Monthly Archives: July 2022

ILD Roundup 7/8/22

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ILD Roundup (7/8/22) 

1. Interstitial pneumonia with autoimmune features (IPAF) was favored as a differential consideration in a patient who presented to NMH for a third opinion for her ILD 

ERS/ATS research statement (Eur Respiratory Journal 2015;46:976-987) 

On the spectrum between idiopathic interstitial pneumonias (IIP) and connective-tissue disease associated ILDs (CT-ILD) are patients with IPAF. Oftentimes patients with an “autoimmune flavor” of ILD do not meet criteria for CTD diagnosis. 

Why does the distinction matter?  

  • Identifying underlying etiology impacts treatment and prognosis 
  • Expedites linkage to rheumatology care, potentially facilitating CTD diagnosis 
  • Accurate disease epidemiology depends on it 
  • May aid in elucidation of pathophysiologic mechanism of disease 
  • Defined criteria facilitate clinical trial design for future research 

What are the consensus criteria?  

All of the following must be fulfilled: 

  1. Presence of interstitial pneumonia (HRCT/SLB) 
  2. Exclusion of alternative etiologies 
  3. Does not meet criteria for defined connective tissue disease 
  4. At least one feature from 2/3 domains: 
  • Clinical 
  • Serologic 
  • Morphologic 

Pearl from case discussion: If histopathology pattern does not fit expectation but another criterion in this  domain is met (histopathology predominantly UIP pattern, however, there was presence of lymphoid aggregates), the diagnostic criteria for IPAF may still be satisfied!

2. In the same patient as above, we discussed and ultimately decided against use of azathioprine, because she had some HRCT features suggestive of a UIP pattern 

We know that nintedanib (INPULSIS – 2014) and pirfenidone (ASCEND – 2014) are associated with decreased rate of FVC decline in patients with IPF, hence the rationale for their use. Before the advent of antifibrotics, immunosuppressive agents had been used in patients with IPF. Several retrospective studies and small RCTs suggested mortality benefit with combination of steroid + AZA or cyclophosphamide though they were confounded by inclusion of patients who did not meet diagnostic criteria for IPF. Guidelines thus differed: the British Thoracic Society weakly recommended N-acetylcysteine (NAC), prednisolone, and azathioprine based on results from IFIGENIA (decreased decline in FVC and DLCO); whereas, the ATS/ERS recommended lung transplantation and participation in clinical trials. The IFIGENIA trial was limited by substantial drop-out and lack of “no treatment” arm.

Why do we now avoid the use of immunosuppressive medications – and azathioprine in particular – in suspected IPF? 

PANTHER-IPF (NEJM 2012;366:1968-1977) 

  • A double blind RCT wherein a commonly used cocktail of prednisone/azathioprine/NAC was used in 1:1:1 fashion with placebo and NAC alone 
  • A previous study had shown that triple therapy performed superiorly with regards to VC and DLco preservation compared with prednisone/azathioprine alone, but no placebo-controlled data existed 
  • Stopped at interim analysis when control group was found to have significant increase in death and hospitalization rates compared to placebo 

 

3. In another patient, the presenter mentioned that hypersensitivity pneumonitis had not been considered in a patient because he did not have any “clear exposure history”.  

How often is a diagnosis of HP arrived upon without a clear exposure history? Does identification of an exposure matter in patients with HP? 

CHEST 2013;144(5):1644-1651 

  • In a retrospective review of a longitudinal ILD database, 134 consecutive patients with clinico-radiologic diagnosis of HP found that inciting antigen was not identified in 53% of cases.  
  • Inability to identify target antigen was associated with significantly shorter survival (HR 1.76; 1.01-3.07) in this same cohort.  

 

“Incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis,” AJRCCM, 2017, Netherlands

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“Incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis,” AJRCCM, 2017, Netherlands

Question: What is the incidence of new-onset atrial fibrillation/atrial flutter (AF) in ICU patients with sepsis and is the development of AF associated with mortality?

Study Type: Sub-study of a prospective cohort study at two hospitals in the Netherlands

Study Population: Adults admitted to the ICU with sepsis over a two-year period were included.  Exclusion criteria included a history of AF, recent cardiotomy, or cardiac arrest.

Study Groups: AF detection based on hourly recordings of the rhythm observed by the bedside nurse.  AF needed to be sustained for 1 hour or require pharmacologic treatment or cardioversion to be included.

Primary Outcome: Incidence of new-onset AF

Results: 1,782 patients included in analysis.  Notable patient characteristics: Age (»62), immunosuppression (26%), malignancy (10%), lung as source of infection (62%), mechanical ventilation (83%), surgical admission (23%), 90-day mortality (34%).  The overall incidence of AF was 23%.  For patients with septic shock, the risk of AF was 40%.  The most common treatments administered were amiodarone (71%), magnesium (69%), electrical cardioversion (11%), and sotalol (8%).  After multivariable regression, AF remained associated with ICU mortality (HR 2.10; 95% CI, 1.61-2.73).  An AF risk score was developed (the “SAFE” score) and validated in an independent cohort.  The score can be accessed here: https://safescore.shinyapps.io/safe/.

Caveats: Unmeasured confounding a concern in observational studies, unable to prove AF has causal role in poor outcomes, relied on identification and classification of arrhythmia by bedside nurse so possible missed or misclassified episodes, data collected from only two centers.

Take-home Point: New-onset AF is common in ICU patients with sepsis and may lead to increased mortality.

Commentary 

–        Part of a growing body of literature helping to describe the incidence and significance of new-onset AF in critical illness.  Certainly notable that the incidence of AF in septic shock approaches 50%

–        The SAFE score still needs to be independently validated, but it is an interesting attempt by the authors to come up with a way to predict the development of sepsis-induced AF (and, in doing so, potentially identify a group of septic patients to enroll in trials of AF prophylaxis).​

 

 

Annual Landsberg Research Day abstract submission

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Abstract submissions opening soon for Landsberg Research Day, a campuswide event scheduled for September 15, 2022. Prizes for winning posters, and anyone affiliated with Feinberg School of Medicine (residents, fellows, grad students, postdocs, faculty, students) can submit!

Abstract submission window 7/28-8/11!

https://www.feinberg.northwestern.edu/research/events/research-day/

 

ILD roundup 7/1/22

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1. Association of ANA pattern with CTD-ILDs 

We often talk about ANA titers & pattern in our ILD evaluations – what do they signify?  

  • Cut-off for positive test suggested at 1:160 
  • Variability based on lab/technician 
  • 25-30% of health controls with low Ab titers 
  • 56% +ANA with ILD of unclear cause, despite lower rate of CTD diagnosis (4-20%) in ILD population
  • Increasing age associated with higher prevalence of ANA positivity

General associations to be aware of: 

  • Homogenous –> dsDNA –> SLE 
  • Speckled –> MCTD, Sjogren, SLE, DM 
  • Centromeric or Nucleolar –> SSc 
  • Cytoplasmic –> anti-synthetase syndrome 

ANA profiles

2. Acute interstitial pneumonia/Hamman-Rich Syndrome

What are the clinical characteristics and prognosis of this rare illness? 

  • Rapidly progressive (1-2 weeks) hypoxemic respiratory failure with high mortality (~50%), with bilateral GGOs and consolidation within dependent lung, no clear trigger (ddx ARDS) and without antecedent ILD (ddx flare ILD, esp IPF)
  • Pathology shows diffuse alveolar damage, alveolar wall thickening and pneumocyte hyperplasia
  • Progresses to pattern similar to fibrotic NSIP Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia

HRCT of AIP

Image source: European Respiratory Journal 2009 33:68-76.

3.Idiopathic NSIP

A retrospective analysis of 83 patients with radiological & pathological criteria for iNSIP conducted in the pre-antifibrotic era (between 1991-2006).

Interesting findings included:

  • 10% of patients with iNSIP developed clinically manifest CTD during follow-up
  • Scleroderma, PM/DM, RA, MCTD, PMR
  • These patients tended to be younger and did not have increased risk for recurrence
  • Deterioration of FVC at 6 months correlated most strongly with disease-specific mortality

“The timing of early antibiotics and hospital mortality in sepsis” AJRCCM, 2017, USA

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“The timing of early antibiotics and hospital mortality in sepsis” AJRCCM, 2017, USA

Question: Does the timing of antibiotic administration in patients presenting with sepsis impact mortality?

Study Type: Retrospective study of a large healthcare database

Study Population: Adult patients presenting with sepsis (defined by ICD 9 codes + the receipt of abx within 6 hours of ED registration) to any of the 21 hospitals in the Kaiser Permanente Northern California system between 7/2010 and 12/2013.

Study Groups: Septic shock defined as need for vasopressors or initial serum lactate ³4; severe sepsis as a lactate ³2, ³1 instance of hypotension, need for invasive or non-invasive ventilation, or laboratory-determined organ dysfunction; all other patients classified as having sepsis. All vital signs obtained during the first hour were recorded and averaged. Abx administration calculated from the time of ED registration to the administration of the first abx in hours. Logistic regression was used to estimate the odds of hospital mortality based on abx timing and patient factors.

Primary Outcome: Hospital mortality

Results: 35,000 patients randomly selected. Notable patient characteristics: sepsis (35%), severe sepsis (52%), septic shock (13%), median age (73), mean first lactate (1.8), mechanical ventilation (1.4%), mortality of entire group (9.4%), mortality of patients with sepsis (3.9%), mortality of patients with severe sepsis (8.8%), mortality of patients with septic shock (26%). The fully adjusted odds ratio for hospital mortality based on abx timing was 1.09 (95% CI, 1.05-1.13) per elapsed hour after ED presentation. The absolute increase in mortality associated with a 1-hr delay in abx administration was 0.3% (95% CI, 0.01%-0.6%) for sepsis, 0.4% (95% CI, 0.1%-0.8%) for severe sepsis, and 1.8% (95% CI, 0.8%-3%) for shock.

Caveats: Retrospective, only able to describe an association not prove causation, no data provided on other aspects of early resuscitation which may impact outcome (IVF, did abx given cover causative pathogen, etc), only included patients presenting to the ED not patients who develop sepsis while hospitalized, relied upon ICD 9 codes to identify patients with sepsis.

Take-home Point: Among patients presenting to the ED with sepsis, severe sepsis, and septic shock, delays in abx administration are associated with increased mortality.

Commentary 

–        The most frequently cited paper on this subject is by Kumar (CCM, 2006) which retrospectively analyzed 2,731 patients with septic shock and found that for each hour delay in appropriate abx therapy after the onset of hypotension, mortality increased by 7.6%.

–        The result is less dramatic here (1.8% increase for each hour delay in patients with shock) and the authors highlight several methodological differences which may account for their findings.

–        The study has flaws, but it perhaps provides a more accurate look at the true mortality benefit of early abx in the modern era of sepsis management.