Monthly Archives: July 2022

Alpha-1 antitrypsin (AAT) deficiency, by PD Clara Schroedl

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Alpha-1 antitrypsin (AAT) deficiency

AAT = protease inhibitor (PI), synthesized in hepatocytes

Emphysema results from an imbalance between neutrophil elastase in the lung (destroys elastin), and the elastase inhibitor AAT = “toxic loss of function”

  • Lung degradation occurs with increased elastase burden in the lungs (smoking)

Liver disease: “toxic gain of function”; accumulation within the hepatocytes of unsecreted variant AAT protein; almost always PI*ZZ

Genetics: autosomal co-dominant; 150 alleles of AAT

  • Normal = M -> PI*MM
  • AAT = Z (most common) -> PI*ZZ
  • AAT = S (compound heterozygote) -> PI*SZ
  • Heterozygotes (PI*MZ): conflicting data re emphysema risk

AAT phenotypes: protective threshold 11 micromol/L (57 mg/dL)

  • Normal: MM
  • Deficient: AAT level < 35% normal
  • Null: no detectable AAT (rare, most severe lung disease, no liver disease)
  • Dysfunctional: normal levels but dysfunctional (PI*F)

Epidemiology: 2-3% of patients with COPD; 80-100K individuals in the US

Clinical manifestations:

  • Emphysema onset at young age, basilar-predominant (although substantial variability), PTX, bronchiectasis
  • Hepatitis, cirrhosis, HCC, panniculitis, IBD, intracranial and inta-abdominal aneurysms, fibromuscular dysplasia, glomerulonephritis

From: https://radiopaedia.org/cases/alpha-1-antitrypsin-deficiency-15?lang=us

Diagnosis: screen all adults with persistent airflow obstruction, emphysema, FH or emphysema/liver disease, adult onset asthma, panniculitis, unexplained liver disease

  •  Send Alpha-1 Antitrypsin Phenotype and Quant

Monitoring:

  • Asymptomatic with normal spiro: spiro Q6-12 mths; augment if/when FEV1 < 80%
  • LFTs annually, +/- CBC (Plts) and liver US Q6-12 mths
  • Lung function decline strongly affected by smoking

Treatment (i.e., Augmentation)

  • Pooled human AAT intravenous infusion (weekly) -> goal is to slow disease progression
  • Never or ex-smokers, > 18 y/o, with low serum AAT and high-risk genetic variant
  • FEV1 35-65% (other societies suggest FEV1 25-80%); uncertainty regarding a lower limit of FEV1 – probably protecting additional lung function decline is favorable although study do not demonstrate clinical improvement
  • Check pre-treatment IgA levels, vaccinate for Hep A and B
  • Efficacy: modest effect in slowing lung function decline (23% slower decline); greatest benefit for those with moderate obstruction.  Achieving a “protective” serum threshold is not necessary.
  • Cost: > $100,000 per year

Screening of Family:

  • Genotype first-degree relatives: siblings, parents, children of PI*ZZ individuals; first degree relatives of individulas with other PI*MZ can be offered testing

Good reference: https://www.alpha1.org/alphas-friends-family/resources/find-an-alpha-1-specialist/

Thank you, Dr. Schroedl, our fearless Program Director, for summarizing!

Clara Schroedl, MD, MSc, Medicine – Pulmonary/Critical Care

 

Chylothorax Review

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A review from Amy Ludwig’s AM Report.  Answer to follow in comments

Liberation from mechanical ventilation in critically ill adults

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“Liberation from mechanical ventilation in critically ill adults: an official American College of Chest Physicians/American Thoracic Society clinical practice guideline,” CHEST, 2017

Question: In acutely hospitalized patients ventilated more than 24 hours, should the spontaneous breathing trial (SBT) be conducted with or without inspiratory pressure augmentation? (1 of 6 questions addressed in the guidelines).

Study Type: Systematic review, meta-analysis, and multidisciplinary expert panel discussion

Methods: Panel co-chairs were selected by CHEST and ATS leadership.  14 panelists were then selected by co-chairs (7 pulm/CCM MDs, 4 CC MDs, 1 CC RN, 1 physical therapist, 1 pharmacist).   Co-chairs drafted 6 key questions which were reviewed by the panelists.  After finalization of search terms, inclusion/exclusion criteria, and databases to be searched, a systematic review was performed by a methodologist.  Studies were screened, reviewed, and extracted by panelists.  Final recommendations required 75% panel participation and 80% consensus.

Studies Included: Systematic reviews, RCTs, or observational studies comparing SBT with inspiratory pressure augmentation (PS or automatic tube compensation) to SBT without pressure augmentation in acutely hospitalized patients ventilated for >24 hrs.  This review excluded patients who did not pass an initial SBT (i.e. the 1994 Brochard and 1995 Esteban RCTs we reviewed were excluded).

Outcomes: Duration of ventilation, ventilator-free days, successful SBT, extubation success (not requiring NIV or reintubation for 48 hrs), duration of ICU stay, short-term mortality (<60 days), and long-term mortality.

Results: 560 articles screened, 14 included in full text review, 5 included in qualitative synthesis, 4 included in quantitative synthesis.  When the 4 trials were pooled through meta-analysis, conducting an SBT with pressure augmentation was more likely to be successful (84.6% vs 76.7%; RR 1.11; 95% CI, 1.02-1.18), produced a higher rate of extubation success (75.4% vs 68.9%; RR, 1.09; 95% CI, 1.02-1.18), and was associated with a trend toward lower ICU mortality (8.6% vs 11.6%; RR, 0.74; 95% CI, 0.45-1.24).

Caveats: Only 4 trials included in analysis (including studies from the Croatian Medical Journal and the American Journal of Medical Sciences), 3 of the 4 trials were single-center studies, all trials non-blinded.

ACCP/ATS Recommendation: “We suggest that the initial SBT be conducted with inspiratory pressure augmentation (5-8 cmH2O) rather than without (T-piece or CPAP). Conditional recommendation, moderate quality evidence.”

Comments:

– The 1997 study by Esteban is by far the most rigorous.

– To summarize, in parts 1 and 2 of this review we looked at landmark RCTs by Brochard and Esteban.  I chose these trials because they are frequently mentioned on rounds and in textbooks when discussing liberation from MV.  It’s important to be familiar with these trials and also to understand how their unique methodologies (only randomized patients who failed a 2-hr T-piece trial, step-wise decrease in PS, multiple SBTs per day) do not apply to usual practice today.

– In my opinion, the ACCP/ATS recommendations are sensible but it’s important to acknowledge that they are based on limited data (only 4 trials of varied quality) and that the confidence intervals for both SBT success and extubation success are underwhelming and very nearly include 1

– I think for the vast majority of patients, a PS trial is a reasonable strategy for SBTs.  However, at NMH we see a lot of patients with COPD and CHF.  In these patients, the 5 cmH20 of PEEP used with traditional PS SBTs may be physiologically relevant by easing work of breathing in the setting of dynamic hyperinflation (COPD) or improving LV performance by decreasing LV afterload (CHF).  In these settings, passing a PS SBT may falsely reassure providers that a patient is ready to be liberated from MV.  When caring for these specific patients, I still find T-piece trials very helpful.  In the end, probably what matters much than the weaning strategy used is making sure you are performing daily SBTs in patients who are eligible, extubating those who pass, and aggressively treating reversible problems in those who fail.  I would be interested in the opinions of attendings on this list.

ILD Roundup 7/15/22

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  1. Necrobiotic rheumatoid nodules were discovered on biopsy in a patient with RA-ILD

What are the observed pulmonary manifestations of Rheumatoid arthritis?

Graingers and Allison’s Diagnostic Radiology, 9, 206-230.

 

What is epidemiology, clinical, radiologic, and pathologic criteria associated with necrobiotic rheumatoid nodules?

 

  • Rare complication (1% with RA)
  • More common in:
    • Men > Women
    • Long-standing disease
    • RF positivity
    • Active disease (esp cutaneous rheumatoid nodules’ also with joint disease, and elevated RA serologies)
  • Morphology:
    • Single or multiple
    • mm to several cm in diameter
    • Well-circumscribed
    • May cavitate à leading to pneumothorax or bronchopleural fistula
    • May wax/wane
    • May be PET avid (although those >8 mm are not typically)
  • Pulmonary nodules can paradoxically worsen with the start of RA therapy (most well observed with methotrexate)
  • Nodules with upper/midzone predilection, located along interlobular septa or subpleural regions
  • May cavitate (due to proteolytic enzymes) or rupture (leading to PTX or bronchopleural fistula)

 

European Respiratory Review 2015 24:1-16 (link)

Fishman’s Pulmonary Disease and Disorders, Chp 60, 5e.

 

In our case, a VATS biopsy was performed to rule out malignancy and infection as other causes of cavitating lung lesions.

 

2. Our second case featured a patient with history of Sjogren Syndrome (SS) with cystic lung disease. In this case, the mural thickening and nodularity of the cysts and presence of lymphadenopathy raised our concern for potential malignancy. Gabby Liu raised MALT lymphoma as a potential diagnosis.

 

What is the association between SS and MALT lymphoma?

  • Among autoimmune disorders, SS is most strongly associated with the development of lymphoma
  • In a small retrospective study describing biopsy-proven MALT lymphoma with lung involvement, 54% met criteria for SS

 

What are the commonly associated patterns of ILD in SS, and how are cystic lung diseases characterized and distinguished?

  • Follicular bronchiolitis
  • Lymphocytic interstitial pneumonia (LIP)
  • Non-specific interstitial pneumonia (NSIP)
  • Amyloidosis
  • Lymphoproliferative disorders, including lymphoma

Clin Med Res. 2017; 15(1-2):6-12 (link)

AJRCCM 2015; 191(12) 1354-1666 (links 1 and 2 included below)

 

3. The third case involved a former smoker with CT findings of a probable UIP pattern with air trapping. The differential diagnosis included fibrotic hypersensitivity pneumonitis (fHP) vs IPF (i.e., CPFE). A bronchoscopy with BAL and lung biopsy were discussed as potential next steps for establishing diagnosis.

How is the diagnosis fHP arrived upon? How is fHP distinguished from other fibrotic ILDs?

AJRCCM 2020; 202(3):e36-e69. (link)

 

Congratulations, Dr. Nandita Nadig!

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Congratulations are in order for Dr. Nandita Nadig, MD, MSCR, who was recently awarded both the NUCATS Dixon Translational Research Grant and the Eleanor Wood-Prince Grant. The Dixon Grants fund “innovative, multi-disciplinary clinical and translational research collaborations…that can make an impact in medical science at a national level,” established after a $20 million pledge from Suzanne and Wesley Dixon, the largest contribution for a single program in hospital history. The Eleanor Wood-Prince Grant Initiatives are a project of The Women’s Board of Northwestern Medicine, and has awarded over $1.7 million to recipients since 2001.

As the Medical Director of Critical Care Integration, Dr. Nadig’s research and clinical interests have focused on reducing healthcare disparities in ICU transfers and right-sizing care using telehealth and regional outreach approaches. She was a 2019 Parker B. Francis fellow and has also recently been awarded the Diversity Grant from the American Thoracic Society for her project, “Inter-ICU Transfer Telehealth Tool (IITT)-Family Centered Care through Telehealth”.

We had the pleasure of speaking with Dr. Nadig on her recent accomplishments and advice she has for fellows and junior faculty. She described having found these opportunities on the NUCATS website, which “seemed to be a good fit and the right avenue to build a new team”. She feels like the often quoted, “success begets more success” oversimplifies reality, because “people who are successful have in fact participated more, have had more failures, more rejections, more experiential learning.” She encourages everyone to “persist, practice resilience, incorporate feedback and adapt as it will serve you well not only in your research but in your career!”

As she “look[s] forward to embedding healthcare equity principles while developing and implementing the vision for critical care integration,” we too look forward to seeing her work develop further and appreciate her guidance and mentorship!

“Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department, the LIPS-A randomized clinical trial” JAMA, 2016, USA

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“Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department, the LIPS-A randomized clinical trial” JAMA, 2016, USA

Question: Does aspirin prevent the development of ARDS in at-risk patients?

Study Type:  Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial at 16 medical centers across the United States

Study Population: Adults presenting to the emergency department with a Lung Injury Prediction score ≥ 4 were eligible (see commentary for more regarding LIPS).  Numerous exclusions included ARDS on presentation, chronic use of antiplatelet therapy, admission for elective surgery, chronic tracheostomy, presentation due to CHF, active peptic ulcer disease, bleeding disorders, and severe chronic liver disease.  Randomization had to occur within 12 hours of presentation.

Study Groups: Patients were randomized to either placebo or daily ASA given as a 325mg loading dose within 24 hours of presentation followed by 81mg daily up to hospital day 7, discharge, or death.  Clinicians were encouraged to use the Checklist for Lung Injury Prevention to guide clinical care.

Primary Outcome: Development of ARDS requiring mechanical ventilation within 7 days of hospital admission

Results: 390 patients included in intention-to-treat analysis. Notable patient characteristics: median age (67), Caucasian (72%), suspected sepsis (78%), non-cardiogenic shock (21%), possible PNA (61%), ventilated on day of randomization (17%), median LIPS (≈5.75).  ASA did not decrease the development of ARDS (10.3% in ASA group, 8.7% in placebo group, P=0.53). ASA did not significantly impact any secondary outcome measures.  There was no difference in adverse events between groups

Caveats: Generalizability a concern as 95% of the 7,673 patients screened were excluded (with prior antiplatelet use, inability to consent with 12 hours, and suspected active bleeding being the most common reasons for exclusions), delay between consent and medication administration (median delay 12.7 hours), development of ARDS occurred almost half as frequently as anticipated.

Take-home Point: Among at-risk patients presenting to the emergency department, daily ASA use did not decrease the development of ARDS at 7 days.

Commentary

–       I chose to review this study because it is important for residents to be aware of the increasing focus on ARDS prevention.  Indeed, the NHLBI-funded ARDS clinical trial network is named PETAL (Prevention and Early Treatment of Acute Lung Injury).  This refocusing of ARDS clinical trials is based on the observation that ARDS incidence has decreased (suggesting perhaps that through early abx, thoughtful IVF, less injurious ventilator strategies, and restrictive transfusion thresholds we have shown that ARDS prevention is possible) and the hypothesis that so many therapeutic trials in ARDS have been negative because therapies have been initiated AFTER significant alveolar-capillary injury has already occurred.

–       The Lung Injury Prediction Score has been found to have an AUC for the prediction for ARDS of 0.8 (see attached AJRCCM article).  LIPS variables include shock, aspiration, sepsis, PNA, high-risk surgery, high-risk trauma, EtOH abuse, obesity, low albumin, chemotherapy, FIO2>0.35, RR>30, SpO2<95%, pH <7.35, DM.  At a cut-off of 4, LIPS has a sensitivity of 69% and specificity of 78% for the development of ARDS.  Based on the AJRCCM data, with a LIPS of 6 (roughly the average of pts in the JAMA trial), you would expect roughly 15% to develop ARDS.

–       ASA was chosen given the known pathogenic role of platelet activation and aggregation in the development of ARDS, the anti-inflammatory effects of ASA, and encouraging pre-clinical data.

Morning Report 7/13/22 – Air Trapping

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Today’s Morning Report from second-year fellow Elen Gusman featured a case of dyspnea with HRCT and PFT findings of air trapping without other parenchymal abnormalities. Below are some of the take-away points from her engaging discussion.

Air trapping – areas of lung parenchyma with less than normal increase in attenuation and lack of volume reduction with expiration (Fleischner Society, 2008)

Image – isolated air trapping due to bronchiolitis obliterans Source: Annals ATS 2014; 11(6):874-881

Expiratory findings:

  • Heterogenous hypoattenuation (air trapped) alongside hyperattenuation (normal ventilation)
  • Areas of air trapping do not decrease in volume like adjacent normal lung

Highlights from Gabby Liu’s BMJ State of the Art review on pulmonary fibrosis!

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Amazing work by Gabby Liu (@gliunit, PCCM Fellowship Class of 2022) on this BMJ State of the Art Review: https://www.bmj.com/content/377/bmj-2021-066354

Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis

Highlights from the review, kindly summarized for us by the author:

  • Discusses the conceptualization and pathophysiology of progressive pulmonary fibrosis
  • 2022 ATS/ERS/JRS/ALAT guidelines define how to identify progressive pulmonary fibrosis:
    • ILD dx other than IPF
    • Radiologic evidence of pulmonary fibrosis
    • Evidence of progression, defined as meeting at least two of three criteria within the previous year with no alternative explanation:
  1. Absolute decline in FVC >/=5% predicted or absolute decline in DLCOc >/=10% predicted
  2. Worsening respiratory symptoms
  3. Radiologic evidence of progression
  • Therapies in the pipeline for treatment of IPF, undergoing phase 3 clinical trials:
    • Recombinant human pentraxin 2 – rhPTX
      • Inhibits recruitment of monocyte derived alveolar macrophages to areas of fibrosis
    • Pamrevlumab
      • Anti-CTGF antibody
      • CTGF mediates tissue remodeling, acting downstream of TGF-beta
    • Inhaled treprostinil
      • Prostacyclin analog approved for treatment of PAH and pHTN associated with ILD
    • NAC among IPF patients with TOLLIP TT genotype
      • Tripeptide precursor of glutathione that has antioxidant effects
  • Treatment of inflammatory ILDs:
    • Only RCT data supporting immunosuppression comes from studies of patients with SSc-ILD
    • Tocilizumab is the only immunosuppressive drug approved by FDA for treatment of SSc-ILD
      • Based on FaSScinate and focuSSced trials
    • Cyclophosphamide (CYC) and MMF are not approved by FDA for treatment of SSc-ILD but use is supported by Scleroderma Lung Studies I and II
      • SLS I : CYC reduced decline in FVC compared to placebo
      • SLS II: MMF non-inferior to CYC
  • Treatment of progressive pulmonary fibrosis:
    • Nintedanib, supported by 2 RCTs:
      • SENSCIS: patients with SSc-ILD, no evidence of disease progression required for enrollment
        • Nintedanib reduced rate of FVC decline compared to placebo
        • ½ of patients on MMF at enrollment, nintedanib effective regardless of MMF use
      • INBUILD: Patients with non-IPF progressive fibrosing ILD, not allowed to be on immunosuppression
        • Nintedanib reduced rate of FVC decline compared to placebo
    • Pirfenidone, data less robust, RCTs ongoing
  • Emerging diagnostics:
    • Envisia genomic classifier can help differentiate UIP from non-UIP histologic patterns from transbronchial lung biopsy and lung cryobiopsy by recognizing transcriptomic signature of UIP

 

Great work, Gabby!