Download Toxic Oil Syndrome: A new disease A perspective of interaction

Toxic Oil Syndrome:
A new disease
A perspective of interaction
between host and environment
Manuel Posada de la Paz, M.D.
Toxic Oil Research Centre
Centro de Investigación sobre el
Síndrome del Aceite Tóxico (CISAT)
Instituto de Salud Carlos III
In 1981 when the epidemic started, and in my position as a
specialist in internal medicine I had to face a strange lung disease.
Inmediately, my colleagues and I were surprised by an illness
with the appearance of an infectious disease but presenting a
clinical course that could not be improved by the use of
antibiotics. Most of our patients came from the same family and
same geographical areas.
The evolution of the disease with scleroderma and neuropathy
arouse my interest as we had been working in scleroderma and
this situation gave us the opportunity to try to know what could be
the cause and pathogenesis of this type of illness
Later, I was involved in clinical investigation and finally I was
introduced in the epidemiology field. Since then, I have been
devoted to the study of the etiology and pathogenesis of this
interesting disease.
Mystery: What is this Disease?
What is its origin?
How can we prevent it?
TOXIC OIL SYNDROME: A
Brief Summary
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New Disease
Rate of Toxic Oil Syndrome Cases by Province
Spain, 1981
Point Source Epidemic
Rapeseed Oil Denatured
with 2% Aniline
Systemic Disease
Three Clinical Phases
Vasculopathy
(Endothelium)
Number of cases per 100.000
Evolution Unknown
>290 211-290 141-210 140-71 1-71 no
Descriptive Epidemiology
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•
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First Case 1st May, 1981
20,643 affected
10,000 hospital admissions
80 deaths in the first
month
303 deaths as to 31 Dec
1982
2,500 deaths by all causes
Ratio M/F= 1.5/1
Central and northwestern
areas
Age distribution by sex in Toxic
Oil Syndrome patients
2500
Number of patients
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•
•
•
2000
1500
Males
1000
Males
Females
500
Females
0
0-9
20-29
40-49
60-69
>80
0-9 Decades
40-49 >80
20-29 60-69
EPIDEMIC CURVE FOR TOS
Epidemic Curve for TOS
New cases
1800
1600
1400
1200
1000
800
600
400
200
0
Weeks
May 1 June 10 August 1 October 15
1981, weeks
May 1
June 10
August 1
1981
October 15
Toxic Oil Syndrome: Acute Phase
• Rash
• Interstitial
pattern in X-ray
• Pruritus
• Eosinophilia
• Fever
• Cramps
• Cephalea
Toxic Oil Syndrome: Chronic Phase
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•
•
•
•
Scleroderma
Neuropathy
Contractures
Hepatopathy
Pulmonary
Hypertension
• Sicca Syndrome
Frequency of Major Events in TOS
Acute Lung disease
Sclerodermiform changes
70.0
21.3
Neuropathy
Pulmonary Hypertension
32.0
8.2
Liver disease
Sicca Syndrome
7.2
35.0
Eosinophilia
Myalgias
78.0
80.0
First Case-Control study:
Hospital Niño Jesús
Case
Consumed
fraudulent oil
Did not
consume
Control
62
4
0
58
Odds Ratio > 1,000
CI 95% ( 145.6 - Inf)
Second Group of Studies: Navas del
Marqués study
Study number 1
Case
Consumed
fraudulent
oil
Did not
consume
Control
27
30
0
108
Odds Ratio=194
CI 95% (19.2 - Inf)
Study number 2
Case
Control
Bought oil from
24
“good woman”
in April or May,1981
12
Bought oil from
other salesmen or
other time Odds Ratio=7.2
CI 95% (2.2 - 23.2)
5
18
Case Control Studies Made at the Beginnig of the TOS
Outbreak after the Official Anouncement of the Cause
Location
Cases
• Pozuelo
42/48
• Chozas (León) 19/19
• Cerezo (Seg) 13/13
• San Cristobal 10/10
• Bocigas (Soria) 11/11
• Arconada (Pal) 18/18
• Colmenar (Mad)16/20
• Madrid
52/58
• Madrid (nuns) 23/35
• Madrid (nuns) 42/43
Controls
32/96
15/19
25/44
8/19
22/33
9/21
6/20
615/1,725
0/56
0/70
OR (CI) or “p” value
21 (7.7-64.8)
Inf. (p=0.05)
Inf (p=0.002)
Inf (p=0.002)
Inf (p=0.03)
Inf (p=0.001)
9.3 (1.8-52.7)
15.6 (6.7-44.8)
Inf (p=4x10-13)
Inf (p=2.3x10-31)
Ethiologic Research
Toxi-Epi Study
Dose Response
• Accuracy in the
definition of the
vehicle of
exposure
• Dose-Response
relationship
Log Odds Ratio
4
3
2
1
0
00
200 400
400 600
600 800
800 1000
1000 1200
1200 1400
1400
200
Oleyl Anilide (m g / g )
1
2
Typical Bottle (number 1) and
Contents in Oleyl-anilide
3
4
DISTRIBUTION OF TYPE OF
BOTTLE BY OLEYL-ANILIDE
CONTENTS
positive
Negative
negative
Oleyl-anilide Positive
100%
80%
531
Potential Misclassification
Bias in the First CaseControl Studies
60%
100 101 176 165
69
79
98
24
1
5B
0
6
0
7
0
8
40%
20% 319
0%
1
6
2
1
3
1
4
1
5A
Type of Bottle
TOXI-EPI- I study
TOXI-EPI- II study
(Oleyl-anilides)
(Oleyl-anilides)
Case
+
-
Control
Case
Control
18
16
30
10
11
48
29
60
Odds Ratio=4.91
Odds Ratio=6.21
CI 95% (1.74-14.01)
CI 95% (2.50-16.04)
Dose-Response: OOPAP against
4
Oleyl-anilide
3
Log Odds Ratio
OOPAP
2
Oleyl Anilide
1
0
0
-1
200
400
600
800
1000
1200
m
Oleyl Anilide and OOPAP(
1400
g / g)
Rapeseed oil
not
denatured
sold in
France
Refineries
OA
Contents
Catalonian
OOPAP
Contents
<100 ppm Not detectable
Sabater
Circuit
France
Aniline
added
Danesa-Bau
450 ppm Not detectable
ITHSeville
1,900 ppm 150 ppm
Central
Circuit
EPIDEMIC CURVE FOR TOS
DANESA-BAU
New
cases
2000
1800
1600
1400
1200
1000
800
ITH
600
400
200
0
May 1 June
June
10 10 August
August 1 1
May 1
1981
October
October 15 15
Weeks
Weeks
IMMUNOLOGICAL MECHANISM(S)
LIKELY INVOLVED
Some humoral evidence
- Eosinophilia
- In acute phase of soluble IL-2 receptor
- Serum Major Basic Protein increased in all phases
- Major Basic Protein deposits in tissues from acute
phase (eosinophile degranulation)
- GM-CSF in acute phase
T-Cell activation
IMMUNOLOGICAL MECHANISM(S)
LIKELY INVOLVED- II
Some histological evidence
• IL-4 and IL-5 deposits in cases pulmonary tissues from
the deceased in the acute phase
• High proportion of HLA DR2 in death patients
• Controversial findings with HLA DR3-DR4 and DQ3-8
• CD4 lymphocytes surrounded the main lesions
• NAT2 genotype is a risk factor of the disease
6
TOS COHORT: Standart Mortality Ratio
5
4
IL 95
SMR
SL 95
3
2
1
0
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
Conclusions
• Our data suggest that TOS is a Point Source
Epidemic. This assertion is based on:
– Linkage between rapeseed oil denatured with 2% aniline
and the disease
– Presence of a chemical marker (OOPAP) in the oil refined
in ITH (Seville)
– The OOPAPs are new chemical compounds very difficult
to obtain in a regular refining process
• Causal agent responsible for this disease is produced
by only one or various compounds from OOPAPs
derivatives
• Further studies in toxicology are being performed