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.

I Inhaled Viruses As A Last-Ditch Effort To Fight A Drug-Resistant Bacterial Infection

By Ella Balasa

A few months ago I tried an experimental treatment called phage therapy to treat the relentless Pseudomonas in my lungs. This treatment was documented by the Associated Press and since then I have received many questions from individuals asking how I feel now. Well, I wrote a piece to tell the story from my perspective and hopefully provide some information that you can’t gather from just a news blurb.

I also discuss the importance of understanding scientific knowledge about treatments and disease prognosis. Without this, I would have shied away from trying this treatment that significantly helped me. It’s a vital aspect of being a receiver of health care ― asking questions, probing for answers, and gaining the knowledge to feel empowered to take an active role in shaping your health journey.

If anyone is interested in learning more about this experience, take a read at HuffPost here.

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.

Aridis Enrolling CF Patients to Test AR-501 in Chronic Lung Infections

By:
ALICE MELÃO

Aridis Pharmaceuticals has enrolled the first healthy participant in its Phase 1/2a clinical trial to evaluate the antibacterial potential of its investigational candidate, AR-501 (gallium citrate), against chronic lung infections in patients with cystic fibrosis (CF).

The study (NCT03669614) is expected to enroll approximately 48 healthy adult volunteers and 48 adult CF patients with chronic lung infections across 15 sites in the United States.

Participants will be randomized to receive one of three doses of AR-501, or a placebo, self-administered once a week using a hand-held nebulizer.

The company expects to announce results from Phase 1 during the fourth quarter of 2019, and from Phase 2a in the fourth quarter of 2020.

“We are pleased to initiate this exciting program with the first subject enrolled,” Wolfgang Dummer, MD, PhD, chief medical officer of Aridis, said in a press release. “Through this trial, we anticipate safety, pharmacokinetic, and exploratory efficacy data that will enable us to further explore the potential of AR-501 in the treatment of life-threatening bacterial infections in cystic fibrosis patients.”

AR-501 is an inhalable formulation of gallium being developed to treat pulmonary bacterial infections. It works by starving bacteria of iron, and inhibiting their iron-dependent metabolic processes necessary for the infection to progress, a mechanism very different from that of common antibiotics.

Preclinical studies have demonstrated that AR-501 holds a broad antibacterial activity with unique benefits, compared to current standard-of-care antibiotics, working against antibiotic-resistant strains such as Pseudomonas aeruginosa and B. cepaciaaccording to the company.

Also, data from a Phase 2 clinical trial (NCT02354859) showed that intravenous gallium is safe and can effectively improve the lung function of CF patients.

“The recent safety and efficacy demonstration of intravenous gallium from a Phase 2 clinical study in CF patients gives us optimism of the prospect inhaled delivery of gallium (AR-501), which is a more direct, local route of delivery to the site of infection in the lungs and less systemic exposure,” Dummer said.

The new Phase 1/2a trial is being conducted in collaboration with the Cystic Fibrosis Foundation (CFF), and is led by Noah Lechtzin, MD, director of the Adult Cystic Fibrosis Program and associate professor of medicine at Johns Hopkins University.

The U.S. Food and Drug Administration recently granted Fast Track Designation and Qualified Infectious Disease Product Designation (QIDP) to AR-501. These are expected to support and expedite the therapy’s development and regulatory review.

Original article: https://cysticfibrosisnewstoday.com/2018/12/14/aridis-started-enrolling-in-phase-1-2a-trial-to-test-ar-501-antibacterial-potential/

For Use in CF, New 2-in-1 Powder More Effective Against Resistant Bacteria

https://cysticfibrosisnewstoday.com/2018/12/18/new-powder-inhalation-more-effective-killing-antibiotic-resistant-bacteria/?utm_source=Cystic+Fibrosis&utm_campaign=c31e0676bf-RSS_MONDAY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_b075749015-c31e0676bf-71418393

By Albert Molano

Originally published in Cystic Fibrosis News Today

12/18/2018

Purdue University researchers have invented a new way of delivering two antibiotics (colistin and ciprofloxacin) deep into the lungs of cystic fibrosis (CF) patients, enabling much more effective killing of antibiotic-resistant bacteria without exposing patients to high systemic doses of these therapies.

“We are providing a promising option to fight the global crisis of antimicrobial resistance,” Qi (Tony) Zhou, PhD, assistant professor at Purdue’s College of Pharmacy, who led the research team, said in a press release.

Respiratory infections caused by multidrug-resistant bacteria in CF patients can be deadly because they are resistant to most available antibiotics. In addition, therapies given intravenously (by injection into the vein) or orally have a hard time reaching the lungs, potentially requiring high doses for the therapy to be effective.

Last-resort antibiotics can still be effective, but these can be very toxic if they are given systemically. Colistin, for example, can damage the kidneys.

The existing alternative is to nebulize the antibiotics and deliver them directly into the lungs, which increases their local concentrations while reducing the risk of systemic toxicity. However, this requires expensive and complicated delivery devices, and prolonged administration times.

Now, Zhou’s team has succeeded in combining two antibiotics — colistin and ciprofloxacin — into a single particle that can be delivered as a dry powder.

According to the team, with this new formulation, more than 60 percent of the antibiotics reach the lungs, as opposed to only 10 percent with a jet nebulizer. In addition, the dry formulation offers improved chemical stability, and it is easier to use than conventional inhalation products.

“It has been a worldwide challenge to incorporate two antibiotics with different chemical properties into a single particle. Our novel formulation allows for a much more effective killing of drug-resistant bacteria in the deep lungs as two synergistic antibiotics can be simultaneously delivered to the same infection site,” Zhou said.

The team believes this technology can be applied to several antibiotic and compound combinations, potentially saving tens of thousands of lives from several deadly lung infections, including those affecting CF patients and people with ventilator-assisted pneumonia.

The Purdue Office of Technology Commercialization has filed a patent for the new technology, and researchers are looking for partners to continue its development.

As Both Patient and Scientist, I’m Putting Nature’s Medicine to the Test

By Ella Balasa

I peered into one of the incubators that stored my petri dishes for 24 hours, anxious to see whether I would discover discoloration and unevenness on the surface, which would have indicated that my experiment produced favorable results. I wanted to see a visual representation of whether manuka honey kills the stubborn Pseudomonas bacterium, which dwells in nearly half of the lungs affected by CF.

I’m a microbiology lab scientist, plus an inquisitive writer. I also consider myself an informed, self-advocating realist. Life experiences have taught me that I am solely responsible for my health. I strive to keep my health stable through prescribed medications, healthy diet, and some natural supplements.

During my college years, I focused on the environment, especially the living parts that we can’t see but that are essential to the cycle of life — bacteria. It just so happens that certain ones are, understatedly, little pests for people with CF. The lung bacteria of people with CF birth many symptoms and infections.

I continually fight Pseudomonas aeruginosa, my nemesis bacterium that spikes fevers within days of overwhelming my immune system and that has caused countless infections, leaving my lungs with pockets of dead tissue. I take antibiotics frequently, but I also believe that naturally derived compounds can have positive effects. So, despite my disdain and nausea, I sometimes supplement garlic, which contains the antibacterial compound ajoene. I’ve also consumed manuka honey; this I’ve done more religiously, as it tastes more like candy than any “medication.” Manuka honey contains the natural antibiotic methylglyoxal, a compound that fights relentless Pseudomonas by causing its cells to burst and die. I took a spoonful a day for a few years until recently. Maybe I stuck to this exorbitantly priced, palatable remedy merely because of its taste and the flawed logic that expensiveness is indicative of effectivity.

I had the idea to test the effectiveness of the honey on my sputum. My mucus grows many species of bacteria, but Pseudomonas is a primary component, so it’s easy to propagate in the lab setting.

Yes, I took a sputum cup of mucus into work. When inoculating the vials with the bacteria, I was slightly anxious that my lab mates might freak out at the sight of the hazardous and vile-looking green blobs. Then again, they work with wastewater from treatment plants, so it really shouldn’t phase them.

I tested a concentration of 15 percent weight per volume of manuka honey, a choice informed by published studies. I tested half of the petri dishes with honey mixed into the nutrients for the bacteria and the other half without the honey. The dishes with the honey should have less bacterial growth if the treatment works. (If you want more detail on the process, drop a comment below this column.)

The yellow dish has the honey added and the white dish doesn’t. (Photo by Ella Balasa)

After the 24-hour incubation period, I was excited to see the results of science that we as patients typically do not participate in. We provide our sputum samples during doctor’s appointments, then labs perform antibiotic resistance tests, and results are returned as values on a piece of paper indicating resistance or susceptibility. We don’t see the process. I was doing this same research on my own, and in a sense, taking the utmost control of my health.

To continue reading, click here.

Nutritional Well-Being After Transplant Measure of Likely Lung Health

By Joana Carvalho

The study, “Impact of nutritional status on pulmonary function after lung transplantation for cystic fibrosis,” was published in the United European Gastroenterology Journal.

CF is the third most common cause for lung transplants worldwide (16.8 percent of all cases). Although the disease is mostly associated with respiratory symptoms, gastrointestinal complications are also known to afflict patients, such as diarrhea, constipation, malnutrition, and inflammation in the pancreas, liver and intestines.

Previous studies suggest that malnutrition is linked to a poor prognosis in those needing a lung transplant. However, data on the impact of nutritional status on pulmonary function in those who have received a transplant is still quite limited.

In a retrospective study, a team of researchers at the Medical University of Vienna set out to evaluate the impact of nutritional status on pulmonary function of CF patients who underwent a double lung transplant within a median of 2.3 years.

Patients’ nutritional status was assessed using two different criteria: body mass index (BMI; kg/m2), and body composition measured by bioelectrical impedance analysis (BIA) — a technique that allows researchers to estimate body composition, especially fat content, by calculating the resistance posed by body tissues to the passage of an electrical current.

Lung health was analyzed by spirometry, a common test based on the amount of air a person can inhale and quickly exhale.

Investigators analyzed a total of 147 spirometries and BIAs performed on 58 CF patients (median age, 30.1), who were divided into four groups depending on their BMI scores. These groups were set according to BMI the guidelines defined by the World Health Organization (WHO), were: malnutrition (less than 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), or obese (more than 30 kg/m2).

Data showed that malnourished patients (27.6%) had a significantly poorer in lung function than those of normal weight (63.8%) or overweight (8.6%), as measured by the percentage of forced expiratory volume in one second (FEV1% predicted, 57% vs 77%), and the percentage of maximum vital capacity (percent predicted, 62% vs 75%).

Investigators also found that lung function measured by FEV1% worsened over time in malnourished patients (decreasing by up to 15%), unlike normal weight and overweight individuals. In these patients, FEV1% remained stable throughout the observation period (median of 10.3 months).

Further analysis also showed that the ratio of extracellular mass (ECM) over body cell mass (BCM), as measured by BIA, accurately predicted lung function over time in CF transplant recipients, suggesting that BIA is superior to BMI in predicting patients’ pulmonary function.

The team concluded “nutritional status assessed by BIA predicted lung function in CF transplant recipients,” and suggested that “BIA represents a non-invasive, safe, fast, mobile, and easy-to-use procedure to evaluate body composition. Thus, it may be used in everyday clinical practice and bears the advantage of repeatability at every patient follow-up.”

The researchers also emphasized the importance of multidisciplinary patient care provided by dietitians and gastroenterologists to try and prevent or diminish malnourishment in CF patients, and so help preserve lung function after a transplant.

Original article here. 

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

Cinnamon Oil Compound Might Block Bacteria Like P. aeruginosa from Forming Biofilms

By: Alice Melao

A natural component found in cinnamon oil, known as cinnamaldehyde or CAD, may be able to prevent Pseudomonas aeruginosa bacteria from spreading in an organism and inhibit their ability to form antibiotic-resistant biofilms, researchers show.

These findings may support further study into anti-microbial medications that can help control the behavior of these so-called superbugs, or treatment-resistant bacteria, which represent a serious healthcare problem for people with cystic fibrosis and other diseases.

The discovery was reported in “Cinnamaldehyde disrupts biofilm formation and swarming motility of Pseudomonas aeruginosa,” published in the journal Microbiology.

“Humans have a long history of using natural products to treat infections, and there is a renewed focus on such antimicrobial compounds,” Sanjida Halim Topa, PhD, a researcher at Swinburne University of Technology in Australia, and lead study author, said in a university news release. “Natural products may offer a promising solution to this problem.”

Cinnamaldehyde, one of the major components of cinnamon oil, is responsible for its characteristic flavor. This compound is known to have antimicrobial activity against many bacteria, including P. aeruginosa; a stomach ulcer-causing bacteria called Helicobacter pylori; and Listeria monocytogenes, which is responsible for the food-borne infection listeriosis.

“We hypothesized that using natural antimicrobials, such as essential oils, might interfere in [drug-resistant] biofilm formation,” Topa said. “Though many previous studies have reported antimicrobial activity of cinnamon essential oil, it is not widely used in the pharmaceutical industry.”

Working with researchers at Nanyang Technological University in Singapore, the team conducted several experiments to evaluate the impact of different concentrations of cinnamaldehyde on P. aeruginosa biofilms.

They found that non-lethal amounts of the essential oil compound could disrupt by 75.6 % antibiotic-resistant, preformed P. aeruginosa biofilms. Cinnamaldehyde was found to prevent the production of a bacterial-signaling protein essential for bacteria communication and biofilm formation. [Biofilms, or microbe communities whose growth is facilitated by the thick and sticky mucus that marks CF, are known to promote antibiotic resistance in P. aeruginosa lung infections.]

In a concentration-dependent manner, cinnamaldehyde also could reduce the motility of the bacteria, preventing them from spreading elsewhere, the scientists reported.

These findings, the researchers wrote, show “CAD can disrupt biofilms and other surface colonization phenotypes through the modulation of intracellular signaling processes.”

They are now investigating the use of cinnamaldehyde embedded-wound dressings as a way to treat skin infections.

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