Mixed mold mycotoxicosis

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November 17, 2006 Mixed mold mycotoxicosis: immunological changes

in humans following exposure in water-damaged buildings Volume 1

Issue 244

Pure Air Control Services

http://www.imakenews.com/pureaircontrols/e_article000699605.cfm?

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Mixed mold mycotoxicosis: immunological changes in humans following

exposure in water-damaged buildings

by R. Gray , Pubmed.gov

THE POTENTIAL HARMFUL EFFECTS of exposure to mixed molds in

inhabited buildings were recognized in early Biblical times. In the

Old Testament, (1) Leviticus put forth a detailed protocol for the

remediation of mold-contaminated structures, including the

destruction of dwellings and personal belongings if remediation

failed. Today, it is recognized that water intrusion into buildings

leads to amplification of molds, (2-7) often requiring remediation.

Potentially toxic and immunogenic byproducts of fungi and molds

include mycotoxins; 1,3-alpha-D-glucans; extracellular

polysaccharides (EPS); enzymes; and solvents. (8-19) Occupants of

affected structures can develop symptoms in multiple organ systems,

including the upper and lower respiratory systems, central and

peripheral nervous systems, skin, gastrointestinal tract, urinary

tract, connective tissue, and the musculoskeletal system. (3,6,20-

26) Human illness can result from 1 or all of the following: mycotic

infections, or mycoses (27-32); immunoglobulin (Ig)E-mediated

sensitivity and asthma (33-35); hypersensitivity pneumonitis and

related inflammatory pulmonary diseases (36-39); cytotoxicity (40-

44); immune suppression/modulation (45-47); mitochondrial toxicity

(48-51); carcinogenicity (52,53); nephrotoxicity (54); and the

formation of nuclear and mitochondrial deoxyribonucleic acid

adducts. (55-58) Finally, in the infectious state, molds secrete

exodigestive enzymes (EES) that cause tissue destruction,

angioinvasion, thrombosis, infarction, and other manifestations of

mycosis. (27,59-63)

We have evaluated and treated more than 209 patients who presented

with multiorgan system symptoms resulting from exposure to molds in

their homes, schools, or workplaces. Recognizing the complexity of

health problems associated with mixed mold exposure, we undertook a

multicenter investigation of patients with chronic health complaints

attributed to exposure to mixed colonies of indoor fungi and molds.

We employed detailed health and environmental history-gathering

questionnaires, environmental monitoring data, physical examination,

pulmonary function testing protocols, routine clinical chemistries,

neurocognitive testing, and 16-channel quantitative

electroencephalograms (QEEGs). In addition, we measured lymphocyte

phenotypic markers (on T, B, and natural killer [NK] cells),

antibodies to molds and mycotoxins, neuronal antigen antibodies, and

leukocyte apoptosis. Herein we present data on symptoms, alterations

in peripheral lymphocyte phenotypes, and autoantibodies observed in

adult patients. Future communications will detail pulmonary

abnormalities, antibodies to molds and mycotoxins, and

neurobehavioral and QEEG changes observed in these patients, and

will report the statistically significant multisystem correlations

observed. Currently, we refer to the illness of these individuals as

a " mixed mold mycotoxicosis " involving the immune system, the lungs,

and the central and peripheral nervous systems, as well as a

generalized inflammatory and irritant response to exposure to

spores, hyphal fragments, mycotoxins, solvents, and other byproducts

(e.g., EPS and EES).

Materials and Method

Patients. Two hundred nine adult patients with a history of exposure

to mixed colonies of molds resulting from structural water intrusion

in residential, workplace, or school-based settings were included in

this study. Adults were considered to be males older than 12 yr of

age and females older than 11 yr of age. The patients, 42.7 [+ or -]

16 yr of age (mean [+ or -] standard deviation), were evaluated from

early 1994 through June 2003 and comprised 126 females (43.1 [+ or -

] 15.2 yr) and 83 males (42.3 [+ or -] 17.1 yr). Patients involved

in litigation numbered 71 (40.1 [+ or -] 16.7 yr) and nonlitigants

numbered 1,368 (44.5 [+ or -] 15.3 yr). Litigation status was

uncertain for 4 adult patients. Females under age 11 and males under

age 12 were not considered as adults with respect to immune

parameters and symptoms, and were therefore excluded from the data

presented in this report, although many of these children were

clinically ill.

Questionnaires. We asked the patients to complete 2 self-

administered questionnaires developed by 1 of the authors (MRG),

seeking information from the following areas of concern: (a) medical

history, ( occupational and general environmental history, ©

lifestyle and habits, and (d) a review of systems. The symptom

frequency review entailed questions on 58 specific symptoms. In

accordance with methods provided by Ziem, (64) we report on the 38

most frequently experienced symptoms. In brief, the symptoms were

scored by the patient as occurring: 1 = daily to almost daily, 2 =

several times a week, 3 = weekly, 4 = several times a month, 5 =

monthly, 6 = rarely, if ever (considered a negative response), and 7

= unsure. For statistical purposes, the scores were reversed to

reflect the ascending frequency of the reported symptoms when

tabulated. The mean value and standard deviation for the frequency

score for each symptom were determined for the whole group, for

males alone, for females alone, and for litigant and nonlitigant

patients.

Controls for the historical questionnaires were obtained by auditing

responses to the same questionnaires administered to 28 consecutive

adult patients presenting to our general medical clinic for

initial " database " comprehensive physical examinations. The results

from the first 28 consecutive Ziem symptom audits were used as

controls for comparison with the mold-exposed patients' responses.

Physical examinations. Each patient underwent a thorough physical

examination, performed by MRG. A standardized form for entering

relevant physical findings was used to facilitate uniformity of the

exam and recording of findings. Clinical laboratory samples were

collected by certified phlebotomists at the community hospital

located adjacent to the clinic in which the exams were conducted.

All samples were either processed at the local hospital's American

College of Pathology (ACP)-accredited clinical laboratory

facilities, or forwarded to the appropriate ACP-accredited reference

laboratories. Guidelines of the U.S. Centers for Disease Control and

Prevention (CDC) were followed for the handling of all lymphocyte

tissue cultures tested.

Clinical laboratory tests. The following standard diagnostic

laboratory tests were performed by Clinical Laboratory Improvement

Amendment and

Medicare-certified national reference and specialty laboratories:

complete blood count (CBC); comprehensive metabolic panel (CMP);

urinalysis; urine culture (if indicated); stool (occult blood,

fungal, and mold) culture; erythrocyte sedimentation rate (ESR); C-

reactive protein (CRP); thyroid profile (thyroid-stimulating hormone

[TSH], free T4, and free T3); antinuclear autoantibodies (ANA); and

rheumatoid factor (RF). All clinical laboratory tests were compared

with the laboratories' published expected reference ranges,

according to generally accepted procedures and practices. Serology

was performed for the following herpes viruses: herpes I, II, VI,

and varicella; Epstein Barr; and cytomegalovirus.

Peripheral lymphocyte phenotype determination. Whole venous blood

was sent in laboratory-provided silicon-treated, sodium-heparinized

glass e-vac tubes by overnight courier to Antibody Assay

Laboratories (AAL), Santa Ana, California, following procedures

prescribed by the lab to ensure that the cells were viable in

accordance with CDC requirements. AAL performed mitogen tests with

phytohemagglutinin (PHA), and with pokeweed and concanavalin A (Con

A). Tuberculin purified protein derivative (PPD), tetanus toxoid,

and Candida albicans mannoprotein were used as control mitogens. Any

blood samples that failed to meet CDC requirements were discarded

and redrawn. Quality assurance was performed using negative and

positive controls. Mononuclear cells were isolated using

Ficollisopaque density gradient centrifugation. (65) Not all of the

209 adults had all of the tests performed; therefore, n varies

slightly for some of the parameters, as noted in the relevant tables.

Peripheral white blood cells (i.e., total white cell count and total

lymphocyte count) were enumerated by AAL. in addition, the

percentages of the following lymphocyte phenotypes were determined:

B cells (CD20+); T cells (CD3+); T-helper (CD4+) and T-suppressor

(CD8+) cells; interleukin (IL)-2 receptor-bearing T cells

(CD5+CD25+); activated T cells (CD3+CD26+ and CD3+HLA-DR+);

activated T-suppressor cells (CD8+CD38+ and CD8+HLA-DR+); complement

receptor-bearing T-suppressor cells (CD8+CD11b+); and NK cells (CD3-

CD16+CD56+). Monoclonal antibodies to CD antigens were purchased

from Becton Dickinson (Los Angeles, California), except for CD26

(Beckman Coulter [Miami, Florida]). Flow cytometry was performed

using a Coulter Epic XL MCL flow cytometer (Beckman Coulter), in

accordance with the manufacturer's instructions.

Mitogenesis. Mitogenesis responses to PHA and Con A were evaluated

on peripheral lymphocytes of all 209 patients, using the

colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-

diphenyltetrazolium bromide] assay. (66) Viable cells activate the

MTT, which is measured colormetrically at 570 nm with an EAR 400

microplate reader (SLT Labinstruments [salzburg, Austria]).

Mononuclear cells were isolated and suspended in 0.1 ml RPMI 1640

medium at [10.sup.6] cells/ml. They were cultured in RPMI 1640

supplemented with 10% fetal calf serum and antibiotics (i.e.,

penicillin and streptomycin) (Irvine Scientific [santa Ana,

California]). Cells from each individual were tested at 3 different

concentrations of the mitogens for optimum stimulation. The tests

were performed in triplicate and were reported as the average of 3

concentrations.

NK cell function testing. NK cell function was evaluated by AAL,

using K562 cells (immortal cell line) (Coriell Institute for Medical

Research [Camden, New Jersey]) as target cells. In brief, the

patient's NK cells were incubated with K562 cells and a fluorescein

derivative that is hydrolyzed by live K562 cells. The percentage of

cells that retained the dye following killing was measured with an

Epics Flow cytometer. The result is expressed as a percentage of

kill.

Autoantibody determinations. Autoantibodies against smooth muscle

(ASM), brush border (ABB), parietal cells (APC), mitochondria

(AMIT), and nucleic acids/nucleoproteins (ANA) were determined with

standard indirect immunofluoresence. (67,68) The controls for ASM

and ANA were reported previously. (69) Immunoglobulin (Ig)A, IgM,

and IgG antibodies to myelin sheath were detected with frozen monkey

spinal cord (CNS) and sciatic nerve (PNS) as substrates, employing

an indirect immunofluorescent technique for which antihuman

immunoglobulin conjugated to fluorescein was used. (68,69) The

controls for antimyelin antibody testing consisted of 32

chiropractic students (20 males and 12 females), 29 + 9 yr of age,

as reported previously. (69) Antibodies against thyroglobulin and

thyroid peroxidase were measured by automated assays performed using

chemoluminescence on DPC Immulite 2000 (Diagnostic Products Corp.

[Los Angeles, California]), with DPC reagents.

Statistical analysis. All statistical analyses were performed using

Statistica 10.0 for Windows (StatSoft, Inc. [Tulsa, Oklahoma]).

Statistical tests included basic descriptive statistics, critical t

tests, critical z tests, odds ratios, and analysis of variance

(ANOVA).

Results

Physical examinations and routine diagnostic tests. Physical exams

revealed (a) nasal mucosal hyperproliferation and inflammatory

changes, ( relative alopecia, © cough and wheezing, (d) frequent

balance problems (Romberg positive), and (e) increased dermal

fluorescence on ultraviolet inspection. The CBC, CMP, ESR, CRP, RF,

thyroid panel, urine analyses, urine cultures, and stool analyses

and stool cultures did not vary from expected values, except for a

low mean total bilirubin of 0.40 (reference range: 0.4-10).

Serology tests for all viruses were negative for either active or

reactivation infections. Lymphadenopathy indicative of acute or

reactivation herpes viral infections was absent in all cases.

Symptoms. Initially, litigants were compared with nonlitigants for

each symptom. Critical t tests for each symptom revealed no

difference between the 2 groups (data not shown). The responses of

males vs. females for each symptom were also compared (data not

shown). Critical t tests showed that females had a greater frequency

of the following symptoms: excessive fatigue, headache, memory

problems, " spaciness " /disorientation, lightheadedness, slurred

speech, weak voice, spasms, coordination problems, vision changes,

rash, cold intolerance, heat intolerance, chest discomfort,

excessive thirst, swallowing problems, flushing skin, rapid pulse,

palpitations, bruising, and swelling ankles.

Results for males and females were grouped together, and the

frequency of each symptom expressed by the mold-exposed patients was

compared with frequencies reported by the 28 controls (Table 1). As

indicated in the table, exposed patients had an increased frequency

of expression for the following symptoms: excessive fatigue,

headache, nasal symptoms, memory problems, spaciness and

disorientation, sinus discomfort, coughing, watery eyes, throat

discomfort, slurred speech, lightheadedness, dizziness, weakness,

bloating, insomnia, spasms, coordination problems, vision changes,

rash, chest tightness, and wheezing.

Peripheral lymphocytes. The percentage of lymphocyte phenotypes

measured in the peripheral blood of the patients was compared for

litigants vs. nonlitigants. Critical t tests revealed no significant

difference between the 2 groups for each lymphocyte phenotype (data

not shown). Table 2 summarizes our observations following a

comparison of males vs. females with respect to each phenotype.

Critical t tests revealed no difference between males and females.

As a result of these observations, all data were grouped into

an " all patients " category. The mean percentages of total

lymphocytes for all patients exceeded the expected laboratory ranges

(95% confidence intervals [CIs]). The percentages of complement-

receptor-bearing suppressor cells and NK cells were within expected

laboratory ranges, but were on the low side of the 95% CI for each

cell type. The percentages Of individuals with results outside of

the expected laboratory ranges for each phenotype also are presented

in Table 2.

Mitogenesis. The results of mitogenic stimulation with PHA and Con A

are summarized in Table 2, along with laboratory expected ranges at

95% CI. The average mitogen responses to PHA and Con A were on the

low side of the expected ranges. The percentages of all patients

with mitogenesis below the expected ranges were 26.2% for PHA and

5.9% for Con A.

NK cell activity. NK cell (CD3-CD16+CD56+) activity was normal for

all study subjects.

Autoantibodies. IgG, IgM, and IgA antimyelin antibodies against CNS

and PNS myelin were compared for litigants vs. nonlitigants and for

males vs. females. Critical z tests revealed no difference between

males and females (data not shown). Similarly, no difference was

observed in myelin autoantibodies when litigants were compared with

nonlitigants, except for PNS IgA (< 0.05 and > 0.02, respectively).

However, given the number of tests applied (6), this difference was

considered insignificant. Thus, antimyelin antibodies were grouped

for all patients and compared with controls (Table 3). Observations

for antibodies (IgG, IgM, and IgA) against neurofilament antigen in

the mold-exposed patients, compared with controls, are presented in

Table 4.

The percentages of patients with increased ANA and ASM

autoantibodies were compared for males vs. females and for litigants

vs. nonlitigants (data not shown). The percentages of males and

females with elevated ANA autoantibodies were 25.9% and 31.7%,

respectively, and with elevated ASM autoantibodies were 34.6% and

30.3%, respectively. Similar values for litigants vs. nonlitigants

were 27.5% and 30.6%, respectively, for ANA, and 27.5% and 25%,

respectively, for ASM. Critical z tests revealed no differences in

the percentages for males vs. females or for litigants vs.

nonlitigants. Results for male and female patients were then

combined and compared with the controls on the basis of odds ratios.

The controls' values for ANA and ASM were 1.8% and 14.6%,

respectively (n = 55). The ORs at 95% CI for ANA and ASM were 11.00

and 2.58, respectively, both being significant (Table 5).

Discussion

We made the following observations with respect to the 38 most

frequently reported symptoms in our study (Table 1): (a) The mixed-

mold-exposed patients expressed symptoms at a greater frequency than

the controls; ( Exposure to mixed molds caused significant

morbidity, leading affected individuals to seek medical assistance;

© The difference in symptoms between litigants and nonlitigants

was not significant; (d) A statistically significant increase was

seen in the frequency of symptoms among women compared with men; and

(e) The most frequently reported symptoms were neurological (i.e.,

headache, memory difficulty, slurred speech, spaciness,

lightheadedness, dizziness, weakness, coordination problems, and

changes in vision), state of well-being (excessive fatigue,

bloating, rash, discomfort, and muscle spasms), and ophthalmic and

upper/lower respiratory (nasal symptoms, sinus discomfort, coughing,

watery eyes, throat discomfort, weak voice, chest tightness, and

wheezing). Overall, the symptom complex we observed was consistent

with observations reported by others. (3,6,12,20-26) The

preponderance of symptoms involving the CNS and state of well-being

are reflective of injury to the CNS, as reported by Kilburn25 and

Anyanwu et al. (26) The increased frequency of symptoms in females

is consistent with their greater representation in several other

clinical conditions (e.g., fibromyalgia and related disorders,

(70,71) autoimmune diseases, (72-74) and exposure to molds (6)). The

greater representation of females with respect to symptoms may

suggest that xenobiotics, estrogenic solvents, and/or mycoestrogens

in their mold-contaminated environs play a role in their illnesses.

(75,76) And, finally, the absence of a difference in symptoms

between litigants and nonlitigants supports the assertion that

individuals who exercise their legal rights through litigation do

not exaggerate their symptoms, nor are they prone to malingering.

(77-79)

The lymphocytes measured in our mold-exposed patients demonstrated

increased expression of various activation markers when compared

with expected laboratory ranges (Table 2), as follows: CD3+CD26+

(activated T cell), 91.2% of patients; CD3+HLA-DR+ (class II major

histocompatibility molecule [MHC] and marker of activation), 95.1%;

CD5+CD25+ (IL-2 receptor-bearing T cell), 68.9%; CD20+ (mature

antigen-producing B cells), 75.6%; and CD8+HLA-DR+, 62%. In light of

these observations, the functional role of each of these activation

markers should be considered. Expression of CD26, reflecting

cellular activation, is diagnostic of (or prognostic for) a variety

of nonallergic clinical conditions (e.g., autoimmune disorders,

various tumors, hematological malignancies, and inflammatory

conditions) (80) and is also increased in individuals ill from

exposure to other xenobiotics. (69,81) HLA-DR, a class II MHC,

recognizes either allogenic (self) MHC molecules or foreign protein,

which means that it has recognized foreign antigens bound to self

class II MHC molecules. (82) HLA-DR is expressed on immune cells in

inflammationy, (83) asthma, (84) autoimmune diseases, (85) and

neurological disorders. (86) CD25 is considered to be a natural

regulatory marker of T cells and plays a major role in IL-10

production and in controlling the immune response to self and

foreign antigens. (87,88) CD20 ( cells produce antibodies and are

the source of immunoglobulins directed against foreign and self-

antigens; they also play a central role in autoimmunity. Currently,

these cells are the focus of anti-CD20 compounds directed toward

immunotherapy in B-cell malignancies and autoimmune diseases.

(89,90) Collectively, the increased presence of activated T cells,

and increased 13 cells, implies a proinflammatory state. Moreover,

the reduction of CD8+CD11b+ (complement-receptor-bearing suppressor)

cells is commensurate with increased expression of activation

markers. This level of overexpression of activation markers is

related to dramatic antigenic stimulation in patients with a history

of mixed mold exposure. In addition, the increase in HLA-DR+

expression reflects the presence of increased autoimmunity. In the

aggregate, this situation represents a proinflammatory, immune toxic

state.

The effects of mold exposure on the human immune system have been

reported previously. Johanning et al. (6) found a significant

decrease in CD3 T cells, along with a slight decrease in mitogenesis

to both Con A and PHA, following mold exposure in a water-damaged

building. However, activation markers were not studied. In children

exposed to high levels of residential mold contamination (vs.

control children from a low-contamination environment) there was a

significant increase in CD3CD45RO (memory T cell) expression, with a

concomitant decrease in the helper/suppressor ratio that persisted

for 12 mo. (91) Finally, animal feed production workers exposed to

mixed mycotoxins, with aflatoxin concentrations of 1.55 to 6.25 ng/

[m.sup.3], had an increase in tumor necrosis factor-alpha (TNF-

[alpha]). (92) In addition, the animal feed workers had a shift in

lactic dehydrogenase (LDH) isoenzymes, with a significant increase

in LDH1 (spleen) and LDH3 (lungs). These observations corroborate

the immune changes reported herein and support the conclusion that

exposure to mixed molds and their byproducts causes the expression

of immune markers of activation, as well as at least 1 inflammatory

cytokine--TNF-[alpha]. Furthermore, the decreases we observed in the

percentage of peripheral blood NK cells and response to PHA further

support the concept that immune dysregulation is occurring, and

represents a " promoter " state for the expression and development of

malignancies.

The subjects in our study exhibited a high risk for producing

autoantibodies to nuclei, smooth muscle, CNS and PNS myelin, and

neurofilament (Tables 3-5). The presence of autoantibodies ANA, ASM,

and CNS and PNS myelin has been reported following exposure to other

xenobiotics. (69,81,93) High titers of ANA are associated with

various types of connective tissue injury and/or connective tissue

diseases. (94) ASM antibodies are nonspecific, occurring in a

variety diseases, including autoimmune hepatitis, (95,96) vascular

events, (97) rheumatoid arthritis, (98) Mycoplasma pneumoniae, (99)

bronchial suppuration, (100) autoimmunity, (101) and asthmatic

bronchitis (102) The antimyelin autoantibodies--initially identified

in Guillian-Barre syndrome (68)--are now recognized to represent

several different neuronal antigens, including various gangliosides,

tubulin, chondroitin sulfate, and sulfatide, found in neuropathies

(103-108) Thus, we have recently incorporated neuron neurofilament

antigen into our protocol and have found increased neurofilament

antibodies in these patients (Table 5). In summary, individuals

exposed to mixed molds produce several different autoantibodies.

Work is in progress to determine the significance of these

antibodies in conditions such as lupus erythematosus, autoimmune

neuropathy, and a multiple-sclerosis-type syndrome.

A systemic shift in the Th1/Th2 balance to a Th2 immune profile

(e.g., TNF-[alpha], IL-4, and IL-10 cytokines) has been reported for

Gulf War veterans and chronic fatigue patients, as well as in asthma

and lupus erythematosus. (109-112) Shift to Th2 profile leads to an

increase in various diseases that are exacerbated by decreased Th1.

Therefore, future research into immunological alterations should

include testing for Th2 profile and cytokines, particularly because

CD5+CD25+ (IL-2) and multiple autoantibodies were present in the

patients in our study.

The single limitation of our study needs to be addressed. The immune

profiles (Table 3) were compared with expected laboratory ranges,

rather than with healthy control subjects. However, the absence of

controls should not be considered excessively limiting in the

evaluation of immune profiles of these mold-exposed patients. First,

the percentage of individuals with increased activation expression

on T cells greatly exceeded the maximum expected range as published

by the testing laboratory For example, the maximum percentages of

total recorded lymphocytes for controls in regard to CD5+CD25+,

CD3+CD26+, CD3+HLA-DR+, CD8+ CD38+, and CD8+HLA-DR+ were 8%, 30%,

7%, 8%, and 3%, respectively. The percentages of mold-exposed

patients that exceeded these values were 68.9%, 91.2%, 95.1%, 56.6%,

and 62.0%, respectively, for each of the phenotypes. In addition,

the mean percentages for CD20+, CD5+CD25+, CD3+CD26+, CD3+HLA-DR+,

CD8+CD38+, and CD8+HLA-DR+ cell counts exceeded the laboratory's 95%

CI, which further supports the preceding observation. This

represents a greatly increased frequency of activation markers when

compared with maximum expected ranges. Second, expression of the

autoantibodies ANA, ASM, CNS and PNS myelin, and neurofilament was

significant in the mold-exposed patients vs. controls. Thus, the

presence of autoantibodies is commensurate with immune activation,

and, finally, the antineuronal antigen (neurofilament)-specific

antibodies are strongly associated with a wide array of degenerative

neurological disorders of undetermined origin.

In this study, we have shown that individuals exposed to mixed

colonies of molds in water-damaged buildings have several

abnormalities among their immune parameters. These include (a)

immune activation markers, with elevated CD26+, HLR-DR+, CD25+, and

CD38+ phenotypes in the peripheral blood; ( the presence of

autoantibodies (ANA, ASM, CNS and PNS myelin, and neurofilament);

and © decreased complement-receptor-bearing T-suppressor (CD11b+)

cells. Future research should be directed toward clarifying the

Thl/Th2 profile, and accompanying cytokines, in humans affected

adversely by mixed mold exposure. Also, efforts should be made to

correlate the abnormal immune parameters with other measured

abnormalities found in individuals exposed to mixed colonies of

structural fungi and molds, and their associated mycotoxins,

extracellular polysaccharides, exodigestive enzymes, hyphae

fragments, and spores.

Table 1.--Frequency of Occurrence of the 38 Most Frequently Reported

Symptoms, in Mold-Exposed Patients vs. Controls

Mold-

exposed

patients Controls

(n = 209) (n = 28)

Symptom * x SD x SD p

Excessive fatigue 5.8 1.9 4.3 2.1 0.0001

Headache 5.2 1.9 4.1 2.0 0.005

Nasal symptoms 5.1 2.2 4.1 2.0 0.02

Memory problems 5.1 2.1 3.3 1.6 0.0002

" Spaciness " /disorientation 4.8 2.3 3.2 1.8 0.0007

Sinus discomfort 4.7 2.2 3.6 1.8 0.01

Coughing 4.6 2.2 3.2 1.6 0.001

Watery eyes 4.6 2.1 3.4 1.7 0.004

Throat discomfort 4.5 2.1 3.4 1.7 0.008

Slurred speech 4.5 2.3 3.1 2.0 0.002

Lightheadedness 4.4 2.2 3.2 1.4 0.006

Joint discomfort 4.4 2.3 3.7 2.1 NS

Dizziness 4.3 2.1 3.1 1.4 0.005

Weakness 4.2 2.3 3.0 1.7 0.008

Bloating 4.2 2.2 3.2 1.6 0.02

Insomnia 4.1 2.2 3.8 2.0 NS

Weak voice 4.1 2.2 2.8 1.4 0.003

Spasms 4.0 2.2 3.8 2.1 NS

Coordination problems 4.0 2.2 2.9 1.4 0.01

Vision changes 3.9 2.3 2.9 1.4 0.02

Rash 3.9 2.2 2.9 1.7 0.02

Numbness 3.9 2.2 3.4 1.7 NS

Cold intolerance 3.9 2.4 3.1 1.8 NS

Heat intolerance 3.8 2.4 3.6 2.0 NS

Chest tightness 3.8 2.2 2.6 1.3 0.006

Chest discomfort 3.7 2.2 3.0 1.3 NS

Frequent urination 3.7 2.3 3.8 2.1 NS

Excessive thirst 3.6 2.3 3.4 2.0 NS

Ringing ears 3.6 2.2 4.4 2.4 NS

Wheezing 3.6 2.0 2.6 1.3 0.02

Swallowing problems 3.2 2.0 3.0 1.7 NS

Skin flushing 3.1 2.1 2.8 1.6 NS

Bladder control problems 3.1 2.0 2.8 1.4 NS

Rapid pulse 3.0 2.0 2.6 0.9 NS

Palpitations 2.8 1.9 2.4 0.8 NS

Bruising 2.8 1.7 2.4 0.9 NS

Swelling ankles 2.7 1.8 2.6 1.5 NS

Hearing changes 2.7 1.8 2.6 1.5 NS

Symptom * p females

Excessive fatigue 0.001

Headache < 0.006

Nasal symptoms

Memory problems 0.005

" Spaciness " /disorientation < 0.01

Sinus discomfort

Coughing

Watery eyes

Throat discomfort

Slurred speech < 0.02

Lightheadedness 0.01

Joint discomfort

Dizziness

Weakness

Bloating

Insomnia

Weak voice 0.02

Spasms 0.04

Coordination problems 0.009

Vision changes 0.008

Rash 0.02

Numbness

Cold intolerance 0.002

Heat intolerance 0.003

Chest tightness

Chest discomfort 0.02

Frequent urination

Excessive thirst 0.01

Ringing ears

Wheezing

Swallowing problems 0.008

Skin flushing 0.04

Bladder control problems

Rapid pulse 0.04

Palpitations 0.003

Bruising 0.003

Swelling ankles 0.02

Hearing changes

Notes: x = mean, SD = standard deviation, and NS = not significant.

* Symptoms were compared for females vs. males.

Table 2.--Lymphocyte Phenotypes Observed in Males vs. Females, and in

Combined Sexes (All Patients)

%

Expected

variation

range from

Cell type Designation (95% CI)

expected

B CD20+ 5, 15 > 15

IL-2 receptor bearing T CD5+CD25+ 0, 8 > 8

Activated T CD3+CD26+ 0, 30 > 30

CD3+HLA-DR+ 0, 7 > 7

Activated and suppressor CD8+CD38+ 0, 8 > 8

CD8+HLA-DR+ 0, 3 > 3

Complement-receptor-bearing

suppressor CD8+CD11b+ 5, 45 < 5

Natural killer CD3-CD16+CD56+ 5, 20 < 5

Phytohemagglutinin PHA 96, 195 < 96

Concanavalin A Con A 94, 354 < 94

All patients *

(n = 206)

%

Cell type x SD abnormal

B 17.9 6.1 75.6

IL-2 receptor bearing T 9.2 4.7 68.9

Activated T 45.9 11.8 91.2

11.8 5.9 95.1

Activated and suppressor 15.4 6 56.6

4.7 5 62

Complement-receptor-bearing

suppressor 5.7 3.7 ([dagger]) 15.6

Natural killer 7.6 11 38.5

Phytohemagglutinin 104 23.5 26.2

([double dagger])

Concanavalin A 108 27.2 5.9

([double dagger])

Males

(n = 83)

%

Cell type x SD abnormal

B 18.1 6.9 75.6

IL-2 receptor bearing T 8.9 4.7 70.7

Activated T 44.0 12.2 91.5

11.9 7.5 92.7

Activated and suppressor 15.6 6.4 54.9

5.2 6.4 61.0

Complement-receptor-bearing

suppressor 6.3 4 ([section]) 18.3

Natural killer 9.8 16.1 48.8

Phytohemagglutinin 104.0 21.4 (#) 25

Concanavalin A 108.0 23.9 (#) 6.3

Females

(n = 123)

%

Cell type x SD abnormal

B 17.7 5.5 75.6

IL-2 receptor bearing T 9.4 4.7 67.5

Activated T 47 11.3 91.0

11.7 4.5 96.7

Activated and suppressor 15.3 5.8 57.8

4.4 3.7 63.6

Complement-receptor-bearing

suppressor 5.3 3.5 ** 13.1

Natural killer 6.1 3 31.7

Phytohemagglutinin 104 25 ** 27

Concanavalin A 108 29.2 ** 5.7

Notes: CI = confidence interval, z = mean, and SD = standard

deviation.

Not all tests were performed on all individuals, as noted.

* t and z tests of males and females revealed no significant

differences; therefore, the 2 sexes were combined to form All

Patients.

([dagger]) n = 204.

([double dagger]) n = 202.

([section]) n = 82.

(#) n = 80.

** n = 123.

Table 3.--Percentage of Individuals with Antibody Titers > 1:4

against

Central Nervous System (CNS) Myelin and Peripheral Nervous System

(PNS)

Myelin for Each Isotype, in Mold-Exposed Patients vs. Controls

CNS myelin antibodies

IgG IgM

Subject n % n %

All patients 199 67.3 201 43.3

Controls * 32 12.5 32 12.5

Odds ratio 14.40 5.34

95% CI 4.85, 42.9 1.8, 15.8

CNS myelin PNS myelin

antibodies antibodies

IgA IgG

Subject n % n %

All patients 201 55.7 201 61.7

Controls * 32 12.5 32 12.5

Odds ratio 10.59 14.40

95% CI 3,58, 31.3 4.86, 42.87

PNS myelin antibodies

IgM IgA

Subject n % n %

All patients 201 45.8 201 60.2

Controls * 32 12.5 32 6.25

Odds ratio 5.39 19.10

95% CI 1.82, 15.93 4.44, 82.6

Notes: Ig = immunoglobulin, and CI = confidence interval.

* The percentage of controls that exceeded 1:4 had antimyelin titers

of 1:8.

Table 4.--Percentage of Individuals with Abnormally High

Titers to Neurofilament Antigen, in Mold-Exposed Patients

vs. Controls

% abnormal

Subject IgG IgM IgA

Patients (n = 93) 6.45 31.6 36.2

Controls (n = 100) 0.0 2.0 2.1

Odds ratio Infinity 22.615 27.767

95% CI 5.224, 99.900 6.437, 119.784

Notes: Ig = immunoglobulin, and CI = confidence interval.

Table 5.--Odds Ratios (ORs) and 95% Confidence

Intervals (CIs) for Antinuclear Autoantibodies (ANA) and

Autoantibodies against Smooth Muscle (ASM)

Autoantibody OR 95% CI

ANA 11.00 2.56, 46.50

ASM 2.58 1.26, 6.26

Note: Autoantibodies for males and females were combined

and compared with combined controls A and B.

Submitted for publication September 16, 2003; revised; accepted for

publication November 24, 2003.

Requests for reprints should be sent to Gray, M.D., M.P.H.,

C.I.M.E., 300 S. Ocotillo Road, Benson, AZ 85602.

E-mail: docmike007@...

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