Microbes and Mental Illness: Past, Present, and Future.

A review of the association between microbes and mental illness is performed, including the history, relevant definitions, infectious agents associated with mental illnesses, complex interactive infections, total load theory, pathophysiology, psychoimmunology, psychoneuroimmunology, clinical presentations, early-life infections, clinical assessment, and treatment. Perspectives on the etiology of mental illness have evolved from demonic possession toward multisystem biologically based models that include gene expression, environmental triggers, immune mediators, and infectious diseases. Microbes are associated with a number of mental disorders, including autism, schizophrenia, bipolar disorder, depressive disorders, and anxiety disorders, as well as suicidality and aggressive or violent behaviors. Specific microbes that have been associated or potentially associated with at least one of these conditions include Aspergillus, Babesia, Bartonella, Borna disease virus, Borrelia burgdorferi (Lyme disease), Candida, Chlamydia, coronaviruses (e.g., SARS-CoV-2), Cryptococcus neoformans, cytomegalovirus, enteroviruses, Epstein-Barr virus, hepatitis C, herpes simplex virus, human endogenous retroviruses, human immunodeficiency virus, human herpesvirus-6 (HHV-6), human T-cell lymphotropic virus type 1, influenza viruses, measles virus, Mycoplasma, Plasmodium, rubella virus, Group A Streptococcus (PANDAS), Taenia solium, Toxoplasma gondii, Treponema pallidum (syphilis), Trypanosoma, and West Nile virus. Recognition of the microbe and mental illness association with the development of greater interdisciplinary research, education, and treatment options may prevent and reduce mental illness morbidity, disability, and mortality.

Lyme borreliosis in pregnancy and associations with parent and offspring health outcomes: An international cross-sectional survey.

Background: Lyme disease (LD) is a complex tick-borne pathology caused by Borrelia burgdorferi sensu lato bacteria. Currently, there are limited data regarding the health outcomes of people infected during pregnancy, the potential for perinatal transmission to their fetus, and the long-term effects on these children. Therefore, the primary objective of this survey study was to investigate the impact of LD in pregnancy on both the parent and their offspring. Methods: A seven-section survey was developed and administered in REDCap. Although recruitment was primarily through LD-focused organizations, participation was open to anyone over the age of 18 who had been pregnant. Participant health/symptoms were compared across those with "Diagnosed LD," "Suspected LD," or "No LD" at any time in their lives. The timing of LD events in the participants' histories (tick bite, diagnosis, treatment start, etc.) were then utilized to classify the participants' pregnancies into one of five groups: "Probable Treated LD," "Probable Untreated LD," "Possible Untreated LD," "No Evidence of LD," and "Unclear." Results: A total of 691 eligible people participated in the survey, of whom 65% had Diagnosed LD, 6% had Suspected LD, and 29% had No LD ever. Both the Diagnosed LD and Suspected LD groups indicated a high symptom burden (p < 0.01). Unfortunately, direct testing of fetal/newborn tissues for Borrelia burgdorferi only occurred following 3% of pregnancies at risk of transmission; positive/equivocal results were obtained in 14% of these cases. Pregnancies with No Evidence of LD experienced the fewest complications (p < 0.01) and were most likely to result in a live birth (p = 0.01) and limited short- and long-term offspring pathologies (p < 0.01). Within the LD-affected pregnancy groups, obtaining treatment did not decrease complications for the parent themselves but did ameliorate neonatal health status, with reduced rates of rashes, hypotonia, and respiratory distress (all p < 0.01). The impact of parent LD treatment on longer-term child outcomes was less clear. Conclusion: Overall, this pioneering survey represents significant progress toward understanding the effects of LD on pregnancy and child health. A large prospective study of pregnant people with LD, combining consistent diagnostic testing, exhaustive assessment of fetal/newborn samples, and long-term offspring follow-up, is warranted.

Symptom Clusters and Functional Impairment in Individuals Treated for Lyme Borreliosis.

Context: Persistent fatigue, pain, and neurocognitive impairment are common in individuals following treatment for Lyme borreliosis (LB). Poor sleep, depression, visual disturbance, and sensory neuropathies have also been reported. The cause of these symptoms is unclear, and widely accepted effective treatment strategies are lacking. Objectives: To identify symptom clusters in people with persistent symptoms previously treated for LB and to examine the relationship between symptom severity and perceived disability. Methods: This was a retrospective chart review of individuals with a history of treatment of LB referred to The Dean Center for Tick-Borne Illness at Spaulding Rehabilitation Hospital between 2015 and 2018 (n = 270) because of persistent symptoms. Symptoms and functional impairment were collected using the General Symptom Questionnaire-30 (GSQ-30), and the Sheehan Disability Scale. Clinical tests were conducted to evaluate for tick-borne co-infections and to rule out medical disorders that could mimic LB symptomatology. Exploratory factor analysis was performed to identify symptom clusters. Results: Five symptom clusters were identified. Each cluster was assigned a name to reflect the possible underlying etiology and was based on the majority of the symptoms in the cluster: the neuropathy symptom cluster, sleep-fatigue symptom cluster, migraine symptom cluster, cognitive symptom cluster, and mood symptom cluster. Symptom severity for each symptom cluster was positively associated with global functional impairment (p < 0.001). Conclusion: Identifying the interrelationship between symptoms in post-treatment LB in a cluster can aid in the identification of the etiological basis of these symptoms and could lead to more effective symptom management strategies. Key Message: This article describes symptom clusters in individuals with a history of Lyme borreliosis. Five clusters were identified: sleep-fatigue, neuropathy, migraine-like, cognition, and mood clusters. Identifying the interrelationship between symptoms in each of the identified clusters could aid in more effective symptom management through identifying triggering symptoms or an underlying etiology.

Association of small fiber neuropathy and post treatment Lyme disease syndrome.

OBJECTIVES: To examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction. METHODS: This single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored. RESULTS: 10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv. CONCLUSIONS: SFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

Predictors of immunologic long-term nonprogression in HIV-infected children: implications for initiating therapy.

BACKGROUND: Early markers that predict immunologic long-term nonprogression in infants with perinatally acquired HIV infection might assist in subsequent antiretroviral treatment decisions. OBJECTIVES: We sought to identify early markers of immunologic long-term HIV disease nonprogression. METHODS: We analyzed immunologic and virologic characteristics at 1 and 2 months of age in HIV-infected children who were enrolled in the Women and Infants Transmission Study and born before 1995, comparing immunologic long-term nonprogressors (ILTNPs; n = 10) with non-ILTNPs (n = 127). ILTNPs were children who survived to 8 years or older with CD4 percentages of 25% or greater and counts of 500 cells/mm 3 or more without receiving highly active antiretroviral therapy. Non-ILTNPs were defined as all other HIV-infected children. Receiver operating characteristic curve analysis was used to assess combined sensitivity and specificity for each of these characteristics and to determine potential threshold values to discriminate between ILTNPs and non-ILTNPs. RESULTS: Characteristics in the first 2 months of life associated with ILTNP status in univariate analysis included higher CD4 percentages, lower CD8 + percentages, lower CD8 + HLA-DR + percentages, and lower HIV-1 RNA PCR values. In receiver operating characteristic analysis CD8 + HLA-DR + percentage had the best combined sensitivity and specificity for discriminating between ILTNPs and non-ILTNPs. CD8 + HLA-DR + percentages of 5% or less predicted ILTNP status with 80% sensitivity and 80% specificity. In multivariate analysis CD8 + HLA-DR+ percentage of 5% or less remained a significant predictor of ILTNP status after adjusting for CD3 + CD4 + percentage and HIV-1 RNA PCR value (odds ratio, 15.4; 95% CI, 1.9-124.7). CONCLUSION: CD8 + HLA-DR + T-lymphocyte percentage of less than 5% at 1 to 2 months of age might be predictive for ILTNP status but should not be used at this time to make treatment-deferral decisions. Immune activation in HIV-infected infants might herald more disease progression. Further study of the use of this subpopulation in early infancy to predict ILTNP status is warranted.

Reconstitution of virus-specific CD4 proliferative responses in pediatric HIV-1 infection.

Gag-specific CD4 proliferative responses correlate inversely with HIV-1 RNA levels in infected adults, and robust responses are characteristic of long-term nonprogressive infection. However, strong responses are seldom detected in adult subjects with progressive infection and are not generally reconstituted on highly active antiretroviral therapy (HAART). To date, the role of HIV-1-specific Th responses in children has not been thoroughly examined. We characterized Gag-specific CD4 responses among 35 perinatally infected subjects, including 2 children who spontaneously control viremia without antiretroviral therapy, 21 children with viral loads (VL) of <400 on HAART, and 12 viremic children. Gag-specific Th activity was assessed by lymphoproliferative assay, and responses were mapped using overlapping Gag peptides in an IFN-gamma ELISPOT. Robust proliferative responses were detected in the children exhibiting spontaneous control of viremia, and mapping of targeted Gag regions in one such subject identified multiple epitopes. Among children >or=5 years old, 14 of 17 subjects with VL of <400 on HAART demonstrated a significant p24 proliferative response (median p24 stimulation index, 20), in contrast with only 1 of 9 viremic children (median p24 stimulation index, 2.0; p = 0.0008). However, no subject younger than 5 years of age possessed a significant response, even when viremia was fully suppressed. When compared with adults with VL of <400 on HAART, Th responses among children with VL of <400 were both more frequent (p = 0.009) and of greater magnitude (p = 0.002). These data suggest that children may have a greater intrinsic capacity to reconstitute HIV-1-specific immunity than adults, and may be excellent candidates for immune-based therapies.