Federal Practitioner

Tinea versicolor (TV) is a common, chronic, and recurrent superficial fungal infection caused by Malassezia species, most commonly Malassezia furfur (M. furfur)—a dimorphic fungus that is a part of the normal skin flora and resides in the stratum corneum.¹ TV manifests as hypopigmented, hyperpigmented, or erythematous macules and patches with scaling, typically found on the trunk and proximal upper extremities. The condition is most common among young to middle-aged individuals exposed to high temperatures and humidity.¹

While many cases respond to topical antifungal treatment, application can be cumbersome, particularly in large areas that are difficult to reach. An efficient and cost effective in-office treatment option could alleviate patient burden and improve satisfaction. This article presents a case of TV successfully treated with an in-office salicylic acid (SA) 30% peel, an uncommon application of this medication.

Case Presentation

An 18-year-old female active-duty US Army service member with a history of acne vulgaris presented to a dermatology clinic with a mildly pruritic rash that had been present for several weeks. An examination revealed hyperpigmented macules and patches with overlying fine scales across the patient’s back and bilateral arms (Figures 1 and 2). She reported no history of similar lesions. The patient had recently completed a military basic training course during which she wore a uniform jacket and trousers daily in hot and humid conditions. A skin scraping was obtained. Microscopic examination with potassium hydroxide preparation revealed hyphae and spores, consistent with TV.

The diagnosis of TV and treatment options (topical ketoconazole 2% shampoo, topical terbinafine, or oral fluconazole) were discussed with the patient. Due to military training-related constraints, residence in the barracks, and personal preference, the patient felt unable to regularly apply topical medications to the entirety of the affected area and preferred to avoid oral medication. The decision was made to pursue in-clinic treatment with a SA 30% peel. The affected areas (back and bilateral arms) were thoroughly cleansed and prepped with alcohol. SA 30% in hydroethanolic solution was applied evenly to the affected area. The patient was observed for pseudofrosting, a precipitation of SA crystals that indicates peel completion (Figure 3). The peel was left in place, as it is self-neutralizing, and the patient was instructed to shower that same day with a gentle cleanser. This procedure was repeated 10 days later. Both treatments were well tolerated, with only a transient burning sensation reported during the application. At 3-week follow-up, the patient presented with complete resolution of her arm lesions and significant improvement of the back lesions (Figures 4 and 5). She also reported improvement in the acne vulgaris on her back.

Discussion

SA 30% is a lipid-soluble hydroxybenzoic acid with comedolytic and desmolytic qualities. This results in the disruption of epidermal cell cohesion and promotes exfoliation.² Lipophilic properties allow SA to penetrate sebaceous glands and disrupt sebum production, making it particularly effective in seborrheic conditions such as acne. This mechanism may have increased therapeutic effect in this case.³ Additionally, as a salicylate, SA possesses anti-inflammatory properties, though this effect is most pronounced at lower concentrations. SA 30% is considered a superficial peel, as the depth of chemexfoliation is limited to the epidermis.³ A modified SA preparation is a safe and effective treatment for moderate-to-severe acne vulgaris. The apparent pseudofrost during application is due to precipitated SA, rather than the precipitation of dermal proteins seen in deeper peels, such as trichloroacetic acid.² Unlike glycolic or pyruvic acid peels, SA does not require neutralization.

SA is cost-effective and has been used safely in all skin types to treat various epidermal conditions, including acne vulgaris, melasma, photodamage, freckles, lentigines and postinflammatory hyperpigmentation (PIH).² Mild adverse effects occur in about 15% to 30% of patients and include prolonged erythema, intense exfoliation, dryness, crusting, and pigmentary dyschromias. Rare adverse effects include systemic toxicity (salicylism) and hypoglycemia. Contraindications to SA 30% peels include history of allergy to salicylates, active bacterial or viral infection, dermatitis in the treatment area, pregnancy, and skin malignancy.²

Chemical peels are typically used with caution in patients with skin of color due to a higher risk of PIH. However, SA 30% has been shown to be safe and effective in these populations.⁴ A study by Grimes found that 88% of patients with Fitzpatrick skin types V and VI experienced significant improvement in PIH, melasma, or enlarged pores with minimal to no adverse effects.⁴ Subsequent larger studies have reinforced these findings. In a study involving 250 patients with Fitzpatrick skin types IV and V, no patients experienced PIH, confirming the safety of SA in darker skin tones. This is likely due to the superficial nature of the peel, which does not affect the basal layer of the epidermis where melanocytes reside, reducing the risk of pigmentary complications. Additionally, SA peels are self-neutralizing, unlike glycolic or trichloroacetic acid peels, which require manual neutralization and carry a higher risk of PIH if not neutralized properly.⁵

SA has been as shown to be a moderately successful treatment for PIH. The Grimes study found that 4 of 5 patients with Fitzpatrick skin types IV and V saw a 75% improvement in PIH after SA peels.⁴ Davis et al found a nonsignificant trend toward skin lightening in Korean adults treated for acne and PIH, with significant decreases in erythema and improvements in greasiness, dryness, and scaliness.⁶ Importantly, the risk of PIH following TV is higher in patients with skin of color.⁷ SA may be effective in treating TV and PIH, offering a multifactorial approach by addressing both conditions while posing a low risk for causing PIH.⁸

TV and other Malassezia spp infections are common concerns in dermatology and primary care, with Malassezia-associated superficial mycoses (eg, dandruff, pityriasis versicolor, and folliculitis) affecting up to 50% of the population worldwide.⁹ Despite this, there has been little recent advancement in antifungal treatments. Ketoconazole, terbinafine, and fluconazole have been in use since the 1980s and 1990s.⁸ Most antifungal drugs target ergosterol, a component of the fungal cell wall.¹⁰ Additionally, Malassezia spp have been increasingly reported to cause invasive infections in immunocompromised patients.¹¹ Given the rise in antifungal resistance, the judicious use of antifungals and implementation of novel treatment strategies is essential.

While SA lacks intrinsic antifungal properties, different combinations (Whitfield ointment consisting of 3% SA and 6% benzoic acid; 2% sulfur and 2% SA) have been effective in the treatment of TV.¹ It is theorized that the effectiveness of SA against TV is due to its ability to exfoliate and acidify the stratum corneum, the natural habitat of M. furfur.

SA also reduces sebum production by downregulating sebocyte lipogenesis via the sterol regulatory element-binding protein-1 pathway and suppressing the nuclear factor κB (NF-κB) pathway, a key pathway in inflammation.¹² These mechanisms make SA an effective acne treatment. Additionally, M. furfur is a lipid-dependent yeast, thus the decreased lipogenesis by sebocytes may be beneficial in treating TV as well.¹² A study of 25 patients with TV in India found that 88% achieved clinical and microbiological cure after 4 once-weekly treatments of a SA 30% peel.⁸

In a study of deployed military personnel, fungal infections affected about 11% of participants.¹³ Contributing factors to the development of fungal infections included excessive sweating, humid conditions, and limited access to hygiene facilities. In such settings, traditional antifungal therapies may be less effective or challenging to adhere to, making alternative treatments more desirable. SA peels could offer a practical solution in these circumstances, as they are easily applied in the clinic, require no neutralization or downtime, and do not require the patient to apply medications between visits.

In this case, the patient demonstrated significant improvement with 2 SA peels, with noted improvement in her acne. SA 30% peel was highlighted as a useful treatment option for patients with TV who struggle with topical medication adherence; furthermore, it may be particularly beneficial for patients with concomitant acne.

Conclusions

This case demonstrates the successful use of in-office SA 30% peel as a treatment for TV. The rapid improvement and resolution of lesions with minimal adverse effects suggest that SA peel may serve as a valuable alternative for patients with extensive disease in difficult-to-reach affected areas, or those who are dissatisfied with traditional therapies. Additionally, the concurrent improvement of the patient’s back acne underscores the dual therapeutic potential of this treatment. Given the ease of application, cost effectiveness, and favorable safety profile, SA 30% peel is a viable option in the management of TV, especially in cases where topical or oral antifungals are impractical. Further studies could help establish standardized protocols and assess long-term outcomes of this treatment modality.

Tinea versicolor (TV) is a common, chronic, and recurrent superficial fungal infection caused by Malassezia species, most commonly Malassezia furfur (M. furfur)—a dimorphic fungus that is a part of the normal skin flora and resides in the stratum corneum.¹ TV manifests as hypopigmented, hyperpigmented, or erythematous macules and patches with scaling, typically found on the trunk and proximal upper extremities. The condition is most common among young to middle-aged individuals exposed to high temperatures and humidity.¹

While many cases respond to topical antifungal treatment, application can be cumbersome, particularly in large areas that are difficult to reach. An efficient and cost effective in-office treatment option could alleviate patient burden and improve satisfaction. This article presents a case of TV successfully treated with an in-office salicylic acid (SA) 30% peel, an uncommon application of this medication.

Case Presentation

An 18-year-old female active-duty US Army service member with a history of acne vulgaris presented to a dermatology clinic with a mildly pruritic rash that had been present for several weeks. An examination revealed hyperpigmented macules and patches with overlying fine scales across the patient’s back and bilateral arms (Figures 1 and 2). She reported no history of similar lesions. The patient had recently completed a military basic training course during which she wore a uniform jacket and trousers daily in hot and humid conditions. A skin scraping was obtained. Microscopic examination with potassium hydroxide preparation revealed hyphae and spores, consistent with TV.

The diagnosis of TV and treatment options (topical ketoconazole 2% shampoo, topical terbinafine, or oral fluconazole) were discussed with the patient. Due to military training-related constraints, residence in the barracks, and personal preference, the patient felt unable to regularly apply topical medications to the entirety of the affected area and preferred to avoid oral medication. The decision was made to pursue in-clinic treatment with a SA 30% peel. The affected areas (back and bilateral arms) were thoroughly cleansed and prepped with alcohol. SA 30% in hydroethanolic solution was applied evenly to the affected area. The patient was observed for pseudofrosting, a precipitation of SA crystals that indicates peel completion (Figure 3). The peel was left in place, as it is self-neutralizing, and the patient was instructed to shower that same day with a gentle cleanser. This procedure was repeated 10 days later. Both treatments were well tolerated, with only a transient burning sensation reported during the application. At 3-week follow-up, the patient presented with complete resolution of her arm lesions and significant improvement of the back lesions (Figures 4 and 5). She also reported improvement in the acne vulgaris on her back.

Discussion

SA 30% is a lipid-soluble hydroxybenzoic acid with comedolytic and desmolytic qualities. This results in the disruption of epidermal cell cohesion and promotes exfoliation.² Lipophilic properties allow SA to penetrate sebaceous glands and disrupt sebum production, making it particularly effective in seborrheic conditions such as acne. This mechanism may have increased therapeutic effect in this case.³ Additionally, as a salicylate, SA possesses anti-inflammatory properties, though this effect is most pronounced at lower concentrations. SA 30% is considered a superficial peel, as the depth of chemexfoliation is limited to the epidermis.³ A modified SA preparation is a safe and effective treatment for moderate-to-severe acne vulgaris. The apparent pseudofrost during application is due to precipitated SA, rather than the precipitation of dermal proteins seen in deeper peels, such as trichloroacetic acid.² Unlike glycolic or pyruvic acid peels, SA does not require neutralization.

SA is cost-effective and has been used safely in all skin types to treat various epidermal conditions, including acne vulgaris, melasma, photodamage, freckles, lentigines and postinflammatory hyperpigmentation (PIH).² Mild adverse effects occur in about 15% to 30% of patients and include prolonged erythema, intense exfoliation, dryness, crusting, and pigmentary dyschromias. Rare adverse effects include systemic toxicity (salicylism) and hypoglycemia. Contraindications to SA 30% peels include history of allergy to salicylates, active bacterial or viral infection, dermatitis in the treatment area, pregnancy, and skin malignancy.²

Chemical peels are typically used with caution in patients with skin of color due to a higher risk of PIH. However, SA 30% has been shown to be safe and effective in these populations.⁴ A study by Grimes found that 88% of patients with Fitzpatrick skin types V and VI experienced significant improvement in PIH, melasma, or enlarged pores with minimal to no adverse effects.⁴ Subsequent larger studies have reinforced these findings. In a study involving 250 patients with Fitzpatrick skin types IV and V, no patients experienced PIH, confirming the safety of SA in darker skin tones. This is likely due to the superficial nature of the peel, which does not affect the basal layer of the epidermis where melanocytes reside, reducing the risk of pigmentary complications. Additionally, SA peels are self-neutralizing, unlike glycolic or trichloroacetic acid peels, which require manual neutralization and carry a higher risk of PIH if not neutralized properly.⁵

SA has been as shown to be a moderately successful treatment for PIH. The Grimes study found that 4 of 5 patients with Fitzpatrick skin types IV and V saw a 75% improvement in PIH after SA peels.⁴ Davis et al found a nonsignificant trend toward skin lightening in Korean adults treated for acne and PIH, with significant decreases in erythema and improvements in greasiness, dryness, and scaliness.⁶ Importantly, the risk of PIH following TV is higher in patients with skin of color.⁷ SA may be effective in treating TV and PIH, offering a multifactorial approach by addressing both conditions while posing a low risk for causing PIH.⁸

TV and other Malassezia spp infections are common concerns in dermatology and primary care, with Malassezia-associated superficial mycoses (eg, dandruff, pityriasis versicolor, and folliculitis) affecting up to 50% of the population worldwide.⁹ Despite this, there has been little recent advancement in antifungal treatments. Ketoconazole, terbinafine, and fluconazole have been in use since the 1980s and 1990s.⁸ Most antifungal drugs target ergosterol, a component of the fungal cell wall.¹⁰ Additionally, Malassezia spp have been increasingly reported to cause invasive infections in immunocompromised patients.¹¹ Given the rise in antifungal resistance, the judicious use of antifungals and implementation of novel treatment strategies is essential.

While SA lacks intrinsic antifungal properties, different combinations (Whitfield ointment consisting of 3% SA and 6% benzoic acid; 2% sulfur and 2% SA) have been effective in the treatment of TV.¹ It is theorized that the effectiveness of SA against TV is due to its ability to exfoliate and acidify the stratum corneum, the natural habitat of M. furfur.

SA also reduces sebum production by downregulating sebocyte lipogenesis via the sterol regulatory element-binding protein-1 pathway and suppressing the nuclear factor κB (NF-κB) pathway, a key pathway in inflammation.¹² These mechanisms make SA an effective acne treatment. Additionally, M. furfur is a lipid-dependent yeast, thus the decreased lipogenesis by sebocytes may be beneficial in treating TV as well.¹² A study of 25 patients with TV in India found that 88% achieved clinical and microbiological cure after 4 once-weekly treatments of a SA 30% peel.⁸

In a study of deployed military personnel, fungal infections affected about 11% of participants.¹³ Contributing factors to the development of fungal infections included excessive sweating, humid conditions, and limited access to hygiene facilities. In such settings, traditional antifungal therapies may be less effective or challenging to adhere to, making alternative treatments more desirable. SA peels could offer a practical solution in these circumstances, as they are easily applied in the clinic, require no neutralization or downtime, and do not require the patient to apply medications between visits.

In this case, the patient demonstrated significant improvement with 2 SA peels, with noted improvement in her acne. SA 30% peel was highlighted as a useful treatment option for patients with TV who struggle with topical medication adherence; furthermore, it may be particularly beneficial for patients with concomitant acne.

Conclusions

This case demonstrates the successful use of in-office SA 30% peel as a treatment for TV. The rapid improvement and resolution of lesions with minimal adverse effects suggest that SA peel may serve as a valuable alternative for patients with extensive disease in difficult-to-reach affected areas, or those who are dissatisfied with traditional therapies. Additionally, the concurrent improvement of the patient’s back acne underscores the dual therapeutic potential of this treatment. Given the ease of application, cost effectiveness, and favorable safety profile, SA 30% peel is a viable option in the management of TV, especially in cases where topical or oral antifungals are impractical. Further studies could help establish standardized protocols and assess long-term outcomes of this treatment modality.

Tinea versicolor (TV) is a common, chronic, and recurrent superficial fungal infection caused by Malassezia species, most commonly Malassezia furfur (M. furfur)—a dimorphic fungus that is a part of the normal skin flora and resides in the stratum corneum.¹ TV manifests as hypopigmented, hyperpigmented, or erythematous macules and patches with scaling, typically found on the trunk and proximal upper extremities. The condition is most common among young to middle-aged individuals exposed to high temperatures and humidity.¹

While many cases respond to topical antifungal treatment, application can be cumbersome, particularly in large areas that are difficult to reach. An efficient and cost effective in-office treatment option could alleviate patient burden and improve satisfaction. This article presents a case of TV successfully treated with an in-office salicylic acid (SA) 30% peel, an uncommon application of this medication.

Case Presentation

An 18-year-old female active-duty US Army service member with a history of acne vulgaris presented to a dermatology clinic with a mildly pruritic rash that had been present for several weeks. An examination revealed hyperpigmented macules and patches with overlying fine scales across the patient’s back and bilateral arms (Figures 1 and 2). She reported no history of similar lesions. The patient had recently completed a military basic training course during which she wore a uniform jacket and trousers daily in hot and humid conditions. A skin scraping was obtained. Microscopic examination with potassium hydroxide preparation revealed hyphae and spores, consistent with TV.

The diagnosis of TV and treatment options (topical ketoconazole 2% shampoo, topical terbinafine, or oral fluconazole) were discussed with the patient. Due to military training-related constraints, residence in the barracks, and personal preference, the patient felt unable to regularly apply topical medications to the entirety of the affected area and preferred to avoid oral medication. The decision was made to pursue in-clinic treatment with a SA 30% peel. The affected areas (back and bilateral arms) were thoroughly cleansed and prepped with alcohol. SA 30% in hydroethanolic solution was applied evenly to the affected area. The patient was observed for pseudofrosting, a precipitation of SA crystals that indicates peel completion (Figure 3). The peel was left in place, as it is self-neutralizing, and the patient was instructed to shower that same day with a gentle cleanser. This procedure was repeated 10 days later. Both treatments were well tolerated, with only a transient burning sensation reported during the application. At 3-week follow-up, the patient presented with complete resolution of her arm lesions and significant improvement of the back lesions (Figures 4 and 5). She also reported improvement in the acne vulgaris on her back.

Discussion

SA 30% is a lipid-soluble hydroxybenzoic acid with comedolytic and desmolytic qualities. This results in the disruption of epidermal cell cohesion and promotes exfoliation.² Lipophilic properties allow SA to penetrate sebaceous glands and disrupt sebum production, making it particularly effective in seborrheic conditions such as acne. This mechanism may have increased therapeutic effect in this case.³ Additionally, as a salicylate, SA possesses anti-inflammatory properties, though this effect is most pronounced at lower concentrations. SA 30% is considered a superficial peel, as the depth of chemexfoliation is limited to the epidermis.³ A modified SA preparation is a safe and effective treatment for moderate-to-severe acne vulgaris. The apparent pseudofrost during application is due to precipitated SA, rather than the precipitation of dermal proteins seen in deeper peels, such as trichloroacetic acid.² Unlike glycolic or pyruvic acid peels, SA does not require neutralization.

SA is cost-effective and has been used safely in all skin types to treat various epidermal conditions, including acne vulgaris, melasma, photodamage, freckles, lentigines and postinflammatory hyperpigmentation (PIH).² Mild adverse effects occur in about 15% to 30% of patients and include prolonged erythema, intense exfoliation, dryness, crusting, and pigmentary dyschromias. Rare adverse effects include systemic toxicity (salicylism) and hypoglycemia. Contraindications to SA 30% peels include history of allergy to salicylates, active bacterial or viral infection, dermatitis in the treatment area, pregnancy, and skin malignancy.²

Chemical peels are typically used with caution in patients with skin of color due to a higher risk of PIH. However, SA 30% has been shown to be safe and effective in these populations.⁴ A study by Grimes found that 88% of patients with Fitzpatrick skin types V and VI experienced significant improvement in PIH, melasma, or enlarged pores with minimal to no adverse effects.⁴ Subsequent larger studies have reinforced these findings. In a study involving 250 patients with Fitzpatrick skin types IV and V, no patients experienced PIH, confirming the safety of SA in darker skin tones. This is likely due to the superficial nature of the peel, which does not affect the basal layer of the epidermis where melanocytes reside, reducing the risk of pigmentary complications. Additionally, SA peels are self-neutralizing, unlike glycolic or trichloroacetic acid peels, which require manual neutralization and carry a higher risk of PIH if not neutralized properly.⁵

SA has been as shown to be a moderately successful treatment for PIH. The Grimes study found that 4 of 5 patients with Fitzpatrick skin types IV and V saw a 75% improvement in PIH after SA peels.⁴ Davis et al found a nonsignificant trend toward skin lightening in Korean adults treated for acne and PIH, with significant decreases in erythema and improvements in greasiness, dryness, and scaliness.⁶ Importantly, the risk of PIH following TV is higher in patients with skin of color.⁷ SA may be effective in treating TV and PIH, offering a multifactorial approach by addressing both conditions while posing a low risk for causing PIH.⁸

TV and other Malassezia spp infections are common concerns in dermatology and primary care, with Malassezia-associated superficial mycoses (eg, dandruff, pityriasis versicolor, and folliculitis) affecting up to 50% of the population worldwide.⁹ Despite this, there has been little recent advancement in antifungal treatments. Ketoconazole, terbinafine, and fluconazole have been in use since the 1980s and 1990s.⁸ Most antifungal drugs target ergosterol, a component of the fungal cell wall.¹⁰ Additionally, Malassezia spp have been increasingly reported to cause invasive infections in immunocompromised patients.¹¹ Given the rise in antifungal resistance, the judicious use of antifungals and implementation of novel treatment strategies is essential.

While SA lacks intrinsic antifungal properties, different combinations (Whitfield ointment consisting of 3% SA and 6% benzoic acid; 2% sulfur and 2% SA) have been effective in the treatment of TV.¹ It is theorized that the effectiveness of SA against TV is due to its ability to exfoliate and acidify the stratum corneum, the natural habitat of M. furfur.

SA also reduces sebum production by downregulating sebocyte lipogenesis via the sterol regulatory element-binding protein-1 pathway and suppressing the nuclear factor κB (NF-κB) pathway, a key pathway in inflammation.¹² These mechanisms make SA an effective acne treatment. Additionally, M. furfur is a lipid-dependent yeast, thus the decreased lipogenesis by sebocytes may be beneficial in treating TV as well.¹² A study of 25 patients with TV in India found that 88% achieved clinical and microbiological cure after 4 once-weekly treatments of a SA 30% peel.⁸

In a study of deployed military personnel, fungal infections affected about 11% of participants.¹³ Contributing factors to the development of fungal infections included excessive sweating, humid conditions, and limited access to hygiene facilities. In such settings, traditional antifungal therapies may be less effective or challenging to adhere to, making alternative treatments more desirable. SA peels could offer a practical solution in these circumstances, as they are easily applied in the clinic, require no neutralization or downtime, and do not require the patient to apply medications between visits.

In this case, the patient demonstrated significant improvement with 2 SA peels, with noted improvement in her acne. SA 30% peel was highlighted as a useful treatment option for patients with TV who struggle with topical medication adherence; furthermore, it may be particularly beneficial for patients with concomitant acne.

Conclusions

This case demonstrates the successful use of in-office SA 30% peel as a treatment for TV. The rapid improvement and resolution of lesions with minimal adverse effects suggest that SA peel may serve as a valuable alternative for patients with extensive disease in difficult-to-reach affected areas, or those who are dissatisfied with traditional therapies. Additionally, the concurrent improvement of the patient’s back acne underscores the dual therapeutic potential of this treatment. Given the ease of application, cost effectiveness, and favorable safety profile, SA 30% peel is a viable option in the management of TV, especially in cases where topical or oral antifungals are impractical. Further studies could help establish standardized protocols and assess long-term outcomes of this treatment modality.

The extensive surface of the gastrointestinal tract presents an interface between the human body and its environment. Residing within the intestinal lumen, ingested food and various microorganisms are an essential aspect of this relationship. The trillions of microorganisms, primarily commensal bacteria hosted by the human gut, constitute the human gut microbiome.

There is growing evidence that the human gut microbiome plays a role in maintaining normal body function and homeostasis.¹ Research, such as the National Institute of Health Microbiome Project, is helping to show the impact of gut microorganisms and their negative influence on metabolic diseases and chronic inflammatory disorders.^2-5 An imbalance in the microbiota, known as dysbiosis, has been associated with metabolic and cardiovascular diseases (CVD), including hypertension, diabetes mellitus, obesity, and coronary artery disease (CAD). Gut dysbiosis has also been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (Figure).^6-12

Whether gut dysbiosis is a cause or effect of the human disease process is unclear. While further research is warranted, some evidence of causation has been found. In 2018, Yoshida et al demonstrated an association between patients with CAD who had a significantly lower burden of the gut bacteria species Bacteroides vulgatus and Bacteroides dorei compared to that of patients without CAD. The study found that administration of these Bacteroides species reduced atherosclerotic lesion formation in atherosclerosis-prone mice.¹³ If altering gut microbial composition can affect the disease process, it may indicate a causative role for gut dysbiosis in disease pathogenesis. Furthermore, this finding also suggests agents may be used to alter the gut microbiome and potentially prevent and treat diseases. An altered gut microbiome may serve as an early marker for human disease, aiding in timely diagnosis and institution of disease-modifying treatments.

This review outlines the broad relationship of the pathways and intermediaries that may be involved in mediating the interaction between the gut microbiome and cardiac arrhythmias based on rapidly increasing evidence. A comprehensive search among PubMed and Google Scholar databases was conducted to find articles relevant to the topic.

Potential Intermediaries

Potential pathways for how the gut microbiome and cardiovascular system interact are subjects of active research. However, recent research may point to potential mechanisms of the association between the systems. The gut microbiome may influence human physiology through 3 principal routes: the autonomic nervous system, inflammatory pathways, and metabolic processes.

Autonomic Nervous System

The concept of bidirectional communication between the gut and central nervous system, known as the microbiota-gut-brain axis, is widely accepted.¹⁴ Proposed mediators of this interaction include the vagus nerve, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis; cytokines produced by the immune system, tryptophan metabolism, and the production of short-chain fatty acids (SCFAs).^15,16

The gut microbiome appears to have a direct impact on the autonomic nervous system, through which it can influence cardiovascular function. Muller et al described how the gut microbiome modulated gut-extrinsic sympathetic neurons and that the depletion of gut microbiota led to activation of both brainstem sensory nuclei and efferent sympathetic premotor glutamatergic neurons.¹⁶ Meng et al found that systemic injection of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) led to significantly increased activity in the paraventricular nucleus, a hypothalamic structure essential to the central autonomic network. Their study demonstrated that systemic TMAO also led to increased left stellate ganglion (LSG) activity, a known contributor to cardiac sympathetic tone.¹²

Inflammatory Pathways

Inflammatory responses are another pathway for the gut microbiome to influence the cardiovascular system. SCFAs are a set of gut microbial metabolites produced in the colon by bacterial fermentation and decomposition of resistant starches and dietary fibers.¹⁷ These metabolites are increasingly recognized for their role in modulating disease processes, including cardiac disease. Aguilar et al found that the progression of atherosclerosis was slowed in apolipoprotein E (Apo-E) knockout mice by a chow diet supplemented with butyrate, a SCFA, suggesting it is an atheroprotective therapeutic agent. Less adhesion and migration of macrophages, reduced inflammation, improved plaque stability, and lowered atherosclerosis progression.¹⁸ Wei et al demonstrated in animal models that direct microinjection of the proinflammatory factors interleukin (IL)-1Β and tumor necrosis factor (TNF)-αdirectly into the subfornical organ increased heart rate, mean blood pressure, and renal sympathetic nerve activity.¹⁹

Metabolic Processes

Serotonin (5-HT), a metabolite of tryptophan, is a neurotransmitter that regulates many bodily functions and plays a significant role in the microbiota-brain gut axis.²⁰ Oral ingestion of the bacterial species Bifidobacterium infantis increased plasma tryptophan in rat models.²¹ Additionally, many other microorganisms, including species of Candida, Streptococcus, Escherichia, and Enterococcus are known to produce 5-HT.²² While a relationship between the gut microbiome and plasma 5-HT has been established, interactions between 5-HT and the cardiovascular system are complex. Research has shown that stimulation of 5-HT_1A receptors produces bradycardic and vasopressor effects, while stimulation of the 5-HT₂ receptor induces vasoconstriction and tachycardia.²³

A high-fiber diet can lower the incidence of hypertension, although the mechanisms are not clear. One potential reason could be alteration in gut bacteria, as a diet high in fiber has been shown to increase the prevalence of acetate-producing bacteria.²⁴

Atherosclerosis

Research investigating the relationship of the gut microbiome with arrhythmias is in its early stages; however, the connection of the gut microbiome and atherosclerosis is more established.²⁵ Contemporary studies have shown various gut microorganisms associated with atherosclerosis.²⁶ Jie et al reported that patients with atherosclerotic cardiovascular disease had increased Enterobacteriaceae loads and oral cavity-associated bacteria with lower levels of butyrate producing bacteria when compared with healthy controls.²⁷ In addition, microbial metabolites such as TMAO appear to promote atherosclerosis by increasing vascular inflammation and platelet reactivity.²⁶ Researchers are investigating the modulation of these associations to help reduce atherosclerotic burden. Kasahara et al found that Roseburia intestinalis could reduce atherosclerotic disease in mice through the production of butyrate.²⁸ Roberts et al established that administration of TMAO inhibitors reduced TMAO levels while reducing thrombus formation without observable toxicity or increased bleeding risk.²⁹

Atrial Arrhythmias

The gut microbiome can also specifically affect cardiac arrhythmogenesis, and multiple studies suggest possible mediators of this interaction. Certain gut microbiome derived metabolites like TMAO may have a role in promoting AF.³⁰ Other gut microbial metabolites like lipopolysaccharides and indoxyl sulfate are implicated in atrial electrical instability.^31,32 Microbe-derived free fatty acids such as palmitic acid and adrenic acid can precipitate arrhythmogenesis. ^33,34 Preponderances of certain gut bacteria like Ruminococcus, Streptococcus, and Enterococcus, as well as reductions of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila have been detected in patients with AF.⁸ Tabata et al found that certain clusters of bacterial groups led by Ruminococcus species seem to show higher prevalence in patients with AF, whereas the genus Enterobacter was significantly lower compared with control subjects. That study also noted that gut microbial composition is affected by diet and antacid use.³⁵ Gut microbiome-derived serotonin may be another mediator for AF, which may be related to the fact that 5-HT₄ receptors are present in atrial tissue.³⁶

Ventricular Arrhythmias

A critical component to the development of malignant ventricular arrhythmias is an imbalance in autonomic tone; in particular, the overactivation of the sympathetic nervous system.³⁷ Animal models have shown that augmentation of the sympathetic nervous system plays an essential role in the subsequent development of ventricular arrhythmias. ³⁸ Several studies have established the LSG as an important component of the cardiac sympathetic nervous system pathway. ^38,39 Ablation of the LSG has been shown to effectively reduce the burden of malignant arrhythmias, further pointing toward the role of excess sympathetic activity.^37,39 Stellate ganglion denervation has become an established method for managing life-threatening ventricular arrhythmias.⁴⁰

Gut metabolites may have significant effects on cardiac sympathetic activity. Meng et al investigated the effect of TMAO on the LSG in animals and its overall effect on the incidence of ventricular arrhythmias under ischemic conditions. To fully explore this interaction, they examined the effect of TMAO on LSG function though 2 mechanisms: local administration of TMAO within the LSG and systemic administration of TMAO leading to activation of the central sympathetic nervous system. In both protocols, left anterior descending coronary artery occlusion was performed after TMAO administration. Injection of TMAO directly into the LSG was found to significantly increase the cardiac sympathetic tone and incidence of ventricular arrhythmias. In the systemic administration control arm, ventricular arrhythmias were also significantly increased.¹²

Increased inflammatory states appear to correlate with an increase in sympathetic tone and ventricular arrhythmias.¹² In an animal study, direct injection of the proinflammatory factor IL-1Β into the LSG not only resulted in increased inflammation, but aggravated cardiac sympathetic remodeling. This led to a decreased effective refractory period and action potential duration, leading to an increased maximal slope of the restitution curve and higher occurrence of ventricular arrhythmias.⁴¹ Shi et al demonstrated that paraventricular nucleus microinjection with TNF-α and IL-1Β also enhanced the cardiac sympathetic afferent reflex, showing that these proinflammatory cytokines not only upregulate the inflammatory response, but can also have excitatory effects that stimulate sympathetic activity and have the potential to be proarrhythmic.^19,42 Local and systemic administration of the gut microbe-derived TMAO increased the expression of IL-1Β and TNF-α, thus implicating the microbiome as a potential mediator of the inflammatory response and as another potential pathway for increased ventricular arrhythmias.¹²

The N-methyl-d-aspartate receptor (NMDAR) is found in multiple organs—including the heart—but more specifically in the conducting system and myocardium.43,44 Research has discovered an upregulation of NMDARs in the setting of cardiac sympathetic hyperinnervation in rat models both with healed myocardial necrotic injury and without. The infusion of their ligand, NMDA, provoked ventricular tachycardia and ventricular fibrillation in rat models with sympathetic hyperinnervation and healed myocardial necrotic injury.⁴⁵ Another study found that NMDAR activation provoked ventricular arrhythmias, but also prolonged repolarization and induced electrical instability.⁴⁶ Proinflammatory markers have been shown to upregulate the expression of NMDARs; more importantly, NMDAR expression has been shown to be significantly increased in the setting of TMAO administration.^12,47,48

5-HT also appears to have a substantial association with ventricular arrhythmias in addition to atrial arrhythmias. el-Mahdy demonstrated in anesthetized rats with acute coronary ligation that systemic doses of 5-HT represented a significant dose-dependent increase in the duration of ventricular tachycardia and ventricular fibrillation, while also increasing the number of ventricular ectopic beats.⁴⁹ Certain gut microorganisms are known to produce 5-HT, including those in the genera Streptococcus, Escherichia, and Enterococcus.²² Additionally, oral ingestion of the Bifidobacterium infantis increased plasma levels of tryptophan in rat models.²¹ The gut microbiome may have significant effects on plasma serotonin levels, and thus have the potential to alter the risk for ventricular arrhythmias.

The deleterious effects of the gut microbiome have been documented. However, it appears to have potential protective effects, and several studies point to the possible mechanisms of this beneficial interaction. Propionate is a SCFA microorganism produced by gut microbial fermentation.⁵⁰ In a rat model study, Zhou et al found that infusion of sodium propionate significantly reduced ventricular arrhythmias during acute myocardial ischemia or burst stimulation, thus confirming cardioprotective effects.^50,51

Proposed mechanisms for reduced susceptibility to ventricular arrhythmias with propionate infusion include parasympathetic activation via the gut-brain axis, anti-inflammatory pathways, and improved cardiac electrophysiology instability.⁵⁰ In addition butyrate has been found to reduce inflammation and myocardial hypertrophy. Jiang et al demonstrated in rats postmyocardial infarction that butyrate promoted expression of anti-inflammatory M2 macrophage markers, decreased expressions of nerve growth factor and norepinephrine, and decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase. The cumulative impact of butyrate led to suppression of inflammation and the inhibition of sympathetic neural remodeling, ultimately resulting in improved cardiac function and reduction in ventricular arrhythmias after myocardial infarction.⁵²

Gut bacteria-derived acetate-mediated reduction in cardiac fibrosis may be another mechanism for the effects on ventricular arrhythmias. Cardiac fibrosis and scar are established as the primary substrate for reentrant ventricular arrhythmias seen in various cardiomyopathies.

Future Directions

The microbiome residing in the human gut has a significant impact on cardiac arrhythmias, the details of which remain unknown. A likely bidirectional relationship exists in which the gut microbiome may affect arrhythmogenesis and in turn be affected by cardiac arrhythmias. The mechanisms of action are not well understood, but likely involve the autonomic nervous system, inflammation, and metabolic pathways.

The gut microbiome is a complex collection of heterogenous microorganisms that have dramatic effects on the human body. Additional research is necessary to identify further associations and causations of gut microorganisms with various human body processes, as well as cardiovascular disease. The microbiome has been shown to directly and indirectly influence the development of different disease states, including the cardiovascular system and cardiac arrhythmias. Several pathways have been proposed through which the gut microbiome can potentially affect cardiac arrhythmogenesis. There are likely several mechanisms simultaneously in operation. Understanding the role of human gut microbiome in the genesis of cardiac arrhythmias not only may improve our understanding of arrhythmias, but also may result in novel treatment options. This could potentially lead to the development of therapeutic options and strategies to modulate the gut microbiome to help detect, prevent, and treat cardiac arrhythmias.

The extensive surface of the gastrointestinal tract presents an interface between the human body and its environment. Residing within the intestinal lumen, ingested food and various microorganisms are an essential aspect of this relationship. The trillions of microorganisms, primarily commensal bacteria hosted by the human gut, constitute the human gut microbiome.

There is growing evidence that the human gut microbiome plays a role in maintaining normal body function and homeostasis.¹ Research, such as the National Institute of Health Microbiome Project, is helping to show the impact of gut microorganisms and their negative influence on metabolic diseases and chronic inflammatory disorders.^2-5 An imbalance in the microbiota, known as dysbiosis, has been associated with metabolic and cardiovascular diseases (CVD), including hypertension, diabetes mellitus, obesity, and coronary artery disease (CAD). Gut dysbiosis has also been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (Figure).^6-12

Whether gut dysbiosis is a cause or effect of the human disease process is unclear. While further research is warranted, some evidence of causation has been found. In 2018, Yoshida et al demonstrated an association between patients with CAD who had a significantly lower burden of the gut bacteria species Bacteroides vulgatus and Bacteroides dorei compared to that of patients without CAD. The study found that administration of these Bacteroides species reduced atherosclerotic lesion formation in atherosclerosis-prone mice.¹³ If altering gut microbial composition can affect the disease process, it may indicate a causative role for gut dysbiosis in disease pathogenesis. Furthermore, this finding also suggests agents may be used to alter the gut microbiome and potentially prevent and treat diseases. An altered gut microbiome may serve as an early marker for human disease, aiding in timely diagnosis and institution of disease-modifying treatments.

This review outlines the broad relationship of the pathways and intermediaries that may be involved in mediating the interaction between the gut microbiome and cardiac arrhythmias based on rapidly increasing evidence. A comprehensive search among PubMed and Google Scholar databases was conducted to find articles relevant to the topic.

Potential Intermediaries

Potential pathways for how the gut microbiome and cardiovascular system interact are subjects of active research. However, recent research may point to potential mechanisms of the association between the systems. The gut microbiome may influence human physiology through 3 principal routes: the autonomic nervous system, inflammatory pathways, and metabolic processes.

Autonomic Nervous System

The concept of bidirectional communication between the gut and central nervous system, known as the microbiota-gut-brain axis, is widely accepted.¹⁴ Proposed mediators of this interaction include the vagus nerve, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis; cytokines produced by the immune system, tryptophan metabolism, and the production of short-chain fatty acids (SCFAs).^15,16

The gut microbiome appears to have a direct impact on the autonomic nervous system, through which it can influence cardiovascular function. Muller et al described how the gut microbiome modulated gut-extrinsic sympathetic neurons and that the depletion of gut microbiota led to activation of both brainstem sensory nuclei and efferent sympathetic premotor glutamatergic neurons.¹⁶ Meng et al found that systemic injection of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) led to significantly increased activity in the paraventricular nucleus, a hypothalamic structure essential to the central autonomic network. Their study demonstrated that systemic TMAO also led to increased left stellate ganglion (LSG) activity, a known contributor to cardiac sympathetic tone.¹²

Inflammatory Pathways

Inflammatory responses are another pathway for the gut microbiome to influence the cardiovascular system. SCFAs are a set of gut microbial metabolites produced in the colon by bacterial fermentation and decomposition of resistant starches and dietary fibers.¹⁷ These metabolites are increasingly recognized for their role in modulating disease processes, including cardiac disease. Aguilar et al found that the progression of atherosclerosis was slowed in apolipoprotein E (Apo-E) knockout mice by a chow diet supplemented with butyrate, a SCFA, suggesting it is an atheroprotective therapeutic agent. Less adhesion and migration of macrophages, reduced inflammation, improved plaque stability, and lowered atherosclerosis progression.¹⁸ Wei et al demonstrated in animal models that direct microinjection of the proinflammatory factors interleukin (IL)-1Β and tumor necrosis factor (TNF)-αdirectly into the subfornical organ increased heart rate, mean blood pressure, and renal sympathetic nerve activity.¹⁹

Metabolic Processes

Serotonin (5-HT), a metabolite of tryptophan, is a neurotransmitter that regulates many bodily functions and plays a significant role in the microbiota-brain gut axis.²⁰ Oral ingestion of the bacterial species Bifidobacterium infantis increased plasma tryptophan in rat models.²¹ Additionally, many other microorganisms, including species of Candida, Streptococcus, Escherichia, and Enterococcus are known to produce 5-HT.²² While a relationship between the gut microbiome and plasma 5-HT has been established, interactions between 5-HT and the cardiovascular system are complex. Research has shown that stimulation of 5-HT_1A receptors produces bradycardic and vasopressor effects, while stimulation of the 5-HT₂ receptor induces vasoconstriction and tachycardia.²³

A high-fiber diet can lower the incidence of hypertension, although the mechanisms are not clear. One potential reason could be alteration in gut bacteria, as a diet high in fiber has been shown to increase the prevalence of acetate-producing bacteria.²⁴

Atherosclerosis

Research investigating the relationship of the gut microbiome with arrhythmias is in its early stages; however, the connection of the gut microbiome and atherosclerosis is more established.²⁵ Contemporary studies have shown various gut microorganisms associated with atherosclerosis.²⁶ Jie et al reported that patients with atherosclerotic cardiovascular disease had increased Enterobacteriaceae loads and oral cavity-associated bacteria with lower levels of butyrate producing bacteria when compared with healthy controls.²⁷ In addition, microbial metabolites such as TMAO appear to promote atherosclerosis by increasing vascular inflammation and platelet reactivity.²⁶ Researchers are investigating the modulation of these associations to help reduce atherosclerotic burden. Kasahara et al found that Roseburia intestinalis could reduce atherosclerotic disease in mice through the production of butyrate.²⁸ Roberts et al established that administration of TMAO inhibitors reduced TMAO levels while reducing thrombus formation without observable toxicity or increased bleeding risk.²⁹

Atrial Arrhythmias

The gut microbiome can also specifically affect cardiac arrhythmogenesis, and multiple studies suggest possible mediators of this interaction. Certain gut microbiome derived metabolites like TMAO may have a role in promoting AF.³⁰ Other gut microbial metabolites like lipopolysaccharides and indoxyl sulfate are implicated in atrial electrical instability.^31,32 Microbe-derived free fatty acids such as palmitic acid and adrenic acid can precipitate arrhythmogenesis. ^33,34 Preponderances of certain gut bacteria like Ruminococcus, Streptococcus, and Enterococcus, as well as reductions of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila have been detected in patients with AF.⁸ Tabata et al found that certain clusters of bacterial groups led by Ruminococcus species seem to show higher prevalence in patients with AF, whereas the genus Enterobacter was significantly lower compared with control subjects. That study also noted that gut microbial composition is affected by diet and antacid use.³⁵ Gut microbiome-derived serotonin may be another mediator for AF, which may be related to the fact that 5-HT₄ receptors are present in atrial tissue.³⁶

Ventricular Arrhythmias

A critical component to the development of malignant ventricular arrhythmias is an imbalance in autonomic tone; in particular, the overactivation of the sympathetic nervous system.³⁷ Animal models have shown that augmentation of the sympathetic nervous system plays an essential role in the subsequent development of ventricular arrhythmias. ³⁸ Several studies have established the LSG as an important component of the cardiac sympathetic nervous system pathway. ^38,39 Ablation of the LSG has been shown to effectively reduce the burden of malignant arrhythmias, further pointing toward the role of excess sympathetic activity.^37,39 Stellate ganglion denervation has become an established method for managing life-threatening ventricular arrhythmias.⁴⁰

Gut metabolites may have significant effects on cardiac sympathetic activity. Meng et al investigated the effect of TMAO on the LSG in animals and its overall effect on the incidence of ventricular arrhythmias under ischemic conditions. To fully explore this interaction, they examined the effect of TMAO on LSG function though 2 mechanisms: local administration of TMAO within the LSG and systemic administration of TMAO leading to activation of the central sympathetic nervous system. In both protocols, left anterior descending coronary artery occlusion was performed after TMAO administration. Injection of TMAO directly into the LSG was found to significantly increase the cardiac sympathetic tone and incidence of ventricular arrhythmias. In the systemic administration control arm, ventricular arrhythmias were also significantly increased.¹²

Increased inflammatory states appear to correlate with an increase in sympathetic tone and ventricular arrhythmias.¹² In an animal study, direct injection of the proinflammatory factor IL-1Β into the LSG not only resulted in increased inflammation, but aggravated cardiac sympathetic remodeling. This led to a decreased effective refractory period and action potential duration, leading to an increased maximal slope of the restitution curve and higher occurrence of ventricular arrhythmias.⁴¹ Shi et al demonstrated that paraventricular nucleus microinjection with TNF-α and IL-1Β also enhanced the cardiac sympathetic afferent reflex, showing that these proinflammatory cytokines not only upregulate the inflammatory response, but can also have excitatory effects that stimulate sympathetic activity and have the potential to be proarrhythmic.^19,42 Local and systemic administration of the gut microbe-derived TMAO increased the expression of IL-1Β and TNF-α, thus implicating the microbiome as a potential mediator of the inflammatory response and as another potential pathway for increased ventricular arrhythmias.¹²

The N-methyl-d-aspartate receptor (NMDAR) is found in multiple organs—including the heart—but more specifically in the conducting system and myocardium.43,44 Research has discovered an upregulation of NMDARs in the setting of cardiac sympathetic hyperinnervation in rat models both with healed myocardial necrotic injury and without. The infusion of their ligand, NMDA, provoked ventricular tachycardia and ventricular fibrillation in rat models with sympathetic hyperinnervation and healed myocardial necrotic injury.⁴⁵ Another study found that NMDAR activation provoked ventricular arrhythmias, but also prolonged repolarization and induced electrical instability.⁴⁶ Proinflammatory markers have been shown to upregulate the expression of NMDARs; more importantly, NMDAR expression has been shown to be significantly increased in the setting of TMAO administration.^12,47,48

5-HT also appears to have a substantial association with ventricular arrhythmias in addition to atrial arrhythmias. el-Mahdy demonstrated in anesthetized rats with acute coronary ligation that systemic doses of 5-HT represented a significant dose-dependent increase in the duration of ventricular tachycardia and ventricular fibrillation, while also increasing the number of ventricular ectopic beats.⁴⁹ Certain gut microorganisms are known to produce 5-HT, including those in the genera Streptococcus, Escherichia, and Enterococcus.²² Additionally, oral ingestion of the Bifidobacterium infantis increased plasma levels of tryptophan in rat models.²¹ The gut microbiome may have significant effects on plasma serotonin levels, and thus have the potential to alter the risk for ventricular arrhythmias.

The deleterious effects of the gut microbiome have been documented. However, it appears to have potential protective effects, and several studies point to the possible mechanisms of this beneficial interaction. Propionate is a SCFA microorganism produced by gut microbial fermentation.⁵⁰ In a rat model study, Zhou et al found that infusion of sodium propionate significantly reduced ventricular arrhythmias during acute myocardial ischemia or burst stimulation, thus confirming cardioprotective effects.^50,51

Proposed mechanisms for reduced susceptibility to ventricular arrhythmias with propionate infusion include parasympathetic activation via the gut-brain axis, anti-inflammatory pathways, and improved cardiac electrophysiology instability.⁵⁰ In addition butyrate has been found to reduce inflammation and myocardial hypertrophy. Jiang et al demonstrated in rats postmyocardial infarction that butyrate promoted expression of anti-inflammatory M2 macrophage markers, decreased expressions of nerve growth factor and norepinephrine, and decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase. The cumulative impact of butyrate led to suppression of inflammation and the inhibition of sympathetic neural remodeling, ultimately resulting in improved cardiac function and reduction in ventricular arrhythmias after myocardial infarction.⁵²

Gut bacteria-derived acetate-mediated reduction in cardiac fibrosis may be another mechanism for the effects on ventricular arrhythmias. Cardiac fibrosis and scar are established as the primary substrate for reentrant ventricular arrhythmias seen in various cardiomyopathies.

Future Directions

The microbiome residing in the human gut has a significant impact on cardiac arrhythmias, the details of which remain unknown. A likely bidirectional relationship exists in which the gut microbiome may affect arrhythmogenesis and in turn be affected by cardiac arrhythmias. The mechanisms of action are not well understood, but likely involve the autonomic nervous system, inflammation, and metabolic pathways.

The gut microbiome is a complex collection of heterogenous microorganisms that have dramatic effects on the human body. Additional research is necessary to identify further associations and causations of gut microorganisms with various human body processes, as well as cardiovascular disease. The microbiome has been shown to directly and indirectly influence the development of different disease states, including the cardiovascular system and cardiac arrhythmias. Several pathways have been proposed through which the gut microbiome can potentially affect cardiac arrhythmogenesis. There are likely several mechanisms simultaneously in operation. Understanding the role of human gut microbiome in the genesis of cardiac arrhythmias not only may improve our understanding of arrhythmias, but also may result in novel treatment options. This could potentially lead to the development of therapeutic options and strategies to modulate the gut microbiome to help detect, prevent, and treat cardiac arrhythmias.

The extensive surface of the gastrointestinal tract presents an interface between the human body and its environment. Residing within the intestinal lumen, ingested food and various microorganisms are an essential aspect of this relationship. The trillions of microorganisms, primarily commensal bacteria hosted by the human gut, constitute the human gut microbiome.

There is growing evidence that the human gut microbiome plays a role in maintaining normal body function and homeostasis.¹ Research, such as the National Institute of Health Microbiome Project, is helping to show the impact of gut microorganisms and their negative influence on metabolic diseases and chronic inflammatory disorders.^2-5 An imbalance in the microbiota, known as dysbiosis, has been associated with metabolic and cardiovascular diseases (CVD), including hypertension, diabetes mellitus, obesity, and coronary artery disease (CAD). Gut dysbiosis has also been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (Figure).^6-12

Whether gut dysbiosis is a cause or effect of the human disease process is unclear. While further research is warranted, some evidence of causation has been found. In 2018, Yoshida et al demonstrated an association between patients with CAD who had a significantly lower burden of the gut bacteria species Bacteroides vulgatus and Bacteroides dorei compared to that of patients without CAD. The study found that administration of these Bacteroides species reduced atherosclerotic lesion formation in atherosclerosis-prone mice.¹³ If altering gut microbial composition can affect the disease process, it may indicate a causative role for gut dysbiosis in disease pathogenesis. Furthermore, this finding also suggests agents may be used to alter the gut microbiome and potentially prevent and treat diseases. An altered gut microbiome may serve as an early marker for human disease, aiding in timely diagnosis and institution of disease-modifying treatments.

This review outlines the broad relationship of the pathways and intermediaries that may be involved in mediating the interaction between the gut microbiome and cardiac arrhythmias based on rapidly increasing evidence. A comprehensive search among PubMed and Google Scholar databases was conducted to find articles relevant to the topic.

Potential Intermediaries

Potential pathways for how the gut microbiome and cardiovascular system interact are subjects of active research. However, recent research may point to potential mechanisms of the association between the systems. The gut microbiome may influence human physiology through 3 principal routes: the autonomic nervous system, inflammatory pathways, and metabolic processes.

Autonomic Nervous System

The concept of bidirectional communication between the gut and central nervous system, known as the microbiota-gut-brain axis, is widely accepted.¹⁴ Proposed mediators of this interaction include the vagus nerve, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis; cytokines produced by the immune system, tryptophan metabolism, and the production of short-chain fatty acids (SCFAs).^15,16

The gut microbiome appears to have a direct impact on the autonomic nervous system, through which it can influence cardiovascular function. Muller et al described how the gut microbiome modulated gut-extrinsic sympathetic neurons and that the depletion of gut microbiota led to activation of both brainstem sensory nuclei and efferent sympathetic premotor glutamatergic neurons.¹⁶ Meng et al found that systemic injection of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) led to significantly increased activity in the paraventricular nucleus, a hypothalamic structure essential to the central autonomic network. Their study demonstrated that systemic TMAO also led to increased left stellate ganglion (LSG) activity, a known contributor to cardiac sympathetic tone.¹²

Inflammatory Pathways

Inflammatory responses are another pathway for the gut microbiome to influence the cardiovascular system. SCFAs are a set of gut microbial metabolites produced in the colon by bacterial fermentation and decomposition of resistant starches and dietary fibers.¹⁷ These metabolites are increasingly recognized for their role in modulating disease processes, including cardiac disease. Aguilar et al found that the progression of atherosclerosis was slowed in apolipoprotein E (Apo-E) knockout mice by a chow diet supplemented with butyrate, a SCFA, suggesting it is an atheroprotective therapeutic agent. Less adhesion and migration of macrophages, reduced inflammation, improved plaque stability, and lowered atherosclerosis progression.¹⁸ Wei et al demonstrated in animal models that direct microinjection of the proinflammatory factors interleukin (IL)-1Β and tumor necrosis factor (TNF)-αdirectly into the subfornical organ increased heart rate, mean blood pressure, and renal sympathetic nerve activity.¹⁹

Metabolic Processes

Serotonin (5-HT), a metabolite of tryptophan, is a neurotransmitter that regulates many bodily functions and plays a significant role in the microbiota-brain gut axis.²⁰ Oral ingestion of the bacterial species Bifidobacterium infantis increased plasma tryptophan in rat models.²¹ Additionally, many other microorganisms, including species of Candida, Streptococcus, Escherichia, and Enterococcus are known to produce 5-HT.²² While a relationship between the gut microbiome and plasma 5-HT has been established, interactions between 5-HT and the cardiovascular system are complex. Research has shown that stimulation of 5-HT_1A receptors produces bradycardic and vasopressor effects, while stimulation of the 5-HT₂ receptor induces vasoconstriction and tachycardia.²³

A high-fiber diet can lower the incidence of hypertension, although the mechanisms are not clear. One potential reason could be alteration in gut bacteria, as a diet high in fiber has been shown to increase the prevalence of acetate-producing bacteria.²⁴

Atherosclerosis

Research investigating the relationship of the gut microbiome with arrhythmias is in its early stages; however, the connection of the gut microbiome and atherosclerosis is more established.²⁵ Contemporary studies have shown various gut microorganisms associated with atherosclerosis.²⁶ Jie et al reported that patients with atherosclerotic cardiovascular disease had increased Enterobacteriaceae loads and oral cavity-associated bacteria with lower levels of butyrate producing bacteria when compared with healthy controls.²⁷ In addition, microbial metabolites such as TMAO appear to promote atherosclerosis by increasing vascular inflammation and platelet reactivity.²⁶ Researchers are investigating the modulation of these associations to help reduce atherosclerotic burden. Kasahara et al found that Roseburia intestinalis could reduce atherosclerotic disease in mice through the production of butyrate.²⁸ Roberts et al established that administration of TMAO inhibitors reduced TMAO levels while reducing thrombus formation without observable toxicity or increased bleeding risk.²⁹

Atrial Arrhythmias

The gut microbiome can also specifically affect cardiac arrhythmogenesis, and multiple studies suggest possible mediators of this interaction. Certain gut microbiome derived metabolites like TMAO may have a role in promoting AF.³⁰ Other gut microbial metabolites like lipopolysaccharides and indoxyl sulfate are implicated in atrial electrical instability.^31,32 Microbe-derived free fatty acids such as palmitic acid and adrenic acid can precipitate arrhythmogenesis. ^33,34 Preponderances of certain gut bacteria like Ruminococcus, Streptococcus, and Enterococcus, as well as reductions of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila have been detected in patients with AF.⁸ Tabata et al found that certain clusters of bacterial groups led by Ruminococcus species seem to show higher prevalence in patients with AF, whereas the genus Enterobacter was significantly lower compared with control subjects. That study also noted that gut microbial composition is affected by diet and antacid use.³⁵ Gut microbiome-derived serotonin may be another mediator for AF, which may be related to the fact that 5-HT₄ receptors are present in atrial tissue.³⁶

Ventricular Arrhythmias

A critical component to the development of malignant ventricular arrhythmias is an imbalance in autonomic tone; in particular, the overactivation of the sympathetic nervous system.³⁷ Animal models have shown that augmentation of the sympathetic nervous system plays an essential role in the subsequent development of ventricular arrhythmias. ³⁸ Several studies have established the LSG as an important component of the cardiac sympathetic nervous system pathway. ^38,39 Ablation of the LSG has been shown to effectively reduce the burden of malignant arrhythmias, further pointing toward the role of excess sympathetic activity.^37,39 Stellate ganglion denervation has become an established method for managing life-threatening ventricular arrhythmias.⁴⁰

Gut metabolites may have significant effects on cardiac sympathetic activity. Meng et al investigated the effect of TMAO on the LSG in animals and its overall effect on the incidence of ventricular arrhythmias under ischemic conditions. To fully explore this interaction, they examined the effect of TMAO on LSG function though 2 mechanisms: local administration of TMAO within the LSG and systemic administration of TMAO leading to activation of the central sympathetic nervous system. In both protocols, left anterior descending coronary artery occlusion was performed after TMAO administration. Injection of TMAO directly into the LSG was found to significantly increase the cardiac sympathetic tone and incidence of ventricular arrhythmias. In the systemic administration control arm, ventricular arrhythmias were also significantly increased.¹²

Increased inflammatory states appear to correlate with an increase in sympathetic tone and ventricular arrhythmias.¹² In an animal study, direct injection of the proinflammatory factor IL-1Β into the LSG not only resulted in increased inflammation, but aggravated cardiac sympathetic remodeling. This led to a decreased effective refractory period and action potential duration, leading to an increased maximal slope of the restitution curve and higher occurrence of ventricular arrhythmias.⁴¹ Shi et al demonstrated that paraventricular nucleus microinjection with TNF-α and IL-1Β also enhanced the cardiac sympathetic afferent reflex, showing that these proinflammatory cytokines not only upregulate the inflammatory response, but can also have excitatory effects that stimulate sympathetic activity and have the potential to be proarrhythmic.^19,42 Local and systemic administration of the gut microbe-derived TMAO increased the expression of IL-1Β and TNF-α, thus implicating the microbiome as a potential mediator of the inflammatory response and as another potential pathway for increased ventricular arrhythmias.¹²

The N-methyl-d-aspartate receptor (NMDAR) is found in multiple organs—including the heart—but more specifically in the conducting system and myocardium.43,44 Research has discovered an upregulation of NMDARs in the setting of cardiac sympathetic hyperinnervation in rat models both with healed myocardial necrotic injury and without. The infusion of their ligand, NMDA, provoked ventricular tachycardia and ventricular fibrillation in rat models with sympathetic hyperinnervation and healed myocardial necrotic injury.⁴⁵ Another study found that NMDAR activation provoked ventricular arrhythmias, but also prolonged repolarization and induced electrical instability.⁴⁶ Proinflammatory markers have been shown to upregulate the expression of NMDARs; more importantly, NMDAR expression has been shown to be significantly increased in the setting of TMAO administration.^12,47,48

5-HT also appears to have a substantial association with ventricular arrhythmias in addition to atrial arrhythmias. el-Mahdy demonstrated in anesthetized rats with acute coronary ligation that systemic doses of 5-HT represented a significant dose-dependent increase in the duration of ventricular tachycardia and ventricular fibrillation, while also increasing the number of ventricular ectopic beats.⁴⁹ Certain gut microorganisms are known to produce 5-HT, including those in the genera Streptococcus, Escherichia, and Enterococcus.²² Additionally, oral ingestion of the Bifidobacterium infantis increased plasma levels of tryptophan in rat models.²¹ The gut microbiome may have significant effects on plasma serotonin levels, and thus have the potential to alter the risk for ventricular arrhythmias.

The deleterious effects of the gut microbiome have been documented. However, it appears to have potential protective effects, and several studies point to the possible mechanisms of this beneficial interaction. Propionate is a SCFA microorganism produced by gut microbial fermentation.⁵⁰ In a rat model study, Zhou et al found that infusion of sodium propionate significantly reduced ventricular arrhythmias during acute myocardial ischemia or burst stimulation, thus confirming cardioprotective effects.^50,51

Proposed mechanisms for reduced susceptibility to ventricular arrhythmias with propionate infusion include parasympathetic activation via the gut-brain axis, anti-inflammatory pathways, and improved cardiac electrophysiology instability.⁵⁰ In addition butyrate has been found to reduce inflammation and myocardial hypertrophy. Jiang et al demonstrated in rats postmyocardial infarction that butyrate promoted expression of anti-inflammatory M2 macrophage markers, decreased expressions of nerve growth factor and norepinephrine, and decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase. The cumulative impact of butyrate led to suppression of inflammation and the inhibition of sympathetic neural remodeling, ultimately resulting in improved cardiac function and reduction in ventricular arrhythmias after myocardial infarction.⁵²

Gut bacteria-derived acetate-mediated reduction in cardiac fibrosis may be another mechanism for the effects on ventricular arrhythmias. Cardiac fibrosis and scar are established as the primary substrate for reentrant ventricular arrhythmias seen in various cardiomyopathies.

Future Directions

The microbiome residing in the human gut has a significant impact on cardiac arrhythmias, the details of which remain unknown. A likely bidirectional relationship exists in which the gut microbiome may affect arrhythmogenesis and in turn be affected by cardiac arrhythmias. The mechanisms of action are not well understood, but likely involve the autonomic nervous system, inflammation, and metabolic pathways.

The gut microbiome is a complex collection of heterogenous microorganisms that have dramatic effects on the human body. Additional research is necessary to identify further associations and causations of gut microorganisms with various human body processes, as well as cardiovascular disease. The microbiome has been shown to directly and indirectly influence the development of different disease states, including the cardiovascular system and cardiac arrhythmias. Several pathways have been proposed through which the gut microbiome can potentially affect cardiac arrhythmogenesis. There are likely several mechanisms simultaneously in operation. Understanding the role of human gut microbiome in the genesis of cardiac arrhythmias not only may improve our understanding of arrhythmias, but also may result in novel treatment options. This could potentially lead to the development of therapeutic options and strategies to modulate the gut microbiome to help detect, prevent, and treat cardiac arrhythmias.

Systemic lupus erythematosus (SLE), or lupus, is a rare autoimmune disease estimated to occur in about 5.1 cases per 100,000 person-years in the United States in 2018.¹ The disease predominantly affects females, with an incidence of 8.7 cases per 100,000 person-years vs 1.2 cases per 100,000 person-years in males, and is most common in patients aged 15 to 44 years.^1,2

Lupus presents with a constellation of clinical signs and symptoms that evolve, along with hallmark laboratory findings indicative of immune dysregulation and polyclonal B-cell activation. Consequently, a wide array of autoantibodies may be produced, although the combination of epitope specificity can vary from patient to patient.3 Nevertheless, > 98% of individuals diagnosed with lupus produce antinuclear antibodies (ANA), making ANA positivity a near-universal serologic feature at the time of diagnosis.

The pathogenesis of lupus is complex. Research from the past 5 decades supports the role of certain viral infections—such as Epstein-Barr virus (EBV) and cytomegalovirus—as potential triggers.⁴ These viruses are thought to initiate disease through mechanisms including activation of interferon pathways, exposure of cryptic intracellular antigens, molecular mimicry, and epitope spreading. Subsequent clonal expansion and autoantibody production occur to varying degrees, influenced by viral load and host susceptibility factors.

During the COVID-19 pandemic, it became evident that SARS-CoV-2 exerts profound effects on immune regulation, influencing infection outcomes through mechanisms such as hyperactivation of innate immunity, especially in the lungs, leading to acute respiratory distress syndrome. Additionally, SARS-CoV-2 has been associated with polyclonal B-cell activation and the generation of autoantibodies. This association gained attention after Bastard et al identified anti–type I interferon antibodies in patients with severe COVID-19, predominantly among males with a genetic predisposition. These autoantibodies were shown to impair antiviral defenses and contribute to life-threatening pneumonia.⁵

Subsequent studies demonstrated the production of a wide spectrum of functional autoantibodies, including ANA, in patients with COVID-19.^6,7 These findings were attributed to the acute expansion of autoreactive clones among naïve-derived immunoglobulin G1 antibody-secreting cells during the early stages of infection, with the degree of expansion correlating with disease severity.^8,9 Although longitudinal data up to 15 months postinfection suggest this serologic abnormality resolves in more than two-thirds of patients, the number of individuals infected globally has raised serious public health concerns regarding the potential long-term sequelae, including the onset of lupus or other autoimmune diseases in COVID-19 survivors.^6-9 A limited number of case reports describing the onset of lupus following SARS-CoV-2 infection support this hypothesis.¹⁰

This surveillance analysis investigates lupus incidence among patients within the Military Health System (MHS), encompassing all TRICARE beneficiaries, from January 2018 to December 2022. The objective of this analysis was to examine lupus incidence trends throughout the COVID-19 pandemic, stratified by sex, age, and active-duty status.

Methods

The MHS provides health care services to about 9.5 million US Department of Defense (DoD) beneficiaries. Outpatient health records and laboratory results for individuals receiving care at military treatment facilities (MTFs) between January 1, 2018, and December 31, 2022, were obtained from the Comprehensive Ambulatory/ Professional Encounter Record and MHS GENESIS. For beneficiaries receiving care in the private sector, data were sourced from the TRICARE Encounter Data—Non-Institutional database.

Laboratory test results, including ANA testing, were available only for individuals receiving care at MTFs. These laboratory data were extracted from the Composite Health Care System Chemistry database and MHS GENESIS laboratory systems for the same time frame. Inpatient data were not included in this analysis. Data from 2017 were used solely as a look-back (or washout) period to identify and exclude prevalent lupus cases diagnosed before 2018 and were not included in the final results.

Lupus cases were identified by the presence of a positive ANA test and appropriate International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. A positive ANA result was defined as either a qualitative result marked positive or a titer ≥ 1:80. The ICD-10-CM codes considered indicative of lupus included variations of M32, L93, or H01.12.

M32, L93, or H01.12. For cases with a positive ANA test, a lupus diagnosis required the presence of ≥ 2 lupus related ICD-10-CM codes. In the absence of ANA test results, a stricter criterion was applied: ≥ 4 lupus ICD-10-CM diagnosis codes recorded on separate days were required for inclusion.

Beneficiaries were excluded if they had a negative ANA result, only 1 lupus ICD- 10-CM diagnosis code, 1 positive ANA with only 1 corresponding ICD-10-CM code, or if their diagnosis occurred outside the defined study period. Patients and members of the public were not involved in the design, conduct, reporting, or dissemination of this study.

Results

Between January 1, 2017, and December 31, 2022, 99,946 TRICARE beneficiaries had some indication of lupus testing or diagnosis in their health records (Figure 1). Of these beneficiaries, 5335 had a positive ANA result and ≥ 2 ICD-10-CM lupus diagnosis codes. An additional 28,275 beneficiaries had ≥ 4 ICD-10-CM lupus diagnosis codes but no ANA test results. From these groups, the final sample included 10,760 beneficiaries who met the incident case definitions for SLE during the study period (2018 through 2022).

Most cases (85.1%, n = 9157) were diagnosed through TRICARE claims, while 1205 (11.2%) were diagnosed within the MHS. Another 398 (3.7%) had documentation of care both within and outside the MHS. Incident SLE cases declined by an average of 16% annually during the study period (Figure 2). This trend amounted to an overall reduction of 48.2%, from 2866 cases in 2018 to 1399 cases in 2022. This decline occurred despite total medical encounters among DoD beneficiaries remaining relatively stable during the pandemic years, with only a 3.5% change between 2018 and 2022.

The disease was more prevalent among female beneficiaries, with a female to- male ratio of 7:1 (Table 1). Among women, the number of new cases declined from 2519 in 2018 to 1223 in 2022, while the number of cases among men remained consistently < 350 annually. Similar trends were observed across other strata. Incident SLE cases were more common among nonactive-duty beneficiaries than active-duty service members, with a ratio of 18:1. New cases among active-duty members remained < 155 per year. Age-stratified data revealed that SLE was diagnosed predominantly in individuals aged ≥ 18 years, with a ratio of 37:1 compared with individuals aged < 18 years. Among children, the number of new cases remained < 75 per year throughout the study period.

A mean 56,850 ANA tests were conducted annually in centralized laboratories using standardized protocols (Table 2). The mean ANA positivity rate was 17.3%, which remained relatively stable from 2018 through 2022.

Discussion

This study examined the annual incidence of newly diagnosed SLE cases among all TRICARE beneficiaries from January 1, 2018, through December 31, 2022, covering both before and during the peak years of the COVID-19 pandemic. This analysis revealed a steady decline in SLE cases during this period. The reliability of these findings is reinforced by the comprehensiveness of the MHS, one of the largest US health care delivery systems, which maintains near-complete medical data capture for about 9.5 million DoD TRICARE beneficiaries across domestic and international settings.

SLE is a rare autoimmune disorder that presents a diagnostic challenge due to its wide range of nonspecific symptoms, many of which resemble other conditions. To reduce the likelihood of false-positive results and ensure diagnostic accuracy, this study adopted a stringent case definition. Incident cases were identified by the presence of ANA testing in conjunction with lupus-specific ICD-10-CM codes and required ≥ 4 lupus related diagnostic entries. This criterion was necessary due to the absence of ANA test results in data from private sector care settings. Our case definition aligns with established literature. For example, a Vanderbilt University chart review study demonstrated that combining ANA positivity with ≥ 4 lupus related ICD-10-CM codes achieves a positive predictive value of 100%, albeit with a sensitivity of 45%.¹¹ Other studies similarly affirm the diagnostic validity of using recurrent ICD-10-CM codes to improve specificity in identifying lupus cases.^12,13

The primary objective of this study was to examine the temporal trend in newly diagnosed lupus cases, rather than derive precise incidence rates. Although the TRICARE system includes about 9.5 million beneficiaries, this number represents a dynamic population with continual inflow and outflow. Accurate incidence rate calculation would require access to detailed denominator data, which were not readily available. In comparison with our findings, a study limited to active-duty service members reported fewer lupus cases. This discrepancy likely reflects differences in case definitions—specifically, the absence of laboratory data, the restricted range of diagnostic codes, and the requirement that diagnoses be rendered by specialists.¹⁴ Despite these differences, demographic patterns were consistent, with higher incidence observed in females and individuals aged ≥ 20 years.

A Centers for Disease Control and Prevention (CDC) study of lupus incidence in the general population also reported lower case counts.¹ However, the CDC estimates were based on 5 state-level registries, which rely on clinician-reported cases and therefore may underestimate true disease burden. Moreover, the DoD beneficiary population differs markedly from the general population: it includes a large cohort of retirees, ensuring an older demographic; all members have comprehensive health care access; and active-duty personnel are subject to pre-enlistment medical screening. Taken together, these factors suggest this study may offer a more complete and systematically captured profile of lupus incidence.

We observed a marked decline of newly diagnosed SLE cases during the study period, which coincided with the widespread circulation of COVID-19. This decrease is unlikely to be attributable to reduced access to care during the pandemic. The MHS operates under a single-payer model, and the total number of patient encounters remained relatively stable throughout the pandemic.

To our knowledge, this is the only study to monitor lupus incidence in a large US population over the 5-year period encompassing before and during the COVID-19 pandemic. To date, only 4 large-scale surveillance studies have addressed similar questions. ^14-17 Our findings are consistent with the most recent of these reports: an analysis limited to active-duty members of the US Armed Forces identified 1127 patients with newly diagnosed lupus between 2000 and 2022 and reported stable incidence trends throughout the pandemic.¹⁴ The other 3 studies adopted a different approach, comparing the emergence of autoimmune diseases, including lupus, between individuals with confirmed SARS-CoV-2 infection and those without. Each of these trials concluded that COVID-19 increases the risk of various autoimmune conditions, although the findings specific to lupus were inconsistent.^15-17

Chang et al reported a significant increase in new lupus diagnoses (n = 2,926,016), with an adjusted hazard ratio (aHR) of 2.99 (95% CI, 2.68-3.34), spanning all ages and both sexes. The highest incidence was observed in individuals of Asian descent.¹⁵ Using German routine health care data from 2020, Tesch et al identified a heightened risk of autoimmune diseases, including lupus, among patients with a history of SARS-CoV-2 infection (n = 641,407; 9.4% children, 57.3% female, 6.4% hospitalized), compared with matched infection-naïve controls (n = 1,560,357).¹⁶ Both studies excluded vaccinated individuals.

These 2 studies diverged in their assessment of the relationship between COVID-19 severity and subsequent autoimmune risk. Chang et al found a higher incidence among nonhospitalized ambulatory patients, while Tesch et al reported that increased risk was associated with patients requiring intensive care unit admission.^15,16

In contrast, based on a cohort of 4,197,188 individuals, Peng et al found no significant difference in lupus incidence among patients with SARS-CoV-2 infection (aHR, 1.05; 95% CI, 0.79-1.39).¹⁷ Notably, within the infected group, the incidence of SLE was significantly lower among vaccinated individuals compared with the unvaccinated group (aHR, 0.29; 95% CI, 0.18-0.47). Similar protective associations were observed for other antibody-mediated autoimmune disorders, including pemphigoid, Graves’ disease, and antiphospholipid antibody syndrome.

Limitations

Due to fundamental differences in study design, we were unable to directly reconcile our findings with those reported in the literature. This study lacked access to reliable documentation of COVID-19 infection status, primarily due to the widespread use of home testing among TRICARE beneficiaries. Additionally, the dataset did not include inpatient records and therefore did not permit evaluation of disease severity. Despite these constraints, it is plausible that the overall burden of COVID-19 infection within the study population was lower than that observed in the general US population.

As of December 2022, the DoD had reported about 750,000 confirmed COVID-19 cases among military personnel, civilian employees, dependents, and DoD contractors.¹⁸ Given that TRICARE beneficiaries represent about 2.8% of the total US population—and that > 90 million US individuals were infected between 2020 and 2022—the implied infection rate in our cohort appears to be about one-third of what might be expected.¹⁹ This discrepancy may be due to higher adherence to mitigation measures, such as social distancing and mask usage, among DoD-affiliated populations. COVID-19 vaccination was mandated for all active-duty service members, who constitute 5.4% of the study population. The remaining TRICARE beneficiaries also had access to guaranteed health care and vaccination coverage, likely contributing to high overall vaccination rates.

Because > 80% of the study population was composed of individuals from diverse civilian backgrounds, we expect the distribution of infection severity within the DoD beneficiary population to approximate that of the general US population.

Future Directions

The findings of this study offer circumstantial yet real-time evidence of the complexity underlying immune dysregulation at the intersection of host susceptibility and environmental exposures. The stability in ANA positivity rates during the study period mitigates concerns regarding undiagnosed subclinical lupus and may suggest that, overall, immune homeostasis was preserved among DoD beneficiaries.

It is noteworthy that during the COVID-19 pandemic, the incidence of several common infections—such as influenza and EBV—declined markedly, likely as a result of widespread social distancing and other public health interventions.²⁰ Mitigation strategies implemented within the military may have conferred protection not only against COVID-19 but also against other community-acquired pathogens.

In light of these observations, we hypothesize that for COVID-19 to act as a trigger for SLE, a prolonged or repeated disruption of immune equilibrium may be required—potentially mediated by recurrent infections or sustained inflammatory states. The association between viral infections and autoimmunity is well established. Immune dysregulation leading to autoantibody production has been observed not only in the context of SARS-CoV-2 but also following infections with EBV, cytomegalovirus, enteroviruses, hepatitis B and C viruses, HIV, and parvovirus B19.²¹

This dysregulation is often transient, accompanied by compensatory immune regulatory responses. However, in individuals subjected to successive or overlapping infections, these regulatory mechanisms may become compromised or overwhelmed, due to emergent patterns of immune interference of varying severity. In such cases, a transient immune perturbation may progress into a bona fide autoimmune disease, contingent upon individual risk factors such as genetic predisposition, preexisting immune memory, and regenerative capacity.²¹

Therefore, we believe the significance of this study is 2-fold. First, lupus is known to develop gradually and may require 3 to 5 years to clinically manifest after the initial break in immunological tolerance.³ Continued public health surveillance represents a more pragmatic strategy than retrospective cohort construction, especially as histories of COVID-19 infection become increasingly complete and definitive. Our findings provide a valuable baseline reference point for future longitudinal studies.

The interpretation of surveillance outcomes—whether indicating an upward trend, a stable baseline, or a downward trend—offers distinct analytical value. Within this study population, we observed neither an upward trajectory that might suggest a direct causal link, nor a flat trend that would imply absence of association between COVID-19 and lupus pathogenesis. Instead, the observation of a downward trend invites consideration of nonlinear or protective influences. From this perspective, we recommend that future investigations adopt a holistic framework when assessing environmental contributions to immune dysregulation—particularly when evaluating the long-term immunopathological consequences of the COVID-19 pandemic on lupus and related autoimmune conditions.

Conclusions

This study identified a declining trend in incident lupus cases during the COVID-19 pandemic among the DoD beneficiary population. Further investigation is warranted to elucidate the underlying factors contributing to this decline. Conducting longitudinal epidemiologic studies and applying multivariable regression analyses will be essential to determine whether incidence rates revert to prepandemic baselines and how these trends may be influenced by evolving environmental factors within the general population.

Systemic lupus erythematosus (SLE), or lupus, is a rare autoimmune disease estimated to occur in about 5.1 cases per 100,000 person-years in the United States in 2018.¹ The disease predominantly affects females, with an incidence of 8.7 cases per 100,000 person-years vs 1.2 cases per 100,000 person-years in males, and is most common in patients aged 15 to 44 years.^1,2

Lupus presents with a constellation of clinical signs and symptoms that evolve, along with hallmark laboratory findings indicative of immune dysregulation and polyclonal B-cell activation. Consequently, a wide array of autoantibodies may be produced, although the combination of epitope specificity can vary from patient to patient.3 Nevertheless, > 98% of individuals diagnosed with lupus produce antinuclear antibodies (ANA), making ANA positivity a near-universal serologic feature at the time of diagnosis.

The pathogenesis of lupus is complex. Research from the past 5 decades supports the role of certain viral infections—such as Epstein-Barr virus (EBV) and cytomegalovirus—as potential triggers.⁴ These viruses are thought to initiate disease through mechanisms including activation of interferon pathways, exposure of cryptic intracellular antigens, molecular mimicry, and epitope spreading. Subsequent clonal expansion and autoantibody production occur to varying degrees, influenced by viral load and host susceptibility factors.

During the COVID-19 pandemic, it became evident that SARS-CoV-2 exerts profound effects on immune regulation, influencing infection outcomes through mechanisms such as hyperactivation of innate immunity, especially in the lungs, leading to acute respiratory distress syndrome. Additionally, SARS-CoV-2 has been associated with polyclonal B-cell activation and the generation of autoantibodies. This association gained attention after Bastard et al identified anti–type I interferon antibodies in patients with severe COVID-19, predominantly among males with a genetic predisposition. These autoantibodies were shown to impair antiviral defenses and contribute to life-threatening pneumonia.⁵

Subsequent studies demonstrated the production of a wide spectrum of functional autoantibodies, including ANA, in patients with COVID-19.^6,7 These findings were attributed to the acute expansion of autoreactive clones among naïve-derived immunoglobulin G1 antibody-secreting cells during the early stages of infection, with the degree of expansion correlating with disease severity.^8,9 Although longitudinal data up to 15 months postinfection suggest this serologic abnormality resolves in more than two-thirds of patients, the number of individuals infected globally has raised serious public health concerns regarding the potential long-term sequelae, including the onset of lupus or other autoimmune diseases in COVID-19 survivors.^6-9 A limited number of case reports describing the onset of lupus following SARS-CoV-2 infection support this hypothesis.¹⁰

This surveillance analysis investigates lupus incidence among patients within the Military Health System (MHS), encompassing all TRICARE beneficiaries, from January 2018 to December 2022. The objective of this analysis was to examine lupus incidence trends throughout the COVID-19 pandemic, stratified by sex, age, and active-duty status.

Methods

The MHS provides health care services to about 9.5 million US Department of Defense (DoD) beneficiaries. Outpatient health records and laboratory results for individuals receiving care at military treatment facilities (MTFs) between January 1, 2018, and December 31, 2022, were obtained from the Comprehensive Ambulatory/ Professional Encounter Record and MHS GENESIS. For beneficiaries receiving care in the private sector, data were sourced from the TRICARE Encounter Data—Non-Institutional database.

Laboratory test results, including ANA testing, were available only for individuals receiving care at MTFs. These laboratory data were extracted from the Composite Health Care System Chemistry database and MHS GENESIS laboratory systems for the same time frame. Inpatient data were not included in this analysis. Data from 2017 were used solely as a look-back (or washout) period to identify and exclude prevalent lupus cases diagnosed before 2018 and were not included in the final results.

Lupus cases were identified by the presence of a positive ANA test and appropriate International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. A positive ANA result was defined as either a qualitative result marked positive or a titer ≥ 1:80. The ICD-10-CM codes considered indicative of lupus included variations of M32, L93, or H01.12.

M32, L93, or H01.12. For cases with a positive ANA test, a lupus diagnosis required the presence of ≥ 2 lupus related ICD-10-CM codes. In the absence of ANA test results, a stricter criterion was applied: ≥ 4 lupus ICD-10-CM diagnosis codes recorded on separate days were required for inclusion.

Beneficiaries were excluded if they had a negative ANA result, only 1 lupus ICD- 10-CM diagnosis code, 1 positive ANA with only 1 corresponding ICD-10-CM code, or if their diagnosis occurred outside the defined study period. Patients and members of the public were not involved in the design, conduct, reporting, or dissemination of this study.

Results

Between January 1, 2017, and December 31, 2022, 99,946 TRICARE beneficiaries had some indication of lupus testing or diagnosis in their health records (Figure 1). Of these beneficiaries, 5335 had a positive ANA result and ≥ 2 ICD-10-CM lupus diagnosis codes. An additional 28,275 beneficiaries had ≥ 4 ICD-10-CM lupus diagnosis codes but no ANA test results. From these groups, the final sample included 10,760 beneficiaries who met the incident case definitions for SLE during the study period (2018 through 2022).

Most cases (85.1%, n = 9157) were diagnosed through TRICARE claims, while 1205 (11.2%) were diagnosed within the MHS. Another 398 (3.7%) had documentation of care both within and outside the MHS. Incident SLE cases declined by an average of 16% annually during the study period (Figure 2). This trend amounted to an overall reduction of 48.2%, from 2866 cases in 2018 to 1399 cases in 2022. This decline occurred despite total medical encounters among DoD beneficiaries remaining relatively stable during the pandemic years, with only a 3.5% change between 2018 and 2022.

The disease was more prevalent among female beneficiaries, with a female to- male ratio of 7:1 (Table 1). Among women, the number of new cases declined from 2519 in 2018 to 1223 in 2022, while the number of cases among men remained consistently < 350 annually. Similar trends were observed across other strata. Incident SLE cases were more common among nonactive-duty beneficiaries than active-duty service members, with a ratio of 18:1. New cases among active-duty members remained < 155 per year. Age-stratified data revealed that SLE was diagnosed predominantly in individuals aged ≥ 18 years, with a ratio of 37:1 compared with individuals aged < 18 years. Among children, the number of new cases remained < 75 per year throughout the study period.

A mean 56,850 ANA tests were conducted annually in centralized laboratories using standardized protocols (Table 2). The mean ANA positivity rate was 17.3%, which remained relatively stable from 2018 through 2022.

Discussion

This study examined the annual incidence of newly diagnosed SLE cases among all TRICARE beneficiaries from January 1, 2018, through December 31, 2022, covering both before and during the peak years of the COVID-19 pandemic. This analysis revealed a steady decline in SLE cases during this period. The reliability of these findings is reinforced by the comprehensiveness of the MHS, one of the largest US health care delivery systems, which maintains near-complete medical data capture for about 9.5 million DoD TRICARE beneficiaries across domestic and international settings.

SLE is a rare autoimmune disorder that presents a diagnostic challenge due to its wide range of nonspecific symptoms, many of which resemble other conditions. To reduce the likelihood of false-positive results and ensure diagnostic accuracy, this study adopted a stringent case definition. Incident cases were identified by the presence of ANA testing in conjunction with lupus-specific ICD-10-CM codes and required ≥ 4 lupus related diagnostic entries. This criterion was necessary due to the absence of ANA test results in data from private sector care settings. Our case definition aligns with established literature. For example, a Vanderbilt University chart review study demonstrated that combining ANA positivity with ≥ 4 lupus related ICD-10-CM codes achieves a positive predictive value of 100%, albeit with a sensitivity of 45%.¹¹ Other studies similarly affirm the diagnostic validity of using recurrent ICD-10-CM codes to improve specificity in identifying lupus cases.^12,13

The primary objective of this study was to examine the temporal trend in newly diagnosed lupus cases, rather than derive precise incidence rates. Although the TRICARE system includes about 9.5 million beneficiaries, this number represents a dynamic population with continual inflow and outflow. Accurate incidence rate calculation would require access to detailed denominator data, which were not readily available. In comparison with our findings, a study limited to active-duty service members reported fewer lupus cases. This discrepancy likely reflects differences in case definitions—specifically, the absence of laboratory data, the restricted range of diagnostic codes, and the requirement that diagnoses be rendered by specialists.¹⁴ Despite these differences, demographic patterns were consistent, with higher incidence observed in females and individuals aged ≥ 20 years.

A Centers for Disease Control and Prevention (CDC) study of lupus incidence in the general population also reported lower case counts.¹ However, the CDC estimates were based on 5 state-level registries, which rely on clinician-reported cases and therefore may underestimate true disease burden. Moreover, the DoD beneficiary population differs markedly from the general population: it includes a large cohort of retirees, ensuring an older demographic; all members have comprehensive health care access; and active-duty personnel are subject to pre-enlistment medical screening. Taken together, these factors suggest this study may offer a more complete and systematically captured profile of lupus incidence.

We observed a marked decline of newly diagnosed SLE cases during the study period, which coincided with the widespread circulation of COVID-19. This decrease is unlikely to be attributable to reduced access to care during the pandemic. The MHS operates under a single-payer model, and the total number of patient encounters remained relatively stable throughout the pandemic.

To our knowledge, this is the only study to monitor lupus incidence in a large US population over the 5-year period encompassing before and during the COVID-19 pandemic. To date, only 4 large-scale surveillance studies have addressed similar questions. ^14-17 Our findings are consistent with the most recent of these reports: an analysis limited to active-duty members of the US Armed Forces identified 1127 patients with newly diagnosed lupus between 2000 and 2022 and reported stable incidence trends throughout the pandemic.¹⁴ The other 3 studies adopted a different approach, comparing the emergence of autoimmune diseases, including lupus, between individuals with confirmed SARS-CoV-2 infection and those without. Each of these trials concluded that COVID-19 increases the risk of various autoimmune conditions, although the findings specific to lupus were inconsistent.^15-17

Chang et al reported a significant increase in new lupus diagnoses (n = 2,926,016), with an adjusted hazard ratio (aHR) of 2.99 (95% CI, 2.68-3.34), spanning all ages and both sexes. The highest incidence was observed in individuals of Asian descent.¹⁵ Using German routine health care data from 2020, Tesch et al identified a heightened risk of autoimmune diseases, including lupus, among patients with a history of SARS-CoV-2 infection (n = 641,407; 9.4% children, 57.3% female, 6.4% hospitalized), compared with matched infection-naïve controls (n = 1,560,357).¹⁶ Both studies excluded vaccinated individuals.

These 2 studies diverged in their assessment of the relationship between COVID-19 severity and subsequent autoimmune risk. Chang et al found a higher incidence among nonhospitalized ambulatory patients, while Tesch et al reported that increased risk was associated with patients requiring intensive care unit admission.^15,16

In contrast, based on a cohort of 4,197,188 individuals, Peng et al found no significant difference in lupus incidence among patients with SARS-CoV-2 infection (aHR, 1.05; 95% CI, 0.79-1.39).¹⁷ Notably, within the infected group, the incidence of SLE was significantly lower among vaccinated individuals compared with the unvaccinated group (aHR, 0.29; 95% CI, 0.18-0.47). Similar protective associations were observed for other antibody-mediated autoimmune disorders, including pemphigoid, Graves’ disease, and antiphospholipid antibody syndrome.

Limitations

Due to fundamental differences in study design, we were unable to directly reconcile our findings with those reported in the literature. This study lacked access to reliable documentation of COVID-19 infection status, primarily due to the widespread use of home testing among TRICARE beneficiaries. Additionally, the dataset did not include inpatient records and therefore did not permit evaluation of disease severity. Despite these constraints, it is plausible that the overall burden of COVID-19 infection within the study population was lower than that observed in the general US population.

As of December 2022, the DoD had reported about 750,000 confirmed COVID-19 cases among military personnel, civilian employees, dependents, and DoD contractors.¹⁸ Given that TRICARE beneficiaries represent about 2.8% of the total US population—and that > 90 million US individuals were infected between 2020 and 2022—the implied infection rate in our cohort appears to be about one-third of what might be expected.¹⁹ This discrepancy may be due to higher adherence to mitigation measures, such as social distancing and mask usage, among DoD-affiliated populations. COVID-19 vaccination was mandated for all active-duty service members, who constitute 5.4% of the study population. The remaining TRICARE beneficiaries also had access to guaranteed health care and vaccination coverage, likely contributing to high overall vaccination rates.

Because > 80% of the study population was composed of individuals from diverse civilian backgrounds, we expect the distribution of infection severity within the DoD beneficiary population to approximate that of the general US population.

Future Directions

The findings of this study offer circumstantial yet real-time evidence of the complexity underlying immune dysregulation at the intersection of host susceptibility and environmental exposures. The stability in ANA positivity rates during the study period mitigates concerns regarding undiagnosed subclinical lupus and may suggest that, overall, immune homeostasis was preserved among DoD beneficiaries.

It is noteworthy that during the COVID-19 pandemic, the incidence of several common infections—such as influenza and EBV—declined markedly, likely as a result of widespread social distancing and other public health interventions.²⁰ Mitigation strategies implemented within the military may have conferred protection not only against COVID-19 but also against other community-acquired pathogens.

In light of these observations, we hypothesize that for COVID-19 to act as a trigger for SLE, a prolonged or repeated disruption of immune equilibrium may be required—potentially mediated by recurrent infections or sustained inflammatory states. The association between viral infections and autoimmunity is well established. Immune dysregulation leading to autoantibody production has been observed not only in the context of SARS-CoV-2 but also following infections with EBV, cytomegalovirus, enteroviruses, hepatitis B and C viruses, HIV, and parvovirus B19.²¹

This dysregulation is often transient, accompanied by compensatory immune regulatory responses. However, in individuals subjected to successive or overlapping infections, these regulatory mechanisms may become compromised or overwhelmed, due to emergent patterns of immune interference of varying severity. In such cases, a transient immune perturbation may progress into a bona fide autoimmune disease, contingent upon individual risk factors such as genetic predisposition, preexisting immune memory, and regenerative capacity.²¹

Therefore, we believe the significance of this study is 2-fold. First, lupus is known to develop gradually and may require 3 to 5 years to clinically manifest after the initial break in immunological tolerance.³ Continued public health surveillance represents a more pragmatic strategy than retrospective cohort construction, especially as histories of COVID-19 infection become increasingly complete and definitive. Our findings provide a valuable baseline reference point for future longitudinal studies.

The interpretation of surveillance outcomes—whether indicating an upward trend, a stable baseline, or a downward trend—offers distinct analytical value. Within this study population, we observed neither an upward trajectory that might suggest a direct causal link, nor a flat trend that would imply absence of association between COVID-19 and lupus pathogenesis. Instead, the observation of a downward trend invites consideration of nonlinear or protective influences. From this perspective, we recommend that future investigations adopt a holistic framework when assessing environmental contributions to immune dysregulation—particularly when evaluating the long-term immunopathological consequences of the COVID-19 pandemic on lupus and related autoimmune conditions.

Conclusions

This study identified a declining trend in incident lupus cases during the COVID-19 pandemic among the DoD beneficiary population. Further investigation is warranted to elucidate the underlying factors contributing to this decline. Conducting longitudinal epidemiologic studies and applying multivariable regression analyses will be essential to determine whether incidence rates revert to prepandemic baselines and how these trends may be influenced by evolving environmental factors within the general population.

Systemic lupus erythematosus (SLE), or lupus, is a rare autoimmune disease estimated to occur in about 5.1 cases per 100,000 person-years in the United States in 2018.¹ The disease predominantly affects females, with an incidence of 8.7 cases per 100,000 person-years vs 1.2 cases per 100,000 person-years in males, and is most common in patients aged 15 to 44 years.^1,2

Lupus presents with a constellation of clinical signs and symptoms that evolve, along with hallmark laboratory findings indicative of immune dysregulation and polyclonal B-cell activation. Consequently, a wide array of autoantibodies may be produced, although the combination of epitope specificity can vary from patient to patient.3 Nevertheless, > 98% of individuals diagnosed with lupus produce antinuclear antibodies (ANA), making ANA positivity a near-universal serologic feature at the time of diagnosis.

The pathogenesis of lupus is complex. Research from the past 5 decades supports the role of certain viral infections—such as Epstein-Barr virus (EBV) and cytomegalovirus—as potential triggers.⁴ These viruses are thought to initiate disease through mechanisms including activation of interferon pathways, exposure of cryptic intracellular antigens, molecular mimicry, and epitope spreading. Subsequent clonal expansion and autoantibody production occur to varying degrees, influenced by viral load and host susceptibility factors.

During the COVID-19 pandemic, it became evident that SARS-CoV-2 exerts profound effects on immune regulation, influencing infection outcomes through mechanisms such as hyperactivation of innate immunity, especially in the lungs, leading to acute respiratory distress syndrome. Additionally, SARS-CoV-2 has been associated with polyclonal B-cell activation and the generation of autoantibodies. This association gained attention after Bastard et al identified anti–type I interferon antibodies in patients with severe COVID-19, predominantly among males with a genetic predisposition. These autoantibodies were shown to impair antiviral defenses and contribute to life-threatening pneumonia.⁵

Subsequent studies demonstrated the production of a wide spectrum of functional autoantibodies, including ANA, in patients with COVID-19.^6,7 These findings were attributed to the acute expansion of autoreactive clones among naïve-derived immunoglobulin G1 antibody-secreting cells during the early stages of infection, with the degree of expansion correlating with disease severity.^8,9 Although longitudinal data up to 15 months postinfection suggest this serologic abnormality resolves in more than two-thirds of patients, the number of individuals infected globally has raised serious public health concerns regarding the potential long-term sequelae, including the onset of lupus or other autoimmune diseases in COVID-19 survivors.^6-9 A limited number of case reports describing the onset of lupus following SARS-CoV-2 infection support this hypothesis.¹⁰

This surveillance analysis investigates lupus incidence among patients within the Military Health System (MHS), encompassing all TRICARE beneficiaries, from January 2018 to December 2022. The objective of this analysis was to examine lupus incidence trends throughout the COVID-19 pandemic, stratified by sex, age, and active-duty status.

Methods

The MHS provides health care services to about 9.5 million US Department of Defense (DoD) beneficiaries. Outpatient health records and laboratory results for individuals receiving care at military treatment facilities (MTFs) between January 1, 2018, and December 31, 2022, were obtained from the Comprehensive Ambulatory/ Professional Encounter Record and MHS GENESIS. For beneficiaries receiving care in the private sector, data were sourced from the TRICARE Encounter Data—Non-Institutional database.

Laboratory test results, including ANA testing, were available only for individuals receiving care at MTFs. These laboratory data were extracted from the Composite Health Care System Chemistry database and MHS GENESIS laboratory systems for the same time frame. Inpatient data were not included in this analysis. Data from 2017 were used solely as a look-back (or washout) period to identify and exclude prevalent lupus cases diagnosed before 2018 and were not included in the final results.

Lupus cases were identified by the presence of a positive ANA test and appropriate International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. A positive ANA result was defined as either a qualitative result marked positive or a titer ≥ 1:80. The ICD-10-CM codes considered indicative of lupus included variations of M32, L93, or H01.12.

M32, L93, or H01.12. For cases with a positive ANA test, a lupus diagnosis required the presence of ≥ 2 lupus related ICD-10-CM codes. In the absence of ANA test results, a stricter criterion was applied: ≥ 4 lupus ICD-10-CM diagnosis codes recorded on separate days were required for inclusion.

Beneficiaries were excluded if they had a negative ANA result, only 1 lupus ICD- 10-CM diagnosis code, 1 positive ANA with only 1 corresponding ICD-10-CM code, or if their diagnosis occurred outside the defined study period. Patients and members of the public were not involved in the design, conduct, reporting, or dissemination of this study.

Results

Between January 1, 2017, and December 31, 2022, 99,946 TRICARE beneficiaries had some indication of lupus testing or diagnosis in their health records (Figure 1). Of these beneficiaries, 5335 had a positive ANA result and ≥ 2 ICD-10-CM lupus diagnosis codes. An additional 28,275 beneficiaries had ≥ 4 ICD-10-CM lupus diagnosis codes but no ANA test results. From these groups, the final sample included 10,760 beneficiaries who met the incident case definitions for SLE during the study period (2018 through 2022).

Most cases (85.1%, n = 9157) were diagnosed through TRICARE claims, while 1205 (11.2%) were diagnosed within the MHS. Another 398 (3.7%) had documentation of care both within and outside the MHS. Incident SLE cases declined by an average of 16% annually during the study period (Figure 2). This trend amounted to an overall reduction of 48.2%, from 2866 cases in 2018 to 1399 cases in 2022. This decline occurred despite total medical encounters among DoD beneficiaries remaining relatively stable during the pandemic years, with only a 3.5% change between 2018 and 2022.

The disease was more prevalent among female beneficiaries, with a female to- male ratio of 7:1 (Table 1). Among women, the number of new cases declined from 2519 in 2018 to 1223 in 2022, while the number of cases among men remained consistently < 350 annually. Similar trends were observed across other strata. Incident SLE cases were more common among nonactive-duty beneficiaries than active-duty service members, with a ratio of 18:1. New cases among active-duty members remained < 155 per year. Age-stratified data revealed that SLE was diagnosed predominantly in individuals aged ≥ 18 years, with a ratio of 37:1 compared with individuals aged < 18 years. Among children, the number of new cases remained < 75 per year throughout the study period.

A mean 56,850 ANA tests were conducted annually in centralized laboratories using standardized protocols (Table 2). The mean ANA positivity rate was 17.3%, which remained relatively stable from 2018 through 2022.

Discussion

This study examined the annual incidence of newly diagnosed SLE cases among all TRICARE beneficiaries from January 1, 2018, through December 31, 2022, covering both before and during the peak years of the COVID-19 pandemic. This analysis revealed a steady decline in SLE cases during this period. The reliability of these findings is reinforced by the comprehensiveness of the MHS, one of the largest US health care delivery systems, which maintains near-complete medical data capture for about 9.5 million DoD TRICARE beneficiaries across domestic and international settings.

SLE is a rare autoimmune disorder that presents a diagnostic challenge due to its wide range of nonspecific symptoms, many of which resemble other conditions. To reduce the likelihood of false-positive results and ensure diagnostic accuracy, this study adopted a stringent case definition. Incident cases were identified by the presence of ANA testing in conjunction with lupus-specific ICD-10-CM codes and required ≥ 4 lupus related diagnostic entries. This criterion was necessary due to the absence of ANA test results in data from private sector care settings. Our case definition aligns with established literature. For example, a Vanderbilt University chart review study demonstrated that combining ANA positivity with ≥ 4 lupus related ICD-10-CM codes achieves a positive predictive value of 100%, albeit with a sensitivity of 45%.¹¹ Other studies similarly affirm the diagnostic validity of using recurrent ICD-10-CM codes to improve specificity in identifying lupus cases.^12,13

The primary objective of this study was to examine the temporal trend in newly diagnosed lupus cases, rather than derive precise incidence rates. Although the TRICARE system includes about 9.5 million beneficiaries, this number represents a dynamic population with continual inflow and outflow. Accurate incidence rate calculation would require access to detailed denominator data, which were not readily available. In comparison with our findings, a study limited to active-duty service members reported fewer lupus cases. This discrepancy likely reflects differences in case definitions—specifically, the absence of laboratory data, the restricted range of diagnostic codes, and the requirement that diagnoses be rendered by specialists.¹⁴ Despite these differences, demographic patterns were consistent, with higher incidence observed in females and individuals aged ≥ 20 years.

A Centers for Disease Control and Prevention (CDC) study of lupus incidence in the general population also reported lower case counts.¹ However, the CDC estimates were based on 5 state-level registries, which rely on clinician-reported cases and therefore may underestimate true disease burden. Moreover, the DoD beneficiary population differs markedly from the general population: it includes a large cohort of retirees, ensuring an older demographic; all members have comprehensive health care access; and active-duty personnel are subject to pre-enlistment medical screening. Taken together, these factors suggest this study may offer a more complete and systematically captured profile of lupus incidence.

We observed a marked decline of newly diagnosed SLE cases during the study period, which coincided with the widespread circulation of COVID-19. This decrease is unlikely to be attributable to reduced access to care during the pandemic. The MHS operates under a single-payer model, and the total number of patient encounters remained relatively stable throughout the pandemic.

To our knowledge, this is the only study to monitor lupus incidence in a large US population over the 5-year period encompassing before and during the COVID-19 pandemic. To date, only 4 large-scale surveillance studies have addressed similar questions. ^14-17 Our findings are consistent with the most recent of these reports: an analysis limited to active-duty members of the US Armed Forces identified 1127 patients with newly diagnosed lupus between 2000 and 2022 and reported stable incidence trends throughout the pandemic.¹⁴ The other 3 studies adopted a different approach, comparing the emergence of autoimmune diseases, including lupus, between individuals with confirmed SARS-CoV-2 infection and those without. Each of these trials concluded that COVID-19 increases the risk of various autoimmune conditions, although the findings specific to lupus were inconsistent.^15-17

Chang et al reported a significant increase in new lupus diagnoses (n = 2,926,016), with an adjusted hazard ratio (aHR) of 2.99 (95% CI, 2.68-3.34), spanning all ages and both sexes. The highest incidence was observed in individuals of Asian descent.¹⁵ Using German routine health care data from 2020, Tesch et al identified a heightened risk of autoimmune diseases, including lupus, among patients with a history of SARS-CoV-2 infection (n = 641,407; 9.4% children, 57.3% female, 6.4% hospitalized), compared with matched infection-naïve controls (n = 1,560,357).¹⁶ Both studies excluded vaccinated individuals.

These 2 studies diverged in their assessment of the relationship between COVID-19 severity and subsequent autoimmune risk. Chang et al found a higher incidence among nonhospitalized ambulatory patients, while Tesch et al reported that increased risk was associated with patients requiring intensive care unit admission.^15,16

In contrast, based on a cohort of 4,197,188 individuals, Peng et al found no significant difference in lupus incidence among patients with SARS-CoV-2 infection (aHR, 1.05; 95% CI, 0.79-1.39).¹⁷ Notably, within the infected group, the incidence of SLE was significantly lower among vaccinated individuals compared with the unvaccinated group (aHR, 0.29; 95% CI, 0.18-0.47). Similar protective associations were observed for other antibody-mediated autoimmune disorders, including pemphigoid, Graves’ disease, and antiphospholipid antibody syndrome.

Limitations

Due to fundamental differences in study design, we were unable to directly reconcile our findings with those reported in the literature. This study lacked access to reliable documentation of COVID-19 infection status, primarily due to the widespread use of home testing among TRICARE beneficiaries. Additionally, the dataset did not include inpatient records and therefore did not permit evaluation of disease severity. Despite these constraints, it is plausible that the overall burden of COVID-19 infection within the study population was lower than that observed in the general US population.

As of December 2022, the DoD had reported about 750,000 confirmed COVID-19 cases among military personnel, civilian employees, dependents, and DoD contractors.¹⁸ Given that TRICARE beneficiaries represent about 2.8% of the total US population—and that > 90 million US individuals were infected between 2020 and 2022—the implied infection rate in our cohort appears to be about one-third of what might be expected.¹⁹ This discrepancy may be due to higher adherence to mitigation measures, such as social distancing and mask usage, among DoD-affiliated populations. COVID-19 vaccination was mandated for all active-duty service members, who constitute 5.4% of the study population. The remaining TRICARE beneficiaries also had access to guaranteed health care and vaccination coverage, likely contributing to high overall vaccination rates.

Because > 80% of the study population was composed of individuals from diverse civilian backgrounds, we expect the distribution of infection severity within the DoD beneficiary population to approximate that of the general US population.

Future Directions

The findings of this study offer circumstantial yet real-time evidence of the complexity underlying immune dysregulation at the intersection of host susceptibility and environmental exposures. The stability in ANA positivity rates during the study period mitigates concerns regarding undiagnosed subclinical lupus and may suggest that, overall, immune homeostasis was preserved among DoD beneficiaries.

It is noteworthy that during the COVID-19 pandemic, the incidence of several common infections—such as influenza and EBV—declined markedly, likely as a result of widespread social distancing and other public health interventions.²⁰ Mitigation strategies implemented within the military may have conferred protection not only against COVID-19 but also against other community-acquired pathogens.

In light of these observations, we hypothesize that for COVID-19 to act as a trigger for SLE, a prolonged or repeated disruption of immune equilibrium may be required—potentially mediated by recurrent infections or sustained inflammatory states. The association between viral infections and autoimmunity is well established. Immune dysregulation leading to autoantibody production has been observed not only in the context of SARS-CoV-2 but also following infections with EBV, cytomegalovirus, enteroviruses, hepatitis B and C viruses, HIV, and parvovirus B19.²¹

This dysregulation is often transient, accompanied by compensatory immune regulatory responses. However, in individuals subjected to successive or overlapping infections, these regulatory mechanisms may become compromised or overwhelmed, due to emergent patterns of immune interference of varying severity. In such cases, a transient immune perturbation may progress into a bona fide autoimmune disease, contingent upon individual risk factors such as genetic predisposition, preexisting immune memory, and regenerative capacity.²¹

Therefore, we believe the significance of this study is 2-fold. First, lupus is known to develop gradually and may require 3 to 5 years to clinically manifest after the initial break in immunological tolerance.³ Continued public health surveillance represents a more pragmatic strategy than retrospective cohort construction, especially as histories of COVID-19 infection become increasingly complete and definitive. Our findings provide a valuable baseline reference point for future longitudinal studies.

The interpretation of surveillance outcomes—whether indicating an upward trend, a stable baseline, or a downward trend—offers distinct analytical value. Within this study population, we observed neither an upward trajectory that might suggest a direct causal link, nor a flat trend that would imply absence of association between COVID-19 and lupus pathogenesis. Instead, the observation of a downward trend invites consideration of nonlinear or protective influences. From this perspective, we recommend that future investigations adopt a holistic framework when assessing environmental contributions to immune dysregulation—particularly when evaluating the long-term immunopathological consequences of the COVID-19 pandemic on lupus and related autoimmune conditions.

Conclusions

This study identified a declining trend in incident lupus cases during the COVID-19 pandemic among the DoD beneficiary population. Further investigation is warranted to elucidate the underlying factors contributing to this decline. Conducting longitudinal epidemiologic studies and applying multivariable regression analyses will be essential to determine whether incidence rates revert to prepandemic baselines and how these trends may be influenced by evolving environmental factors within the general population.

The Veterans Health Administration (VHA) paid about $828 million in recruitment and retention incentives from 2020 to 2023, but the process for providing an estimated $340.9 million of that was not “effectively governed” according to a recent US Department of Veterans Affairs (VA) Office of Inspector General (OIG) investigation.

About one-third of incentives were missing forms or signatures, or lacked sufficient justification, for the payments to about 130,000 VHA employees. In the report, the OIG notes the VHA has faced “long-standing challenges related to occupational shortages,” adding that a shortage occupation designation does not mean there are actual shortages at a facility.

“Most shortage occupations continue to experience annual net growth and are not critically understaffed in most facilities,” the report says.

More than 85% of incentive monies in 2022 and 2023 were paid to employees in occupations on staffing shortage lists. OIG estimated the VHA paid incentives to 38,800 employees (about 30%) where the award justification could not be verified or was insufficient.

Amplified by the COVID-19 pandemic and the PACT Act, the need to recruit and retain employees peaked in 2021, when record numbers of health care workers left their jobs. An October 2021 survey of 1000 medical professionals found nearly 1 in 5 health care workers quit during the pandemic, with most citing stress and burnout, and an additional 31% were considering quitting. When the PACT Act was signed into law in August 2022, it created thousands of newly benefits-eligible veterans.

In May 2022, the VA reported it needed to hire 52,000 employees annually for the next 5 years to keep up. In response, the VA released a 10-step plan to support recruitment and retention, focusing on raising wages when possible and finding other incentives when it wasn’t (ie, relocation bonuses or greater flexibility for remote work). The OIG report acknowledged the pandemic exacerbated VHA’s recruitment and retention challenges. 

By 2024, the VA had not only reduced employee turnover by 20% over the prior 2 years, but had also exceeded its hiring goals. The VHA workforce grew by 7.4% in fiscal year 2023, its highest rate of growth in > 15 years.

VA officials must retain the documentation for incentives for 6 years so the process can be reconstructed if necessary. However, the OIG report noted “numerous instances” where documentation couldn’t be produced and therefore could not determine whether the incentives complied with policy. 

The report also identified 28 employees who received retention incentive payments long after their award period had expired. The VA paid about $4.6 million for incentives that should have been terminated. The VA reported that it is pursuing debt collection for 27 of the 28 employees. 

Only if the “identified weaknesses” are addressed will the VHA have assurance that incentives are being used effectively, the OIG said. Its recommendations included enforcing quality control checks and establishing accountability measures. The OIG also recommended establishing oversight procedures to review retention incentives annually, recertify them if appropriate, or terminate them.

The Veterans Health Administration (VHA) paid about $828 million in recruitment and retention incentives from 2020 to 2023, but the process for providing an estimated $340.9 million of that was not “effectively governed” according to a recent US Department of Veterans Affairs (VA) Office of Inspector General (OIG) investigation.

About one-third of incentives were missing forms or signatures, or lacked sufficient justification, for the payments to about 130,000 VHA employees. In the report, the OIG notes the VHA has faced “long-standing challenges related to occupational shortages,” adding that a shortage occupation designation does not mean there are actual shortages at a facility.

“Most shortage occupations continue to experience annual net growth and are not critically understaffed in most facilities,” the report says.

More than 85% of incentive monies in 2022 and 2023 were paid to employees in occupations on staffing shortage lists. OIG estimated the VHA paid incentives to 38,800 employees (about 30%) where the award justification could not be verified or was insufficient.

Amplified by the COVID-19 pandemic and the PACT Act, the need to recruit and retain employees peaked in 2021, when record numbers of health care workers left their jobs. An October 2021 survey of 1000 medical professionals found nearly 1 in 5 health care workers quit during the pandemic, with most citing stress and burnout, and an additional 31% were considering quitting. When the PACT Act was signed into law in August 2022, it created thousands of newly benefits-eligible veterans.

In May 2022, the VA reported it needed to hire 52,000 employees annually for the next 5 years to keep up. In response, the VA released a 10-step plan to support recruitment and retention, focusing on raising wages when possible and finding other incentives when it wasn’t (ie, relocation bonuses or greater flexibility for remote work). The OIG report acknowledged the pandemic exacerbated VHA’s recruitment and retention challenges. 

By 2024, the VA had not only reduced employee turnover by 20% over the prior 2 years, but had also exceeded its hiring goals. The VHA workforce grew by 7.4% in fiscal year 2023, its highest rate of growth in > 15 years.

VA officials must retain the documentation for incentives for 6 years so the process can be reconstructed if necessary. However, the OIG report noted “numerous instances” where documentation couldn’t be produced and therefore could not determine whether the incentives complied with policy. 

The report also identified 28 employees who received retention incentive payments long after their award period had expired. The VA paid about $4.6 million for incentives that should have been terminated. The VA reported that it is pursuing debt collection for 27 of the 28 employees. 

Only if the “identified weaknesses” are addressed will the VHA have assurance that incentives are being used effectively, the OIG said. Its recommendations included enforcing quality control checks and establishing accountability measures. The OIG also recommended establishing oversight procedures to review retention incentives annually, recertify them if appropriate, or terminate them.

The Veterans Health Administration (VHA) paid about $828 million in recruitment and retention incentives from 2020 to 2023, but the process for providing an estimated $340.9 million of that was not “effectively governed” according to a recent US Department of Veterans Affairs (VA) Office of Inspector General (OIG) investigation.

About one-third of incentives were missing forms or signatures, or lacked sufficient justification, for the payments to about 130,000 VHA employees. In the report, the OIG notes the VHA has faced “long-standing challenges related to occupational shortages,” adding that a shortage occupation designation does not mean there are actual shortages at a facility.

“Most shortage occupations continue to experience annual net growth and are not critically understaffed in most facilities,” the report says.

More than 85% of incentive monies in 2022 and 2023 were paid to employees in occupations on staffing shortage lists. OIG estimated the VHA paid incentives to 38,800 employees (about 30%) where the award justification could not be verified or was insufficient.

Amplified by the COVID-19 pandemic and the PACT Act, the need to recruit and retain employees peaked in 2021, when record numbers of health care workers left their jobs. An October 2021 survey of 1000 medical professionals found nearly 1 in 5 health care workers quit during the pandemic, with most citing stress and burnout, and an additional 31% were considering quitting. When the PACT Act was signed into law in August 2022, it created thousands of newly benefits-eligible veterans.

In May 2022, the VA reported it needed to hire 52,000 employees annually for the next 5 years to keep up. In response, the VA released a 10-step plan to support recruitment and retention, focusing on raising wages when possible and finding other incentives when it wasn’t (ie, relocation bonuses or greater flexibility for remote work). The OIG report acknowledged the pandemic exacerbated VHA’s recruitment and retention challenges. 

By 2024, the VA had not only reduced employee turnover by 20% over the prior 2 years, but had also exceeded its hiring goals. The VHA workforce grew by 7.4% in fiscal year 2023, its highest rate of growth in > 15 years.

VA officials must retain the documentation for incentives for 6 years so the process can be reconstructed if necessary. However, the OIG report noted “numerous instances” where documentation couldn’t be produced and therefore could not determine whether the incentives complied with policy. 

The report also identified 28 employees who received retention incentive payments long after their award period had expired. The VA paid about $4.6 million for incentives that should have been terminated. The VA reported that it is pursuing debt collection for 27 of the 28 employees. 

Only if the “identified weaknesses” are addressed will the VHA have assurance that incentives are being used effectively, the OIG said. Its recommendations included enforcing quality control checks and establishing accountability measures. The OIG also recommended establishing oversight procedures to review retention incentives annually, recertify them if appropriate, or terminate them.

A large 20-year study — the longest and most detailed of its kind — shows that posttraumatic stress disorder (PTSD) symptoms can endure for decades, challenging conventional timelines for recovery and offering new insights to guide future treatment.

Researchers analyzed data from the World Trade Center Health Program (WTCHP), which is administered by the US CDC’s National Institute for Occupational Safety and Health (NIOSH), and found symptoms of PTSD persisted for as long as two decades in 10% of first responders involved in the World Trade Center disaster of September 2001.

Participation in the WTCHP is voluntary, but those who enroll receive free assessments, monitoring, and treatment, including psychiatric and behavioral healthcare. It is the longest and most detailed analysis of PTSD and includes 81,298 observations from 12,822 WTC responders.

Participants entered the WTCHP at different timepoints and were assessed annually. Not every enrollee was assessed every year, but the sheer number of participants and observations “just provides much greater density of data over that 20-year course than any previous study,” lead author Frank D. Mann, PhD, told this news organization.

The study was published online on May 27 in Nature Mental Health.

 

Filling the PTSD Knowledge Gap

Most PTSD research has focused on the short term, with limited insight into how symptoms evolve over the long haul. Without long-term data, it’s been difficult to understand whether PTSD resolves, persists, or worsens — hindering efforts to guide treatment and support. This study aimed to fill that gap by tracking symptom patterns over two decades.

Responders were assessed regularly using the PTSD Checklist for a Specific Stressor, a standardized tool that measures symptom severity on an 85-point scale. On average, each participant completed 6.3 assessments over the course of the study.

A score of ≥ 44 was considered indicative of clinically elevated PTSD symptoms. Between 2002 and 2022, the crude prevalence of elevated symptoms ranged from 8% to 15%. At the same time, 16% to 34% of responders each year reported little to no symptoms, scoring at or near the minimum on the scale.

The researchers found that symptom trajectories varied widely. Nearly as many participants experienced worsening symptoms as those who improved. As a result, the overall population average remained relatively flat over the 20-year period.

Among responders who met the threshold for PTSD, the median time to symptom improvement was 8.9 years — and by year 20, about 76% had shown improvement.

 

New Insights

Mann, a senior research scientist at Stony Brook University Renaissance School of Medicine, Stony Brook, New York, said the study not only reinforced existing knowledge about PTSD in responders but also uncovered new insights.

Most notably, it showed that PTSD symptoms tended to peak around a decade after 9/11 — significantly later than delayed-onset patterns reported in previous trauma studies.

He also noted a surprising outcome — the top 10% of responders who experienced worsening symptoms over the long term accounted for the majority of mental health costs. These individuals, Mann said, represent a critical gap in care, with current interventions proving largely ineffective for them.

Mann suggested that ongoing trauma exposure — especially for responders still in high-risk jobs — and potential genetic susceptibility may contribute to late-emerging or persistent symptoms.

“These individuals are an urgent priority for health systems, as available resources have not been effective for them,” the study authors wrote.

Mann and his colleagues also found that occupation offered the strongest protection against developing PTSD. Police officers and firefighters benefit from training designed to help them cope with trauma, and repeated exposure may build a degree of resilience.

In contrast, responders without such training — like construction workers — faced a 50% to 55% higher risk of developing PTSD symptoms. Mann emphasized that occupational status was a more powerful predictor of PTSD risk than the severity of the traumatic exposures themselves.

 

A Valuable Contribution

Commenting on the research for this news organization, Sandra Lowe, MD, medical director of the Mount Sinai WTCMH program, noted that while the study largely confirms what has been known about responders — such as the significant variability in symptom trajectories over time — it still makes a valuable contribution.

“Extending observations for up to 20 years is rare in any study, especially in a cohort this large,” said Lowe, an associate professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York City, who was not involved in the study.

Also commenting, James West, MD, chair of the American Psychiatric Association’s Committee on the Psychiatric Dimensions of Disaster, described the finding that 10% of responders continued to experience symptoms two decades after exposure as “sobering.”

However, he emphasized that it aligns with observations in the disaster recovery community, where the psychological impact “goes way beyond what most people see as the immediate aftermath and recovery.” West stressed the urgent need to develop effective treatments that enable those affected to live fuller, less impaired lives.

“We still need to be finding the effective treatments that can help these people live fuller lives without impairment from their trauma symptoms,” said West.

Lowe pointed out that the symptom peak around 10 years post-exposure is often linked to external factors. Some responders who had been managing symptoms might lose resilience due to major life changes such as retirement.

“One of the things that was able to keep them engaged is now lost,” she said. “They begin to spend more time reflecting on recollections, and symptoms can worsen.”

West agreed, adding that retirement or job loss often leads to symptom increases because it removes a primary coping mechanism. Both Lowe and Mann also highlighted that 9/11 memorial events can trigger new symptoms or exacerbate existing ones.

Lowe noted that responders with stronger coping skills tended to fare better over time. Effective coping strategies include maintaining regular schedules — especially for eating and sleeping — leading a structured life, and employing stress management techniques like meditation, yoga, or enjoyable hobbies. Social connection and being part of a community are also critical for resilience. She added that clinicians should always inquire about trauma history.

Lowe, West, and Mann all pointed out that PTSD is often accompanied by physical health issues, particularly cardiovascular problems, which tend to be worse in those with the disorder.

Responders with stronger coping skills tended to do better over time, said Lowe. Coping skills that can help make a difference include having a regular schedule, especially for eating and sleeping; having a structured life; and stress management tools, such as meditation or yoga or an enjoyable hobby. Social connection — being part of a community — is also critical, Lowe said.

Clinicians should always inquire about trauma, she said. Lowe, West, and Mann all noted that people with PTSD often have physical illness and that cardiovascular outcomes in particular are worse for those individuals.

 

WTCHP Future Uncertain

However, despite advances in understanding PTSD and the importance of ongoing care, the future of the program supporting World Trade Center responders remains uncertain.

Some 140,000 people are now enrolled in the WTCHP, which was established as a federal program in 2010. Congress has generally reauthorized the program whenever its funding came up for renewal.

However, earlier this year, the Trump administration dismissed two thirds of the NIOSH workforce, including John Howard, MD, the administrator of the WTCHP.

In response, members of Congress and advocates for 9/11 survivors urged the US Department of Health and Human Services (HHS) to reinstate Howard and the affected employees. Howard is listed as back on the job has since returned to his position, and HHS reportedly reinstated hundreds of NIOSH workers in May.

An HHS spokesperson told this news organization that the WTCHP continues to provide services and is actively “accepting, reviewing, and processing new enrollment applications and certification requests.”

Meanwhile, the Trump administration’s fiscal year 2026 budget proposal seeks to reduce CDC funding by $3.5 billion — approximately 40% — with a shift in focus toward infectious diseases. It remains unclear how the WTCHP will be affected by this new direction.

Mann said he is not involved in the program’s funding details but added, “Presumably, as long as some funding continues to keep the program alive, we will continue monitoring responders and providing free treatment until the very last World Trade Center responder passes.”

The study was partially funded through National Institutes of Health and CDC grants, the SUNY Research Foundation, and the CDC’s World Trade Center Health Program. Mann, Lowe, and West reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large 20-year study — the longest and most detailed of its kind — shows that posttraumatic stress disorder (PTSD) symptoms can endure for decades, challenging conventional timelines for recovery and offering new insights to guide future treatment.

Researchers analyzed data from the World Trade Center Health Program (WTCHP), which is administered by the US CDC’s National Institute for Occupational Safety and Health (NIOSH), and found symptoms of PTSD persisted for as long as two decades in 10% of first responders involved in the World Trade Center disaster of September 2001.

Participation in the WTCHP is voluntary, but those who enroll receive free assessments, monitoring, and treatment, including psychiatric and behavioral healthcare. It is the longest and most detailed analysis of PTSD and includes 81,298 observations from 12,822 WTC responders.

Participants entered the WTCHP at different timepoints and were assessed annually. Not every enrollee was assessed every year, but the sheer number of participants and observations “just provides much greater density of data over that 20-year course than any previous study,” lead author Frank D. Mann, PhD, told this news organization.

The study was published online on May 27 in Nature Mental Health.

 

Filling the PTSD Knowledge Gap

Most PTSD research has focused on the short term, with limited insight into how symptoms evolve over the long haul. Without long-term data, it’s been difficult to understand whether PTSD resolves, persists, or worsens — hindering efforts to guide treatment and support. This study aimed to fill that gap by tracking symptom patterns over two decades.

Responders were assessed regularly using the PTSD Checklist for a Specific Stressor, a standardized tool that measures symptom severity on an 85-point scale. On average, each participant completed 6.3 assessments over the course of the study.

A score of ≥ 44 was considered indicative of clinically elevated PTSD symptoms. Between 2002 and 2022, the crude prevalence of elevated symptoms ranged from 8% to 15%. At the same time, 16% to 34% of responders each year reported little to no symptoms, scoring at or near the minimum on the scale.

The researchers found that symptom trajectories varied widely. Nearly as many participants experienced worsening symptoms as those who improved. As a result, the overall population average remained relatively flat over the 20-year period.

Among responders who met the threshold for PTSD, the median time to symptom improvement was 8.9 years — and by year 20, about 76% had shown improvement.

 

New Insights

Mann, a senior research scientist at Stony Brook University Renaissance School of Medicine, Stony Brook, New York, said the study not only reinforced existing knowledge about PTSD in responders but also uncovered new insights.

Most notably, it showed that PTSD symptoms tended to peak around a decade after 9/11 — significantly later than delayed-onset patterns reported in previous trauma studies.

He also noted a surprising outcome — the top 10% of responders who experienced worsening symptoms over the long term accounted for the majority of mental health costs. These individuals, Mann said, represent a critical gap in care, with current interventions proving largely ineffective for them.

Mann suggested that ongoing trauma exposure — especially for responders still in high-risk jobs — and potential genetic susceptibility may contribute to late-emerging or persistent symptoms.

“These individuals are an urgent priority for health systems, as available resources have not been effective for them,” the study authors wrote.

Mann and his colleagues also found that occupation offered the strongest protection against developing PTSD. Police officers and firefighters benefit from training designed to help them cope with trauma, and repeated exposure may build a degree of resilience.

In contrast, responders without such training — like construction workers — faced a 50% to 55% higher risk of developing PTSD symptoms. Mann emphasized that occupational status was a more powerful predictor of PTSD risk than the severity of the traumatic exposures themselves.

 

A Valuable Contribution

Commenting on the research for this news organization, Sandra Lowe, MD, medical director of the Mount Sinai WTCMH program, noted that while the study largely confirms what has been known about responders — such as the significant variability in symptom trajectories over time — it still makes a valuable contribution.

“Extending observations for up to 20 years is rare in any study, especially in a cohort this large,” said Lowe, an associate professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York City, who was not involved in the study.

Also commenting, James West, MD, chair of the American Psychiatric Association’s Committee on the Psychiatric Dimensions of Disaster, described the finding that 10% of responders continued to experience symptoms two decades after exposure as “sobering.”

However, he emphasized that it aligns with observations in the disaster recovery community, where the psychological impact “goes way beyond what most people see as the immediate aftermath and recovery.” West stressed the urgent need to develop effective treatments that enable those affected to live fuller, less impaired lives.

“We still need to be finding the effective treatments that can help these people live fuller lives without impairment from their trauma symptoms,” said West.

Lowe pointed out that the symptom peak around 10 years post-exposure is often linked to external factors. Some responders who had been managing symptoms might lose resilience due to major life changes such as retirement.

“One of the things that was able to keep them engaged is now lost,” she said. “They begin to spend more time reflecting on recollections, and symptoms can worsen.”

West agreed, adding that retirement or job loss often leads to symptom increases because it removes a primary coping mechanism. Both Lowe and Mann also highlighted that 9/11 memorial events can trigger new symptoms or exacerbate existing ones.

Lowe noted that responders with stronger coping skills tended to fare better over time. Effective coping strategies include maintaining regular schedules — especially for eating and sleeping — leading a structured life, and employing stress management techniques like meditation, yoga, or enjoyable hobbies. Social connection and being part of a community are also critical for resilience. She added that clinicians should always inquire about trauma history.

Lowe, West, and Mann all pointed out that PTSD is often accompanied by physical health issues, particularly cardiovascular problems, which tend to be worse in those with the disorder.

Responders with stronger coping skills tended to do better over time, said Lowe. Coping skills that can help make a difference include having a regular schedule, especially for eating and sleeping; having a structured life; and stress management tools, such as meditation or yoga or an enjoyable hobby. Social connection — being part of a community — is also critical, Lowe said.

Clinicians should always inquire about trauma, she said. Lowe, West, and Mann all noted that people with PTSD often have physical illness and that cardiovascular outcomes in particular are worse for those individuals.

 

WTCHP Future Uncertain

However, despite advances in understanding PTSD and the importance of ongoing care, the future of the program supporting World Trade Center responders remains uncertain.

Some 140,000 people are now enrolled in the WTCHP, which was established as a federal program in 2010. Congress has generally reauthorized the program whenever its funding came up for renewal.

However, earlier this year, the Trump administration dismissed two thirds of the NIOSH workforce, including John Howard, MD, the administrator of the WTCHP.

In response, members of Congress and advocates for 9/11 survivors urged the US Department of Health and Human Services (HHS) to reinstate Howard and the affected employees. Howard is listed as back on the job has since returned to his position, and HHS reportedly reinstated hundreds of NIOSH workers in May.

An HHS spokesperson told this news organization that the WTCHP continues to provide services and is actively “accepting, reviewing, and processing new enrollment applications and certification requests.”

Meanwhile, the Trump administration’s fiscal year 2026 budget proposal seeks to reduce CDC funding by $3.5 billion — approximately 40% — with a shift in focus toward infectious diseases. It remains unclear how the WTCHP will be affected by this new direction.

Mann said he is not involved in the program’s funding details but added, “Presumably, as long as some funding continues to keep the program alive, we will continue monitoring responders and providing free treatment until the very last World Trade Center responder passes.”

The study was partially funded through National Institutes of Health and CDC grants, the SUNY Research Foundation, and the CDC’s World Trade Center Health Program. Mann, Lowe, and West reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large 20-year study — the longest and most detailed of its kind — shows that posttraumatic stress disorder (PTSD) symptoms can endure for decades, challenging conventional timelines for recovery and offering new insights to guide future treatment.

Researchers analyzed data from the World Trade Center Health Program (WTCHP), which is administered by the US CDC’s National Institute for Occupational Safety and Health (NIOSH), and found symptoms of PTSD persisted for as long as two decades in 10% of first responders involved in the World Trade Center disaster of September 2001.

Participation in the WTCHP is voluntary, but those who enroll receive free assessments, monitoring, and treatment, including psychiatric and behavioral healthcare. It is the longest and most detailed analysis of PTSD and includes 81,298 observations from 12,822 WTC responders.

Participants entered the WTCHP at different timepoints and were assessed annually. Not every enrollee was assessed every year, but the sheer number of participants and observations “just provides much greater density of data over that 20-year course than any previous study,” lead author Frank D. Mann, PhD, told this news organization.

The study was published online on May 27 in Nature Mental Health.

 

Filling the PTSD Knowledge Gap

Most PTSD research has focused on the short term, with limited insight into how symptoms evolve over the long haul. Without long-term data, it’s been difficult to understand whether PTSD resolves, persists, or worsens — hindering efforts to guide treatment and support. This study aimed to fill that gap by tracking symptom patterns over two decades.

Responders were assessed regularly using the PTSD Checklist for a Specific Stressor, a standardized tool that measures symptom severity on an 85-point scale. On average, each participant completed 6.3 assessments over the course of the study.

A score of ≥ 44 was considered indicative of clinically elevated PTSD symptoms. Between 2002 and 2022, the crude prevalence of elevated symptoms ranged from 8% to 15%. At the same time, 16% to 34% of responders each year reported little to no symptoms, scoring at or near the minimum on the scale.

The researchers found that symptom trajectories varied widely. Nearly as many participants experienced worsening symptoms as those who improved. As a result, the overall population average remained relatively flat over the 20-year period.

Among responders who met the threshold for PTSD, the median time to symptom improvement was 8.9 years — and by year 20, about 76% had shown improvement.

 

New Insights

Mann, a senior research scientist at Stony Brook University Renaissance School of Medicine, Stony Brook, New York, said the study not only reinforced existing knowledge about PTSD in responders but also uncovered new insights.

Most notably, it showed that PTSD symptoms tended to peak around a decade after 9/11 — significantly later than delayed-onset patterns reported in previous trauma studies.

He also noted a surprising outcome — the top 10% of responders who experienced worsening symptoms over the long term accounted for the majority of mental health costs. These individuals, Mann said, represent a critical gap in care, with current interventions proving largely ineffective for them.

Mann suggested that ongoing trauma exposure — especially for responders still in high-risk jobs — and potential genetic susceptibility may contribute to late-emerging or persistent symptoms.

“These individuals are an urgent priority for health systems, as available resources have not been effective for them,” the study authors wrote.

Mann and his colleagues also found that occupation offered the strongest protection against developing PTSD. Police officers and firefighters benefit from training designed to help them cope with trauma, and repeated exposure may build a degree of resilience.

In contrast, responders without such training — like construction workers — faced a 50% to 55% higher risk of developing PTSD symptoms. Mann emphasized that occupational status was a more powerful predictor of PTSD risk than the severity of the traumatic exposures themselves.

 

A Valuable Contribution

Commenting on the research for this news organization, Sandra Lowe, MD, medical director of the Mount Sinai WTCMH program, noted that while the study largely confirms what has been known about responders — such as the significant variability in symptom trajectories over time — it still makes a valuable contribution.

“Extending observations for up to 20 years is rare in any study, especially in a cohort this large,” said Lowe, an associate professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York City, who was not involved in the study.

Also commenting, James West, MD, chair of the American Psychiatric Association’s Committee on the Psychiatric Dimensions of Disaster, described the finding that 10% of responders continued to experience symptoms two decades after exposure as “sobering.”

However, he emphasized that it aligns with observations in the disaster recovery community, where the psychological impact “goes way beyond what most people see as the immediate aftermath and recovery.” West stressed the urgent need to develop effective treatments that enable those affected to live fuller, less impaired lives.

“We still need to be finding the effective treatments that can help these people live fuller lives without impairment from their trauma symptoms,” said West.

Lowe pointed out that the symptom peak around 10 years post-exposure is often linked to external factors. Some responders who had been managing symptoms might lose resilience due to major life changes such as retirement.

“One of the things that was able to keep them engaged is now lost,” she said. “They begin to spend more time reflecting on recollections, and symptoms can worsen.”

West agreed, adding that retirement or job loss often leads to symptom increases because it removes a primary coping mechanism. Both Lowe and Mann also highlighted that 9/11 memorial events can trigger new symptoms or exacerbate existing ones.

Lowe noted that responders with stronger coping skills tended to fare better over time. Effective coping strategies include maintaining regular schedules — especially for eating and sleeping — leading a structured life, and employing stress management techniques like meditation, yoga, or enjoyable hobbies. Social connection and being part of a community are also critical for resilience. She added that clinicians should always inquire about trauma history.

Lowe, West, and Mann all pointed out that PTSD is often accompanied by physical health issues, particularly cardiovascular problems, which tend to be worse in those with the disorder.

Responders with stronger coping skills tended to do better over time, said Lowe. Coping skills that can help make a difference include having a regular schedule, especially for eating and sleeping; having a structured life; and stress management tools, such as meditation or yoga or an enjoyable hobby. Social connection — being part of a community — is also critical, Lowe said.

Clinicians should always inquire about trauma, she said. Lowe, West, and Mann all noted that people with PTSD often have physical illness and that cardiovascular outcomes in particular are worse for those individuals.

 

WTCHP Future Uncertain

However, despite advances in understanding PTSD and the importance of ongoing care, the future of the program supporting World Trade Center responders remains uncertain.

Some 140,000 people are now enrolled in the WTCHP, which was established as a federal program in 2010. Congress has generally reauthorized the program whenever its funding came up for renewal.

However, earlier this year, the Trump administration dismissed two thirds of the NIOSH workforce, including John Howard, MD, the administrator of the WTCHP.

In response, members of Congress and advocates for 9/11 survivors urged the US Department of Health and Human Services (HHS) to reinstate Howard and the affected employees. Howard is listed as back on the job has since returned to his position, and HHS reportedly reinstated hundreds of NIOSH workers in May.

An HHS spokesperson told this news organization that the WTCHP continues to provide services and is actively “accepting, reviewing, and processing new enrollment applications and certification requests.”

Meanwhile, the Trump administration’s fiscal year 2026 budget proposal seeks to reduce CDC funding by $3.5 billion — approximately 40% — with a shift in focus toward infectious diseases. It remains unclear how the WTCHP will be affected by this new direction.

Mann said he is not involved in the program’s funding details but added, “Presumably, as long as some funding continues to keep the program alive, we will continue monitoring responders and providing free treatment until the very last World Trade Center responder passes.”

The study was partially funded through National Institutes of Health and CDC grants, the SUNY Research Foundation, and the CDC’s World Trade Center Health Program. Mann, Lowe, and West reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.