Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Baby with Rare, Incurable Disease is First to Receive Personalised Gene Therapy

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NIH-supported gene-editing platform lays groundwork to rapidly develop treatments for other rare genetic diseases.

Photo by Sangharsh Lohakare on Unsplash

A research team supported by the National Institutes of Health (NIH) has developed and safely delivered a personalised gene editing therapy to treat an infant with a life-threatening, incurable genetic disease. The infant, who was diagnosed with the rare condition carbamoyl phosphate synthetase 1 (CPS1) deficiency shortly after birth, has responded positively to the treatment.

The process, from diagnosis to treatment, took only six months and marks the first time the technology has been successfully deployed to treat a human patient. The technology used in this study was developed using a platform that could be tweaked to treat a wide range of genetic disorders and opens the possibility of creating personalised treatments in other parts of the body.

A team of researchers at the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn) developed the customised therapy using the gene-editing platform CRISPR. They corrected a specific gene mutation in the baby’s liver cells that led to the disorder. CRISPR is an advanced gene editing technology that enables precise changes to DNA inside living cells. This is the first known case of a personalised CRISPR-based medicine administered to a single patient and was carefully designed to target non-reproductive cells so changes would only affect the patient.

“As a platform, gene editing – built on reusable components and rapid customisation – promises a new era of precision medicine for hundreds of rare diseases, bringing life-changing therapies to patients when timing matters most: Early, fast, and tailored to the individual,” said Joni L. Rutter, Ph.D., director of NIH’s National Center for Advancing Translational Sciences (NCATS).

CPS1 deficiency is characterized by an inability to fully break down byproducts from protein metabolism in the liver, causing ammonia to build up to toxic levels in the body. It can cause severe damage to the brain and liver. Treatment includes a low protein diet until the child is old enough for a liver transplant. However, in this waiting period there is a risk of rapid organ failure due to stressors such as infection, trauma, or dehydration. High levels of ammonia can cause coma, brain swelling, and may be fatal or cause permanent brain damage.

The child initially received a very low dose of the therapy at six months of age, then a higher dose later. The research team saw signs that the therapy was effective almost from the start. The six-month old began taking in more protein in the diet, and the care team could reduce the medicine needed to keep ammonia levels low in the body. Another telling sign of the child’s improvement to date came after the child caught a cold, and later, had to deal with a gastrointestinal illness. Normally, such infections for a child in this condition could be extremely dangerous, especially with the possibility of ammonia reaching dangerous levels in the brain.

“We knew the method used to deliver the gene-editing machinery to the baby’s liver cells allowed us to give the treatment repeatedly. That meant we could start with a low dose that we were sure was safe,” said CHOP pediatrician Rebecca Ahrens-Nicklas, MD, PhD.

“We were very concerned when the baby got sick, but the baby just shrugged the illness off,” said Penn geneticist and first author Kiran Musunuru, MD, PhD. For now, much work remains, but the researchers are cautiously optimistic about the baby’s progress.

The scientists announced their work at the American Society of Gene & Cell Therapy Meeting on May 15th and described the study in The New England Journal of Medicine.

Source: NIH/Office of the Director

Categories : Diseases, Syndromes and ConditionsTags :

Semaglutide Treats Liver Disease in Two Thirds of Patients

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Human liver. Credit: NIH

Results from the ESSENCE phase 3 clinical trial published in the New England Journal of Medicine shows that treating patients with semaglutide can halt and even reverse the disease.

The placebo-controlled outcome trial of participants with a life-threatening form of liver disease known as Metabolic dysfunction associated steatohepatitis (MASH) was conducted at 253 clinical sites across 37 countries around the world. This is the first regulatory-level trial showing the benefit of semaglutide for people with MASH.

The trial is led by two Chief Investigators, Professor Philip Newsome at King’s College London and Arun Sanyal at the VCU School of Medicine, United States, and funded by Novo Nordisk.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a long-lasting liver condition caused by having too much fat in the liver. MASH is a more severe form of MASLD. It is closely linked with obesity as well as conditions such as type 2 diabetes and heart and circulatory disease. Over time, the build-up of fat in the liver can lead to inflammation, liver fibrosis, cirrhosis and liver cancer. MASLD affects 1 in 5 people in the UK but there are no medicines licensed to specifically treat the disease.

Researchers chose to investigate semaglutide as a potential treatment because this class of drug helps reduce fat and liver scarring for people with MASH. Previous smaller but positive studies by Professor Newsome, published in the Lancet and NEJM, had shown using semaglutide as a treatment for MASH would have benefit for these patients.

Between May 27, 2021 and April 18, 2023, 800 participants were randomly assigned to receive once-weekly injection of 2.4milligrams of semaglutide or placebo, alongside lifestyle counselling. More than half of participants had type 2 diabetes and approximately three-quarters were living with obesity.

Results from the ESSENCE trials after 72 weeks of treatment found 62.9% of participants experienced a reduction in steatohepatitis (inflammation of the liver with fat accumulation in the liver) versus 34.3% for participants who took the placebo. The results also show 36.8% of the semaglutide group had improvements of their liver fibrosis versus 22.4% in the placebo group. Researchers also found other benefits. Those receiving semaglutide also saw improvements in liver enzymes and other blood measures of liver fibrosis, as well as 10.5% weight loss. Gastrointestinal adverse events were more common in the semaglutide group, such as nausea, diarrhoea, constipation, and vomiting.

I’ve been working with GLP-1 treatments for sixteen years and these results are hugely exciting. MASLD is a growing problem worldwide and this trial will provide real hope for patients with MASH. While these results must be treated with caution, the analysis shows semaglutide can be an effective tool to treat this advanced liver disease.

Professor Philip Newsome, Director of the Roger Williams Institute of Liver Studies

The research team will follow close to 1200 participants from 37 countries for up to five years to gather data on semaglutide’s impact on long-term liver complications.

Source: King’s College London

Categories : Diseases, Syndromes and Conditions PaediatricsTags :

Weaker Immune Response to Viruses in Children with Mitochondrial Disorders

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Credit: NIH

In a new study, National Institutes of Health (NIH) researchers found that altered B cell function in children with mitochondrial disorders led to a weaker and less diverse antibody response to viral infections. The study, published in Frontiers in Immunology, was led by researchers at the National Human Genome Research Institute (NHGRI), who analysed the gene activities of immune cells in children with mitochondrial disorders and found that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress.

“Our work is one of the first examples to study how B cells are affected in mitochondrial disease by looking at human patients,” said Eliza Gordon-Lipkin, MD, assistant research physician in NHGRI’s Metabolism, Infection and Immunity Section and co-first author of the paper.

Mitochondria are important components of nearly every cell in the body because they convert food and oxygen into energy. Genomic variants in more than 350 genes have been linked to mitochondrial disorders with varied symptoms depending on which cells are affected.

“For children with mitochondrial disorders, infections can be life threatening or they can worsen the progression of their disorder,” said Peter McGuire, MBBCh, NHGRI investigator, head of the Metabolism, Infection and Immunity Section and senior author of the study. “We wanted to understand how immune cells differ in these patients and how that influences their response to infections.”

Around 1 in 5000 people worldwide have a mitochondrial disorder. Examples of mitochondrial disorders are Leigh’s syndrome, which primarily affects the nervous system, and Kearns-Sayre syndrome, which primarily affects the eyes and heart.

While mitochondrial disorders are known to affect organs such as the heart, liver, and brain, less is known how they affect the immune system.

Using a genomic technique called single-cell RNA sequencing, which analyzes gene activity in different cell types, researchers studied immune cells found in blood. These cells include different types of white blood cells that help the body fight infections. During stressful conditions, these cells produce a microRNA called mir4485. MicroRNAs are small strings of RNA that help control when and where genes are turned on and off. mir4485 controls cellular pathways that help cells survive.

“We think that B cells in these patients undergo cellular stress when they turn into plasma cells and produce antibodies, and these B cells then try to survive by producing the microRNA to cope,” said Dr. McGuire. “But the B cells are too fragile due to their limited energy, so they are unable to survive the stressful conditions.”

Researchers used a technique called VirScan to look at all past viral infections, assess how well the immune system fought those infections and see the effects of B cells and plasma cells on antibody production. With a weaker antibody response, the immune systems in children with mitochondrial disorders are less able to recognize and neutralize invading viruses and clear infections.

Researchers aim to use the results of this study to guide future treatment of patients with mitochondrial disorders, noting that more translational studies are needed in this research area.

Source: National Institutes of Health

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Mpox Could Become a Serious Global Threat, Scientists Warn

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Mpox (monkeypox) virus. Source: NIH

Mpox has the potential to become a significant global health threat if taken too lightly, according to scientists at the University of Surrey. In a letter published in Nature Medicine, researchers highlight how mpox — traditionally spread from animals to humans — is now showing clear signs of sustained human-to-human transmission.

Mpox is a viral infection caused by a virus that belongs to the same family as smallpox.

The virus can cause a painful rash, fever, and swollen glands and, in some cases, lead to more serious illness.

Mpox usually spreads through close contact with an infected person or animal.

Carlos Maluquer de Motes, Reader in Molecular Virology at the University of Surrey, said:

“The most recent outbreaks show that intimate contact is now a significant way the virus spreads. That shift in how it’s transmitted is leading to longer transmission chains and lasting outbreaks.”

The article notes that this change coincided with the rapid spread of clade IIb (a clade is a group of viruses that share a common ancestor) mpox viruses, but different clade I variants are now on the rise too.

Researchers are also concerned because clade I viruses are thought to be more aggressive.

These viruses appear to be accumulating specific genetic mutations — driven by enzymes in the human body — that may be changing viral properties, so the longer these viruses circulate amongst us, the higher the chances these mutations help mpox adapt to humans.

Although mpox was once mainly seen in Central Africa, the virus caused an outbreak worldwide in 2022 and is now causing outbreaks in multiple sub-Saharan countries.

While it currently affects adults the most, the researchers stress that it has the potential to spread among other groups, including children, a group at greater risk of serious illness — although sustained transmission in children has not yet been reported.

Dr Maluquer de Motes added:

“Mpox control has to climb up the global health agenda. We have limited diagnostic tools and even fewer antiviral treatments. We urgently need better surveillance and local or regional capacity to produce what we need — otherwise, we are at risk of future epidemics.”

Unlike smallpox, mpox has an animal reservoir, meaning it can’t be fully eradicated. The authors warn that unless international action is taken now — including investment in point-of-care testing and new treatments — mpox will continue to re-emerge and threaten global health.

Source: University of Surrey

Categories : Diseases, Syndromes and Conditions NeurologyTags :

VZV Reactivation Is Driving CNS Infections

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Varicella zoster vires (VZV). Credit: NIH/NIAID

The varicella zoster virus (VZV), an infectious virus from the herpes virus family, is primarily known to cause varicella in children and shingles in adults. But lately, this virus has also been reported to trigger severe complications like central nervous system (CNS) infections. Researchers from Fujita Health University, Japan, conducted a comprehensive study spanning 10 years (2013–2022), to identify the VZV-related infections affecting the CNS. Their study reveals a marked increase in adult VZV-related CNS infections, particularly since 2019. The findings were published in the journal Emerging Infectious Diseases.

The study was led by Professor Tetsushi Yoshikawa, along with Hiroki Miura and Ayami Yoshikane from the Department of Pediatrics, Fujita Health University School of Medicine. The researchers analysed cerebrospinal fluid samples of 615 adult patients with suspected CNS infections. VZV DNA was most frequently detected in these patients, with its presence in 10.2% of the cases, and aseptic meningitis being the most common infection.

The data from 2019 to 2022 revealed that there was a noticeable rise in VZV DNA-positive cases, forming a distinct temporal cluster during this period. Professor Yoshikawa highlighted the results of the patient demographic analysis, reporting that “the proportion of aseptic meningitis increased from 50% between 2013 and 2018 to 86.8% between 2019 and 2022.” He further adds, “Similar to the rise in herpes zoster cases through VZV reactivation in the elderly, we believe this increase is also linked to VZV reactivation.”

The universal varicella vaccination, introduced in Japan in 2014, has reduced the natural booster effects from re-exposure to the virus. This potentially accelerates the immunity decline, leading to VZV reactivation, especially in cases like shingles. The researchers highlight the connection between the vaccination and the current scenario, saying, “The increase in VZV-induced CNS infections coincides with changes in varicella vaccination programs and emphasises the need for better preventive strategies.”

Furthermore, the researchers examined trends in VZV-induced CNS infection throughout the observation period using Kulldorff’s circular spatial scan statistics. As a result, it was confirmed that there was an accumulation of VZV-related CNS infections from 2019 to 2022. Although no direct causation was established, six patients did develop CNS infections after receiving COVID-19 vaccines.

“Further studies are needed to understand these interactions,” Yoshikawa notes. None of the eligible patients in this study had received the zoster vaccine, which was introduced in Japan in 2016. Increasing the number of VZV-related CNS infections underscores the importance of zoster vaccination in adults.

The research team stresses the broader implications of their findings, stating that the reactivation of VZV in the CNS is linked to an increased risk of dementia, including Alzheimer’s disease. They hypothesize, “If the prevention of VZV-related aseptic meningitis through herpes zoster vaccination is possible, these vaccinations could play a pivotal role in mitigating these risks of dementia.”

To address the growing concern, the research team advocates expanding public health initiatives to promote zoster vaccination among at-risk populations. “Our research underscores the necessity of proactive measures to prevent not just shingles, but also severe neurological complications associated with VZV,” explains Yoshikawa.

With the rise of the aging population and CNS infections, the study calls for urgent action to evaluate and implement comprehensive vaccination strategies to prevent CNS infections in the future.

Source: Fujita Health University

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Interventions to Eliminate Vertical Transmission of Hepatitis B in Africa

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Photo by William Fortunato on Pexels

Researchers at the University of Liverpool have conducted a large-scale analysis that sheds light on the critical steps needed to combat the vertical transmission of chronic hepatitis B virus (HBV) in Africa.

Almost two thirds of all new hepatitis B infections globally occur in Africa. The newly published paper in The Lancet Global Health shows the importance of giving the hepatitis B birth dose vaccine (HepB-BD) within 24 hours of birth, and the potential impact of providing antiviral therapy (antiviral prophylaxis) to mothers during pregnancy. The study estimates for the first time that hepatitis B vertical transmission (passed from mother to baby) could be eliminated in Africa, with increased coverage of these two key interventions.

Chronic hepatitis B is the leading cause of liver cancer and liver cirrhosis in Africa and deaths are rising. Most cases of liver cancer are diagnosed late and are associated with a very poor prognosis in the region. Vertical transmission is one of the commonest routes of infection and is associated with an increased lifetime risk of severe liver disease.

Dr Alexander Stockdale, Senior Clinical Lecturer at the University’s Department of Clinical Infection, Microbiology and Immunology, based at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, together with Dr Nicholas Riches at Liverpool School of Tropical Medicine, led the comprehensive analysis of more than 113 individual studies which reported on the prevalence of hepatitis B in more than 190 000 women and investigated rates of vertical transmission.

The World Health Organization (WHO) African region faces a significant burden, accounting for 63% of the global total of new infections. This amounted to 771 000 new infections and 272 000 deaths in 2022. Among children under 5 years, the prevalence of HBV stands at 2.5% in the WHO African region – the highest globally.

Dr Alexander Stockdale said: “This study makes the case for investment in birth dose vaccination and maternal antiviral prophylaxis, in view of the exciting potential for elimination of vertical transmission in the WHO African region in our lifetime. Vertical transmission is a key route of new hepatitis B infections. Due to limited implementation of interventions, elimination targets are not currently being met. We project that expanding HepB-BD vaccination coverage to 90% could reduce transmission events by 44%, and adding maternal antiviral prophylaxis for 90% of eligible women could further reduce transmission by 86% and achieve the WHO targets for elimination.”

Dr Stockdale and colleagues have also recently been awarded £3million funding from the National Institute of Health and Care Research to conduct implementation research in Malawi and The Gambia. The NIHR Global Health Research Grant will allow researchers in Malawi, led by Dr Stockdale and in The Gambia, led by Professor Maud Lemoine and Dr Gibril Ndow, to evaluate the effectiveness, safety, feasibility and cost-effectiveness of giving antiviral treatment (tenofovir) to all pregnant women living with chronic hepatitis B to prevent transmission. This study will provide vital evidence on the potential impact of this strategy to guide public health policy in Africa, which has been recognised as a key knowledge gap by the WHO in the 2024 hepatitis B guidelines.

Source: University of Liverpool

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Cold Sore Discovery Reveals an Unexpected Trigger for Flare-ups

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Photo by Cottonbro on Pexels

Scientists have a new target to prevent cold sores after University of Virginia researchers discovered an unexpected way the herpes virus re-activates in the body. The finding, published in PNAS, could also have important implications for genital herpes caused by the same virus.

The discovery from UVA’s Anna Cliffe, PhD, and colleagues seems to defy common sense. She and her team found that the slumbering herpes virus will make a protein to trigger the body’s immune response as part of its escape from dormancy. You’d think this would be bad for the virus – that activating the body’s antiviral defences would be like poking a bear. But, instead, it’s the opposite: The virus hijacks the antiviral process in infected neurons to make the type of comeback nobody wants.

“Our findings identify the first viral protein required for herpes simplex virus to wake up from dormancy, and, surprisingly, this protein does so by triggering responses that should act against the virus,” said Cliffe of UVA’s Department of Microbiology, Immunology and Cancer Biology. “This is important because it gives us new ways to potentially prevent the virus from waking up and activating immune responses in the nervous system that could have negative consequences in the long term.”

Herpes Simplex Virus-Associated Disease

Cold sores are caused primarily by herpes simplex virus 1 (HSV-1), one of two forms of the herpes virus. HSV-1 is very contagious, and worldwide more than 60% of people under 50 (more than 3.8 billion) have been infected, the World Health Organization estimates.

In addition to causing cold sores, herpes simplex virus 1 can also cause genital herpes, a condition most often associated with HSV-1’s cousin, herpes simplex virus 2. Now, however, there are more new cases of genital herpes in the United States caused by HSV-1 than HSV-2. Notably, the UVA researchers found that herpes simplex virus 2 also makes this same protein and may use a similar mechanism to reactivate. So UVA’s new discovery may also lead to new treatments for genital herpes. 

In addition to cold sores and genital herpes, HSV-1 can also cause viral encephalitis (brain inflammation) and has been linked to the development of Alzheimer’s disease.

Once HSV-1 makes its way into our bodies, it stays forever. Our immune systems can send it into hiding, allowing infected people to be symptom free. But stress, other infections and even sunburns are known to cause it to flare. UVA’s new discovery adds another, surprising way it can spring back into action.

The researchers found that while the virus can make a protein called UL12.5 to reactivate, the protein was not needed in the presence of another infection. The scientists believe this is because the infections trigger certain “sensing pathways” that act as the home security system for neurons. Detection of a pathogen alone may be sufficient to trigger the herpes virus to begin replicating, the scientists believe, even in instances of “abortive infections” – when the immune system contains the new pathogen before it can replicate.

“We were surprised to find that HSV-1 doesn’t just passively wait for the right conditions to reactivate – it actively senses danger and takes control of the process,” researcher Patryk Krakowiak said. “Our findings suggest that the virus may be using immune signals as a way to detect cellular stress – whether from neuron damage, infections or other threats – as a cue to escape its host and find a new one.” 

With the new understanding of how herpes flares can be triggered, scientists may be able to target the protein to prevent them, the researchers say. 

“We are now following up on this work to investigate how the virus is hijacking this response and testing inhibitors of UL12.5 function,” Cliffe said. “Currently, there are no therapies that can prevent the virus from waking up from dormancy, and this stage was thought to only use host proteins. Developing therapies that specifically act on a viral protein is an attractive approach that will likely have fewer side effects than targeting a host protein.” 

Source: University of Virginia Health System

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Scans of Viking Skulls Reveal a Harsh Life of Disease

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Photo by Gioele Fazzeri on Unsplash

Sweden’s Viking Age population appears to have suffered from severe oral and maxillofacial disease, sinus and ear infections, osteoarthritis, and much more. This is shown in a study from the University of Gothenburg in which Viking skulls were examined using modern X-ray techniques.

About a year ago saw the publication of research based on the examination of a large number of teeth from the Viking Age population of Varnhem, known for its thousands of ancient graves and excavations of well-preserved skeletons.

Now, odontologists at the University of Gothenburg have taken this research further, looking at not only teeth but also entire skulls, by using modern computed tomography, also known as CT scans.

The results, presented in British Dental Journal Open, suggest that the 15 individuals whose skulls were examined suffered from a broad range of diseases. The CT scans show pathological bone growths in the cranium and jawbone, revealing infections and other conditions.

Detailed image analysis

Several individuals showed signs of having suffered from sinus or ear infections that left traces in the adjacent bone structures. Signs of osteoarthritis and various dental diseases were also found. All the skulls came from adults who died between 20 and 60 years of age.

The study lead, Carolina Bertilsson, is an assistant researcher at the University of Gothenburg and a dentist within Sweden’s Public Dental Service. The study was performed with specialists in dental radiology at the University of Gothenburg and an archaeologist from Västergötlands museum.

About a year ago saw the publication of research based on the examination of a large number of teeth from the Viking Age population of Varnhem in the Swedish province of Västergötland. Varnhem is known for its thousands of ancient graves and excavations of well-preserved skeletons.

Now, odontologists at the University of Gothenburg have taken this research further, looking at not only teeth but also entire skulls, by using modern computed tomography, also known as CT scans.

The results presented in British Dental Journal Open suggest that the 15 individuals whose skulls were examined suffered from a broad range of diseases. The CT scans show pathological bone growths in the cranium and jawbone, revealing infections and other conditions.

Detailed image analysis

Several individuals showed signs of having suffered from sinus or ear infections that left traces in the adjacent bone structures. Signs of osteoarthritis and various dental diseases were also found. All the skulls came from adults who died between 20 and 60 years of age.

The study lead, Carolina Bertilsson, is an assistant researcher at the University of Gothenburg and a dentist within Sweden’s Public Dental Service. The study was performed with specialists in dental radiology at the University of Gothenburg and an archaeologist from Västergötlands museum.

“There was much to look at. We found many signs of disease in these individuals. Exactly why we don’t know. While we can’t study the damage in the soft tissue because it’s no longer there, we can see the traces left in the skeletal structures,” says Carolina Bertilsson, and continues:

“The results of the study provide greater understanding of these people’s health and wellbeing. Everyone knows what it’s like to have pain somewhere, you can get quite desperate for help. But back then, they didn’t have the medical and dental care we do, or the kind of pain relief – and antibiotics – we now have. If you developed an infection, it could stick around for a long time.”

The study is described as a pilot study. One important aspect was to test CT as a method for future and more extensive studies.

“Very many of today’s archaeological methods are invasive, with the need to remove bone or other tissue for analysis. This way, we can keep the remains completely intact yet still extract a great deal of information,” says Carolina Bertilsson.

Source: University of Gothenburg

Categories : Diseases, Syndromes and Conditions EbolaTags :

Causes of Fevers of Unknown Origin in sub-Saharan Africa

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Ebola on a cell. Credit: NIH/NIAID

A new retrospective, laboratory-based observational study provides detailed insights into the causes of fevers of unknown origin in sub-Saharan Africa. Researchers examined 550 patients from Guinea who developed a persistent fever at the time of the major Ebola outbreak in 2014, but tested negative for the Ebola virus on site. The goal was to use modern diagnostic methods to better understand the underlying infectious diseases. The study is published in The Journal of Infectious Diseases.

Fever is a common symptom of many diseases, including infections, cancer, and autoimmune diseases. When the cause of a persistent fever remains unclear despite extensive investigation, it is referred to as fever of unknown origin (FUO). Approximately half of all FUO cases worldwide remain undiagnosed. In sub-Saharan Africa, malaria is often suspected and treated without laboratory confirmation or further investigation. However, 90 million pediatric hospitalisations per year in sub-Saharan Africa are due to fevers not caused by malaria but by other infections, often due to various bacteria and viruses.

A research team from the German Center for Infection Research (DZIF) and Charité – Universitätsmedizin Berlin, in collaboration with scientists from Guinea and Slovakia, conducted a retrospective observational study to thoroughly investigate the pathogen diversity of patients from Guinea with fever of unknown cause during a major Ebola outbreak in 2014. They combined epidemiological, phylogenetic, molecular, serological and clinical data.

Using serologic tests, PCR and high-throughput sequencing, at least one pathogen was detected in 275 of 550 patients. In addition to the expected malaria parasite Plasmodium, pathogenic bacteria such as Salmonella and Klebsiella strains were detected in almost one fifth of the patients. The frequent detection of resistance to so-called first-line antibiotics in the samples examined and the high rate of co-infections were also worrying: One in five infected patients had multiple infections at the same time. Pathogens causing malaria and bacterial sepsis were particularly common, occurring together in 12% of adults and 12.5% of children.

Infections with highly pathogenic viruses were also common: Yellow fever, Lassa and Ebola viruses were detected by RT-PCR in about six percent of patients. Of particular note was the detection of infection with Orungo virus, a little-known pathogen for which there are no robust assays. Using immunofluorescence assays, the researchers also identified IgM antibodies against several viruses, including Dengue, West Nile and Crimean-Congo hemorrhagic fever viruses, in patients who were PCR-negative.

“In Africa, febrile illnesses of unknown cause are often recognized and treated as malaria without further diagnosis. In our study, we were able to detect a pathogen in about half of all patients with FUO, including bacterial pathogens that cause sepsis, haemorrhagic fever viruses including Ebola, and, as expected, various strains of the malaria parasite Plasmodium,” explains the study’s last author Prof. Jan Felix Drexler.

The findings underscore the urgent need to further strengthen laboratory capacity in sub-Saharan Africa. Early detection of the infectious causes of FUO is critical for patient care, effective response to outbreaks, and development of regionally appropriate diagnostics.

“Our results show that regionally adapted treatment regimens should be discussed, that quality control in the context of outbreaks needs to be strengthened, and that knowledge of the pathogen spectrum can guide targeted strengthening of regional laboratories and translational research in the sense of point-of-care tests,” Drexler summarises the results of the study.

Source: German Center for Infection Research

Categories : Diseases, Syndromes and Conditions PaediatricsTags :

High Uric Acid Levels Linked to Mortality in Children with Severe Malaria

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Red Blood Cell Infected with Malaria Parasites Colourised scanning electron micrograph of red blood cell infected with malaria parasites (teal). The small bumps on the infected cell show how the parasite remodels its host cell by forming protrusions called ‘knobs’ on the surface, enabling it to avoid destruction and cause inflammation. Uninfected cells (red) have smoother surfaces. Credit: NIAID

Indiana University School of Medicine researchers and their collaborators in Uganda at the Makerere University School of Medicine have uncovered a significant connection between elevated uric acid levels and life-threatening outcomes in children with severe malaria.

Published in Nature Medicine, the study identified hyperuricaemia – high uric acid levels – as a potential contributor to increased mortality and long-term neurodevelopmental challenges in children with severe malaria. These findings open the door to future research that could improve treatment strategies for children affected by severe malaria, a disease caused by mosquito-transmitted parasites and a leading cause of death in African children.

“Our findings show that hyperuricemia is strongly associated with death in the hospital and after discharge and with long-term cognitive impairment in children with severe malaria,” said Chandy C. John, MD, paediatrics professor at IU School of Medicine, who co-led the study. “We also showed several mechanisms by which hyperuricaemia may lead to these outcomes, suggesting that hyperuricaemia is not just associated with bad outcomes but may contribute to them.”  

The researchers analysed data from two independent groups of children with severe malaria in Uganda and found that 25% had hyperuricaemia. This condition is caused by excess uric acid, which is a harmful body waste substance found in blood. The primary drivers of hyperuricaemia in study participants were broken-down infected red blood cells and kidney injury, which reduces the body’s ability to get rid of the extra uric acid. 

In the study, hyperuricemia was linked to four negative outcomes in children with severe malaria: serious health complications like coma and anaemia, a higher risk of death during hospitalisation, a higher risk of death after discharge from the hospital, and long-term cognitive impairment in survivors.  

The study also revealed that children with hyperuricemia had more harmful gut bacteria, which can cross the injured gut lining and cause sepsis. Together, these findings highlight a need for clinical trials to test the effectiveness of uric acid-lowering medications as an additional treatment for severe malaria. 

“Additional studies are needed to determine whether lowering uric acid in children with severe malaria might reduce hospital deaths, post-discharge deaths and long-term cognitive impairment,” said Andrea Conroy, PhD, associate professor of paediatrics at the IU School of Medicine and co-leader of the study. “Our hope is that these studies will provide new insights and potentially lead to improved treatments that save lives.” 

This research builds on the team’s recent discovery of partial resistance to the primary treatment for malaria in African children with severe malaria. Both studies underscore the importance of prioritizing new strategies to combat malaria, which affected 263 million people and caused nearly 600,000 deaths worldwide in 2023.

Source: Indiana University