Asthma Associated with Decreased Sepsis-Related Mortality

By Joe Zein, MD, and Serpil Erzurum, MD

Asthma’s complex immunopathology involves several major mechanisms, including classical type-2 helper cell (Th2) immune responses, activation of interleukin-17-mediated neutrophilic inflammation, and innate toll-like-receptor (TLR) responses to pathogens. These mechanisms are all important to normal host response to pathogens.

Asthma also involves enhanced mast cell degranulation and release of mediators, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), that may counter the impact of infections through enhanced neutrophil influx and killing of bacteria. Heightened innate responses in non-Th2 pathways in patients with asthma would also enable faster pathogen clearance.

Given this heightened activation of pro-inflammatory pathways and the potential enhancement of host defenses in patients with asthma, we hypothesized that the incidence and severity of sepsis would be lower in this patient population.

To test this hypothesis, my colleagues and I designed a study analyzing the 2012 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS). We validated this data with additional sources: 2007, 2008 and 2011 NIS and Cleveland Clinic Health System (CCHS) admissions between 2010 and 2014. We sought to assess the impact of asthma on septicemia, sepsis, severe sepsis, septic shock and mortality in patients hospitalized for pneumonia, urinary tract infection (UTI), or skin and soft tissue infection (SSTI). Diagnoses were defined using ICD9-CM codes. Unlike previous studies, we excluded patients with remote or current smoking history to minimize bias of smoke-related airways disease.

Studies using a large database can take advantage of big data to detect more accurate effect-size estimates using large, real-life data. They provide a valuable tool to predict epidemiological associations relevant to population health.

Asthma = lower sepsis-related mortality

In this analysis we found that asthma is associated with lower sepsis-related mortality. From the NIS 2012 sample, which includes 20 percent of all U.S. hospital discharges, 23,386 patients with asthma and 203,603 without asthma were hospitalized across the U.S. with pneumonia, UTI or SSTI. Asthma patients had decreased risk for:

• hospital mortality (adjOR [95 % CI]: 0.41 [0.37; 0.45]),
• septicemia (adjOR [95 % CI]: 0.60 [0.58; 0.61]),
• sepsis (adjOR [95 % CI]: 0.59 [0.56; 0.62]),
• severe sepsis (adjOR [95 % CI]: 0.60 [0.58; 0.63] and
• septic shock (adjOR [95 % CI]: 0.74 [0.71; 0.78]).

Risk reductions were also consistently significant within each type of infection (pneumonia, UTI, SSTI). Asthma was associated with lower risk for acute kidney injury (adjOR [95 % CI]: 0.65 [0.63; 0.68]) and intensive care unit admission (adjOR [95 % CI]: 0.80 [0.64; 0.99]). Hospital length of stays were shorter, and costs were lower. Analyses of other NIS years and CCHS datasets confirmed the NIS 2012 results.

This protective effect of asthma against sepsis challenges findings in prior case control studies, which suggested asthma was associated with higher risk for invasive pneumococcal and nonrespiratory infections. The results in this study, adjusted for gender, age, income, race and comorbidities across four different years, are consistent across five independent, large datasets that include a total of 99,257 patients with asthma among nearly one million hospitalized individuals.

Future work focusing on further defining the types of immune responses associated with asthma that confer this protective effect may translate into therapeutic approaches to improving sepsis-related outcomes in nonasthmatic individuals.