The Mold Research Committee presents our position statement on the current state of the science regarding human health effects acquired following exposure to the multiple microbes and microbial contaminants and their metabolites found in the interior environment of water-damaged buildings (WDB). These contaminants include but are not limited to fungi, bacteria, actinomycetes, and mycobacteria and their toxins; as well as inflammagens from fragments of fungal structures; and beta glucans, mannans, hemolysins, proteinases, spirocyclic drimanes and microbial volatile organic compounds (VOCs).
Exposure to these WDB environments can cause a readily identifiable illness syndrome characterized by specific metabolic disturbances stemming from lack of neuropeptide control of host inflammatory responses, genetic susceptibility and abnormal downstream inflammatory parameters that not only define the illness but also provide the academic basis for sequential therapeutic interventions.
Our findings are focused on abnormal physiologic changes in health, documented by health care professionals who are actively involved with case management of those made ill from exposure in WDB. The current body of literature describing the multiple adverse health effects acquired following exposure to the interior environments of WDB is extensive. The physiology unveiled by such literature mirrors the physiologic findings in chronic inflammatory response syndromes. The literature we cite throughout this document supports the concept that exposure to the interior environment of WDB creates abnormal inflammatory responses that are both biomarkers for the presence of the illness and guides for therapy. We note that the readily recognized abnormalities in host immune responses are initiated both by (i) the adverse effects of toxins such as mycotoxins, endotoxins and toxins made by actinomycetes; and (ii) effects of inflammagens. As the many possible sources of compounds that are found in WDB can each lead to the diversity of host responses seen, it is impossible to distinguish a unique source of such abnormal immune responses in patients with illness acquired following exposure to the interior environment of WDB.
Several consensus statements have been composed in the past decade. Yet none have included (a) assessments made by physicians involved with diagnosis and treatment of these adverse health effects; (b) academic papers written by physicians reporting both baseline and treatment data on the human illness; (c) reporting of results from published studies using treatment protocols or studies on prospective human or animal experimentation; (d) reporting based on objective parameters found in affected patients; and (e) clinical status after interventions. Despite these substantial shortcomings of pertinent information, these prior consensus statements are being used (i) in legal matters to report the state of human health effects from exposure in WDB and (ii) to serve as the basis for public health policy.
A more current reporting of accepted science that is based on literature review and includes, but is not limited to, experience of actual treating physicians is the foundation for our consensus opinion.
As identified by the US Government Accountability Office (GAO, 2008) report and the World Health Organization report (WHO, 2009), there are many compounds, both toxigens and inflammagens, present in the indoor air of a WDB that have been identified within the complex mixture found in the air and in the dust of the interior environments of WDB. Further, there is clear data showing that each of these compounds can initiate an inflammatory host response such that no single compound can be identified as the sole cause of the inflammatory responses seen in affected patients. Since many sources of inflammatory stimulus exist, some of which are synergistic, and no single causative agent within the WDB can be deemed to be solely responsible for the symptoms exhibited, the sole causative agent becomes the interior environment of the WDB itself. It is our consensus opinion that this syndrome acquired after exposure to water damaged buildings with evidence of amplification of microbial growth shall be referred to as, “Chronic Inflammatory Response Syndrome acquired following exposure to the interior environment of Water-Damaged Buildings (CIRS-WDB).”
We note in recent years a dramatic increase in published studies from the private sector, US governmental agencies and international health agencies with a focus on various and diverse human health effects acquired following exposure to the interior environment of WDB. These substantive papers support the understanding that:
(1) CIRS-WDB is a multisystem, multisymptom illness acquired following exposure to the interior environment of WDB and it exists as a recognizable syndrome. When defined by i) exposure; ii) symptom evaluation; and iii) epidemiologic similarities between studies of similar hosts and similar exposures, CIRS-WDB is both identifiable and treatable. A proven and consistent pattern of symptoms is demonstrated among published research findings involving both animal and human studies.
(2) CIRS-WDB is identified as immunologic in origin, with differential inflammatory responses seen according to (i) genetic susceptibility and (ii) unique aspects of host innate immune responses. Direct effects of microbial toxins, particularly mycotoxins, in pathogenesis are recognized to act synergistically with those toxins made by actinomycetes, gram negative bacteria, and possibly mycobacteria causing the effects shown in CIRS-WDB. Cellular immunity affecting T-cells and Th-17 plays a role in CIRS-WDB, as do immunologic changes activated by both toxins and inflammagens that are found in the interior environment of WDB. It is scientifically demonstrated that innate immune host responses are similar in their appearance following human exposure to many of the toxins and inflammagens that are simultaneously found to be present inside WDB. Documenting those immune abnormalities will not (and cannot) implicate any one, isolated, specific source. Given the current scientific information and readily available physiologic abnormalities that patients with CIRS-WDB experience, we must expand our assessment beyond the known effects of simple, individual toxins when establishing public health policy and private sector physician treatment protocols.
(3) CIRS-WDB consistently involves (but is not limited to) abnormalities in levels of regulatory neuropeptides MSH and VIP; pro-inflammatory cytokines IL-1B, IL-6, 8, 12, 13 and others; split products of complement activation, especially C4a; responses of hypoxia inducible factor, including but not limited to vascular endothelial growth factor (VEGF), erythropoietin and transforming growth factor beta-1 (TGF B-1); and cellular immunity. This type of cellular immunity includes effects on T-regulatory cells; Th-17 immunity impacting IL-17 and IL-23 functions; and auto-immunity, primarily anti- gliadin and anti-cardiolipin antibodies. Additional problems commonly seen are hormonal dysregulation involving corticosteroids (identified when ACTH and cortisol measured simultaneously), regulation of body osmolality (identified when ADH and osmolality measured simultaneously) and androgens; and coagulation factors, especially those represented by von Willebrand’s profile. These laboratory findings are typical of those seen in other forms of CIRS.
(4) Treatment of human illness that is acquired following exposure to the interior environment of WDB is necessarily sequential. No single intervention is likely to correct all the underlying abnormalities in the inflammatory responses. Many approaches to treatment of CIRS-WDB are in current use. To date there has been a paucity of academic papers published on the entire selection of therapies used with success by individual practitioners.
(5) Taken as a whole, CIRS-WDB is a chronic inflammatory response syndrome, resulting from exposure to WDB and is readily identified by current methods of clinical diagnoses, with thorough differential diagnosis the key to linking the abnormal physiology seen to the cause of the illness. This process of diagnosis is supported by (i) identification of unique subsets (“clusters”) of symptoms found in epidemiologic cohorts of affected patients; (ii) identification of unique groupings of biomarkers, such as genetic markers, neuropeptides, inflammatory markers, and autoimmune findings. The required tools of differential diagnosis include showing what patients don’t have as well. Many tests commonly used in day-to-day medical practice, i.e., sedimentation rate, c-reactive protein, lipid profiles, thyroid studies, immunoglobulin studies (including IgE), metabolic profiles and complete blood counts are nearly always normal in CIRS-WDB. They are therefore of little to no value other than a pertinent negative finding in diagnosis of CIRS- WDB serving to rule out other potential causes of chronic symptoms. Regained health in response to sequential comprehensive therapy, published previously, that is founded on the understanding that there is a multiplicity of causative elements is an additional element that affirms the importance of differential diagnosis on an ongoing basis.
(6) We recognize that chronic and recurring systemic inflammation underlies the illness parameters of symptoms, laboratory findings, and neurotoxicological studies seen in the patients of clinical studies. These inflammatory processes mirror the experimental findings in animal models. We note that patients with CIRS-WDB are often given incorrect diagnoses such as depression, stress, allergy, fibromyalgia, Post Traumatic Stress Disorder, and somatization. Those conditions when actually present will not improve with therapies employed in CIRS-WDB. The regained health and improvement of objective laboratory parameters following appropriate treatments aimed at CIRS-WDB demonstrate an additional clinical basis to distinguish CIRS-WDB from other diagnoses. This response to targeted therapy adds weight to the body of evidence that there is a multiplicity of toxigens and inflammagens that are causing a treatable chronic, recurring illness.
(7) CIRS-WDB is acquired primarily from inhalation of microbial products that are contaminants found in the complex mixture of the interior environment of WDB. We are aware that serious health problems, including fatalities, arising from ingesting kilograms of microbial-contaminated foods in developing countries are documented. Dermal contact and ingestion of settled WDB contaminants might theoretically contribute to the exposure burden of CIRS-WDB, but in reality, the quantities necessary to be harmful are unlikely to apply to daily life of patients in an indoor environment.
(8) Re-exposure of previously affected patients will bring about immunological host responses that are enhanced in their rapidity of onset and magnitude, such that these patients are “sicker, quicker.” Without protective immunity being demonstrated either by laboratory methods or clinically, and even though they may have been treated adequately, those with prior CIRS-WDB must avoid contact with the interior environment of any WDB until such time as their abnormal reactivity to the multiplicity of causative agents found in the WDB can be either reduced or restored to pre-illness states. For some patients, such complete restoration is unattainable. As the state of current science dictates, those with especially severe reactivity to the interior of WDB must avoid re- exposures for the remainder of their lives to sustain their individual level of optimum health.
The study on acquisition of human illness following exposure to the interior environment of WDB includes infectious disease. The incidence of filamentous fungal infection is rising rapidly in both immuno-compromised and immuno-competent patients. There is a robust literature on fungal sinusitis leading to chronic rhino-sinusitis based on inflammatory changes induced by organisms such as Alternaria, Aspergillus, Cladosporium and Penicillium. Further, the role of fungal organisms in acquired immune illnesses, such as allergy, asthma, and hypersensitivity pneumonitis is also well described. This position statement accepts that these facts have been confirmed by a robust literature and no additional comment on these illnesses is indicated herein.
The weight of evidence is also overwhelming that respiratory infections, dermal infections, sinus-based inflammation, hypersensitivity pneumonitis and allergy are well understood aspects of illness that are each being adequately addressed in public policy and rapidly advancing physician treatment protocols.
This report will focus on the role of systemic inflammation and neurotoxicity as cardinal elements of CIRS-WDB.
The diverse groups of microbes found in WDB, including fungi, bacteria, actinomycetes and mycobacteria individually and collectively manufacture toxins
(including mycotoxins) and inflammagens on an ongoing basis. These compounds can individually and collectively activate innate immune inflammatory responses enhanced by their synergistic interaction within WDB. Current accepted science and diverse areas of research, individually and collectively, demonstrate the vast significance of the multiple microbial contributors found within WDB to human chronic and systemic inflammation resulting from the compounding synergy of the exposure. Abundant literature demonstrates (i) direct adverse effects of the toxins and inflammagens on animals and humans; and (ii) direct inflammatory effects of the antigens on animals and humans. Response to encompassing treatment for the complex mixture of exposure in the form of regained health validates the growing body of literature that the mixture itself is the underlying causative agent.
Current public health research needs include (i) creation of an HIPAA compliant, de-identified, national data base of patients identified by practitioners that can be accessed by collaborating researchers in the private sector and government agencies; (ii) development of a standard protocol for therapy based on the results of collaboration of actual practicing physicians; (iii) search for newer therapies based on genomics testing. Ongoing illness acquisition creates an opportunity for scientific advancements in diagnosis, therapy and prevention. Assessments of differential gene activation (genomics), with a link to assessment of compounds found in blood (proteomics), coupled with positive results of therapies based on these assessments show great promise in this field. Effective treatments in and of themselves serve as evidence of the cause of illness.
A method of disseminating current, ongoing and accurate information to medical teaching facilities regarding these illnesses and appropriate treatments must be established as a matter of public health policy.
This document describes the current state of the science behind CIRS-WDB provided from the perspective of the treating physician. It is our position that the extensive collaboration among individuals and organizations with direct experience with CIRS- WDB has provided a scientific basis to bring about a change in approach to evaluation and treatment of patients with exposure to the interior environment of WDB. We are grateful for the opportunity to have reviewed the literature and received feedback from academic researchers, practicing clinicians and especially patients commenting on WDB over the years. All written comments in this statement, however, come from the authors.
Disclaimer: This paper was developed and written by an ad hoc group which included the identified authors. The authors' opinions, contributions and conclusions were arrived at independently and do not necessarily represent those of any group, organization, entity, or activity with which they may otherwise be involved.
Policy Holders of America: Research Committee Report on Diagnosis and Treatment of Chronic Inflammatory Response Syndrome Caused by Exposure to the Interior Environment of Water-Damaged Buildings (2010)