Stress Disorders Linked to Life-threatening Infections

Pauline Anderson

October 23, 2019

Posttraumatic stress disorder (PTSD) or other stress-related conditions are associated with a significantly increased risk of life-threatening infection, including sepsis, endocarditis and meningitis, new research suggests.

The link was more pronounced in those diagnosed with a stress-related disorder at a younger age, and those with psychiatric comorbidities.

Dr Huan Song

The findings of this "unique" observational study "represent a huge step forward in our understanding of the role of severe psychiatric reactions to trauma in susceptibility to life-threatening infections," lead investigator Huan Song, MD, PhD, Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

The study was published online today in the The BMJ.

Sibling Controls

This is not the first study to look at a potential link between stress and infection. Earlier this year, a Danish study involving almost 5000 patients suggested an association between PTSD and 34 types of infectious diseases, including central nervous system infections.

Another study by Song and her colleagues published in 2018 indicated that severe stress reactions might play a role in immune dysregulation. In addition, a series of experimental studies suggest there's a link between psychological stress and acute infectious respiratory illness.

However, there has been little research examining the role of stress-­related disorders in major life-threatening infections. In addition, previous studies did not control for familial and comorbidity factors.

The new analysis included 144,919 Swedish-born residents with a first diagnosis of a stress-related disorder between January 1, 1987 and December 31, 2013, identified using a national patient register. Stress-related disorders included PTSD, acute stress reaction, and adjustment disorder and other stress reactions. The mean age of the cohort was 37 years and 38.3% of the participants were men.

Using health registries, researchers identified cases of severe infections characterized by high fatality. These included sepsis, endocarditis, and meningitis or other central nervous system infections, as well as all lethal infections of any other cause.

Researchers constructed a sibling cohort to compare those with a stress-related disorder with their unaffected full siblings, who share similar genetics and early life environment.

This between-sibling comparison "has better control for familial confounding," which is "an important strength of our study," said Song, who is also an adjunct associate professor at the University of Iceland in Reykjavík.

This analysis included 103,072 people with a stress-related disorder and 184,612 siblings.

Researchers also compared individuals with a stress-related disorder with an unaffected general population sample of almost 1.45 million, matched by sex, birth year, and county of birth.

Investigators controlled for known risk factors of infections, including socioeconomic factors, familial background, physical conditions at baseline (including susceptibility to infection), and the occurrence of other severe somatic diseases during follow-­up. The mean follow-up was 8 years.

Causal Link?

In the sibling-based analysis, those with a stress related disorder were at increased risk for a life-threatening infection. Hazard ratios (HRs) were 1.47 (95% confidence interval [CI], 1.37 - 1.58) for any stress related disorder, 1.92 (95% CI, 1.46 - 2.52) for PTSD, and 1.43 (1.29 - 1.58) for acute stress reaction.

For any stress-related disorder, the highest risk was for meningitis (HR, 1.63) and endocarditis (HR, 1.57).

The population-based comparisons between those with and without a stress-related disorder corroborated these associations. The HR for any stress-related disorder was 1.58 (95% CI, 1.51 - 1.65, P = .09 for the difference between sibling and population-based comparison), and for PTSD the HR was 1.95 (1.66 - 2.28, P = .92 for the difference).

The association between life-threatening infections appeared to be strongest among individuals diagnosed with a stress disorder early in life.

"This is in line with previous reports showing that childhood exposure to trauma might have a long-lasting impact on a number of biological processes, possibly through gene-environment interplay, conferring lifelong susceptibility to disease, such as severe infections," said Song.

Psychiatric comorbidities, especially substance use disorders, were associated with additional increased risk.

The long-term risk, defined as more than 1 year of life-threatening infections, appeared to be attenuated with persistent use of selective serotonin reuptake inhibitors (SSRIs) in the first year after diagnosis of a stress-related disorder.

This finding strengthens the evidence for a potential causal link between a stress-related disorder and subsequent life-threatening infections, said Song.

"Clinically, it emphasizes that timely and effective pharmaceutical interventions for patients with severe stress-related disorder might be beneficial, in terms of preventing future life-threatening infections among these patients," she said. "However, these are only first indications, and more research is needed to confirm these findings."

Impaired Immune Function

Although the study shed no light on a potential mechanism, Song hypothesized that severe or prolonged emotional stress causes alterations in multiple bodily functions through dysregulation in the release of stress hormones.

"The hypothesis behind our research is that a severe reaction to trauma or other life stressors, through these pathways, leads to impaired immune function and thereby susceptibility to infection.

"Also, the overproduction of inflammatory cytokines, induced by glucocorticoid receptor resistance, results in chronic inflammation, which can facilitate the progression of infectious diseases."

Alternative mechanistic explanations include behavior-related changes, such as smoking or alcohol use, after a diagnosis of a stress-related disorder, perhaps through increased exposure to pathogens such as through needle sharing among drug users.

However, the authors said it's unlikely that such behavioral factors can fully explain the increase in fatal infections, especially those that appear shortly after diagnosis of a stress-related disorder.

However, they also note the limited information they had on smoking, drug and alcohol use, and other important behavior-related factors.

As stress-related disorders are common in the general population, and severe infections can have a high fatality rate, the new findings underscore the considerable clinical significance and public health implications of the findings.

"This study calls for increased clinical awareness among health professionals caring for patients with stress-related disorders, especially those with a diagnosis at younger age," said Song.

She emphasized that patients with severe emotional reactions after trauma or other life stressors should seek treatment.

"There are now several treatments, both medications and cognitive behavioral approaches, with documented effectiveness of core symptoms of stress-disorders and their comorbidities," she said.

A Major Contribution

A possible limitation of the study was the lack of data on trauma-focused psychotherapy, which, the investigators note, is "the highest priority for PTSD treatment" in many countries, including Sweden.

"Future well-designed studies are needed for exploring the influence of psychotherapy, alone or with drug treatment, on the association between stress-related disorder and risk of severe infections," the investigators write.

The authors also note that the study involved only individuals with a clinical diagnosis of stress-related disorders through a hospital or specialist visit, so the findings may not be generalizable to those with less severe stress reaction or daily stress.

Commenting for Medscape Medical News, Jaimie Gradus, DMSc, DSc, MPH, associate professor of epidemiology at Boston University School of Medicine and an author of the Danish study linking PTSD with incident infections, said the study was "well done."

Gradus said the study "makes a major contribution to the scant literature on stress disorders and infections, and adds to the evidence base on the relationship between stress and immune function."

An "important next step" will be research that builds on this new work by examining the biological and behavioral mechanisms of these associations, she added.

The study was supported by Icelandic Research Fund, European Research Council, the Karolinska Institutet, the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social and Medical Sciences, and the West China Hospital, Sichuan University. The study authors and Gradus have disclosed no relevant financial relationships.

BMJ. Published online October 23, 2019. Full text

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