is Urgent in the COVID-

19 Pandemic: SEIR and Agent Based Models, Empirical

Validation, Policy Recommendations. Physics and Soci-

ety. arXiv:2004.13553v1

7. Brienen N.C. et al. The effect of mask use on the spread of influenza during a pandemic. Risk Anal. 30 (8), 12101218 (2010).

8. Cowling B.J. et al. Face masks to prevent transmis-

sion of influenza virus: a systematic review. Epidemiol

Infect 138 (4), 449-456 (2010).

9. Davies A. et al. Testing the efficacy of homemade masks: Would they protect in an influenza pandemic?

Disaster Med Public Health Prep. 7(4), 413-418 (2013).

10. Morawska, L. & Milton, D.K. It is time to address air-

borne transmission of COVID-19. Clinical Infectious Dis-

eases, ciaa939 (6 July 2020).

11. Cherrie JW, Apsley A, Cowie H, et al. Effectiveness of face masks used to protect Beijing residents against particulate

air

pollution.

2018;75(6):446-452.

Occup

Environ

Med.

12. Langrish JP, Mills NL, Chan JK, et al. Beneficial car-

diovascular effects of reducing exposure to particulate air pollution with a simple facemask. Part Fibre Toxicol. 2009;6:8. Published 2009 Mar 13.

13. Lyu, W. & Wehby, G.L. Community use of face masks

and COVID-19: Evidence from a natural experiment of state mandates in the US. Health Affairs (16 June 2020). 14. Leffler, C. et al. Association of country-wide coronavirus mortality with demographics, testing, lock-

downs, and public wearing of masks. medRxiv (Update August 05, 2020).

15. Carlos Rubio-Romero J. et al. Disposable masks: Dis-

infection and sterilization for reuse, and non-certified manufacturing, in the face of shortages during the

COVID-19 pandemic [published online ahead of print].

Saf Sci. 129, 104830 (13 May 2020).

16. Pless, B. Risk compensation: Revisited and rebutted. Safety 2, 16 (2016).

Issue No.8

C H EN B I N / X I N H UA / A L A M Y S TOC K P H OTO

arguing against them. After all, it seems common sense that putting any barrier in front of your mouth will block at least some infectious droplets. And, importantly, no scientific studies have found evidence that masks could increase anyone’s risk of infection. So, for now the only reasonable arguments against mask use are social, political and economic. For instance, people may feel embarrassed or stigmatized when wearing masks, making them less likely to visit shops and assist in their country’s economic recovery. This behaviour has been observed in previous epidemics, and supports the notion that mask-wearing is best as a universal policy for everyone. That way, a mask can be a positive signal of solidarity in society, rather than something that labels a sick person. On the other hand, some people might proudly wear a mask with a false sense of security, so they neglect other mitigation measures like physical distancing and hand-washing. This dilemma touches on an interesting area of psychology called risk compensation, which often arises when new safety laws are introduced. For example, if we make people wear helmets on motorcycles and seatbelts in cars, will they be more reckless because they think they can’t be hurt? Studies of these situations show that, while a few individuals might take more risks, their behaviour is dwarfed by that of society as a whole, resulting in overall improved safety and well-being16. Therein lies the key – small measures, applied widely, can provide large benefits for the population. Masks are clearly not a panacea that will end the COVID-19 pandemic, but neither are they a significant burden for an individual to bear. For those who have never lived through an epidemic before it may seem strange, but wearing a simple face covering really could save lives. “Masks stand on the first line of defence against COVID-19 along with eye protection, social distancing and hand washing,” says Anan. “It is the answer we have now until vaccines or highly effective treatments are available, and a necessity after the re-opening of economies, to avoid any rebound.”

FEATURE

Hidden immune failure in severe COVID-19 cases Two studies find that genetic anomalies and autoimmune antibodies dampen the immune response in severely ill COVID-19 patients

wo new studies1,2 reveal how the body’s innate immune system reacts to a SARS-COV-2 infection in severe and critical cases, which could indicate new treatment trajectories. The findings show that certain immune defects lead to interferon deficiency, typically worsening prognosis, and that an autoimmune-like antibody response to interferons explains serious infections in some patients. Interferons (IFNs) are proteins that are involved in intercellular signalling and play a role in blocking viral proliferation and modulating the immune response. A lack of the receptors for specific IFNs which provide a defence barrier against viruses and bacteria can make people more susceptible to infectious diseases. The new research demonstrates the critical role played by these antiviral signalling molecules in the immune response to SARS-CoV-2. The studies were led by Jean-Laurent

December 2020

Scientists are studying inborn deficiencies in interferons, proteins that fight off invading pathogens, especially viruses such as SARS-CoV-2.

Casanova and Laurent Abel of the Rockefeller University, in New York, and co-authored by Qian Zhang, Paul Bastard and Lindsey B. Rosen, together with colleagues around the world including Saeed Al Turki of KAIMRC. In the first study, Zhang and his colleagues sequenced the genomes of 659 patients with life-threatening COVID-19 pneumonia and 534 people with an asymptomatic or mild infection. The scientists examined three IFN-related genes that are mutated in patients with life-threatening

influenza pneumonia, along with 10 other genes connected to them. They found that 3.5% of patients with critical COVID-19 pneumonia had lossof-function mutations in genes involved in the type I IFN pathway. In other words, these individuals had innate immune errors that would make them more vulnerable to viruses such as SARS-CoV-2. Despite this, none of these patients had been previously hospitalized for other serious viral illnesses, according to Abel. The second study, led by Bastard,

but were present before infection in the patients who developed severe cases. “The two papers are really two sides of the same coin,” says Bastard. Through a genetic defect in one case and an autoimmune response in the other, the papers demonstrate “two different mechanisms that have the same consequence, which is a defect in this type I interferon.”

The new studies indicate that genetic defects or autoimmunity underlie many of the severe cases of patient SARSCoV-2 infection.

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analysed 987 patients who were hospitalised for critical COVID-19 pneumonia, along with 663 with asymptomatic or mild SARS-CoV-2 infections, and samples collected from 1227 healthy control people before the COVID pandemic. The scientists detected high levels of neutralizing antibodies against type I IFN subgroups in about 10% of patients with COVID-19 pneumonia. These antibodies, which hindered the ability of IFN to fight a SARS-CoV-2 infection, were not found in asymptomatic, mild, or healthy cases,

Akiko Iwasaki, a professor at Yale School of Medicine who focuses on innate immune defence against viruses and adaptive immunity, calls these results “quite surprising,” particularly the neutralising antibody response to interferons. “We know that these kinds of antibodies become prevalent in certain autoimmune conditions,” explains Iwasaki, who was not part of either research team. “But the fact that they are so enriched in patients with severe COVID and that they are functionally blocking interferon would make you just as immunocompromised as if you didn’t have the genes for it.” Casanova and Abel were among a team of scientists who established the COVID Human Genetic Effort4 to understand why SARS-CoV-2 has proven deadly for some patients but has not presented symptoms in others. They hypothesized that severe cases could be related to irregular genetic variations and hidden immunodeficiencies4,5. The new studies lend support to this idea by showing that genetic defects or autoimmunity underlie many of the severe cases. However, it’s unclear why these factors didn’t cause earlier infections or other problems for the patients. “The patients with genetic defects did not have any particular symptoms or comorbidity, and most of them didn’t suffer from any severe infections before,” says Bastard. “We haven’t really had the chance to analyse all the comorbidities in detail because of the COVID situation. We had a hard time getting access to a complete medical history, but so far it doesn’t seem like there’s anything striking about these patients when compared to patients without these genetic or immune defects.” Like Iwasaki, Paul Hertzog, an Issue No.8

K AT E RY N A KO N /S CI E N C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

Prevalence of hidden defects

FEATURE

The male bias and the future of therapy

Understanding the physiology of the severe cases and why a breakdown in the antiviral interferon system happens can open avenues of prevention and early intervention. For instance, patients who cannot produce interferon can be treated using synthetic interferons. “You can very easily give recombinant type I interferon, either IFN alpha or beta, but the really important point is to give it early in the disease,” says Bastard. He adds that patients with IFN

alpha auto-antibodies could be treated by giving them IFN beta, which wouldn’t be inhibited by the antibodies because it has a different structure. Abel concurs. “Having this information for at-risk patients, especially those who haven’t yet developed a severe form, is very important,” he says. “The treatment by interferon is efficient when given at a very early stage of infection. If the person is already hospitalized with a severe form, then it’s likely to be too late.” The findings also have broader implications for therapeutics. For example, both Abel and Bastard point out the need to test all convalescent plasma donated to sick patients to ensure that it is free of IFN-neutralizing auto-antibodies which could make the disease. Hertzog also points out that “together, the patients from the studies probably represent close to 15% of seriously ill people [who] can’t respond to interferon, the body’s best natural defence against the virus.” That’s a significant number of people might not respond to therapeutics that work for the rest of the population. The IFN antibodies may also explain why older males are among the most vulnerable demographic. The neutralizing

auto-antibodies were mostly found in older males—95 of the 101 patients with these antibodies were men. Abel says that it isn’t enough to explain general male susceptibility to severe COVID-19, but it’s certainly part of the story. He and his colleagues plan to build on this by investigating the genetic basis of these auto-antibodies and the reasons for the male bias. “We need to know why these individuals develop auto-antibodies, and if it’s, for example, somehow related to the X-chromosome,” he explains. The researchers also want to replicate their findings and test them more broadly to see if they hold in less milder cases of COVID19 or other viral diseases. 1. Zhang, Q., Bastard, P, et al. Inborn errors of type

I IFN immunity in patients with life-threatening COVID-19. Science 370, 422 (2020).

2. Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, 423 (2020).

3. Lee, A.J., Ashkar, A.A., The Dual Nature of Type I and Type II Interferons. Front. Immunol. 9:2061 (2018).

4. Casanova, J.L., Su, H.C., et al. A Global Effort to Define the Human Genetics of Protective Immunity to SARSCoV-2 Infection. Cell 181, 1194-1199 (2020)

5. Casanova, J.L., Abel, L. Lethal Infectious Diseases as

Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories. Annual Review of Pathol-

ogy: Mechanisms of Disease 16 (2020)

6. Zhang, SY., Zhang, Q., Casanova, JL. et al. Severe COVID19 in the young and healthy: monogenic inborn errors of immunity?. Nat Rev Immunol 20, 455–456 (2020).

7. Richardson S. et al. Presenting Characteristics,

Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.

JAMA. 323 (20):2052–2059 (2020).

8. Grasselli G. et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2

Admitted to ICUs of the Lombardy Region, Italy. JAMA. 323 (16):1574–1581 (2020).

9. Takahashi, T., Ellingson, M.K., Wong, P. et al. Sex dif-

ferences in immune responses that underlie COVID-19 disease outcomes. Nature (2020).

10. Meffre, E., Iwasaki, A. Interferon deficiency can lead to severe COVID. Nature (2020)

11. COVID Human Genetic Effort: https://www.covidhge.com/

12. Genetic Factors Contributing to the Severity of

COVID-19 https://www.annualreviews.org/shot-of-

Recent studies show that certain immune defects could signal a more severe prognosis.

December 2020

science/event/covid-vulnerability-live-panel

E D UA RD O PA RR A / E UR O PA P R ESS VI A G ET T Y I M AG E)

immune biology researcher and the associate director of the Hudson Institute of Medical Research, was surprised by the frequency of the defects found in the studies. “It was very surprising because it was much, much more prevalent than what you would normally see in other susceptibilities to infections,” says Hertzog, who was not involved in either study. “This signals that there might be a lot more similar genetic defects yet to be found. There are dozens more genes involved in interferon production and action, so this could be the tip of the iceberg.”

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