Thread by @MSUPedsPulm

I will be “live tweeting” about #ATS2020 #B2 WHEN CF BECOMES NON-CF BRONCHIECTASIS: THE ONGOING BATTLE AGAINST INFECTION IN CYSTIC FIBROSIS DURING THE CFTR-MODULATOR ERA. (I'm not yelling the ATS program is) #Thread

First up, Mara Cray a 24yo CF patient discusses her perspective. (I hope they put this up for even non-attendees as I can not do it justice via twitter. Sorry twitter) She Has been on several modulators with wonderful results.

She is doing much better but still has exacerbations and recently had ABPA. The asthmatic components of CF are “primally stressful” because of how acute they are and how uncomfortable they are.

She eventually had to explore biologic therapies to get the ABPA under control and saw and allergist which was also hard. “It is always a lot of work to bring another person into your care team.” (Something we should keep in mind when making referrals)

Decreasing the modulator dose because of the antifungals was so frustrating for her. She felt like she could not use the modulator to its maximal capacity. The emotional support provided by her CF physician was valuable to her.

Next up in #ATS2020 #B2 we have Microbiota in the CF Airway Across the Disease Spectrum. Lindsay Caverly, BA, MD. University of Michigan, Ann Arbor, MI. (I just recorded a podcast with her and @Quinn_Labs about this that should be out in a few months) @LindsayJCaverly

Anaerobes also abundant in airways of people with CF. A majority of CF lung microbiota can also be identified on culture. (Whelan FJ et al. Nature Mico 2020)

Anaerobes are also metabolically active. Short chain fatty acids from anaerobes are present and associated with inflammation. (Mirkovic et al. AJRCCM 2015)

CF pathogens and anaerobes are also translationally active in CF airways based on BONCAT labelling. (Valentini TD et al. Nature Comm 2020)

Traditional pathogens increase with age in CF. Decrease in the abundance on anaerobes over time. These changes parallel lung function declines. (Zemanick et al. ERL. 2017)

Advancing age and lung disease stage occurs in parallel with decrease in bacterial diversity. (Coburn et al. 2015)

CF disease aggressiveness (lung function decline) have greater decrease in bacterial diversity. (Zhao et al. PNAS 2012)

Paired exacerbation sputum labs found no changes in bacterial load during exacerbations contrary to conventional wisdom. (Carmody LA et al. AnnalsATS 2013)

Increase in anaerobes at exacerbation compared to baseline. Not all studies find changes though. When separated by disease stage anaerobes increase in early and moderate but not late lung disease. (Carmody LA et al PLOSOne 2018)

Variation of microbiota within baseline periods in CF is greater than controls. Each patient has outlier samples. These change with chronic therapy changes. (Caverly LJ AnnalsATS 2019)

Changes in microbiome in response to inhaled tobramycin are largely in off target bugs not traditional CF pathogens (Nelson MT et al Thorax 2020)

Decreases in total bacterial load and pseudomonas with ivacaftor only seen in patients on consistent antibiotic regimens (Peleg et al JCF 2018)

After a year of ivacaftor decrease in PSA, mucoid PSA and aspergillus. 29% cleared pseudomonas after one year. More likely to clear if FEV1 higher and PSA intermittently cx. (Heltshe et al CID 2015)

Ivacaftor associated with pseudomonas, staph, and aspergillus decline. Reduced PSA acquisition. More likely to clear if FEV1 higher. (Frost et al 2019)

Use of modulator associated with delayed acquisition of CF pathogens. (Singh et al Peds Pulm 2019)

GOAL study: Downward trend in CF pathogen abundance after ivacaftor but no change is diversity, bacterial load, or pseudomonas load. Effect heterogeneous. (Rowe et al AJRCCm 2014)

Early changes is airway microbiota may not be sustained. (Hisert et al AJRCCM 2017)

Next up in #ATS2020 #B2 we have Fungus Among Us: Understanding the Role and Treatment of Fungi in the CFTR Modulator Era. Gina Hong, MD, MHS. Hosp of the Univ of Pennsylvania, Philadelphia, PA.

Aspergillus is increasingly found in CF sputum. Could be related to antibiotics or better testing. (CFF Registry 2017) #ATS2020 #B2

Metagenomic data from 66 CF patients found candida the most common but the fungal profiles were more divers than what is found in culture. (Cuthbertson JCF 2020)

Ivacaftor associated with reduction in aspergillus (Heltshe et al CID 2015) (Frost et al 2019) #ATS2020 #B2

Aspergillus can lead to ABPA, sensitization, colonization, or bronchitis. Guideline only exists for ABPA. (Stevens et al. Clin Infect Dis 2003) #ATS2020 #B2

ABPA and aspergillus sensitization have similar biomarkers making diagnosis difficult. Specific antigens may help distinguish between the two. No clear way to distinguish bronchitis and colonization. #ATS2020 #B2

Aspergillus bronchitis is symptomatic with clinical deterioration and responds to therapy. Parameters not objective or agreed upon. (Shoseyov D et al. Chest 2006, Baxter et al J Clin Immunology 2013, Brandt et al Mycopathologia 2018) #ATS2020 #B2

Significant regional variation in the belief that aspergillus bronchitis exists or requires treatment.

Aspergillus found to be associated with lower CFQR scoring. (Hong et al JCF 2020) #ATS2020 #B2

Other fungi associated with clinical deterioration but variable. Azoles are the best bet for treatment for most of these. Not Rasamsonia though.

Azole absorption in CF, genetic polymorphisms, and modulators all make dosing very difficult. Monitoring is necessary! #ATS2020 #B2

Next up in #ATS2020 #B2 we have The Role of Anti-Staphylococcal Antibiotic Prophylaxis in Young Children with Cystic Fibrosis. Alan Smyth, MD. Nottingham Univ Hosp, Nottingham, United Kingdom

Most bacterial isolates in young children come from upper airway specimens which may not reflect lower airway infection.

Upper airway cultures have poor positive predictive value in children with CF. (Rosenfield et al. Peds Pulm 1999) #ATS2020 #B2

Healthy children grow staph but not pseudomonas (Carlson et al. Peds Pulm 2009, Rosenfield JCF 2012)

BAL directed therapy does not improve outcomes vs usual care. (Wainwright JAMA 2011) #ATS2020 #B2

Induced sputum identifies more pathogens than swabs, feasible, similar to BAL (Ronchetti et al Lancet Resp Med 2018)

2017 Cochrane review: no significant clinical effect of anti-staph prophylaxis & decreased Staph + cultures. Trend towards more PSA after age 3. #ATS2020 #B2

German registry data suggests more pseudomonas with staph prophylaxis but this was using cephalosporins (Ratjen et al. Peds Pulm 2001) #ATS2020 #B2

Flucloxacillin registry data: less staph and PSA in UK with prophylaxis than in US where there is not. Those in UK NOT getting prophylaxis are at LESS risk of acquiring pseudomonas though. Significant confounders in data. (Hurley MN et al. Ann Am Thorac Soc 2018) #ATS2020 #B2

May not need prophylaxis in modulator era. Ivacaftor has intrinsic ant-staph activity. (Payne JE Int J Antimicrob Agents et al. 2017, Reznikoz et al. JCF 2014) #ATS2020 #B2

Next up in #ATS2020 #B2 we have Azithromycin-Tobramycin Interaction Against Pseudomonas Aeruginosa in CF. David Nichols, MD. Seattle Children's Hospital, Seattle, WA.

Tobramycin shows less increase in FEV1 and PSA in recent data with high prior use of tobramycin. (Konstan et al. JCF 2011, Assael BM JCF 2013, Elborn JS JCF 2015) #ATS2020 #B2

FEV1 response to inhaled Tobra may decline with each cycle (Ramsey BW NEJM 1999)

Registry data does suggest survival increase with inhaled Tobra (Peds Pulm 2012) #ATS2020 #B2

Azithromycin leads to ~1/3 risk of exacerbation in those with pseudomonas infection (JAAM 2003;290)

Azithromycin decreases exacerbations in those without pseudomonas. (JAMA 2010;303, Am J Resp Crit Care Med 2018;198) #ATS2020 #B2

Registry data does finds effect on FEV decline in those on azithromycin only if PSA positive (Am J Resp Crit Care Med 2020)

French registry: reduced lung function decline in those on AZM. Did not differentiate between PSA or no PSA. (Ann AM Thoracic Soc 2020;17) #ATS2020 #B2

Lab evidence suggests AZM may reduce TOB ability to kill PSA. Less killing in combo than with TOB alone. Effect not seen in other inhaled antibiotics. (JCF 2017;16)

Majority of TOB FEV1 benefit seen in those not on AZM. (Annals AM Thoac Soc 2014;11) #ATS2020 #B2

Aztreonam was more effective than TOB in patient on AZM. Effect not seen if they were not on AZM. (JCF 2017;16)

Chronic AZM only showed benefit for those on chronic aztreonam not in those on TOB. (Am J Resp Crit Care Med 2020;201) #ATS2020 #B2

IV Tobramycin associated with less improvement if patient on azithromycin. This was not seen with Colistin. (Ann ATS 2019;16) #ATS2020 #B2

Challenges and limitations in considering drug-drug interaction. Indication bias. Limited contemporary trial dataset. Continuous inhaled antibiotic being used more. #ATS2020 #B2

Lastly in #ATS2020 #B2 we have Bacteriophage-Based Therapy for Multi-Drug Resistant Bacteria in CF Jon Koff, MD. Yale School of Medicine, New Haven, CT.

Antimicrobial resistance is an approaching crisis. Worse in CF. Modulator therapies improving outcomes but do not eradicate infection. (Hisert ACRCCM 2017) (We have seen this 3 times now must be important) #ATS2020 #B2

Phages used for therapy for decades much of which was done in Russia. Phages are viruses that infect bacteria. Can be lytic (kill) or lysogenic. Degrade biofilms. Specific to each bacteria. Bacteria can develop resistance. #ATS2020 #B2

Phage therapy used in CF. Improved disease stability and allowed patient to make it to transplant. (Law et al 2019). 3 phage cocktail for NTM improved FEV1 and FVC. (Dedrick et al Nature Medicine) #ATS2020 #B2

Phage resistance will occur. Lytic phages induce receptor downregulation in the receptor they target. Use of phages that target receptors used for antibiotic resistance can make bacteria more susceptible to antibiotics. (Lortright et al Cell Host Microbe 2019) #ATS2020 #B2

Yale obtain sputum to identify phage. Nebulize phage for 7 days. Decreased PSA and improves FEV1. (B Chan Peds Pulm 2019, Koff ATS 2019) #ATS2020 #B2

If you want to learn a little more about phages and CF we did a podcast on this in 2018.

thoracic.org/about/ats-podc…

This concludes my live tweeting. If any of you made it this far let me know with a like. #ATS2020 #B2