The Uncertainties of a Career in Medicine Having Cystic Fibrosis

Guest blog by Jacob Greene

It is a very unique time to have cystic fibrosis. Just over 80 years ago cystic fibrosis was a nameless ailment that caused infants to die months after being born. Today, the CFF’s predicted median life expectancy is just over 40 years. But this statistic does not adequately capture the wide range of CF experiences. Medians, by definition, don’t consider outliers, even though everybody’s CF journey is unique. Another important statistic is that, according to the CFF’s Patient Registry, 50% of people with CF die by the age of 28. Yikes.

Whatever the exact number, my point is that we live in a time in we (people with CF) usually make it to adulthood, but aren’t there for very long. Where does this leave us from an educational/career point of view? Is it worth going to college and graduate school if we are just going to die not too long after getting our degree?

To some people the answer might be “yes, it’s worth it,” to others the answer might be “no, it’s not.” For me personally, my answer aligns with the former. I am currently an undergrad at Stanford pursuing a degree in biochemistry hoping to attend medical school after graduating. To many people this might be unsettling. Two obvious questions that come to mind are, one, “what about bacterial exposure and cross contamination?” and two, “will you be able to keep up with the physical demands of being a doctor?” In response to the first question, there are many specialties that do not deal with infectious patients. Neurology, cardiology, obstetrics and gynecology, most surgical specialties, most oncological specialties, endocrinology, gastroenterology, dermatology, orthopedics, sports medicine, the list goes on. Generally speaking, my CF would not harm these types of patients, and these types of patients would not pose a threat to me. The answer to the second question is less certain. No, I don’t know if I will be physically able to keep up as a doctor. After all CF is a progressive illness. The older I get the sicker I get.

This uncertainty is exactly why I want to pursue a career in medicine. There is a lot of talk about representation in this day in age, but I never hear people talk about individuals with chronic, terminal illnesses becoming doctors. This is unsurprising as it takes many years to become a doctor. We (people with CF) don’t have a lot of time. But that’s why I think it’s so important to pursue a career in medicine. I absolutely adore my doctors and CF team, but every time I go to the hospital I know in the back of my mind that I’m terminal and they’re healthy. As hard as their jobs are, and as much as they see death, there is a fundamental divide between me being sick and their treating sick while being healthy. So, while I hope I can have a long career, I am well aware that this is not a guarantee. In fact, it is an improbability. But that is okay. Even if I drop dead during my residency, I will have been able to help give others life while myself dying. And that’s a pretty beautiful thing.

Immunotherapy May Be Promising Strategy to Treat Chronic Infections of P. aeruginosa in CF Patients

Original article on CF News Today

Blocking the interaction between two molecules involved in immune restraining mechanisms — called PD-1 and PD-L1 — may be an effective therapeutic strategy to boost the immune system and treat chronic infections of Pseudomonas aeruginosa in cystic fibrosis (CF) patients, according to a recent study.

The study, “Pseudomonas aeruginosa colonization causes PD-L1 overexpression on monocytes, impairing the adaptive immune response in patients with cystic fibrosis,” was published in the Journal of Cystic Fibrosis.

Chronic lung infections by P. aeruginosa —a highly antibiotic-resistant bacteria — are the leading cause of death among CF patients.

The high frequency of infections in CF patients suggest they have an impaired immune system. Furthermore, previous studies have shown that these patients have what is called an endotoxin tolerance, meaning a reduced responsiveness to pathogens following a first contact, leading to a desensitization of immune cells against them.

Researchers have proposed that the passage of bacteria to the bloodstream, inducing a systemic exposure to their LPS — a major component of the cell wall of some bacteria, including P. aeruginosa, that is recognized by the body’s immune system as foreign —, either attached to the membrane or in a soluble form, may explain the endotoxin tolerance observed in CF patients.

Recent evidence has shown that PD-L1 is a marker of endotoxin tolerance. PD-L1/PD-1 interaction has emerged as an important mechanism in the immune response, where the binding of PD-L1, present in many cells, to its PD-1 receptor on immune T-cells prevents the activation of T-cells — a type of white blood cell that fights infections and cancer cells.

Targeting and blocking this interaction has been shown to promote T-cell activation, and to be associated with a protective effect against infections.

However, the potential role of PD-L1/PD-1 interaction in CF, and especially in CF patients infected by P. aeruginosa, remains unexplored.

Researchers in Madrid evaluated the levels of PD-L1 and PD-1 in CF patients, and the potential association between PD-L1/PD-1 interaction and P. aeruginosainfection.

The team analyzed the levels of PD-L1 in monocytes — a type of white blood cell that is in the frontline of infection, and communicates with T-cells — and of PD-1 in T-cells of 32 CF patients, 19 of them infected by P. aeruginosa, and of healthy volunteers. These cells also were grown in the lab to assess their proliferation and immune responses.

Results showed that CF patients had significantly higher levels of PD-L1 in monocytes and PD-1 in T-cells than healthy people, and that PD-L1 levels — both in monocytes and in a soluble form in the blood — were even higher in CF patients infected with P. aeruginosa.

These data, combined with the fact that CF patients infected with P. aeruginosaalso showed a significant impairment in T-cell proliferation, highlighted an association between P. aeruginosa infection and an increased suppression of T-cells.

In accordance, additional analysis showed that endotoxin tolerance in monocytes was stronger in CF patients infected with P. aeruginosa than in those who were not.

Interestingly, the addition of an antibody that blocks PD-L1/PD-1 interaction to T-cells from patients infected with the bacteria significantly increased the proliferation of T-cells to levels almost comparable to those of healthy people and patients without the infection, suggesting this type of approach could revert the impaired immune response and benefit these CF patients.

The team also found evidence strengthening the hypothesis that bacteria/LPS presence in the blood induces increased levels of PD-L1 and endotoxin tolerance, as the levels of PD-L1 in monocytes from healthy people were significantly increased when in contact with isolated LPS of P. aeruginosa, or with blood of CF patients infected with the bacteria.

This PD-L1 increase with blood of infected CF patients was reduced when monocytes were pretreated with colistin (polymyxin E), a potent antibiotic that neutralizes or absorbs LPS. CF patients treated with colistin had lower levels of soluble PD-L1 in their blood.

These results suggest that colistin could be used to reduce the effects of bacteria passage to the bloodstream in CF patients infected with P. aeruginosa. Nonetheless, the team noted that future clinical trials are needed to confirm this hypothesis.

Overall, based on the results, the team concluded that “Pseudomonas aeruginosa colonization in patients with CF was associated with PD-L1 overexpression and impaired T-cell response, and LPS from this pathogen induced the observed phenotype.”

“Altogether, our results suggest the possibility of studying antibiotics and antiPD-1/PD-L1 antibody combination as a new potential treatment to provide clinical benefits to patients with P. aeruginosa colonization,” the researchers added.

Antibiotic plus probiotic combination may kill off superbugs

By 

Every year, over 2 million people in the United States develop infections that are resistant to treatment, and approximately 23,000 people die as a result.

These statistics have prompted the Centers for Disease Control and Prevention (CDC) to deem drug resistance “one of the biggest public health challenges of our time.”

Therefore, researchers are hard at work trying to develop ingenious ways of tackling so-called superbugs — bacteria that have become immune to antibiotic treatment.

Lately, researchers have added probiotics to their arsenal against superbugs. Probiotics are beneficial bacteria found in foods, such as yogurt, kefir, pickles, or miso soup.

Only a month ago, for example, a study suggested that simply consuming probiotics on a regular basis could reduce the need for antibiotics, thus helping to curb the drug resistance crisis. Continue reading Antibiotic plus probiotic combination may kill off superbugs

Sound Pharmaceuticals to present initial data on the STOP Ototoxicity Study at Cystic Fibrosis Conference

SEATTLESept. 25, 2018 /PRNewswire/ — Sound Pharmaceuticals (SPI) is pleased to announce that its recent submission to the upcoming North American Cystic Fibrosis Conference (NACFC) Oct. 18-20 has been selected as a late-breaking abstract. This presentation will focus on the incidence and severity of ototoxicity in CF patients undergoing intravenous (IV) tobramycin treatment for acute pulmonary exacerbation. Ototoxicity (hearing loss, tinnitus, vertigo or dizziness) is a common side effect of tobramycin and other aminoglycoside antibiotics (amikacin, gentamycin and streptomycin). Currently, there are no FDA approved therapies for the prevention or treatment of ototoxicity or any other type of sensorineural hearing loss, tinnitus, or dizziness. Continue reading Sound Pharmaceuticals to present initial data on the STOP Ototoxicity Study at Cystic Fibrosis Conference

Monitoring Pulmonary Exacerbation in Cystic Fibrosis: The Hunt for Urine-based Biomarkers Begins

By Michele Wilson PhD

The buildup of mucus in the lungs is an ongoing challenge faced by people with cystic fibrosis, and knowing whether they should seek medical attention is not always clear.

Recently, Mologic – a developer of personalized diagnostics – have developed a tool which they hope will help guide people with cystic fibrosis so they can avoid unnecessary stays in hospital.

The app-embedded algorithm converts data collected from a urinary test to a traffic light result, which indicates whether a patient is stable or in need of medical intervention.

Recently, Mologic, announced that they are launching a clinical trial to assess the company’s urine-based diagnostic tool, ‘HeadsUp’.

To learn more about how this point-of-care diagnostic tool could help improve healthcare for people with cystic fibrosis, we spoke with Gita Parekh, Head of R&D at Mologic.

How do you define pulmonary exacerbation, and why is it important that it is monitored in people with cystic fibrosis? Continue reading Monitoring Pulmonary Exacerbation in Cystic Fibrosis: The Hunt for Urine-based Biomarkers Begins

Cystic Fibrosis Podcast 195 Summiting Mount Everest and Denali with Nick Talbot

In the latest CF Podcast, Nick Talbot shares his incredibly unique journey with cystic fibrosis. From being diagnosed at the age of 13 to his latest climb – a trek up Denali, the highest point in North America – he constantly challenges himself to reach for his dreams. Nick stresses the importance of pushing one’s own personal limits and never being scared to fail – because failure simply means you tried.
Tune in to learn more about Nick and his cystic fibrosis story.

This video podcast was made possible through an unrestricted educational grant from Novartis to the Boomer Esiason Foundation.

Antioxidant-Enriched Multivitamin May Decrease Respiratory Illnesses

MedicalResearch.com Interview with:

Scott D Sagel MD PhD
Professor of Pediatrics
University of Colorado School of Medicine
Aurora, Colorado

MedicalResearch.com: What is the background for this study?

Response: Inflammation is an important feature of cystic fibrosis (CF) lung disease and contributes to lung damage and lung function decline in CF. We need safe and effective anti-inflammatory treatments in CF. Anti-oxidant therapy has been an area of promise, but with mixed results in CF.

This clinical trial, conducted at 15 CF centers affiliated with the cystic fibrosis Foundation Therapeutics Development Network, enrolled 73 patients who were 10 years and older (average age 22 years), with pancreatic insufficiency, which causes malabsorption of antioxidants. Subjects were randomized to either a multivitamin containing multiple antioxidants including carotenoids such as beta(β)-carotene, tocopherols (vitamin E), coenzyme Q10 (CoQ10), and selenium or to a control multivitamin without antioxidant enrichment. The antioxidants used in the study were delivered in a capsule specifically designed for individuals with difficulties absorbing fats and proteins, including those with cystic fibrosis.

MedicalResearch.com: What are the main findings?

Response: Antioxidant supplementation was safe and well-tolerated. Supplemental antioxidants increased antioxidant concentrations in the bloodstream in treated subjects and temporarily reduced inflammation in the blood at four weeks but not 16 weeks. Airway inflammation, as measured in sputum, did not change significantly with antioxidant treatment. Importantly, antioxidant treatment appeared to both prolong the time to the first respiratory illness requiring antibiotics and reduce the frequency of respiratory illnesses they experienced.

MedicalResearch.com: What should readers take away from your report?

Response: Taking a specially formulated antioxidant-enriched multivitamin, containing multiple dietary antioxidants, may decrease respiratory illnesses in people with cystic fibrosis. While more research needs to be done to find a treatment that delivers a sustained anti-inflammatory effect, we believe the prolonged time patients had before their first respiratory illness is clinically meaningful. Also, the cost of a dietary antioxidant-enriched multivitamin is relatively modest compared to other currently available therapies that have been proven to reduce pulmonary exacerbations in cystic fibrosis.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: We still don’t know the optimal dosing of these various dietary antioxidants. We also don’t know the added benefit of antioxidant supplementation in the era of CFTR modulator therapy, emerging treatments that get at the basic protein defect in cystic fibrosis.

MedicalResearch.com: Is there anything else you would like to add?

Response: This clinical trial, funded by a grant from the Cystic Fibrosis Foundation, was an investigator-initiated study led by Scott D. Sagel, MD, PhD, a Professor of Pediatrics at Children’s Hospital Colorado and Director of the University of Colorado Cystic Fibrosis Center. It was not an industry initiated or funded trial. Callion Pharma manufactured the antioxidant-enriched and control multivitamins and provided them at no charge for this study.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:
Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis: Randomized, Controlled, Multicenter Trial
Scott D Sagel , Umer Khan , Raksha Jain , Gavin Graff , Cori L Daines , Jordan M Dunitz , Drucy Borowitz , David M Orenstein , Ibrahim Abdulhamid , Julie Noe , John P Clancy , et al
https://doi.org/10.1164/rccm.201801-0105OC PubMed: 29688760
American Journal of Respiratory and Critical Care Medicine

Published Online: April 24, 2018

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

Original interview article here. 

Importance of Early Diagnosis, Treatment of NTM Infections

By Ashraf Malhas, PhD.

An earlier diagnosis and treatment of nontuberculous mycobacteria (NTM) infection in patients with cystic fibrosis (CF) may positively affect the patient’s lung function, a study suggests.

NTM are a group of bacterial species, found in soil and water, which are not usually associated with human disease, except if they infect susceptible individuals, such as CF patients.

An increasing incidence of NTM infections in CF patients has been observed, with recent studies reporting a prevalence of 32.7%. The exact reasons behind this, the risk factors, the species involved, and effective treatments for NTM infections in CF patients remain largely unknown.

In the study “Clinical course and significance of nontuberculous mycobacteria and its subtypes in cystic fibrosis,” published in the journal BMC Infectious Diseases, researchers analyzed the prevalence of NTM infections in CF patients to identify factors associated with these infections, as well as monitor current treatments.

The study initially involved 360 CF patients, of whom 30 (8%) were identified as being positive for NTM infection. Of these, 28 patients were further analyzed, and their results compared with 26 matched CF patients not infected with NTM (the control group).

Within the NTM group, 17 patients were infected with a class of NTM known as slow-growing, eight patients were infected with rapidly growing NTM, while three were positive for both types.

Those infected with slow-growing NTM were generally older (range of 6.4 to 41.6 years) than those infected with the rapid-growing types (3.1 to 21.5 years), but that difference did not reach statistical significance. However, the age at CF diagnosis was significantly lower in the slow-growing NTM group compared to the rapid-growing NTM group.

When lung function was assessed in the two groups, researchers found that lung function as measured by predicted expiratory flow was significantly higher before NTM infection, regardless of the type of NTM.

Regarding treatment patterns, the team found that significantly more patients infected with slow-growing NTM had received penicillin/beta-lactamase and rifampin following infection compared to before infection.

“An earlier CF diagnosis was associated with a higher isolation of slow-growing NTM and greater antimicrobial use after infection,” the researchers wrote, adding that “NTM acquisition is associated with a worsening of [lung function]. Thus, both the early diagnosis and treatment of an NTM infection in patients with CF may positively impact lung function.”

The team believes that “increased awareness by clinicians on different NTM subtypes and more universal treatment plan for NTM infection in the CF population may positively impact patient management and outcomes.”

Original article here.

Triclosan, often maligned, may have a good side — treating cystic fibrosis infections

By Chris Waters

Maybe you’ve had the experience of wading in a stream and struggling to keep your balance on the slick rocks, or forgetting to brush your teeth in the morning and feeling a slimy coating in your mouth. These are examples of bacterial biofilms that are found anywhere a surface is exposed to bacteria in a moist environment.

Besides leading to falls in streams or creating unhealthy teeth, biofilms can cause large problems when they infect people. Biofilms, multicellular communities of bacteria that can grow on a surface encased in their own self-produced matrix of slime, can block immune cells from engulfing and killing the bacteria or prevent antibodies from binding to their surface.

On top of this, bacteria in a biofilm resist being killed by antibiotics due to the sticky nature of the matrix and activation of inherent resistant mechanisms, such as slow-growing cells or the ability to pump antibiotics out of the cell.

Biofilms are one of the primary growth modes of bacteria, but all antibiotics currently used clinically were developed against free-swimming planktonic bacteria. This is why they do not work well against biofilms.

My laboratory studies how and why bacteria make biofilms, and we develop new therapeutics to target them. Because antibiotic resistance is the most problematic aspect of biofilms during infections, we set out to identify novel molecules that could enhance antibiotic activity against these communities.

We discovered that an antimicrobial that has recently obtained a bad reputation for overuse in many household products could be the secret sauce to kill biofilms.

The hunt for antibiotic superchargers

To find such compounds, we developed an assay to grow plates of 384 tiny biofilms of the bacterium Pseudomonas aeruginosa. We did this to screen for molecules that enhance killing by the antibiotic tobramycin. We chose this bacterium and this antibiotic as our test subjects because they are commonly associated with cystic fibrosis lung infections and treatment.

People with cystic fibrosis (CF) are at particular risk from biofilm-based infections. These infections often become chronic in the lungs of cystic fibrosis patients and are often never cleared, even with aggressive antibiotic therapy.

After we screened 6,080 small molecules in the presence of tobramycin, we found multiple compounds that showed the antibiotic enhancement activity we were searching for. Of particular interest was the antimicrobial triclosan because it has been widely used in household products like toothpaste, soaps and hand sanitizers for decades, indicating that it had potential to be safely used in CF patients. Triclosan has also garnered a bad reputation due to its overuse, and states like Minnesota have banned it from these products. The Food and Drug Administration banned its use from hand soaps in September 2016. This ruling was not based on safety concerns, but rather because the companies that made these products did not demonstrate higher microbial killing when triclosan was added, compared to the base products alone.

Another fact that piqued our interest is that P. aeruginosa is resistant to triclosan. Indeed, treatment with either tobramycin or triclosan alone had very little activity against P. aeruginosa biofilms, but we found that the combination was 100 times more active, killing over 99 percent of the bacteria.

We further studied this combination and found that it worked against P. aeruginosa and other bacterial species that had been isolated from the lungs of CF patients. The combination also significantly enhanced the speed of killing so that at two hours of treatment, virtually all of the biofilm is eradicated.

Our efforts are now focused on pre-clinical development of the tobramycin-triclosan combination. For CF, we envision patients will inhale these antimicrobials as a combination therapy, but it could also be used for other applications such as diabetic non-healing wounds.

Although questions about the safety of triclosan have emerged in the mainstream media, there are actually dozens of studies, including in humans, concluding that it is well tolerated, summarized in this extensive EU report from 2009. My laboratory completely agrees that triclosan has been significantly overused, and it should be reserved to combat life-threatening infections.

The next steps for development are to initiate safety, efficacy and pharmacological studies. And thus far, our own studies indicate that triclosan is well tolerated when directly administered to the lungs. We hope that in the near future we will have enough data to initiate clinical trials with the FDA to test the activity of this combination in people afflicted with biofilm-based infections.

We think our approach of enhancing biofilm activity with the addition of novel compounds will increase the usefulness of currently used antibiotics. Learning about how these compounds work will also shed light on how bacterial biofilms resist antibiotic therapy.

Original article here.

Omega-3 Compound Reduces Inflammation in Cystic Fibrosis Patients in New Pilot Study

By Jennifer Prince

A marine omega-3 compound comprising a docosahexaenoic acid (DHA) sn1-monoacylglyceride (MAG-DHA) may act as an anti-inflammatory for subjects with cystic fibrosis, according to a new pilot study1 published in the journal Marine Drugs. In the study, MaxSimil (Neptune Wellness Solutions; Laval, QC, Canada) increased omega-3 red blood cell levels, helped moderate the ratio of arachidonic acid (AA) to docosahexaenoic acid, and reduced key inflammatory biomarkers in subjects with cystic fibrosis. Continue reading Omega-3 Compound Reduces Inflammation in Cystic Fibrosis Patients in New Pilot Study