Chronic Inflammatory Response Syndrome Research Articles

Pyrroloquinoline Quinone (PQQ): a novel approach to managing chronic inflammatory response syndrome and mitochondrial dysfunction

Chronic Inflammatory Response Syndrome (CIRS) is a complex, multi-system condition associated with persistent inflammation in response to biotoxins like mould or other environmental triggers. Mitochondrial dysfunction has been implicated in the pathophysiology of CIRS, contributing to chronic inflammation and exacerbating symptoms. Pyrroloquinoline quinone (PQQ), a redox cofactor, has gained attention for its potential neuroprotective, anti-inflammatory, and mitochondria-supporting properties. Additionally, CIRS shares overlapping features with cytokine storm effects observed in COVID infection, long COVID, and potential inflammatory reactions related to mRNA vaccine administration. This letter explores the role of PQQ in managing CIRS and addressing mitochondrial dysfunction caused by multiple potential triggers. However, further research is needed to confirm the effectiveness and safety of PQQ in addressing CIRS and related conditions.

Transcriptomics and Brain Volumetrics Define the Causes of Cognitive Impairment in Patients with CIRS and Support the use of VIP in Treatment

Problems with executive cognitive function, including recent memory, concentration, word finding, confusion, decreased assimilation, and disorientation, can have a variety of sources of disease, including inflammation, metabolic disturbances, and degenerative processes that are typically found in diseases where chronic fatigue is present. The problems presented by multiple coexisting cognitive symptoms are finding: 1) a single diagnostic test that has a history of use by clinicians working with brain-injured patients, such as NeuroQuant (NQ); 2) that is affordable, accurate, and reliable to use as a measure of benefits, or lack of same; and 3) screening, causation, and sequential features of therapy. Furthermore, the complexity of brain injury shows us the limitations of human versus machine-based testing, with advances in transcriptomics leading the way in a new world of diagnostics and therapies that follow gene activation studies. The objective of this report was to retrospectively look at results of the transcriptomic testing of white blood cells, combined with a brain volumetric imaging study, in an observational study to provide a basis to identify the specific causation of brain injury caused by exposure to the interior environment of water-damaged buildings (WDB). By comparing transcriptomic abnormalities with known volumetric patterns of injury to cortical grey matter, enlargement of superior lateral ventricles and atrophy of grey matter nuclei, we demonstrate the feasibility of treatment of brain injury employing noninvasive methods in preparation for novel treatments previously shown to be effective. We intend to use these tests sequentially in a before-and-after fashion to show correction of metabolic and inflammatory conditions found in chronic inflammatory response syndrome (CIRS) in a subsequent study.

Exposure to Actinobacteria resident in water-damaged buildings and resultant immune injury in Chronic Inflammatory Response Syndrome

The indoor air quality literature has expanded to include a wider variety of contaminants responsible for adverse human health effects. The increased use of Next Generation Sequencing (NGS), combined with the advent of transcriptomic assays, has defined specific causation of innate immune activation within this growing list of pathogenic microbes. Here we report the correlation of specific Actinobacteria as shown by NGS, with specific differential gene activation, using a transcriptomic assay (GENIE; Progene Dx, LLC, Bedford, Massachusetts). The study provides newly described indices of dominance (DI) and prevalence (PI) for exposure to Actinobacteria that have enabled clinicians to develop targeted treatment protocols to improve health issues as shown by reduction of symptoms, restoration of normal proteomics and transcriptomics, and correcting molecular hypometabolism (MHM), upregulation of MAPKs and TGFBR, as part of a chronic inflammatory response syndrome (CIRS), acquired following exposure to the interior environment of a water-damaged building (WDB). NGS has shown differences in populations of Actinobacteria found in WDB that are paralleled by differences in innate immune responses. Actinobacteria carried on human skin (HH, human habitat), as opposed to dwelling in soils (SH, soil habitat), consistent with prior publications, can now be represented by DI and PI pinpointing of specific areas of WDB requiring remediation. A review of the literature shows the capability of HH organisms to induce inflammatory processes in skin and systemically. In addition, the rapid expansion of research on extracellular vesicles suggests a reasonable basis for a mechanism by which resident HH initiate a cascade of inflammatory and metabolic events leading to adverse health effects following exposure to Gram-positive organisms, particularly lipophilic Corynebacteria, Cutibacteria and Mycobacteria, all of which contain mycolic acids in their cell walls. The role of unique structural differences in specific mycolic acids stratifying those Actinobacteria that are inflammatory may become fertile ground for the treatment of HH-associated illnesses, including CIRS. A review of the biology of receptors for TGF beta-1 adds to the importance of preventing the downstream signaling from upregulated TGFBR in illness associated with elevated PI. The aim of the paper is to identify distinguishing clinical features, including inflammation and immunoreactivity involving MAPK and TGFBR that are seen in illness associated with indoor exposure to Actinobacteria.

Treatable metabolic and inflammatory abnormalities in Post COVID Syndrome (PCS) define the transcriptomic basis for persistent symptoms: Lessons from CIRS

Within three months of the onset of acute SARS-CoV-2 (COVID-19) infections, new and persistent symptoms were noted in survivors. While the world’s medical and research communities focus on saving lives following COVID-19 infection, a relentless march of new cases of Post-COVID Syndrome (PCS) continues to spread around the globe as a second COVID-related pandemic. Efforts to define the physiology of PCS, a multisystem, multi-symptom illness, continue without success, in part due to the markedly different case presentations. Using a transcriptomic assessment of persistently ill cases of PCS, we show the presence of (i) molecular hypometabolism (MHM) and proliferative physiology; (ii) elevated levels of ribosomal stress responses and a concomitant increase in gene activation of TGFBR; and (iii) common co-expression of CD14 and Toll Receptor 4, correlated to exposure of amplified microbial growth in a water-damaged environment, specifically Actinobacteria and endotoxin, respectively, compared to recovered PCS cases. Total symptom scores and visual contrast sensitivity (VCS) results showed statistically significant differences. The data reported here supports the concept that PCS occurs in patients with additional environmental exposures and enhanced TGF signaling. In a strikingly similar condition called Chronic Inflammatory Response Syndrome (CIRS), named in 2010, the transcriptomic abnormalities were identified to respond to treatment with FDA-cleared medications, with salutary benefits for affected cases. Though sparsely reported, PCS cases share proteomic findings with CIRS. While additional studies are indicated, a new approach to the treatment of PCS is suggested.

Pediatrics Norms for Visual Contrast Sensitivity Using an APT VCS Tester

Chronic inflammatory response syndrome (CIRS) is an acute and chronic, systemic inflammatory response syndrome usually acquired following exposure to the interior environment of water-damaged buildings (WDB). Capillary hypoperfusion is a principle mechanism of injury in CIRS patients. Visual contrast sensitivity (VCS) testing is affected by capillary hypoperfusion and has been used to screen patients and track treatment results in CIRS cases. Adult VCS norms for the APT VCS Tester were developed by its manufacturer but pediatric norms have not been made available. This study evaluated VCS testing, using an APT VCS tester, on 157 consecutive pediatric patients presenting for wellness checks at a local pediatric clinic. Thirty children were excluded. For the remaining 127 controls, means for left eyes at each CPD (cycles per degree of visual arc) were the same as for right eyes at the same testing frequency. The mean visual contrast raw score at 1.5 CPD was 8.1 out of a possible 9 (stdev = 0.534). The mean for 3 CPD was 8.2 (stdev = 0.531). The mean for 6 CPD was 8.2 (stdev = 0.450). The mean for 12 CPD was 7.8 (stdev = 0.835). The mean for 18 CPD was 1.8 (stdev = 2.40). Further analysis showed there was no significant difference between boys and girls, between well controlled asthmatics and those without asthma or between the cohort of ages 7-8 and any other age grouping. The pediatric VCS norms calculated were the same as the manufacturer’s reported norms for adults. Pediatric CIRS prevalence in this cohort was calculated as a minimum of 7.6% and a maximum of 12.7%. Pediatric CIRS prevalence is on the same order as pediatric asthma.

An Evaluation of Alternate Means to Diagnose Chronic Inflammatory Response Syndrome and Determine Prevalence

Chronic inflammatory response syndrome (CIRS) is an illness of unreported prevalence first described in 1997 (Shoemaker 1997). This study is the first reporting prevalence and evaluating alternate methods of CIRS diagnosis vs. the existing two case definitions (CD) in the literature. Both CD require improvement with therapy to confirm the diagnosis (Shoemaker and House 2006, GAO 2008). Compliance is difficult and improvement may take months. Definitive diagnosis, via CD, requires time. 1061 consecutive patients of all ages assessed at a CIRS specialty clinic were retrospectively evaluated using CD. 371 met CIRS criteria. Cluster analysis, a series of 10 lab tests and 3 screening tests were applied to these 371 patients in 4 age groups. Clusters demonstrated high sensitivity. The number of abnormal lab tests and failing 3 screening tests each demonstrated good sensitivity. Applying Clusters with Screens or Labs demonstrated excellent diagnostic accuracy with combined age group error rates ranging from 1.24 x 10 x 10-3 to 1.10 x 10-6. These approaches were applied to the 690 patients failing CD criteria. 302 additional patients achieved one or both Clusters and Screens or Labs raising the total to 673 confirmed CIRS cases. Partnership with a pediatric practice revealed 246 of these confirmed cases were from that practice yielding a minimum pediatric prevalence of 7.01%. Adult prevalence is likely even higher. At a prevalence of ≥ 7.01%, CIRS is one of the greatest public health dilemmas in existence.

RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal peptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing

Exposure to the microbial growth in Water Damaged Buildings (WDB) can result in a chronic, multi-symptom, multisystem illness, which can last years, termed Chronic Inflammatory Response Syndrome (CIRS). Symptoms of CIRS include but are not limited to fatigue, respiratory problems, including cough, interstitial lung disease and asthma-like conditions; executive cognitive deficits, neurologic deficits, pain and gastrointestinal distress among others. There are published treatment options for CIRS patients but relatively little is known about the genomic basis of the illness. One of the most striking features of CIRS is the absence of the anti-inflammatory neuropeptides vasoactive intestinal peptide (VIP) and melanocyte stimulating hormone (MSH). Additionally, the master immune regulator, TGFb1 is abnormally high in most patients. This study surveyed 15 patients coming to a specialized clinic for CIRS with refractory symptoms, despite use of a published treatment protocol, who agreed to have their transcriptomes monitored while receiving off label, exogenous VIP nasal spray treatments. Several key immune regulators were found to be differentially expressed over the course of treatment with VIP, such as CD244, CD3D, CD48 and CD52, granzymes, defensins, and the Ikaros family of lymphoid transcription factors. In addition to down regulated innate immune functions, there appears to be an overall metabolic shift, with a down regulation of ribosomal and mitochondrial gene expression, possibly indicating a calming of components of immune responses. Understanding the need for accurate diagnosis of CIRS in order to effectively treat patients, this transcriptomic study sheds important light on new aspects of pathophysiology.

Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin.

BackgroundCiguatoxins (CTXs) are polyether marine neurotoxins found in multiple reef-fish species and are potent activators of voltage-gated sodium channels. It is estimated that up to 500,000 people annually experience acute ciguatera poisoning from consuming toxic fish and a small percentage of these victims will develop a chronic, multisymptom, multisystem illness, which can last years, termed a Chronic Inflammatory Response Syndrome (CIRS). Symptoms of ciguatera CIRS include fatigue, cognitive deficits, neurologic deficits, pain and sensitivity to light. There are few treatment options for ciguatera CIRS since little is known about its pathophysiology.MethodsThis study characterizes the transcriptional profile in whole blood of 11 patients with ciguatera-induced CIRS and 11 normal controls run in duplicate using Agilent one color whole genome microarrays. Differential expression was determined by using a combination of moderated t-test p-value and fold change (FC). Significant genes were subjected to gene ontology, principal component analysis and SVM classification. Seven significant genes found by microarray were validated by PCR.ResultsUsing a low stringency (p < 0.05 and FC > 1.4) and a high stringency (p < 0.01 and FC > 1.5) filter, the resulting gene sets of 185 and 55, respectively, showed clear separation of cases and controls by PCA as well as 100% classification accuracy by SVM, indicating that the gene profiles can separate patients from controls. PCR results of 7 genes showed a 95% correlation to microarray data. Several genes identified by microarray are important in wound healing (CD9, CD36, vWF and Factor XIII), adaptive immunity (HLA-DQB1, DQB2, IL18R1 and IL5RA) and innate immunity (GZMK, TOLLIP, SIGIRR and VIPR2), overlapping several areas shown to be disrupted in a mouse model of acute exposure to ciguatoxin. Another area of interest was differential expression of long, non-coding sequences, or lncRNA.ConclusionsDisruptions of innate and adaptive immune mechanisms were recorded at both the genomic and proteomic level. A disruption in the HLA-T cell receptor axis could indicate HLA haplotype sensitivity for this chronic syndrome, as noted in many autoimmune conditions. Taken together, these indicators of illness provide additional insights into pathophysiology and potential therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0089-x) contains supplementary material, which is available to authorized users.

Structural brain abnormalities in patients with inflammatory illness acquired following exposure to water-damaged buildings: A volumetric MRI study using NeuroQuant®

Executive cognitive and neurologic abnormalities are commonly seen in patients with a chronic inflammatory response syndrome (CIRS) acquired following exposure to the interior environment of water-damaged buildings (WDB), but a clear delineation of the physiologic or structural basis for these abnormalities has not been defined. Symptoms of affected patients routinely include headache, difficulty with recent memory, concentration, word finding, numbness, tingling, metallic taste and vertigo. Additionally, persistent proteomic abnormalities in inflammatory parameters that can alter permeability of the blood–brain barrier, such as C4a, TGFB1, MMP9 and VEGF, are notably present in cases of CIRS-WDB compared to controls, suggesting a consequent inflammatory injury to the central nervous system. Findings of gliotic areas in MRI scans in over 45% of CIRS-WDB cases compared to 5% of controls, as well as elevated lactate and depressed ratios of glutamate to glutamine, are regularly seen in MR spectroscopy of cases. This study used the volumetric software program NeuroQuant® (NQ) to determine specific brain structure volumes in consecutive patients (N=17) seen in a medical clinic specializing in inflammatory illness. Each of these patients presented for evaluation of an illness thought to be associated with exposure to WDB, and received an MRI that was evaluated by NQ. When compared to those of a medical control group (N=18), statistically significant differences in brain structure proportions were seen for patients in both hemispheres of two of the eleven brain regions analyzed; atrophy of the caudate nucleus and enlargement of the pallidum. In addition, the left amygdala and right forebrain were also enlarged. These volumetric abnormalities, in conjunction with concurrent abnormalities in inflammatory markers, suggest a model for structural brain injury in “mold illness” based on increased permeability of the blood–brain barrier due to chronic, systemic inflammation.

Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings

Exposure in water-damaged buildings (WDB) to airborne bioaerosols including metabolic products of toxigenic fungi, bacteria and actinomycetes; and inflammagens, can lead to a persistent innate immune inflammatory illness. This illness, termed a chronic inflammatory response syndrome (CIRS-WDB), is systemic with symptoms acquired from multiple organ systems. Treatment of CIRS-WDB has progressed rapidly as a better understanding of the inflammatory pathophysiology has led to targeted, sequential therapies. The fundamental basis of uncontrolled innate immune responses, the humoral deficiency of regulatory neuropeptides melanocyte stimulating hormone (MSH) or vasoactive intestinal polypeptide (VIP), seen in over 98% of pa tients, has not consistently responded to any treatment modality. Use of replacement VIP has been attempted anecdotally; VIP replacement therapies show promise in short term studies but longer therapies have not been attempted. Here we report an open label trial of 20 patients with refractory CIRS-WDB illness who took replacement VIP in a nasal spray for at least 18 months with confirmation of durable efficacy and absence of significant side effects. These 20 patients were similar in symptoms and lab find- ings to three previously published cohorts in- volving 1829 patients and 169 controls. Dosage of VIP was titrated downwards from four to zero doses a day to determine minimum effective dose, and retitrated upwards for maximum improvement over time. The trial showed that VIP therapy safely 1) reduced refractory symptoms to equal controls; 2) corrected inflammatory parameters C4a, TGF beta-1, VEGF, MMP9; 3) corrected estradiol, testosterone and 25-OH Vitamin D; 4) returned pulmonary artery systolic pressure (PASP) during exercise to normal; and 5) enhanced quality of life in 100% of trial patients. Subsequent identification of correction of T-regulatory cell levels supports the potential role of VIP in both innate and adaptive immune function.