Pneumonia diagnoses are marked by pronounced uncertainty, according to an AI-based analysis of over 2 million hospital visits. The study, published in Annals of Internal Medicine, found that more than half the time, a pneumonia diagnosis made in the hospital will change from a patient’s entrance to their discharge – either because someone who was initially diagnosed with pneumonia ended up with a different final diagnosis, or because a final diagnosis of pneumonia was missed when a patient entered the hospital (not including cases of hospital-acquired pneumonia).
Understanding that uncertainty could help improve care by prompting doctors to continue to monitor symptoms and adapt treatment accordingly, even after an initial diagnosis.
Barbara Jones, MD, pulmonary and critical care physician at University of Utah Health and the first author on the study, found the results by searching medical records from more than 100 VA medical centres across the country, using AI-based tools to identify mismatches between initial diagnoses and diagnoses upon discharge from the hospital. More than 10% of all such visits involved a pneumonia diagnosis, either when a patient entered the hospital, when they left, or both.
“Pneumonia can seem like a clear-cut diagnosis,” Jones says, “but there is actually quite a bit of overlap with other diagnoses that can mimic pneumonia.” A third of patients who were ultimately diagnosed with pneumonia did not receive a pneumonia diagnosis when they entered the hospital. And almost 40% of initial pneumonia diagnoses were later revised.
The study also found that this uncertainty was often evident in doctors’ notes on patient visits; clinical notes on pneumonia diagnoses in the emergency department expressed uncertainty more than half the time (58%), and notes on diagnosis at discharge expressed uncertainty almost half the time (48%). Simultaneous treatments for multiple potential diagnoses were also common.
When the initial diagnosis was pneumonia, but the discharge diagnosis was different, patients tended to receive a greater number of treatments in the hospital, but didn’t do worse than other patients as a general rule. However, patients who initially lacked a pneumonia diagnosis, but ultimately ended up diagnosed with pneumonia, had worse health outcomes than other patients.
A path forward
The new results call into question much of the existing research on pneumonia treatment, which tends to assume that initial and discharge diagnoses will be the same. Jones adds that doctors and patients should keep this high level of uncertainty in mind after an initial pneumonia diagnosis and be willing to adapt to new information throughout the treatment process. “Both patients and clinicians need to pay attention to their recovery and question the diagnosis if they don’t get better with treatment,” she says.
Professor Shabir Madhi of Wits University. Photo: supplied.
The Sabin Vaccine Institute presented the Albert B. Sabin Gold Medal to physician-researchers Keith Klugman and Shabir Madhi.
Nicole Basta, an associate professor at Canada’s McGill University and Canada Research Chair in Infectious Disease Prevention, received Sabin’s 2024 Rising Star Award.
The awards were made on 18 April 2024 at a ceremony in the National Academy of Sciences building in Washington D.C.
Formidable Wits alumni are world leaders in vaccinology
Klugman and Madhi received the Sabin Gold Medal, one of the highest recognitions for vaccinologists globally, for their seminal combined contributions to the development of vaccines against pneumonia and diarrhoeal disease – major causes of death in children in low- and middle-income countries (LMICs).
Klugman is a Wits University alumnus who received an honorary doctorate from his alma mater in 2023.
Madhi, also a Wits alumnus, is currently Professor of Vaccinology and Dean of the Faculty of Health Sciences at Wits University.
The Gold Medal is Sabin’s highest scientific honour. It has been given annually for more than three decades to a distinguished member of the global health community who has made exceptional contributions to vaccinology or a complementary field.
Klugman first met his then-graduate student Madhi at Wits University, where Klugman established, and Madhi expanded, a now globally renowned infectious diseases research institute. Apart from pneumonia, their work focused on maternal and children’s vaccines including influenza, respiratory syncytial virus (RSV), typhoid, and Group B streptococcus (GBS).
The evidence produced by these two awardees has and continues to inform the World Health Organization’s recommendations for vaccines. Klugman and Madhi’s research has helped pave the way for the introduction of lifesaving vaccines in public immunization programs – including the pneumococcal conjugate vaccine where their findings were pivotal in influencing vaccination policy in many low- and middle-income countries (LMICs).
Klugman’s efforts help prevent babies from dying of pneumonia
Fuelled by an early interest in science as a child in South Africa – in part due to a physician father – Klugman holds both a medical as well as a science doctorate degree from Wits University and was the first student in the school’s history to obtain them simultaneously.
He began his research career nearly five decades ago investigating the typhoid vaccine and has since distinguished himself as a formidable infectious diseases’ scientist.
Klugman is widely known for his work on pneumonia, which still kills a child under five every 43 seconds, many in the world’s poorest countries.
As the director of the pneumonia programme at the Seattle-based Bill & Melinda Gates Foundation, Klugman orchestrates strategic initiatives aimed at reducing deaths from pneumonia, RSV, neonatal sepsis, and meningitis.
He has authored hundreds of publications that have been cited over 50 000 times to date and has been elected to the National Academy of Medicine in the United States. He is also a professor emeritus of global health at Atlanta’s Emory University.
His scientific achievements aside, Klugman has long championed the need for the world’s poorest children to have equitable access to vaccines. While in South Africa he joined in Wits University’s struggle to allow access to the institution for all students.
“It is absolutely wonderful to be receiving this award, especially together with Shabir,” he says. “When I look down the list of previous awardees, I recognize the great majority of them, and it is extraordinary to now be numbered among them.”
Past award recipients include leaders of vaccinology and vaccine advocacy such as Drs. Barney Graham, Carol Baker, Bill Foege, Anne Gershon, Stanley Plotkin, and Kathrin Jansen.
Madhi’s research informed WHO recommendations on universal rotavirus vaccination
With a career spanning more than 25 years, Madhi, also from South Africa, is a trained paediatrician whose research continues to be instrumental in prioritising the rollout of vital vaccines and guiding global public health policies. At Wits University, he led clinical trials focused on respiratory and meningeal pathogens, including vaccines targeted at pregnant women and their unborn babies.
Madhi led the first study showing that a rotavirus vaccine could significantly prevent severe diarrhoea during the first year of life in African infants. That research served as a key piece of evidence for the WHO’s recommendation of universal rotavirus vaccination. In addition, he also led the first two COVID-19 vaccine trials in Africa, and a number of COVID-19 epidemiology studies which led to the first evidence suggesting that infection-induced immunity and vaccinations played a role in reducing severity of disease.
In addition to serving as Professor of Vaccinology and Dean of Health Sciences at Wits University, Madhi heads South Africa’s widely respected South African Medical Research Council (SAMRC) Vaccines and Infectious Diseases Analytics Research Unit (Wits VIDA). He is also the co-founder and co-Director of the African Leadership Initiative for Vaccinology Expertise (ALIVE).
He has co-authored hundreds of publications which have been cited over 59 000 times. Madhi is a recipient of numerous lifetime achievement awards in South Africa, as well being bestowed an Honorary Commander of the Order of the British Empire (CBE) from the British Government for his services to science and public health in a global pandemic.
“It is really humbling for me to be acknowledged for my contributions in the field of vaccinology along with those who have received the Gold Medal award,” says Madhi. “It makes me realise that the work my team and I have done is acknowledged by my peers as being of substance. Most significantly, we contributed to protecting lives in those settings where a majority of death and suffering occurs, and that is in LMICs.”
Amy Finan, Sabin’s chief executive officer, says, “I am honoured to award the Sabin Gold Medal to Dr Klugman and D. Madhi for their extraordinary work on vaccines that have saved lives in communities most in need of these interventions. Their pneumonia research has been particularly transformative in shaping our understanding of the disease and strengthening global health strategies to protect children from this vaccine-preventable disease.”
The World Health Organization (WHO) noted an upsurge of unidentified pneumonia-like respiratory illnesses among children in Northern China, and asked China for more information. This is significant as previous outbreaks of severe respiratory illnesses have started out in this fashion, but such WHO requests for more information on disease clusters are routine as part of its monitoring. No “unusual or novel pathogens” have been found, according to China, which attributed it to an increase in multiple pathogens and the lifting of COVID restrictions.
Earlier this month, China’s National Health Commission reported a nationwide increase in respiratory disease incidence, mostly among children. This increase was attributed to lifting of COVID restrictions and the arrival of the cold season, and due to circulating known pathogens including Mycoplasma pneumonia and RSV, which are known to affect children more than adults.
On 22 November 2023, the WHO identified media and ProMED reports about clusters of undiagnosed pneumonia in children’s hospitals in Beijing, Liaoning and other places in China. The WHO requested from China additional epidemiologic and clinical information, as well as lab results from these cases and data about recent trends in circulating respiratory pathogens.
The WHO held a teleconference with Chinese health authorities and received data indicating an increase in outpatient consultations and hospital admissions of children due to Mycoplasmapneumoniae pneumonia since May, and RSV, adenovirus and influenza virus since October. Some of these increases are earlier in the season than usual, but not unexpected given the lifting of COVID restrictions, as similarly experienced in other countries. No changes in the disease presentation were reported by the Chinese health authorities, who said no unusual or novel pathogens or unusual clinical presentations had been detected, but only the general increase in respiratory illnesses by known pathogens. Local hospitals had not been overloaded by new cases.
Risk assessment
In the current outbreak of respiratory illness, the reported symptoms are common to several respiratory diseases and, as of now, at the present time, Chinese surveillance and hospital systems report that the clinical manifestations are caused by known pathogens in circulation. M. pneumoniae is a common respiratory pathogen and a common cause of paediatric pneumonia, and is readily treated with antibiotics.
China has stepped up its influenza-like illness (ILI) and severe acute respiratory infections (SARI) sentinel surveillance system since mid-October, including for M. pneumoniae.
There is limited detailed information available to fully characterize the overall risk of these reported cases of respiratory illness in children. However, due to the arrival of the winter season, the increasing trend in respiratory illnesses is expected; co-circulation of respiratory viruses may increase burden on health care facilities.
According to surveillance data reported to WHO’s FluNet and published by the National Influenza Centre in China, ILI was above usual levels for this time of year and increasing in the northern provinces. Influenza detections were predominantly A(H3N2) and B/Victoria lineage viruses.
WHO advice
The WHO advice was for people in China to take measures against respiratory illnesses, including vaccines, masking and social distancing. It also does not recommend any specific measures for travellers to China.
A new study published in The Lancet Global Health, highlights the impact indoor air pollution can have on the development of child pneumonia, showing that increases in airborne particulate matter results in greater carriage of Streptococcus pneumoniae.
Streptococcus pneumoniae is a major human pathogen causing more than two million deaths per year; more than HIV/AIDS, measles and malaria combined, but it is also part of the normal microbial community of the nasopharynx. It is the leading cause of death due to infectious disease in children under five years of age; in sub-Saharan Africa, the burden of pneumococcal carriage and pneumonia is especially high.
Household air pollution from solid fuels increases the risk of childhood pneumonia. Nasopharyngeal carriage of S. pneumoniae is a necessary step in the development of pneumococcal pneumonia. More than 2.6 billion people are exposed to household air pollution worldwide. Inefficient indoor biomass burning is estimated to cause 3.8 million premature deaths annually and approximately 45% of all pneumonia deaths in children aged younger than five years. However, a causal pathway between household air pollution and pneumonia had not yet been identified.
In order to understand the connection between exposure to household air pollution and the risk of childhood pneumonia researchers from the UK, Malawi and the United States conducted the MSCAPE (Malawi Streptococcus pneumoniae Carriage and Air Pollution Exposure) study embedded in the ongoing CAPS (Child And Pneumonia Study) trial. The MSCAPE study assessed the impact of PM2.5, the single most important health-damaging pollutant in household air pollution, on the prevalence of pneumococcal carriage in a large sample of 485 Malawian children.
Through exposure-response analysis, a statistically significant 10% increase in risk of S. pneumoniae carriage in children was observed for a unit increase (deciles) of exposure to PM2.5 (ranging from 3.9 μg/m³ to 617.0 μg/m³).
Dr. Mukesh Dherani, the study principal investigator, indicated: “This study provides us with greater insight into the impact household air pollution can have on the development of child pneumonia. These findings provide important new evidence of intermediary steps in the causal pathway of household air pollution exposure to pneumonia and provide a platform for future mechanistic studies.”
Study author Professor Dan Pope said: “Moving forward further studies, particularly new randomized controlled trials comparing clean fuels (e.g. liquefied petroleum gas) with biomass fuels, with detailed measurements of PM2.5 exposure, and studies of mechanisms underlying increased pneumococcal carriage, are required to strengthen causal evidence for this component of the pathway from household air pollution exposure to ALRI in children.”
Professor Nigel Bruce, co-principal investigator, stated: “This study provides further important evidence that emphasises the need to accelerate to cleaner fuels, such as LPG, which are now being promoted by many governments across the continent in order to meet SDG7 by 2030.”
A newly installed solar-powered medical oxygen system at a hospital in central Somalia is proving effective in saving lives, Somali and World Health Organization doctors told Voice of America.
The innovative solar oxygen system, the first of its kind in the country, was installed at Hanaano hospital, in the central town of Dhusamareb a year ago. Doctors say the system is having an impact and helping save the lives of very young patients.
“This innovation is giving us promise and hopes,” says Dr Mamunur Rahman Malik, WHO Somalia Representative.
According to Dr Malik, 171 patients received oxygen at the hospital from the solar-powered system from February to October 2021. Of these, only three patients died, and five others were referred to other hospitals.
Every year some 15 000 to 20 000 deaths occur in Somalia among children under five years of age due to pneumonia, said Dr Malik, making it the deadliest disease among under-fives.
The director of Hanaano hospital, Dr Mohamed Abdi, said the innovation is making a difference.
“It has helped a lot, it has saved more than a hundred people who received the service,” he said to VOA Somali.
“It was a problem for the children under one year and the children who are born six months to get enough oxygen. Now we are not worried about oxygen availability if the electricity goes out because there are the oxygen concentrators.”
One patient was Abdiaziz Omar Abdi, admitted to the hospital on January 16 with severe pneumonia and was struggling to breathe normally. The oxygen rate in his body had dropped to 60%, Dr Abdi said. Doctors immediately put him on oxygen along with ampicillin and dexamethasone medications. When discharged three days later, he was breathing normally. His oxygen was up to 90%.
Dr Malik said the oxygen is being used to treat a wide range of medical conditions – asphyxia, pneumonia, injuries, trauma, and road traffic accidents.
“We have seen in other countries that use of solar-powered medical oxygen (if applied in a timely manner) can save up to 35% of deaths from childhood pneumonia,” he said, adding that it could save the lives of at least 7000 children who die “needlessly” due to pneumonia.
The initiative to install solar-powered bio-medical equipment at Hanaano hospital emerged during the height of COVID in 2020, at a time when people were dying due to respiratory problems. Hospitals were unable to keep up with case loads and the cost of a cylinder of oxygen rose to between $400 to $600, and only 20% of health facilities had any kind of access to oxygen, said Dr Malik.
“If you look at the current situation, as of today Somalia needs close to 3000 or 4000 cubic metres of oxygen per day. So, oxygen was the biggest need in all the hospitals.”
Solar power can also be used for medical refrigerators, and their use is becoming widespread in Africa.
Scientists may have hit upon a way to make frontline antibiotics once again effective against the deadly bacteria that cause pneumonia.
The international team originally developed this as a potential treatment for disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases to break bacterial resistanceto commonly used frontline antibiotics.
Led by University of Melbourne Professor Christopher McDevitt, this discovery may see the comeback of readily available and cheap antibiotics, such as penicillin and ampicillin, as effective weapons in the fight against the rapidly rising threat of antibiotic resistance.
In a paper published in Cell Reports, Prof McDevitt and colleagues described how they discovered a way to break bacterial drug resistance and then developed a therapeutic approach to rescue the use of the antibiotic ampicillin to treat drug-resistant bacterial pneumonia caused by Streptococcus pneumoniae in a mouse model of infection.
The World Health Organization (WHO) last year named antibiotic resistance as one of the greatest threats to global health, food security, and development. Rising numbers of bacterial infections such as pneumonia, tuberculosis, gonorrhoea, and salmonellosis are becoming harder to treat as the antibiotics lose effectiveness against them.
Prof McDevitt’s prior work on bacterial antibiotic resistance using zinc ionophores led to collaborations with University of Queensland’s Professor Mark Walker and Griffith University’s Professor Mark von Itzstein from the Institute for Glycomics.
“We knew that some ionophores, such as PBT2, had been through clinical trials and shown to be safe for use in humans,” Prof von Itzstein said.
Prof Walker said that “as a group, we realised that if we could repurpose these safe molecules to break bacterial resistance and restore antibiotic efficacy, this would be a pathway to a therapeutic treatment. What we had to do was show whether PBT2 broke bacterial resistance to antibiotic treatment without leading to even greater drug resistance.”
“We focused on bacterial pneumonia and the most commonly used antibiotics. We thought that if we could rescue frontline antibiotics and restore their use for treating common infections, this would solve a global problem,” Prof McDevitt added.
An important component was the research from Prof McDevitt’s group that led to making the treatment effective.
“We knew from earlier research that the immune system uses zinc as an innate antimicrobial to fight off infection. So, we developed our therapeutic approach with PBT2 to use the body’s antimicrobial zinc to break antibiotic resistance in the invading bacteria,” he said.
“This rendered the drug-resistant bacteria susceptible to the antibiotic ampicillin, restoring the effectiveness of the antibiotic treatment in the infected animals.”
Collecting the data required for a clinical trial of PBT2 in combination with antibiotics is the next step, said Prof McDevitt.
“We also want to find other antibiotic-PBT2 combinations that have therapeutic potential for treatment of other bacterial infections,” he said.
“Our work shows that this simple combination therapy is safe, but the combinations require testing in clinical trials. What we need now is to move forward with further testing and pharmacology.”
Only 21 percent of patients with severe pneumonia caused by SARS-CoV-2 have a documented bacterial superinfection at the time of intubation, resulting in potential overuse of antibiotics, according to new research.
Superinfection occurs when another, usually different, infection is superimposed on the initial infection. In this case, it is bacterial pneumonia during severe viral pneumonia.
Dr Wunderink and co-authors reported their findings in a study published online in the Journal of Respiratory and Critical Care Medicine, which shows that the usual clinical criteria used to diagnose bacterial pneumonia could not distinguish between those with bacterial superinfection and those with severe SARS-CoV-2 infection only.
According to the authors, there is weak evidence behind current guidelines recommending that patients with SARS-CoV-2 pneumonia receive empirical antibiotics on hospital admission for suspected bacterial superinfection. In other published clinical trials of patients with SARS-CoV-2 pneumonia, rates of superinfection pneumonia are unexpectedly low. “More accurate assessment other than just reviewing clinical parameters is needed to enable clinicians to avoid using antibiotics in the majority of these patients, but appropriately use antibiotics in the 20-25 percent who have a bacterial infection as well,” said Dr Wunderink.
The team conducted an observational study to determine the prevalence and cause of bacterial superinfection at the time of initial intubation and the incidence and cause of subsequent bacterial ventilator-associated pneumonia (VAP) in 179 patients with severe SARS-CoV-2 pneumonia which required mechanical ventilation.
The researchers analysed 386 bronchoscopic bronchoalveolar lavage fluid samples from patients, and actual antibiotic use was compared with guideline-recommended therapy. Bacterial superinfection within 48 hours of intubation was detected in 21 percent of patients; 72 patients (44.4 percent) developed at least one VAP episode; and 15 (20.8 percent) of initial VAPs were caused by difficult-to-treat bacteria.
The authors found that in patients with severe SARS-CoV-2 pneumonia, bacterial superinfection at the time of intubation occurred in less than 25 percent of patients. Guideline-based empirical antibiotic management at the time of intubation would have resulted in antibiotic overuse.
The researchers believe that their findings have multiple implications for antibiotic guidelines: “Rapid diagnostic tests are important for helping identify suspected pneumonia in intubated patients. This can have major clinical implications because the current approach of using clinically defined risk factors for suspected methicillin-resistant staphylococcus aureus (MRSA) or pseudomonas bacteria as the cause of pneumonia still grossly overestimate the true incidence of these pathogens. In addition, the recommendation for empirical antibiotic treatment of worsening viral community-acquired pneumonia (now requiring intubation) may need to be revisited. This is not only true for SARS-CoV-2 but potentially for severe influenza as well.”
“An accurate diagnosis of suspected pneumonia allows clinicians to safely avoid or use narrow spectrum antibiotics for many patients,” Dr Wunderink added. “While multiple interventions impact mortality in these critically ill patients, the low mortality in our study with more limited antibiotic treatment suggests that our approach was safe.”
Streptococcus pneumoniae bacteria. Image by CDC on Unsplash
Researchers have found a further reason for why flu and Streptococcus pneumonia are such a deadly combination, by a surface protein causing it to stick to dead or dying lung cells. The finding by University of Alabama at Birmingham (UAB) follows thirty years after the discovery of the surface protein, called pneumococcal surface protein A, or PspA.
This new mechanism had been overlooked because it facilitates bacterial adherence only to dead or dying lung epithelial cells, not to living cells. Previously, researchers typically used healthy lung cell monolayers to search for bacterial adhesins that aid infection. In flu, the virus killing off lung cells was found to set the stage for S. pneumonia attachment to the airway, thereby worsening disease and pneumonia.
Study leaders Carlos Orihuela, PhD, and David Briles, PhD, professor at UAB, said their findings provide further explanation for how an infection by influenza A flu virus — followed by S. pneumoniae superinfection — causes severe pneumonia and a high death rate. Understanding of this mechanism could also lead to improvements for disease treatment and vaccination.
A historical example of the deadly synergy of flu infection followed by S. pneumoniae superinfection is found in banked lung samples from the 1918 Spanish influenza pandemic that killed 40 million to 50 million people — the vast majority of these samples showed co-infection or secondary infection with S. pneumonia.
The UAB research on PspA began with puzzling results from experimental lung infections of mice with influenza A, followed by either wild-type S. pneumonia that has the intact PspA gene, or a mutant S. pneumoniae that lacks PspA. Lung homogenates from mice infected with the wild-type had much higher numbers of S. pneumonia bacteria than lungs infected with the mutant. However, when researchers washed the interiors of the lungs and collected that bronchoalveolar lavage fluid, they counted similar numbers of the wild-type S. pneumonia and the mutant.
“This unexpected result was interpreted to mean that wild-type S. pneumoniae were more resistant to dislodgement than S. pneumonia with a pspA gene deletion, and it served as rationale for further experimentation,” Dr Orihuela said.
From this, the researchers were then able to show that PspA functions as an adhesin to dying host cells, as well as its previously established virulence mechanisms. The researchers also detailed the molecular mechanism of this bacterial adherence.
Both influenza A infection and release of the S. pneumoniae toxin pneumolysin cause death of lung epithelial cells. As they are dying, cells’ phosphatidylserine residues wind up on the outer cell membrane, where they bind the host enzyme glyceraldehyde-3-phosphate dehydrogenase, or GAPDH. In turn, the S. pneumoniae PspA on the bacteria surface binds to the GAPDH. PspA-GAPDH-mediated binding to lung cells increased S. pneumoniae localisation in the lower airway, and this was enhanced by pneumolysin exposure or co-infection with influenza A virus.
One of the fragments of protein responsible for the binding was introduced into the lungs of influenza-infected mice and reduced the disease severity of S. pneumoniae superinfection, presumably through binding competition.
“Our findings support the targeting of regions of PspA for therapeutic and vaccine development against influenza A/Streptococcus pneumoniae superinfections,” Dr Orihuela said. “Importantly, and despite more than 30 years since its discovery, PspA was not previously shown to function as an adhesin. Thus, our finding of PspA’s role in adherence substantially advances our knowledge on the interactions of S. pneumoniae with its host.”
