Tag: epidemiology

Categories : HIV Respiratory DiseasesTags :

What we can Learn about TB at the Autopsy Table

On By ModernMedia
Credit: Scientific Animations CC4.0

By Tiyese Jeranji for Spotlight

In addition to shedding light on what people actually die of, autopsies can also play an important role in helping us to better understand disease. Tiyese Jeranji unpacks tuberculosis-related autopsy research in the Western Cape and delves into some of the fascinating complexities of this branch of TB research.

Figuring out how many people in South Africa die every year of tuberculosis (TB) is not straight-forward. On the one hand, Stats SA’s frequent mortality reports put the number at under 30 000, on the other hand, the World Health Organization (WHO) estimates that it is over 50 000.

While this may at first glance seem like a large discrepancy, there is a simple explanation. The Stats SA figures are based on what is written on death notifications, and these notifications very often do not tell the full story of what a person died of. The WHO estimate, is derived using mathematical modelling that triangulates estimates based on several data sources.

Looking at the numbers from studies that determine the cause of death (or what people actually died of) is one of the ways we know that relying on death notifications result in an undercount of TB deaths. Such autopsy studies have consistently found that many people had undiagnosed TB at the time of death and that the undiagnosed TB was often the actual cause of death.

One review study published in the journal AIDS concluded that “in resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths” and that “almost half of this disease remains undiagnosed at the time of death”. According to WHO figures, of the estimated 280 000 people who fell ill with TB in South Africa in 2022, over 65 000 were not diagnosed.

Importance of autopsy research

Dr Muhammad Osman, Academic Portfolio Lead and Senior Lecturer: Public Health at the University of Greenwich, tells Spotlight that it is important to do TB autopsy studies because it enables us to identify TB that was not diagnosed during life – and this helps us understand the true burden of the disease.

Osman says identifying TB at autopsies has significant benefits. He says by overlaying health seeking behaviour (how people visit clinics), we can identify missed opportunities for TB screening and design interventions to improve screening for TB. “We could trace family contacts of the deceased and offer TB screening and prevention. This is not taking place at present,” he says.

Osman and his colleagues published a paper in the International Journal of Infectious diseases in 2021  looking at TB in people with sudden unexpected death (SUD) in Cape Town. They found that active TB was identified at post-mortems in 6.2% of the 770 cases they studied. More strikingly, in around 92% of those cases the TB had not been diagnosed while the person was alive.

Osman says that these days there is an increasing awareness of undiagnosed and untreated TB. He points out that new interventions to improve TB testing and diagnosis have been implemented such as targeted universal testing — an approach by which people who do not have any TB symptoms, but who are considered to be at high risk of TB, are routinely offered TB tests.

He says these days healthcare worker risk is considered more carefully and he stresses the importance of protecting forensic and pathology teams. (Forensics focuses on determining the cause and manner of death while  pathology  is the study and diagnosis of disease through examination of tissue, cells, autopsies, and so on.)

Closing the gaps

Osman says their study also identified a gap between the pathology services and access to routine health service records. “We thought that this is an essential gap to close – the forensic/pathology services need access to routine health service. For a limited number of these deaths we were able to match their records to the public health clinic and hospital records – and many of them had contact with the health services in the six months before death,” he says.

“If forensic pathologists are given full access to the health records, they would know the timing of previous TB and the treatment outcomes of those episodes. The lung changes seen with TB are different in the case of active TB and healed/recovered TB. There are well documented macroscopic (what’s is seen by the examination) and microscopic (seen through histology and microbiology) findings,” says Osman.

A complex disease

The study of TB is complicated by the fact that TB can occur at several stages on a continuum and can impact several different parts of the body.

Professor Threnesan Naidoo, research pathologist at the African Health Research Institute (AHRI), tells Spotlight that when people think of TB, they usually think of the person who’s been coughing for a few months, loss of weight, loss of appetite, having night sweats, and maybe coughing up some blood. “But there’s a journey to that point and then generally beyond that point, and clinically, there’s a continuum of the disease. We refer to it as latent disease, subclinical, active and then healed TB,” he says. It is an area in which things are changing fast – a paper published in the Lancet medical journal last week proposed dividing TB into five stages.

Naidoo says autopsies provide an opportunity to study TB at different stages (latent, subclinical, active, healed) especially when someone with TB dies of another cause. He says they  can encounter people at any stage along the TB continuum because at any point someone could be shot, stabbed, or involved in a motor vehicle accident. “You (pathologist) have a unique opportunity to study the effect of TB on cells and tissue physically under a microscope and not through imaging (x-ray),” Naidoo says.

Autopsies also presents the opportunity to look at TB disease not only in the lung, but also the brain, thyroid gland, kidney or urinary system since TB has the capacity to spread everywhere, explains Naidoo.

“Autopsy gives you the opportunity to study TB everywhere,” he says. “Clinically (when someone is alive), you don’t  go about investigating the entire body. Neither is it practical nor feasible or safe. But [with an] autopsy you’re examining the entire body anyway. We study TB in totality,” he says.

How it is done

The standard manner of doing an autopsy involves a thorough examination of the body. Naidoo explains that the process starts with an external examination to document injuries, marks, and other physical characteristics that are visible. The internal examination involves dissecting organs, tissues, and body cavities to identify any abnormalities or signs of disease. Samples may be taken for further analysis, such as toxicology tests, histological examination, or TB research.

Any findings from the samples, Naidoo notes, must be interpreted taking into account changes that occur in a dead body. “[In] the living, you know, it’s a living person and they’re able to do things and you’re able to see things on imaging (X-Ray), but in the dead you have to account for the fact that the person has now demised and certain changes occur after death.”

Autopsy study at UCT

An ongoing study at the University of Cape Town is exploring the role of lymph nodes in the spread or containment of TB disease by looking at tissue of the deceased.

Much TB research so far have been done on animals and not on humans, points out Dr Virginie Rozot, research officer at the South African TB Vaccine Initiative (SATVI) and co-principal investigator of the UCT study. “We have great non-human primate and great mice studies that try to underline the mechanism of the  disease progression. However, animal models are not a true reflection of what happens in humans.

“For the longest time in these human studies, most studies have been done in the blood and what is happening in the blood has been taken to correlate with what is happening in the lung.”

In short, autopsies allow researchers to look directly at lung, brain and other tissue in a way that simply isn’t feasible in living people.

“So the only way you can actually access tissues is to do post mortem studies. Post mortem studies have been happening since the beginning of last century. And they were like fantastic studies, but the tools were not the same as we have today.  I think that should come back to the front of the scene of research because then you can ask all the questions we’ve been trying to answer on what is happening in the tissue by looking into the blood,” she says. “Autopsy allows us to study the exact part we want to study not just the blood.”

Collecting samples

In collaboration with the Western Cape Forensic Pathology Service, UCT has created  a postmortem sample collection platform to help with TB research. By leveraging the Inquest Act of 1959, which states that people that die of unnatural causes  must undergo a medico-legal investigation to determine the cause of death, Rozot and her team come in to conduct a post-mortem to get their samples. They aim to do the post-mortem in less than 24 hours after death.

Since starting this study about eight months ago, they have done 125 autopsies , with a consent rate of 64%. “I think our consent rate is incredible. We are still putting together our findings to determine how many cases of TB we have found so far by looking at autopsies,” says Rozot.

Representative samples

Dr Laura Taylor, forensic pathologist at the Western Cape Forensic Pathology Services, says the bodies that they look at, in line with the Inquest Act relating to unnatural deaths, are representative of people in South Africa. “However, they are not exactly representative of the entire South African population because there are certain socio economic groups that are more likely to die of unnatural deaths due to increased prevalence of trauma and violence in their communities,” she says.

Because there is no central database, Taylor couldn’t say how many cases of TB they find among the deceased. “[T]here are autopsy records or reports which are written for each case, but there is no central database for TB specifically detected [through] autopsy,” she says.

Forensic autopsy and other diseases

Rozot and Naidoo share the view that, if done well, TB autopsy studies can help shed light on other diseases.

The value of this information is that people dying with or from TB will also have any of  the other conditions such as hypertension, HIV, and diabetes, Naidoo says.

“You can work out all those variables… [people] don’t just come with diabetes, the diabetes changes the face of TB, HIV changes the face of TB and TB changes the face of those diseases as well. So, the complexity of it becomes something that we need to pay attention to, and look at all the common variables, like the association of TB and HIV is a big one. So studies might look at HIV infection and how it may affect TB and vice versa. Same with diabetes, hypertension, any of the other non-communicable diseases as well,” he concludes.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight

Categories : COVIDTags :

How Will SARS-COV-2 Continue to Evolve?

On By ModernMedia
Image from Pixabay

A report in Nature examines why Omicron was such a surprise, and how the possible evolutionary pathways available to SARS-CoV-2 shape future scenarios of the COVID pandemic. 

Currently, Delta and its descendants still dominate worldwide, and they were expected to eventually outcompete the last holdouts. But Omicron has undermined those predictions. “A lot of us were expecting the next weird variant to be a child of Delta, and this is a bit of a wild card,” said Aris Katzourakis, a specialist in viral evolution at the University of Oxford, UK.

The Omicron surge in South Africa suggests that the new variant has a fitness advantage over Delta, said Tom Wenseleers, an evolutionary biologist and biostatistician at the Catholic University of Leuven in Belgium. Omicron has some of the mutations associated with Delta’s high infectivity – but if increased infectivity alone explained its rapid growth, it would mean an R0 (reproduction number) in the 30s, said Wenseleers. “That’s very implausible.”

At present, Omicron appears to have an R0 of 1.36, after its initial surge, based on a continually updated estimate by Louis Rossouw, head of research and analytics at Gen Re. Weneseelers and other researchers instead suspect that Omicron’s rise may be due to its re-infection and vaccine evasion ability.

If Omicron is spreading, in part, because of its ability to evade immunity, it fits in with theoretical predictions about how SARS-CoV-2 is likely to evolve, says Sarah Cobey, an evolutionary biologist at the University of Chicago in Illinois.

As SARS-CoV-2’s infectivity gains start to slow, the virus will maintain its fitness by overcoming immune responses, said Cobey. If mutation halved a vaccine’s transmission blocking ability, this could open up a vast number of hosts. It’s hard to imagine any future infectivity gains providing the same boost.

The evolutionary path towards immune evasion and away from infectivity gains, is common among established respiratory viruses such as influenza, said Adam Kucharski, a mathematical epidemiologist at the London School of Hygiene and Tropical Medicine. “The easiest way for the virus to cause new epidemics is to evade immunity over time. That’s similar to what we see with the seasonal coronaviruses.”

Analysis has shown a wealth of Spike protein mutations that weaken the potency of neutralising antibodies resulting from infection and vaccination. Variants like Beta that have such mutations, have degraded – but not destroyed – vaccine effectiveness particularly against severe disease.

Compared with other variants, Omicron contains many more of these mutations, particularly in the region of spike that recognises host cells. Preliminary analysis from evolutionary biologist Jesse Bloom suggests that these mutations might render some portions of Spike unrecognisable to the antibodies raised by vaccines and previous infection with other strains. But lab experiments and epidemiological studies will be needed to fully appreciate the effects of these mutations.

Evolutionary costs and benefits
Evolving to evade immune responses such as antibodies could also carry some evolutionary costs. A Spike mutation that dodges antibodies might reduce the virus’s ability to recognise and bind to host cells. The receptor-binding region of Spike, the main target for neutralising antibodies. is relatively small, explained Jason McLellan, a structural biologist at the University of Texas at Austin. Thus, the region might tolerate only small changes if it retains its main function of attaching itself to host cells’ ACE2 receptors.

Repeat exposures to different Spike versions, through infection with different virus strains, vaccine updates or both, eventually might build up a wall of immunity that SARS-CoV-2 will have difficulty overcoming. Mutations that overcome some individuals’ immunity might not work on the whole population, and T-cell-mediated immunity, another arm of the immune response, seems to be more resilient to changes in the viral genome.

SARS-CoV-2’s evasion of immunity might be slowed by these constraints, but they are unlikely to stop it, said Bloom. Evidence shows that some antibody-dodging mutations do not carry large evolutionary costs, said McLellan. “The virus will always be able to mutate parts of the Spike.”

A virus in transition
How SARS-CoV-2 evolves in response to immunity has implications for its transition to an endemic virus. There wouldn’t be a steady baseline level of infections, says Kucharski. “A lot of people have a flat horizontal line in their head, which is not what endemic infections do.” Instead, the virus is likely to cause outbreaks and epidemics of varying size, like influenza and most other common respiratory infections do.

To predict what these outbreaks will look like, scientists are investigating how quickly a population becomes newly susceptible to infection, says Kucharski, and whether that happens mostly through viral evolution, waning immune responses, or the birth of new children without immunity to the virus. “My feeling is that small changes that open up a certain fraction of the previously exposed population to reinfection may be the most likely evolutionary trajectory,” said Rambaut.

The best outlook for SARS-CoV-2, but also the least likely, would be for it to follow measles. Lifetime protection results from infection or vaccination and the virus circulates largely on the basis of new births. “Even a virus like measles, which has essentially no ability to evolve to evade immunity, is still around,” said Bloom.

A more likely, but still relatively hopeful, parallel for SARS-CoV-2 is a pathogen called respiratory syncytial virus (RSV). Most people get infected in their first two years of life. RSV is a leading cause of hospitalisation of infants, but most childhood cases are mild. Waning immunity and viral evolution together allow new strains of RSV to sweep across the planet each year, infecting adults in large numbers, but with mild symptoms thanks to childhood exposure. If SARS-CoV-2 follows this path – aided by vaccines that provide strong protection against severe disease – “it becomes essentially a virus of kids,” Rambaut said.

Influenza offers two other scenarios. The influenza A virus, which drives global seasonal influenza epidemics each year, is characterised by the rapid evolution and spread of new variants able to escape the immunity elicited by past strains. The result is seasonal epidemics, propelled largely by spread in adults, who can still develop severe symptoms. Flu jabs reduce disease severity and slow transmission, but influenza A’s fast evolution means the vaccines aren’t always well matched to circulating strains.

But if SARS-CoV-2 evolves to evade immunity more sluggishly, it might come to resemble influenza B. That virus’s slower rate of change, compared with influenza A, means that its transmission is driven largely by infections in children, who have less immunity than adults.

How quickly SARS-CoV-2 evolves in response to immunity will also determine the need for vaccine updates. The current offerings will probably need to be updated at some point, says Bedford. In a preprint5 published in September, his team found signs that SARS-CoV-2 was evolving much faster than seasonal coronaviruses and even outpacing influenza A, whose major circulating form is called H3N2. Bedford expects SARS-CoV-2 to eventually slow down to a steadier state of change. “Whether it’s H3N2-like, where you need to update the vaccine every year or two, or where you need to update the vaccine every five years, or if it’s something worse, I don’t quite know,” he says.

Although other respiratory viruses, including seasonal coronaviruses such as 229E, offer several potential futures for SARS-CoV-2, the virus may go in a different direction entirely, say Rambaut and others. The sky-high circulation of the Delta variant and the rise of Omicron, aided by inequitable vaccine roll-outs to lower-income countries and minimal control measures in certain large developed countries such as the US, offer fertile ground for SARS-CoV-2 to take additional surprising evolutionary leaps.

For instance, a document prepared by a UK government science advisory group in July raised the possibility that SARS-CoV-2 could become more severe or evade current vaccines by recombining with other coronaviruses. Continued circulation in animal reservoirs, such as mink or white-tailed deer, brings more potential for surprising changes, such as immune escape or heightened severity.

It may be that the future of SARS-CoV-2 is still in human hands. Vaccinating as many people as possible, while the jabs are still highly effective, could stop the virus from unlocking changes that drive a new wave. “There may be multiple directions that the virus can go in,” said Rambaut, “and the virus hasn’t committed.”

Source: Nature

Categories : COVID Diseases, Syndromes and ConditionsTags :

Normal Breathing Can Transport Viruses Over 2 Metres

On By ModernMedia

Researchers have demonstrated that normal breathing can transport viruses in saliva droplets up a distance of up to 2.2 metres in 90 seconds.

The World Health Organization and the Centers for Disease Control recommend social distancing to prevent the spread of COVID. The distances are estimated from various studies, but there is a need for further research into how viruses are transported from one person to another. 
Previous studies considered aerosol transport after coughing or sneezing, while this study focused on normal human breathing, using computer simulations with a more realistic model than prior studies. A normal breath produces periodic jet flows that contain saliva droplets, but those jets’ velocity is less than a tenth that of a cough or sneeze.

Wearing a face mask greatly reduces the distance which these droplets can travel. Saliva droplets restricted by a mask had travelled only 0.72 metres after two minutes, far short of the distance of 1.8 metres suggested by the CDC.

The investigators found even normal breathing produces a complex field of vortices that can move saliva droplets away from the person’s mouth. The role of these vortices has not previously been understood.

Study author, Ali Khosronejad, American Institute of Physics said: “Our results show that normal breathing without a facial mask generates periodic trailing jets and leading circular vortex rings that propagate forward and interact with the vortical flow structures produced in prior breathing cycles.”

This complex vorticity field can enable the transport of aerosol droplets over long distances despite the slow speeds. A face mask serves to dissipate the kinetic energy of the jet produced by an exhaled breath, thereby disrupting the vortices and limiting the travel of virus-laden droplets.

The researchers also took into account evaporation of the saliva droplets. With no mask, they found the saliva droplets near the front of the plume of exhaled breath had partially evaporated, reaching a size of only one-tenth of a micrometre. In stagnant indoor air, it would take days for droplets this small to settle to the ground.

Masks partially redirect the exhaled breath downward, significantly restricting forward motion of the plume, so the risk of suspended droplets remaining in the air is substantially reduced.

“To simplify the breathing process, we did not consider the flow of air-saliva mixture through the nose and solely accounted for the flow through the mouth,” Khosronejad said. “In future studies, we will explore the effect of normal breathing via both the nose and mouth.”

Source: News-Medical.Net

Journal reference: Khosronejad, A., et al. (2021) A computational study of expiratory particle transport and vortex dynamics during breathing with and without face masks. Physics of Fluids. doi.org/10.1063/5.0054204.

Categories : COVID Expert OpinionTags :

COVID Deaths Exceeded Worst Predictions of The Public and Most Experts

On By ModernMedia


Experts such as epidemiologists and statisticians made much more accurate predictions about COVID than the public, but both groups substantially underestimated the true extent of the pandemic, a study from the University of Cambridge has found.

Researchers from the Winton Centre for Risk and Evidence Communication surveyed 140 UK experts and 2086 UK laypersons in April 2020 and asked them to make predictions about the impact of COVID by the end of 2020. Participants were also asked to assign confidence in their predictions by providing upper and lower bounds of where they were 75% sure that the true answer would fall—for example, a participant would say they were 75% sure that the total number of infections would be between 300 000 and 800 000.

While only 44% of predictions from the expert group fell within their own 75% confidence ranges, only 12% of predictions from the non-experts fell within their ranges, though more numerate individuals performed a little better. The results were published in the journal PLOS ONE.

“Experts perhaps didn’t predict as accurately as we hoped they might, but the fact that they were far more accurate than the non-expert group reminds us that they have expertise that’s worth listening to,” said lead author Dr Gabriel Recchia from the Winton Centre for Risk and Evidence Communication,. “Predicting the course of a brand-new disease like COVID-19 just a few months after it had first been identified is incredibly difficult, but the important thing is for experts to be able to acknowledge uncertainty and adapt their predictions as more data become available.”

Expert opinion is important for those making decisions at any level from individual to policy. The quality of expert intuition can vary greatly depending on the field of expertise and the type of judgment required, so it is important to determine how good expert predictions really are, especially in where they could shape public opinion or government policy.

“People mean different things by ‘expert’: these are not necessarily people working on COVID-19 or developing the models to inform the response,” said Dr Recchia. “Many of the people approached to provide comment or make predictions have relevant expertise, but not necessarily the most relevant.” Dr Recchia noted that in the early stages of the pandemic, clinicians, epidemiologists, statisticians, and other individuals seen as experts by the media and the general public, were often asked to give off-the-cuff answers to questions about how bad the pandemic might get. “We wanted to test how accurate some of these predictions from people with this kind of expertise were, and importantly, see how they compared to the public.”

Participants in the survey were asked to predict how many people living in their country would have died and would have been infected by the end of 2020; they were also asked to predict infection fatality rates both for their country and worldwide.

The expert group and the non-expert group both underestimated the total number of deaths and infections in the UK. The official UK death toll at 31 December was 75 346. The median prediction of the expert group was 30 000, while that of the the non-expert group was 25 000.

For COVID fatality rates, the median expert prediction was that 10 out of every 1000 people with the virus worldwide would die from it, and 9.5 out of 1000 people with the virus in the UK would die from it. The median non-expert response to the same questions was 50 out of 1000 and 40 out of 1000. The true infection fatality rate at the end of 2020—as best could be estimated—was nearer to 4.55 out of 1000 worldwide and 11.8 out of 1000 in the UK.

“There’s a temptation to look at any results that says experts are less accurate than we might hope and say we shouldn’t listen to them, but the fact that non-experts did so much worse shows that it remains important to listen to experts, as long as we keep in mind that what happens in the real world can surprise you,” said Dr Recchia.

The researchers cautioned that it is important to differentiate between research on evaluating the forecasts of ‘experts’—individuals involved in relevant fields, such as epidemiologists and statisticians—and research on evaluating specific epidemiological models, though the models may inform experts. Many COVID prediction models have proved accurate in the short term, but rapidly become less accurate for later predictions.

Source: Medical Xpress

Journal information: PLOS ONE (2021). DOI: 10.1371/journal.pone.0250935