New insights into diagnosing and treating invasive fungal infections will help save lives

Thousands of patients suffering from invasive fungal infections in intensive-care units or after organ transplantation will benefit from the latest insights into diagnostic and therapeutic interventions, published today in the prestigious journal The Lancet Infectious Diseases.

Fungal infections invading the bloodstream, lungs or other organs can cause prolonged illness and in extreme cases can lead to permanent disability or even death.

A new review paper has outlined the gold standard for identifying at-risk patients who are critically ill, or in receipt of organ transplants, for preventing, diagnosing and treating invasive fungal infections, potentially saving countless lives across both the developed and developing world.

Senior author, Professor Tania Sorrell from the Westmead Institute for Medical Research and the Marie Bashir Institute for Infectious Diseases and Biosecurity, said that invasive fungal infections can have serious consequences for patients and their families.

“These new insights into diagnosing and treating invasive fungal infections are significant because early and correct treatment clearly leads to better outcomes for the patient.

“These infections are uncommon but potentially life-threatening. Blood infections such as candidaemia and lung infections such as aspergillosis have high mortality rates of up to 85% in critically ill and immune-compromised patients,” Professor Sorrell said.

Professor Sorrell added that invasive fungal infections, overall, are a major problem in both developed and developing nations, killing more than 1.5 million people annually. The cost to the global healthcare system runs into billions of dollars each year.

“This is an important problem in Australia, but an even more serious issue in developing countries where mortality is unacceptably high despite the best available therapies and care.

“The research that has informed the recommendations in this paper will play an important role in educating doctors in both developed and developing countries about these diseases and outlining available diagnostic and therapeutic options in different medical contexts.

“It will allow clinicians to tailor their approach to managing these infections in different countries or when working with specific at-risk populations.

“This is vital, because rapid and accurate diagnosis, together with the right treatment, will significantly increase the chances of recovery for a patient.

“A significant proportion of these infections are preventable. We are also working to improve capability to identify patients at high risk of contracting these infections.

The Westmead team is now expanding their research in prevention, new diagnostic strategies, and therapeutic approaches towards infectious diseases of significant public health importance

UC research examines lung cell turnover as risk factor & target for treatment of influenza pneumonia

Influenza is a recurring global health threat that, according to the World Health Organization, is responsible for as many as 500,000 deaths every year, most due to influenza pneumonia, or viral pneumonia. Infection with influenza most typically results in lung manifestations limited to dry cough and fever, and understanding how the transition to pneumonia occurs could shed light on interventions that reduce mortality. Research led by University of Cincinnati (UC) scientists takes a different approach to investigating how influenza spreads through the lungs by focusing on how resistant or susceptible cells lining the airway are to viral infection.

The work published today in the Proceedings of the National Academy of Sciences (PNAS) shows how stimuli that induce cell division in the lung promote spread of influenza from the airway to the gas exchanging units of the lung, known as the alveoli. The UC study also demonstrates that interventions that prevent alveolar cells from dividing reduce influenza mortality in animal models, suggesting a potential prophylactic and/or therapeutic strategy for influenza pneumonia.

“Almost all research into susceptibility or resistance to influenza focuses on host immune responses,” says Nikolaos Nikolaidis, PhD, research scientist in the Division of Pulmonary, Critical Care and Sleep Medicine in the Department of Internal Medicine at the UC College of Medicine and lead author on the paper. “Our approach was to examine factors that influence the vulnerability of alveolar cells to influenza infection, separate from how the immune system is dealing with the virus.”

“Less than 1 percent of alveolar cells are actively dividing at any given time in the healthy lung, rendering it naturally resistant to influenza infection,” says Frank McCormack, MD, Gordon and Helen Hughes Taylor Professor of Internal Medicine and director of the Division of Pulmonary, Critical Care and Sleep Medicine and senior author on the paper. “Recovery from lung injury due to supplemental oxygen therapy, cigarette smoke or scarring lung diseases is associated with expression of growth factors that result in multiplication of lung cells. Our work demonstrated that these mitogenically stimulated cells are rich targets for influenza infection while they are dividing.”

The researchers found that when sirolimus, which is FDA-approved for use as an anti-growth agent for the rare lung disease, lymphangioleiomyomatosis (LAM), was given to influenza-infected animal models, it prevented alveolar cells from dividing, and as a result, protected the mice from viral pneumonia and death.

“Although sirolimus also has off target immunosuppressive properties that could potentially pose added risks of side effects in virus-infected patients, trials of inhaled sirolimus could lead to approaches that do not entail systemic exposure,” says McCormack.

The McCormack lab expressed optimism that this observation has the potential to ultimately inform understanding of other unexplained risk factors for influenza, including very young age and pregnancy, and perhaps even to change medical management, such as more judicious use of supplemental oxygen in patients admitted with suspected viral pneumonia. Further, the team has hopes that the research could lead to a paradigm shift in the approach to therapy.

Nikolaidis says the next step in this research is to further explore why the multiplying alveolar epithelial cell is a better target for influenza. “Is it because the virus gets into the dividing cell more easily, because multiplying stimuli expand the pool of cellular machinery used by the virus to replicate, or because proliferation is associated with a reduction in innate cellular defenses? We are anxious to explore these and other potential mechanisms of viral susceptibility,” he adds.

Immunotherapy with DNA vaccine shows promise for HPV-related head and neck cancer

A novel vaccine therapy can generate immune responses in patients with head and neck squamous cell carcinoma (HNSCCa), according to researchers at the Abramson Cancer Center of the University of Pennsylvania. The treatment specifically targets human papillomavirus (HPV), which is frequently associated with HNSCCa, to trigger the immune response. Researchers will present the results of their pilot study during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago (Abstract #6073).

HNSCCa is a cancer that develops in the mucous membranes of the mouth, and throat. While smoking and tobacco use are known causes, the number of cases related to HPV infection – a sexually transmitted infection that is so common, the Centers for Disease Control says almost all sexually active adults will contract it at some point in their lifetimes – is on the rise. The CDC now estimates 70 percent of all throat cancers in the United States are HPV-related. Sixty percent are caused by the subtype known as HPV 16/18.

“This is the subtype we target with this new therapy, and we’re the only site in the country to demonstrate immune activation with this DNA based immunotherapeutic vaccine for HPV 16/18 associated head and neck cancer,” said the study’s lead author Charu Aggarwal, MD, MPH, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The vaccine is delivered as an injection of antigens – which leads the immune system to start producing antibodies and activate immune cells. At the time of injection, physicians use a special device to deliver a pulse of electricity to the area, which stimulates the muscles and speeds the intake of the antigens. Aggarwal noted that this study represents a multidisciplinary approach involving the lab and the clinic.

“This is truly bench-to-bedside and shows the value of translational medicine within an academic medical center,” Aggarwal said.

Penn researchers treated 22 patients with the vaccine. All of the patients had already received therapy that was intended to be curative – either surgery or chemotherapy and radiation. When doctors followed up an average of 16 months later, 18 of those patients showed elevated T cell activity that was specific to HPV 16/18. All of the patients in the study are still alive, and none reported any serious side effects.

“The data show the therapy is targeted and specific, but also safe and well-tolerated,” Aggarwal said.

Because of the positive activity, Aggarwal says the next step is to try this therapy in patients with metastatic disease. A multi-site trial will open soon that combines the vaccine with PD-L1 inhibitors, which target a protein that weakens the body’s immune response by suppressing T-cell production.

Yeast Infection Linked to Mental Illness

In a study prompted in part by suggestions from people with mental illness, Johns Hopkins researchers found that a history of Candida yeast infections was more common in a group of men with schizophrenia or bipolar disorder than in those without these disorders, and that women with schizophrenia or bipolar disorder who tested positive for Candida performed worse on a standard memory test than women with schizophrenia or bipolar disorder who had no evidence of past infection.

The researchers caution that their findings, described online on May 4 in npj Schizophrenia — a new publication from Nature Publishing Group — do not establish a cause-and-effect relationship between mental illness and yeast infections but may support a more detailed examination into the role of lifestyle, immune system weaknesses and gut-brain connections as contributing factors to the risk of psychiatric disorders and memory impairment.

“It’s far too early to single out Candida infection as a cause of mental illness or vice versa,” says Emily Severance, Ph.D., assistant professor of pediatrics and member of the Stanley Division of Developmental Neurovirology at the Johns Hopkins University School of Medicine. “However, most Candida infections can be treated in their early stages, and clinicians should make it a point to look out for these infections in their patients with mental illness.” She adds that Candida infections can also be prevented by decreased sugar intake and other dietary modifications, avoidance of unnecessary antibiotics, and improvement of hygiene.

Candida albicans is a yeastlike fungus naturally found in small amounts in human digestive tracts, but its overgrowth in warm, moist environments causes burning, itching symptoms, thrush (rashes in the throat or mouth) in infants and those with weakened immune systems, and sexually transmittable genital yeast infections in men and women. In its more serious forms, it can enter the bloodstream. In most people, the body’s own healthy bacteria and functioning immune system prevent its overgrowth.

Severance says she and her team focused on a possible association between Candida susceptibility and mental illness in the wake of new evidence suggesting that schizophrenia may be related to problems with the immune system, and because some people with weakened immune systems are more susceptible to fungal infections.

Also, she says, patients and parents of patients had shared personal stories and testimonials with the researchers about their experience with yeast infections, and these discussions prompted the investigation into possible links between mental illness and the microbiome — the body’s natural collection of bacteria. The researchers, she adds, chose to focus on Candida because it is one of the most common types of yeast in the body.

For the study, colleagues from the Sheppard Pratt Health System took blood samples from a group of 808 people between the ages of 18 and 65. This group was composed of 277 controls without a history of mental disorder, 261 individuals with schizophrenia and 270 people with bipolar disorder. The researchers used the blood samples to quantify the amount of IgG class antibodies to Candida, which indicates a past infection with the yeast. After accounting for factors like age, race, medications and socioeconomic status, which could skew the results, they looked for patterns that suggested links between mental illness and infection rates.

Significantly, the team says, it found no connection between the presence of Candida antibodies and mental illness overall in the total group. But when the investigators looked only at men, they found 26 percent of those with schizophrenia had Candida antibodies, compared to 14 percent of the control males. There wasn’t any difference found in infection rate between women with schizophrenia (31.3 percent) and controls (29.4 percent). The higher infection rate percentages in women over men likely reflects an increased susceptibility for this type of infection in all women.

Men with bipolar disorder had clear increases in Candida as well, with a 26.4 percent infection rate, compared to only 14 percent in male controls. But, after accounting for additional variables related to lifestyle, the researchers found that the association between men with bipolar disorder and Candida infection could likely be attributed to homelessness. However, the link between men with schizophrenia and Candida infection persisted and could not be explained by homelessness or other environmental factors. Many people who are homeless are subjected to unpredictable changes in stress, sanitation and diet, which can lead to infections like those caused by Candida.

Severance says the data add support to the idea that environmental exposures related to lifestyle and immune system factors may be linked to schizophrenia and bipolar disorder, and that those factors may be different for each illness. Similarly, specific mental illnesses and related symptoms may be very different in men versus women.

This Johns Hopkins research group, led by Robert Yolken, M.D., director of the Stanley Division of Developmental Neurovirology, had previously shown that toxoplasmosis infection could trigger schizophrenia, and this could lead to neurocognitive problems. The organism that causes toxoplasmosis is a parasite that uses cats as its primary host, but it can also infect humans and other mammals.

To determine whether infection with Candida affected any neurological responses, all participants in the new study took a 30-minute assessment of cognitive tasks to measure immediate memory, delayed memory, attention skills, use of language and visual-spatial skills.

Each of the five skills tests are scored based on an adjusted 100-point system. Results showed that control men and women with and without prior Candida infection had no measureable differences in scores in the five neurological responses.

However, the researchers noticed that women with schizophrenia and bipolar disorder who had a history of Candida infection had lower scores on the memory portions of this test compared to those women with no prior infection. For example, women with schizophrenia and the highest Candida antibody levels scored about an average of 11 points lower on the test for immediate memory than the controls, from a score of 68.5 without infection to 57.4 with infection. And the women with schizophrenia and the highest Candida antibody levels scored almost 15 points lower on the test for delayed memory, from a score of 71.4 without infection to 56.2 with infection. The effect of Candida infection in women with bipolar disorder on memory test scores was smaller than that seen in women with schizophrenia but was still measureable.

“Although we cannot demonstrate a direct link between Candida infection and physiological brain processes, our data show that some factor associated with Candida infection, and possibly the organism itself, plays a role in affecting the memory of women with schizophrenia and bipolar disorder, and this is an avenue that needs to be further explored,” says Severance. “Because Candida is a natural component of the human body microbiome, yeast overgrowth or infection in the digestive tract, for example, may disrupt the gut-brain axis. This disruption in conjunction with an abnormally functioning immune system could collectively disturb those brain processes that are important for memory.”

Severance says they plan to take their studies of the gut-brain connection into mouse models to test for a cause-and effect-relationship with Candida and memory deficits.

The researchers emphasized that the current study design had limitations. For example, they were unable to tell where in the body the infection was located and whether or not participants had a current or past infection of Candida. The researchers were also not able to account for every possible lifestyle variable that might contribute to these results.

The researchers in the Stanley Division of Developmental Neurovirology are investigating whether pathogens, such as bacteria or viruses, may contribute or trigger certain mental disorders.

According to the National Institute of Mental Health, about 1 percent of people in the U.S. have schizophrenia and about 2 percent have bipolar disorder. Although these diseases have a genetic component, there is evidence that they may also be triggered by environmental factors and stress.

Researchers Discover Potential Treatment for Sepsis and Other Uncontrollable Responses to Infection

Researchers at the Icahn School of Medicine at Mount Sinai say that tiny doses of a cancer drug may stop the raging, uncontrollable immune response to infection that leads to sepsis and kills up to 500,000 people a year in the U.S. The new drug treatment may also benefit millions of people worldwide who are affected by infections and pandemics.

Their study reported in Science, demonstrates in both cells and animals that a small dose of topoisomerase I (Top 1) inhibitor can dampen an acute inflammatory reaction to infection while still allowing the body’s protective defense to take place. The title of the study is “Topoisomerase 1 inhibition suppresses the transcriptional activation of innate immune responses and protects against inflammation-induced death.”

The treatment may help control not only sepsis — deadly infections often acquired in hospital by patients with a weak immune system — but also new and brutal assaults on human immunity such as novel influenza strains and pandemics of Ebola and other singular infections, says the study’s senior investigator, Ivan Marazzi, PhD, an Assistant Professor of Microbiology at the Icahn School of Medicine at Mount Sinai.

“Our results suggest that a therapy based on Top 1 inhibition could save millions of people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes — what is known as a cytokine, or inflammatory, storm,” says Marazzi.

“These storms occur because the body does not know how to adjust the appropriate level of inflammation that is good enough to suppress an infection but doesn’t harm the body itself,” he says. “This drug appears to offer that life-saving correction.”

Sepsis is caused by an excessive host response to infection, which in turn leads to multiple organ failure and death. With an overall mortality rate between 20 and 50%, sepsis is the tenth leading cause of death in the U.S. — it kills more people than do HIV and breast cancer.

“To date there has been no targeted treatment for sepsis, or for other infections that promote this inflammatory storm,” says Dr. Marazzi. “Such treatment is desperately needed.”

For example, sepsis is a leading cause of death in infants and children, he says. “Septic shock and lung destruction can occur when a child is suffering from a pneumonia caused by co-infection with a virus and a bacteria even when antibiotic therapy is being used. The elderly are also especially vulnerable to sepsis.”

Following a challenge from the National Institutes of Health to repurpose existing drugs for new uses, the research team used a simple cellular screen to find candidate drugs that could tamp down rampant inflammation.

They discovered that the Top 1 inhibitor class of cancer drugs — four have been previously approved for a variety of cancers — also blocks a set of genes that are activated immediately by immune cells to combat an infection. “These genes are the ones that have the strongest inflammatory effects,” says Marazzi.

The Mount Sinai team found that use of one to three doses of a Top 1 inhibitor that is 1/50th the strength of normal chemotherapy was enough to rescue 70-90 % of mice from an inflammatory storm death due to either acute bacterial infection, liver failure, or virus-bacteria co-infection. The treatment did not produce overt side effects.

They also tested the inhibitor in cells infected with influenza, Ebola, and other viral and bacterial microbes that over-stimulate the immune system, and found the drug blunted a dangerous immune reaction.

“We observed a striking effect of Top-1 inhibitors on expression of pro-inflammatory molecules induced by Ebola virus infection. This study contributes our understanding of pathogenesis of Ebola virus disease and also suggests a direction to develop treatments,” says Alexander Bukreyev, PhD, Professor in the Department of Pathology and Microbiology & Immunology at the Galveston National Laboratory at the University of Texas Medical Branch.

“Finding remedies for these infection-induced inflammatory storms is a global focus, and we look forward to testing the ability of Top-1 inhibitors to save lives,” adds Marazzi.