Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Persistent Symptoms, Lyme Disease, and Prior Trauma.

ABSTRACT: One prior study suggests that traumatic events before Lyme disease play an important role in symptom severity. We examined this hypothesis among 60 individuals with persistent symptoms after Lyme disease using validated measures of trauma history, mental and physical symptoms, and functional status. Analysis of variance with Tukey-Kramer multiple comparisons test revealed that a greater number of traumatic events were significantly associated with greater symptom severity on the scales of mood (stress, depression, and anxiety), cognition, multisystem symptom burden, and functional status (mental and physical), but not on measures of pain and fatigue. The effect sizes-meaningful but not large (0.17-0.29)-were mostly produced by comparison with individuals reporting multiple prior traumatic events, representing half of the posttreatment Lyme disease syndrome (PTLDS) group. In conclusion, although PTLDS may be exacerbated by past trauma, trauma plays a role in only a subgroup of PTLDS. Whether addressing prior trauma can improve outcomes in this subgroup requires study.

Religion and Psychiatry in the Age of Neuroscience.

In recent decades, an evolving conversation among religion, psychiatry, and neuroscience has been taking place, transforming how we conceptualize religion and how that conceptualization affects its relation to psychiatry. In this article, we review several dimensions of the dialogue, beginning with its history and the phenomenology of religious experience. We then turn to neuroscientific studies to see how they explain religious experience, and we follow that with two related areas: the benefits of religious beliefs and practices, and the evolutionary foundation of those benefits. A final section addresses neuroscientific and evolutionary accounts of the transcendent, that is, what these fields make of the claim that religious experience connects to a transcendent reality. We conclude with a brief summary, along with the unresolved questions we have encountered.

Depressive Symptoms and Suicidal Ideation Among Symptomatic Patients With a History of Lyme Disease vs Two Comparison Groups.

BACKGROUND: Depression has been reported in 8-45% of patients with posttreatment Lyme symptoms (PTLS), but little is known about suicidal ideation in these patients. METHOD: Depression and suicidal ideation were assessed using the Beck Depression Inventory (BDI-II). Scores from the PTLS group (n = 81) were compared to those from 2 other groups: HIV+ patients being treated for fatigue (n = 70), and a nonpatient comparison group (NPCG; n = 44). ANOVA and t-tests were used to compare groups; logistic regression was used to identify the strongest correlates of suicidal ideation. RESULTS: Mean BDI-II scores fell in the mildly depressed range for PTLS and HIV+ patients, with both groups having higher depression scores than the NPCG. Suicidal ideation was reported by 19.8% of the PTLS patients and 27.1% of the HIV+ patients, a nonsignificant difference. Among those with mild or no depression, suicidal ideation was uncommon (6.5% PTLS and 11.9% HIV+). Among the patients with moderate-to-severe depression, suicidal ideation was more common (63.2% of 19 PTLS and 50% of 28 HIV+); among these, 2 with PTLS and 1 with HIV+ expressed suicidal intent. Further, 4.5% (n = 2) of the NPCG had suicidal ideation, each had scores in the moderate-to-severe depression range. Higher scores on the cognitive symptoms subscale of the BDI-II predicted greater likelihood of suicidal ideation across patient groups. CONCLUSION: As expected, suicidal ideation is increased among patients who are depressed. The fact that 1 in 5 patients with PTLS reported suicidal ideation highlights the importance of screening for depression and suicidality to optimize patient care.

Cyberchondria: Parsing Health Anxiety From Online Behavior.

BACKGROUND: Individuals with questions about their health often turn to the Internet for information about their symptoms, but the degree to which health anxiety is related to online checking, and clinical variables, remains unclear. The clinical profiles of highly anxious Internet checkers, and the relationship to checking behavior itself, have not previously been reported. OBJECTIVE: In this article, we test the hypothesis, derived from cognitive-behavioral models, that individuals with higher levels of illness anxiety would recall having experienced worsening anxiety after reassurance-seeking on the Internet. METHOD: Data from 731 volunteers who endorsed engaging in online symptom-searching were collected using an online questionnaire. Severity of health anxiety was assessed with the Whiteley Index, functional impairment with the Sheehan Disability Scale, and distress recall during and after searching with a modified version of the Clinician׳s Global Impairment scale. Multiple regression analyses were conducted to determine variables contributing to distress during and after Internet checking. RESULTS: Severity of illness anxiety on the Whiteley Index was the strongest predictor of increase in anxiety associated with, and consequent to, online symptom-searching. Individuals with high illness anxiety recalled feeling worse after online symptom-checking, whereas those with low illness anxiety recalled relief. Longer-duration online health-related use was associated with increased functional impairment, less education, and increased anxiety during and after checking. CONCLUSION: Because individuals with moderate-high levels of illness anxiety recall experiencing more anxiety during and after searching, such searching may be detrimental to their health. If replicated in controlled experimental settings, this would suggest that individuals with illness anxiety should be advised to avoid using the Internet for illness-related information.

The Relationship of Hypochondriasis to Anxiety, Depressive, and Somatoform Disorders.

BACKGROUND: Though the phenotype of anxiety about medical illness has long been recognized, there continues to be debate as to whether it is a distinct psychiatric disorder and, if so, to which diagnostic category it belongs. OBJECTIVE: Our objective was to investigate the pattern of psychiatric comorbidity in hypochondriasis (HC) and to assess the relationship of health anxiety to anxiety, depressive, and somatoform disorders. METHODS: Data were collected as part of a clinical trial on treatment methods for HC. In all, 194 participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) HC were assessed by sociodemographic variables, results of structured diagnostic interviews, and validated instruments for assessing various symptom dimensions of psychopathology. RESULTS: Most of the individuals with HC had comorbid psychiatric illness; the mean number of comorbid diagnoses was 1.4, and 35.1% had HC as their only diagnosis. Participants were more likely to have only comorbid anxiety disorders than only comorbid depressive or somatoform disorders. Multiple regression analysis of continuous measures of symptoms revealed the strongest correlation of health anxiety with anxiety symptoms, and a weaker correlation with somatoform symptoms; in multiple regression analysis, there was no correlation between health anxiety and depressive symptoms. CONCLUSION: Our findings suggest that the entity of health anxiety (HC in DSM-IV and illness anxiety disorder in DSM-5) is a clinical syndrome distinct from other psychiatric disorders. Analysis of comorbidity patterns and continuous measures of symptoms suggest that its appropriate classification is with anxiety rather than somatoform or mood disorders.

A comparison of lyme disease serologic test results from 4 laboratories in patients with persistent symptoms after antibiotic treatment.

BACKGROUND: As the incidence of Lyme disease (LD) has increased, a number of "Lyme specialty laboratories" have emerged, claiming singular expertise in LD testing. We investigated the degree of interlaboratory variability of several LD serologic tests-whole cell sonicate (WCS) enzyme-linked immunosorbent assay (ELISA), immunoglobulin M (IgM) and immunoglobulin G (IgG) Western blots (WBs), and an ELISA based on the conserved sixth region of variable major protein-like sequence expressed (C6)-that were performed at 1 university laboratory, 1 commercial laboratory, and 2 laboratories that specialize in LD testing. METHODS: Serum samples from 37 patients with posttreatment Lyme syndrome, as well as 40 medically healthy controls without prior LD, were tested independently at the 4 laboratories. RESULTS: In general, there was little difference among the laboratories in the percentage of positive test results on the ELISAs and IgG WBs, although the number of discordant results was often high. When in-house criteria for positivity were used at the 2 specialty laboratories, specificity at 1 laboratory declined considerably on both the IgM and IgG WBs. The Centers for Disease Control and Prevention (CDC) 2-tiered criteria improved overall concordance. At the 2 laboratories that performed the C6 ELISA, the percentage of positive tests was comparable to that of the WCS ELISA while providing higher specificity. The IgM WB performed poorly in our patient population of individuals with later-stage illness, a result consistent with previous studies. CONCLUSIONS: Although there was surprisingly little difference among the laboratories in percentage of positive results on most assays using CDC criteria, interlaboratory variability was considerable and remains a problem in LD testing.

Bartonella species bacteremia in association with adult psychosis.

Introduction: The potential role of pathogens, particularly vector-transmitted infectious agents, as a cause of psychosis has not been intensively investigated. We have reported a potential link between Bartonella spp. bacteremia and neuropsychiatric symptoms, including pediatric acute onset neuropsychiatric syndrome and schizophrenia. The purpose of this study was to further assess whether Bartonella spp. exposure or infection are associated with psychosis. Methods: In a blinded manner, we assessed the presence of anti-Bartonella antibodies by indirect immunofluorescence assays (IFA), and infection by amplification of bacterial DNA from blood by quantitative polymerase chain reaction (qPCR), digital PCR (dPCR), and droplet digital PCR (ddPCR) in 116 participants. Participants were categorized into one of five groups: 1) controls unaffected by psychosis (n = 29); 2) prodromal participants (n = 16); 3) children or adolescents with psychosis (n = 7); 4) adults with psychosis (n = 44); and 5) relatives of a participant with psychosis (n = 20). Results: There was no significant difference in Bartonella spp. IFA seroreactivity between adults with psychosis and adult controls unaffected by psychosis. There was a higher proportion of adults with psychosis who had Bartonella spp. DNA in the bloodstream (43.2%) compared to adult controls unaffected by psychosis (14.3%, p = 0.021). The Bartonella species was determined for 18 of the 31 bacteremic participants, including infection or co-infection with Bartonella henselae (11/18), Bartonella vinsonii subsp. berkhoffii (6/18), Bartonella quintana (2/18), Bartonella alsatica (1/18), and Bartonella rochalimae (1/18). Discussion: In conjunction with other recent research, the results of this study provide justification for a large national or international multi-center study to determine if Bartonella spp. bacteremia is more prevalent in adults with psychosis compared to adults unaffected by psychosis. Expanding the investigation to include a range of vector-borne and other microbial infections with potential CNS effects would enhance knowledge on the relationship between psychosis and infection.

Prevalence of Powassan Virus Seropositivity Among People with History of Lyme Disease and Non-Lyme Community Controls in the Northeastern United States.

Introduction: Lyme disease (LD) affects ∼476,000 people each year in the United States. Symptoms are variable and include rash and flu-like symptoms. Reasons for the wide variation in disease outcomes are unknown. Powassan virus (POWV) is a tick-borne flavivirus that causes disease ranging from asymptomatic infection to encephalitis, neurologic damage, and death. POWV and LD geographic case distributions overlap, with Ixodes species ticks as the common vectors. Clinical ramifications of coinfection or sequential infection are unknown. Objectives: This study's primary objective was to determine the prevalence of POWV-reactive antibodies in sera samples collected from previously studied cohorts of individuals with self-reported LD history residing in the Northeastern United States. As a secondary objective, we studied clinical differences between people with self-reported LD history and low versus high POWV antibody levels. Methods: We used an enzyme-linked immunosorbent assay (ELISA) to quantify IgG directed at the POWV envelope (E) protein domain III in 538 samples from individuals with self-reported LD history and 16 community controls. The samples were also tested with an ELISA assay to quantify IgG directed at the POWV NS1 protein. Results: The percentage of individuals with LD history and possible evidence of POWV exposure varied depending on the assay utilized. We found no significant difference in clinical symptoms between those with low or high POWV IgG levels in the in-house assay. Congruence of the EDIII and NS1 assays was low with only 12% of those positive in the in-house EDIII ELISA testing positive in the POWV NS1 ELISA. Conclusions: The results highlight the difficulty in flavivirus diagnostic testing, particularly in the retrospective detection of flavivirus exposure. The findings suggest that a prospective study with symptomatic patients using approved clinical testing is necessary to address the incidence and clinical implications of LD and POWV co-infection or sequential infection.

Human antibodies in Mexico and Brazil neutralizing tick-borne flaviviruses.

Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.

Post-treatment lyme syndrome and central sensitization.

Central sensitization is a process that links a variety of chronic pain disorders that are characterized by hypersensitivity to noxious stimuli and pain in response to non-noxious stimuli. Among these disorders, treatments that act centrally may have greater efficacy than treatments acting peripherally. Because many individuals with post-treatment Lyme syndrome (PTLS) have a similar symptom cluster, central sensitization may be a process mediating or exacerbating their sensory processing. This article reviews central sensitization, reports new data on sensory hyperarousal in PTLS, explores the potential role of central sensitization in symptom chronicity, and suggests new directions for neurophysiologic and treatment research.

Correlates of perceived health-related quality of life in post-treatment Lyme encephalopathy.

BACKGROUND: Marked functional impairment has been reported by patients with post-treatment Lyme disease syndrome (PTLDS). OBJECTIVE: We sought to identify the clinical features that contribute most strongly to the impaired health status associated with PTLDS. METHODS: Enrolled patients had a well-documented history of Lyme disease, prior treatment with at least 3 weeks with intravenous ceftriaxone, a positive IgG Western blot, and objective problems with memory. An index score to capture aggregate cognitive functioning, Short-Form 36 physical and mental component summary scores, and scores on other clinical and demographic measures were examined. Multiple linear regressions were performed to determine significant predictors of perceptions of impaired life functioning as delineated by the Short-Form 36. RESULTS: Fatigue was the most important contributor to perceived impairments in overall physical functioning, and fatigue and depression significantly predicted perceived impairments in overall mental functioning. CONCLUSIONS: Because fatigue and depression contribute prominently to reports of impaired physical functioning and mental functioning among patients with PTLDS, clinicians should assess patients for these symptoms and consider targeting these symptoms in the selection of treatment interventions. Future controlled studies should examine the effectiveness of such agents for patients with PTLDS.

Neuropsychiatric Symptoms and Tick-Borne Diseases.

In North America, Lyme disease (LD) is primarily caused by the spirochetal bacterium Borrelia burgdorferi, transmitted to humans by Ixodes species tick bites, at an estimated rate of 476,000 patients diagnosed per year. Acute LD often manifests with flu-like symptoms and an expanding rash known as erythema migrans (EM) and less often with neurologic, neuropsychiatric, arthritic, or cardiac features. Most acute cases of Lyme disease are effectively treated with antibiotics, but 10-20% of individuals may experience recurrent or persistent symptoms. This chapter focuses on the neuropsychiatric aspects of Lyme disease, as these are less widely recognized by physicians and often overlooked. Broader education about the potential complexity, severity, and diverse manifestations of tick-borne diseases is needed.

Language Fluency Deficits in Post-treatment Lyme Disease Syndrome.

OBJECTIVE: Recent neurocognitive studies of patients with post-treatment Lyme disease syndrome (PTLDS) find consistent deficits in memory and processing speed. Language fluency deficits are observed as well but may be secondary to poor memory and slowing rather than an independent deficit. METHOD: This study performed a secondary analysis of data presented previously, including individuals with PTLDS and comparison samples of healthy volunteers (HC) and patients with major depressive disorder (MDD), to determine if language fluency deficits could be accounted for by poor performance in these other neurocognitive domains. RESULTS: Basic verbal abilities, memory, and processing speed were all significantly associated with fluency performance. MDD patients' fluency deficits relative to HC were accounted for by these covariates. However, PTLDS patients' poorer fluency performance relative to both other groups was not. CONCLUSIONS: Language fluency appears to be an independent area of neurocognitive deficit within the constellation of PTLDS symptoms.

Neuropsychiatric Lyme Disease and Vagus Nerve Stimulation.

Lyme disease, the most common tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. While most patients with acute Lyme disease recover completely if treated with antibiotics shortly after the onset of infection, approximately 10-30% experience post-treatment symptoms and 5-10% have residual symptoms with functional impairment (post-treatment Lyme disease syndrome or PTLDS). These patients typically experience pain, cognitive problems, and/or fatigue. This narrative review provides a broad overview of Lyme disease, focusing on neuropsychiatric manifestations and persistent symptoms. While the etiology of persistent symptoms remains incompletely understood, potential explanations include persistent infection, altered neural activation, and immune dysregulation. Widely recognized is that new treatment options are needed for people who have symptoms that persist despite prior antibiotic therapy. After a brief discussion of treatment approaches, the article focuses on vagus nerve stimulation (VNS), a neuromodulation approach that is FDA-approved for depression, epilepsy, and headache syndromes and has been reported to be helpful for other diseases characterized by inflammation and neural dysregulation. Transcutaneous VNS stimulates the external branch of the vagus nerve, is minimally invasive, and is well-tolerated in other conditions with few side effects. If well-controlled double-blinded studies demonstrate that transcutaneous auricular VNS helps patients with chronic syndromes such as persistent symptoms after Lyme disease, taVNS will be a welcome addition to the treatment options for these patients.

Disulfiram: Mechanisms, Applications, and Challenges.

Background: Since disulfiram's discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were "disulfiram" and "Antabuse". Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948-2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a "repurposed" agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.

Somatoform pain: a developmental theory and translational research review.

Somatoform pain is a highly prevalent, debilitating condition and a tremendous public health problem. Effective treatments for somatoform pain are urgently needed. The etiology of this condition is, however, still unknown. On the basis of a review of recent basic and clinical research, we propose one potential mechanism of symptom formation in somatoform pain and a developmental theory of its pathogenesis. Emerging evidence from animal and human studies in developmental neurobiology, cognitive-affective neuroscience, psychoneuroimmunology, genetics, and epigenetics, as well as that from clinical and treatment studies on somatoform pain, points to the existence of a shared neural system that underlies physical and social pain. Research findings also show that nonoptimal early experiences interact with genetic predispositions to influence the development of this shared system and the ability to regulate it effectively. Interpersonal affect regulation between infant and caregiver is crucial for the optimal development of these brain circuits. The aberrant development of this shared neural system during infancy, childhood, and adolescence may therefore ultimately lead to an increased sensitivity to physical and social pain and to problems with their regulation in adulthood. The authors critically review translational research findings that support this theory and discuss its clinical and research implications. Specifically, the proposed theory and research review suggest that psychotherapeutic and/or pharmacological interventions that foster the development of affect regulation capacities in an interpersonal context will also serve to more effectively modulate aberrantly activated neural pain circuits and thus be of particular benefit for the treatment of somatoform pain.

A clinician-administered severity rating scale for illness anxiety: development, reliability, and validity of the H-YBOCS-M.

BACKGROUND: Clinician-administered measures to assess severity of illness anxiety and response to treatment are few. The authors evaluated a modified version of the hypochondriasis-Y-BOCS (H-YBOCS-M), a 19-item, semistructured, clinician-administered instrument designed to rate severity of illness-related thoughts, behaviors, and avoidance. METHODS: The scale was administered to 195 treatment-seeking adults with DSM-IV hypochondriasis. Test-retest reliability was assessed in a subsample of 20 patients. Interrater reliability was assessed by 27 interviews independently rated by four raters. Sensitivity to change was evaluated in a subsample of 149 patients. Convergent and discriminant validity was examined by comparing H-YBOCS-M scores to other measures administered. Item clustering was examined with confirmatory and exploratory factor analyses. RESULTS: The H-YBOCS-M demonstrated good internal consistency, interrater and test-retest reliability, and sensitivity to symptom change with treatment. Construct validity was supported by significant higher correlations with scores on other measures of hypochondriasis than with nonhypochondriacal measures. Improvement over time in response to treatment correlated with improvement both on measures of hypochondriasis and on measures of somatization, depression, anxiety, and functional status. Confirmatory factor analysis did not show adequate fit for a three-factor model. Exploratory factor analysis revealed a five-factor solution with the first two factors consistent with the separation of the H-YBOCS-M items into the subscales of illness-related avoidance and compulsions. CONCLUSIONS: H-YBOCS-M appears to be valid, reliable, and appropriate as an outcome measure for treatment studies of illness anxiety. Study results highlight "avoidance" as a key feature of illness anxiety-with potentially important nosologic and treatment implications.