Interstitial Lung Abnormalities Are Associated with Acute Respiratory Distress Syndrome

To the Editor:

Interstitial lung abnormalities are specific densities on chest computed tomography (CT) scans that have been identified in research participants without a clinical diagnosis of interstitial lung disease (ILD) (1). Interstitial lung abnormalities have been associated with decreased measures of pulmonary function and 6-minute-walk distance, increased respiratory symptoms, and genetic abnormalities, suggesting they may represent an early or mild form of pulmonary fibrosis (1). They have also recently been associated with an increased risk of death, specifically, death from respiratory failure (2).

Patients with fibrotic lung disease can develop acute respiratory failure due to an exacerbation of their underlying disease. These acute exacerbations are characterized pathologically by diffuse alveolar damage (3), which is also the most common pathologic finding in acute respiratory distress syndrome (ARDS) (4, 5). Given the radiologic and pathologic similarities between exacerbations of fibrotic lung disease and ARDS, and to further explore the increased risk of death from respiratory failure associated with interstitial lung abnormalities, we sought to determine whether interstitial lung abnormalities on prior CT imaging were associated with an increased risk of ARDS, in a cohort of patients with sepsis or the systemic inflammatory response syndrome (SIRS). Some of the results have been previously reported in the form of an abstract (6).

Methods

We performed a nested, prospective cohort study using participants from the Institutional Review Board–approved Registry of Critical Illness at Brigham and Women’s Hospital (Boston, MA) (7). All participants screened, consented, and enrolled between September 2008 and February 2015 were included in the analysis if they had sepsis or SIRS. ARDS was defined using the Berlin definition (4) for cases after 2012 and the American–European Consensus Conference (AECC) definition (8) for cases before 2012; ARDS was either present on admission or developed within 7 days of intensive care unit (ICU) admission.

Chest CT scans were reviewed if performed at least 7 days before ICU admission; images were reviewed by up to three readers (one pulmonologist and two radiologists) using a previously described sequential reading method (1). Interstitial lung abnormalities were defined as nondependent changes affecting more than 5% of any lung zone, including ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, or traction bronchiectasis (1, 2) (Figures 1A1 and 1A2). Indeterminate scans were those with focal or unilateral abnormalities (<5% of the lung).

Figure 1.

Chest computed tomography (CT) and pathology images from a patient with interstitial lung abnormalities and subsequent acute respiratory distress syndrome (ARDS). Representative axial images from the CT scans of a participant with interstitial lung abnormalities on chest CT (A1 and A2, arrows demonstrating subpleural reticular changes and, in A1, honeycombing) before the development of ARDS (B1 and B2). A1 and B1 are above the carina, and A2 and B2 are at the level of the right inferior pulmonary vein. The chest CT before ARDS was done for follow-up of a tracheal tumor. At the time of admission to the intensive care unit, the changes seen on the prior CT scan were largely obscured on repeat imaging, and the patient’s presentation was believed to be consistent with ARDS. C is a low-power view of a lung section at the time of autopsy performed on this patient, showing both diffuse alveolar damage (C1 arrow) and evidence of underlying fibrosis (C2 arrow).

Association analyses between pairs of variables were conducted with Fisher’s exact tests (for categorical variables) and two-tailed t tests (for continuous variables). Logistic regression models were used to evaluate the association between interstitial lung abnormalities and ARDS and the association between interstitial lung abnormalities and 28-day mortality. Stepwise selection was used to build multivariable regression models. In primary analyses, patients with a history of ILD were excluded. All P values reported are two sided, and a level of 0.05 was considered statistically significant. SAS version 9.4 (SAS Institute, Cary, NC) was used for analyses.

Results

Baseline characteristics of patients stratified by presence of CT imaging and interstitial lung abnormality status are presented in Table 1. Participants with prior CT imaging were more likely to have a history of malignancy and respiratory disease. Interstitial lung abnormalities were present in 8% (n = 19) of patients with a prior CT scan, 50% (n = 113) did not have interstitial abnormalities, and 42% (n = 95) had indeterminate status. Patients with interstitial lung abnormalities were more likely to be diagnosed with ARDS; 74% (n = 14) of patients with interstitial abnormalities had ARDS compared with 15% (n = 17) of patients without interstitial abnormalities.

Table 1.

Characteristics and Outcomes of Patients Stratified by Presence of Computed Tomography Imaging and Interstitial Lung Abnormality Status

	No Chest CT for Review (n = 233; 51%)	Chest CT Available for Review (n = 227; 49%)			P Value
		No ILA (n = 113; 50%)	Indeterminate (n = 95; 42%)	ILA (n = 19; 8%)
					Comparison of No CT vs. CT	Comparison of No ILA vs. ILA
Baseline characteristics
Age, yr, mean ± SD	58 ± 17	58 ± 15	57 ± 15	58 ± 13	0.9	0.96
Sex, female, n (%)	107 (46)	59 (52)	40 (42)	8 (42)	0.9	0.5
Race, white, n (%)	182 (78)	93 (82)	73 (77)	15 (79)	0.7	0.8
APACHE II score, mean ± SD	25 ± 9	26 ± 9	26 ± 8	25 ± 7	0.08	0.6
History of smoking, yes, n (%)	106 (56)	43 (46)	49 (62)	8 (47)	0.6	1.0
History of respiratory disease, yes, n (%)	74 (32)	35 (31)	45 (47)	8 (42)	0.02	0.4
History of malignancy, yes, n (%)	74 (32)	74 (65)	56 (59)	14 (74)	<0.0001	0.6
Time from CT scan to ICU admission, d, median (IQR)	—	82 (156)	50 (110)	22 (120)	—	0.4
ICU characteristics and outcomes
Among patients with sepsis/SIRS, reason for ICU admission, n (%)
Sepsis/SIRS alone	95 (41)	64 (57)	37 (39)	6 (32)		0.001	0.0005
Plus respiratory failure	68 (29)	28 (25)	43 (45)	13 (68)
Plus encephalopathy	13 (6)	7 (6)	2 (2)	—
Plus cardiac arrest	8 (3)	1 (1)	1 (1)	—
Plus other*	49 (21)	13 (11)	12 (13)	—
ARDS diagnosis, n (%)	33 (14)	17 (15)	26 (27)	14 (74)	0.002	<0.0001
28-day mortality, yes, n (%)	31 (13)	24 (21)	23 (24)	7 (37)	0.004	0.05

Definition of abbreviations: APACHE = Acute Physiology and Chronic Health Evaluation; ARDS = acute respiratory distress syndrome; CT = computed tomography; ICU = intensive care unit; ILA = interstitial lung abnormalities; IQR = interquartile range; SIRS = systemic inflammatory response syndrome.

^*Other includes: pulmonary emboli, thrombotic thrombocytopenic purpura, hyponatremia, diabetic ketoacidosis, hyperkalemia, transfusion reaction, hemorrhagic shock, hyperosmolar hyperglycemic state, anaphylaxis, lung transplant, incarcerated hernia, and pancreatitis.

After adjusting for age and Acute Physiology and Chronic Health Evaluation (APACHE) score, patients with interstitial abnormalities were more likely to have ARDS (odds ratio [OR], 4.2; 95% confidence interval [CI], 2.1–8.2; P < 0.0001), compared with those without interstitial abnormalities (Tables 1 and 2). Similar results were seen when additionally adjusting for history of respiratory disease and malignancy (OR, 4.5; 95% CI, 2.2–9.0; P < 0.0001), when the cohort was narrowed to patients with sepsis alone (OR, 3.9; 95% CI, 2.0–7.9; P = 0.0001), when patients with a history of ILD were included (OR, 2.9; 95% CI, 1.7–4.9; P < 0.0001), and when compared with both those without interstitial abnormalities and with indeterminate status (OR, 15.8; 95% CI, 4.3–58.4; P < 0.0001).

Table 2.

Odds Ratios for the Association between Interstitial Lung Abnormalities and Acute Respiratory Distress Syndrome and Interstitial Lung Abnormalities and 28-Day Mortality

	Unadjusted Comparison of ILA vs. No ILA		Adjusted Comparison of ILA vs. No ILA
	OR (95% CI)	P Value	OR (95% CI)	P Value
ARDS	3.5 (1.9–6.5)	<0.0001	4.2 (2.1–8.2)	<0.0001
28-day mortality	1.8 (1.02–3.1)	0.04	2.3 (1.2–4.2)	0.01
28-day mortality (only patients with ARDS)	2.1 (0.9–4.9)	0.1	2.4 (0.9–6.5)	0.08

Definition of abbreviations: ARDS = acute respiratory distress syndrome; CI = confidence interval; ILA = interstitial lung abnormalities; OR = odds ratio.

Interstitial abnormalities were also associated with an increased risk of 28-day mortality. After adjusting for age and APACHE score, patients with interstitial lung abnormalities had increased odds of death compared with those without interstitial abnormalities (OR, 2.3; 95% CI, 1.2–4.2; P = 0.01). A similar, but nonstatistically significant, association between interstitial lung abnormalities and death was noted when limited to patients with ARDS (OR, 2.4; 95% CI, 0.9–6.5; P = 0.08).

Discussion

The central finding of this study is that, in a cohort of critically ill patients with sepsis and SIRS, patients with interstitial lung abnormalities were significantly more likely to develop ARDS. In addition, after adjustment for age and APACHE score, patients with interstitial lung abnormalities were more likely to die within 28 days after ICU admission.

The criteria in both the AECC and Berlin definitions of ARDS are nonspecific, which has led to concerns that these definitions may incorporate a variety of conditions that may mimic ARDS (9, 10), including exacerbations of fibrotic lung disease. Neither the AECC nor the Berlin definition specifically recommends review of prior imaging when diagnosing ARDS. Although it has recently been reported that interstitial lung abnormalities are associated with an increased risk of death, specifically from respiratory failure (2), larger studies will be needed to determine how often interstitial lung abnormalities precede a diagnosis of ARDS and how often unselected patients with ARDS have evidence for antecedent interstitial lung abnormalities.

This study has a number of important limitations. First, although our findings demonstrate an association between interstitial lung abnormalities and ARDS in patients with a prior clinically indicated CT scan, given the differences in baseline characteristics and outcomes in those without a prior CT scan, we urge caution in extrapolating our findings to patients with ARDS more broadly. Second, we cannot comment about whether these findings apply to patients who did not consent to enroll in the Registry of Critical Illness. Third, small sample size may have limited the statistical power to detect an association between interstitial lung abnormalities and mortality in patients with ARDS.

Our findings suggest that cohorts of patients with sepsis and SIRS may contain patients with undiagnosed interstitial lung abnormalities, and raise the possibility that interstitial lung abnormalities may mimic, or in some cases be a risk factor for, ARDS.