FeaturePerspective

Stress-related diagnosis may increase risk for severe infections

Huan Song, MD, PhD
Huan Song

Findings from a study conducted among more than 144,000 people in Sweden indicated that post-traumatic stress disorder, or PTSD, and other stress-related disorders are associated with a subsequent risk for life-threatening infections, including meningitis, endocarditis and sepsis.

“This is the first study to demonstrate a robust association between stress-related disorders and life-threatening infections, independent of familial background and baseline physical or psychological conditions,” Huan Song, MD, PhD, postdoctoral fellow in the Center of Public Health Sciences at the University of Iceland, told Infectious Disease News.

The impact of stress

Song and colleagues previously published a study in JAMA that demonstrated an association between stress-related disorders and the risk for autoimmune disease. These findings suggested that severe stress reactions play a part in immune dysregulation.

“A series of experimental studies on humans and other animals suggest a link between psychological stress and acute infectious respiratory illness, while data on more severe, life-threatening infections, such as meningitis and sepsis, have been lacking,” she said.

The current study informs this area where research has been limited.

“As experimental designs are not applicable to this scenario, the findings of this unique observational, sibling-controlled study represent a huge step forward in our understanding of the role of severe psychiatric reactions to trauma in susceptibility to life-threatening infections,” Song explained.

According to Gitanjali Pai, MD, AAHIVS, an Infectious Disease News Editorial Board Member and infectious diseases specialist at Memorial Hospital in Stilwell, Oklahoma, the impact stress has on public health is “getting harder to ignore.”

“Let’s face it, stress — physical as well as psychological — to some extent, is an unavoidable reality of life, for all practical purposes,” said Pai, who was not involved with the study. “With stress affecting younger age groups at earlier stages of life, it is important to be cognizant of its short-term as well as long-term repercussions on both physical and psychological well-being.”

A sibling matched cohort study

Song and colleagues identified 144,919 individuals with stress-related disorders between 1987 and 2013, including PTSD, acute stress reaction and adjustment disorder. They compared them with 184,612 full siblings of individuals with a diagnosed stress-related disorder and 1,449,190 matched individuals without a stress-related diagnosis from the general Swedish population.

Diagnosis of a stress-related disorder occurred, on average, at age 37 years, according to the study. Among individuals with a stress-related disorder, there was an incidence of 2.9 life-threatening infections per 1,000 person years over a mean follow-up of 8 years. During the same follow-up period, the incidence of life-threatening infections per 1,000 person years was 1.7 in siblings without a diagnosis and 1.3 in matched individuals without a diagnosis.

Gitanjali Pai, MD, AAHIVS
Gitanjali Pai

Individuals with a stress-related diagnosis were at increased risk for life-threatening infections compared with siblings. Specifically, the HR was 1.47 (95% CI, 1.37-1.58) for any stress-related disorder and 1.92 (95% CI, 1.46-2.52) for PTSD.

When the researchers assessed the population-based analysis, the corresponding estimates were similar, with an HR of 1.58 (95% CI, 1.51-1.65) for any stress related disorder and 1.95 (95% CI, 1.66-2.28) for PTSD.

Although stress-related disorders were associated with all life-threatening infections, the highest RR was for meningitis and endocarditis. In the sibling-based analysis, the HR for meningitis was 1.63 (95% CI, 1.23-2.16), and for endocarditis it was 1.57 (95% CI, 1.08-2.3). Higher HRs were associated with younger age at diagnosis of a stress-related disorder and the presence of psychiatric comorbidity, particularly substance use disorders.

“While there [are] limited data examining the possible link between stress and infections, and while further studies are required to establish a causal association between stress and major life-threatening infections — this study, certainly, is yet another step toward teasing out the plausible causality between stress and life-threatening or fatal infections,” Pai said.

A ‘wake-up call’

The use of selective serotonin reuptake inhibitors (SSRIs) in the first year after a stress-related diagnosis was associated with reduced HRs, Song and colleagues reported.

“This study serves as yet another wake-up call to urge providers to be vigilant as far as screening for stress and stress-related disorders, and subsequent timely interventions to mitigate the widespread effects of stress,” Pai said.

In a related editorial, Jonathan Bisson, DM, a professor in psychiatry at Cardiff University in Wales, said the methodology of the study was “strong” but noted that it had limitations and was unable to determine causality.

“As with many cohort studies of PTSD, not controlling for exposure to trauma and lack of standardized assessment of the PTSD phenotype give further cause for caution when

interpreting the results,” he wrote. “Firm conclusions about the associations between stress-related disorders and physical health would be premature, but mounting evidence suggests that carefully designed studies to identify common or related mechanistic pathways could be fruitful in the future.”

Song mentioned ways clinicians can use these findings to improve patient care.

“Due to the high prevalence of the stress-related disorder, as well as the high fatality of severe infections, this study calls for increased clinical awareness among health professionals caring for patients among those with stress-related disorders, especially those with a diagnosis at a younger age,” she concluded. “Furthermore, our finding of the attenuated relative risk of severe infections after SSRI treatment suggests the persistent use of SSRI medications may [be] beneficial, in terms of preventing future life-threatening infections among these patients.” – by Marley Ghizzone

References:

Bisson J. BMJ. 2019;doi:10.1136/bmj.l5784.

Song H, et al. BMJ. 2019;doi:10.1136/bmj.l5784.

Song H, et al. JAMA. 2018;doi:10.1001/jama.2018.7028.

Disclosures: Pai reports serving on the advisory boards of AbbVie and Gilead Sciences. Bisson and Huan report no relevant financial disclosures.

Huan Song, MD, PhD
Huan Song

Findings from a study conducted among more than 144,000 people in Sweden indicated that post-traumatic stress disorder, or PTSD, and other stress-related disorders are associated with a subsequent risk for life-threatening infections, including meningitis, endocarditis and sepsis.

“This is the first study to demonstrate a robust association between stress-related disorders and life-threatening infections, independent of familial background and baseline physical or psychological conditions,” Huan Song, MD, PhD, postdoctoral fellow in the Center of Public Health Sciences at the University of Iceland, told Infectious Disease News.

The impact of stress

Song and colleagues previously published a study in JAMA that demonstrated an association between stress-related disorders and the risk for autoimmune disease. These findings suggested that severe stress reactions play a part in immune dysregulation.

“A series of experimental studies on humans and other animals suggest a link between psychological stress and acute infectious respiratory illness, while data on more severe, life-threatening infections, such as meningitis and sepsis, have been lacking,” she said.

The current study informs this area where research has been limited.

“As experimental designs are not applicable to this scenario, the findings of this unique observational, sibling-controlled study represent a huge step forward in our understanding of the role of severe psychiatric reactions to trauma in susceptibility to life-threatening infections,” Song explained.

According to Gitanjali Pai, MD, AAHIVS, an Infectious Disease News Editorial Board Member and infectious diseases specialist at Memorial Hospital in Stilwell, Oklahoma, the impact stress has on public health is “getting harder to ignore.”

“Let’s face it, stress — physical as well as psychological — to some extent, is an unavoidable reality of life, for all practical purposes,” said Pai, who was not involved with the study. “With stress affecting younger age groups at earlier stages of life, it is important to be cognizant of its short-term as well as long-term repercussions on both physical and psychological well-being.”

A sibling matched cohort study

Song and colleagues identified 144,919 individuals with stress-related disorders between 1987 and 2013, including PTSD, acute stress reaction and adjustment disorder. They compared them with 184,612 full siblings of individuals with a diagnosed stress-related disorder and 1,449,190 matched individuals without a stress-related diagnosis from the general Swedish population.

Diagnosis of a stress-related disorder occurred, on average, at age 37 years, according to the study. Among individuals with a stress-related disorder, there was an incidence of 2.9 life-threatening infections per 1,000 person years over a mean follow-up of 8 years. During the same follow-up period, the incidence of life-threatening infections per 1,000 person years was 1.7 in siblings without a diagnosis and 1.3 in matched individuals without a diagnosis.

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Gitanjali Pai, MD, AAHIVS
Gitanjali Pai

Individuals with a stress-related diagnosis were at increased risk for life-threatening infections compared with siblings. Specifically, the HR was 1.47 (95% CI, 1.37-1.58) for any stress-related disorder and 1.92 (95% CI, 1.46-2.52) for PTSD.

When the researchers assessed the population-based analysis, the corresponding estimates were similar, with an HR of 1.58 (95% CI, 1.51-1.65) for any stress related disorder and 1.95 (95% CI, 1.66-2.28) for PTSD.

Although stress-related disorders were associated with all life-threatening infections, the highest RR was for meningitis and endocarditis. In the sibling-based analysis, the HR for meningitis was 1.63 (95% CI, 1.23-2.16), and for endocarditis it was 1.57 (95% CI, 1.08-2.3). Higher HRs were associated with younger age at diagnosis of a stress-related disorder and the presence of psychiatric comorbidity, particularly substance use disorders.

“While there [are] limited data examining the possible link between stress and infections, and while further studies are required to establish a causal association between stress and major life-threatening infections — this study, certainly, is yet another step toward teasing out the plausible causality between stress and life-threatening or fatal infections,” Pai said.

A ‘wake-up call’

The use of selective serotonin reuptake inhibitors (SSRIs) in the first year after a stress-related diagnosis was associated with reduced HRs, Song and colleagues reported.

“This study serves as yet another wake-up call to urge providers to be vigilant as far as screening for stress and stress-related disorders, and subsequent timely interventions to mitigate the widespread effects of stress,” Pai said.

In a related editorial, Jonathan Bisson, DM, a professor in psychiatry at Cardiff University in Wales, said the methodology of the study was “strong” but noted that it had limitations and was unable to determine causality.

“As with many cohort studies of PTSD, not controlling for exposure to trauma and lack of standardized assessment of the PTSD phenotype give further cause for caution when

interpreting the results,” he wrote. “Firm conclusions about the associations between stress-related disorders and physical health would be premature, but mounting evidence suggests that carefully designed studies to identify common or related mechanistic pathways could be fruitful in the future.”

Song mentioned ways clinicians can use these findings to improve patient care.

“Due to the high prevalence of the stress-related disorder, as well as the high fatality of severe infections, this study calls for increased clinical awareness among health professionals caring for patients among those with stress-related disorders, especially those with a diagnosis at a younger age,” she concluded. “Furthermore, our finding of the attenuated relative risk of severe infections after SSRI treatment suggests the persistent use of SSRI medications may [be] beneficial, in terms of preventing future life-threatening infections among these patients.” – by Marley Ghizzone

References:

Bisson J. BMJ. 2019;doi:10.1136/bmj.l5784.

Song H, et al. BMJ. 2019;doi:10.1136/bmj.l5784.

Song H, et al. JAMA. 2018;doi:10.1001/jama.2018.7028.

Disclosures: Pai reports serving on the advisory boards of AbbVie and Gilead Sciences. Bisson and Huan report no relevant financial disclosures.

    Perspective

    A now robust literature describes substantial associations between psychological stress and an increased risk of a wide variety of serious medical problems. This large sibling- and population-matched cohort study expands our awareness of those associations into the realm of life-threatening infections in demonstrating significant positive correlations between diagnosis with adjustment disorder, acute stress reaction, PTSD, and other stress reactions and an increased risk of later developing sepsis, endocarditis, meningitis or other central nervous system infections and of dying of other infections. Intriguingly, the associations appeared to attenuate with age starting in the decade leading up to middle age. Combined with the results of prior studies showing associations between psychological stress and aberrations in neuroendocrine and immune system functioning, it is tempting to think that there may be causal physiologic connections between psychological stress and increased susceptibility to infectious disease. The potential confounding variables and biases we know must be accounted for in doing this sort of research are many and continue to grow in number and recognized importance, leaving us unable to move beyond speculation at this point. The authors, who did an admirable job of trying to account for biases and control for confounders, duly note that it was not possible to control for several factors likely to be important, including substance use, diet and exercise. The results encourage further research that will help us better understand the sequelae of psychological trauma, immunology and infectious diseases. An interesting side note in the article is that they found a duration-dependent negative association between treatment with an SSRI during the first year after diagnosis with a stress-related disorder and risk of a subsequent life-threatening infection. Unfortunately, they were unable to do a similar analysis for treatment with psychotherapy, which is the most effective treatment modality for PTSD and other sequelae of psychological trauma. Future research may show if this is a real and causal association, if it is specific to SSRIs or a general effect of treatment of stress-related disorders and what implications it may have for treatment of stress-related disorders and the prevention of life-threatening infections.

    • Nils Westfall, MD
    • Child, adolescent, and adult psychiatrist
      Colorado Permanente Medical Group

    Disclosures: Westfall reports no relevant financial disclosures.