Laboratory Aspects of Neuropsychiatric Disorders in Lyme and

Transcription

Laboratory Aspects of Neuropsychiatric
Disorders in Lyme and Coinfections
Conference of the German Lyme Disease Society in
Wuppertal/Germany
9th Apr. 2011
Armin Schwarzbach M.D. Ph.D.
Specialist for laboratory medicine
Member of the German Borreliosis Society
(Deutsche Borreliose-Gesellschaft e.v.)
Chairman of the laboratory test and international
committee of the International Lyme and
Associated Diseases Society (ILADS) USA
Infectolab
Laboratory for Lyme disease and coinfections
Tel. +49 (821) 455471-0
www.b-c-a.de
Speech / presentation German Lyme Disease Society, Wuppertal/Germany, Apr. 9h, 2010
This document is intellectual property of Armin Schwarzbach MD PhD; reproduction only with permission. Please note the copyright.
1
Borrelia burgdorferi – The chameleon of symptoms and
laboratory
2
Aims of the immune-competent cells
CD57+NK-cells
- Lysis antigen-antibodycomplexes (Borrelia)
NK
TH1
TH2
TCell
Elispot-LTT:
- Borrelia
- Chlamydia
- Anaplasma
Antibodies:
- Borrelia
- Chlamydia, Mycoplasma
- Anaplasma, Babesia …
3
Test sensitivity for Borrelia antibodies by ELISA
screening: New data
Test producer
Aeskulap
Virion
Diasorin
Euroimmun
n=
patients
50
50
50
44
ELISA
negative +
4%
4%
14%
2%
Immunoblot
positive
ELISA
negative +
14%
12%
14%
16%
Immunoblot
borderline
18%
16%
28%
18%
42%
44%
32%
42%
Total
Sensitivity
(-40%)
4
Laboratory example from practice:
Negative EIA / Positive immunoblot
B-C-A GmbH & Co. KG · Morellstraße 33 · 86159 Augsburg
Laboratory results
Patient:
Date of birth:
08/09/1947
Date of testing: 07/08/2009
Antibodies (Humoral immune system)
Results
Reference
Borrelia burgdorferi-IgG-EIA
2.8 RU/ml
<16
Borrelia burgdorferi-IgM-EIA
7.6 RU/ml
<16
Borrelia burgdorferi-IgG-Blot
positive
Bands: OspC +, p41 +, VlsE-Bg +, VlsE-Ba +
Borrelia burgdorferi-IgM-Blot
positive
Bands: OspC-Bg +, OspC-Bb +, OspC-Ba +, p41 (+)
Interpretation:
The specific Borrelia burgdorferi-IgG/IgM-antibodies by immunoblot-technique (falsenegative EIA !) are an indication for a humoral immune-response against Borrelia burgdorferi
in blood.
Doctor for laboratory medicine
5
Insensitivity of ELISA vs. Immunoblot:
New data
Antibodies in Lyme disease patients by current IDSA/CDC
ELISA screening model:
Loss of sensitivity: 16 – 28 %
Every 4th – 6th chronic Lyme patient has a positive or borderline
Immunoblot but no positive ELISA
A great number of patients will be not identified by the
screening ELISA-test and consequently “excluded” for Lyme
disease not using the immunoblot as a screening test
The more specific immunoblot is the more sensitive and the
better screening test
Senselessness of Borrelia ELISA technique in general
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Borrelia Elispot (LTT / T-Cell-test)
1. Success control of an antibiotic therapy - STAGING:
About 2 months after the end of a therapy already
significant reduction
Borrelia IgM-/IgG- titer reduction maybe after 6-12months !
2. Reflecting the actual activity of Lyme disease:
Indication for an active Borrelia infection in cases of
furthermore positive Elispot LTT after the end of therapy
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EliSpot-LTT in chronic Lyme disease
Grey columns: before antibiotic therapy
Black columns: after antibiotic therapy
Pfeiffer et al., 2003
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CD3-/CD57+ T-Lymphocytes
1. Subpopulation of the NK cells
2. Reduction indicates chronic activity of Lyme disease
(symptoms > 1 year)
3. Reduction in untreated and inadequately treated Lyme disease
4. After the therapy end of chronic Lyme disease: normalization
as an expression of therapeutical success
5. Reflection of a progressive (chronic) activity of Borrelia
burgdorferi
CD3-/CD57+ T-Lymphocytes
Reference range (mean/range)
Lyme patient:
46 /ul / 8 – 160 /ul
Healthy:
164 /ul / 60 – 354 /ul
Source: J.J.Burrascano JR., MD, R. Stricker, MD, 2006 ILADS, Crowne Plaza Hotel, Center City Philadelphia
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LYME BORRELIOSE
Borrelia
burgdorferi
and CO-INFECTIONS
+ Babesia
+ Bartonella
+ Ehrlichia/Anaplasma
+ Chlamydia
+ Rickettsia/Coxiella
+ Mycoplasma
+ Viruses (EBV, CMV, HSV)
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Ehrlichia / Anaplasma
Bacteria: Ehrlichia chaffeensis, Anaplasma phagocytophilum (gramnegative, obligatory intracellular in granulocytes)
Vector: Ixodes ricinus
Spectrum of hosts: game (e.g. deer), domestic animals, humans
Symptoms (incubation time: days up to 4 weeks): rapid onset of
beginning illness with fever, headache and prostration,
headaches are “sharp, knife-like and often located behind the
eyes”, muscle pain, not joint pain, neurological/psychiatrical
symptoms, rarely diffuse vasculitic rash, including palms and
soles (<10%)
Risk factors: severe basic illness, immune suppression
(children/older people)
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Diagnosis Ehrlichia/ Anaplasma
Cellular activity test:
Ehrlichia/Anaplasma Elispot-LTT (Lymphocytes
transformation test)
Antibodies: Ehrlichia-IgM and Ehrlichia-IgG: indirect
detection
Ehrlichia/Anaplasma-DNS-PCR in blood (EDTA-blood): direct
detection
Bacteria detection in Giemsa-blood smear
Leucopenia / Thrombocytopenia / Anemia
Elevated liver enzymes
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Babesia
Bacteria: Babesia microti, Babesia divergens
Vector/Transmission: Ixodes ricinus, blood transfusion
Hosts: game (e.g. deer), domestic animals, humans
Symptoms (incubation time 5 days – 9 weeks):
Rapid onset of beginning illness with severe fever, headache (can be
severe-dull, global, involves the whole head, described like the head is in
a vise), sweats (usually at night, but can be day sweats as well), fatigue
(worse with exercise), “air-hunger”, need to sigh and take a deep breath,
dry cough without apparent reason, stiffness of neck, nausea, diminished
appetite, tiredness, feeling of weakness, permanent exhaustion even
worse during stress, haemolytic anemia, hemoglobinuria, seldom
hepatosplenomegalia, muscle pain, dizziness, mental dullness and
slowing of reactions and responses, hypercoaguability, stomach pain,
emotional lability, kidney problems, dyspnoea, influenza like symptoms
could be lethal!
Risk factors: Splenectomia, HIV, immune suppression (children/older
people), organ transplantation
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Babesia: Diagnosis
Antibodies of Babesia-IgM and Babesia-IgG: indirect
detection
Babesia-DNS-FISH/PCR in blood (EDTA-blood): direct detection
Blood smear: direct detection
Rarely:
Hamolytic anemia (erythrocytes, haptoglobin)
Thrombocytopenia
Leucocytopenia
Increase of liver enzymes (sGOT, sGPT, sGGT)
Increase of Creatinine, Urea
Hemoglobinuria
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Chlamydia pneumoniae infection
Bacteria: Chlamydophila pneumoniae (gramnegative, intracellular)
Vector/Transmission: airborne infection, human to
human, ticks ? Or reactivated in Lyme disease
(horses, koalas, frogs are infected)
Symptoms: slight throat pain, hoarseness, sinusitis,
atypical pneumonia, meningoencephalitis,
bronchiolitis obliterans, myocarditis, Guillain-BarreSyndrom; after infection (4-6 weeks): arthritis,
tendovaginitis
Associations: e.g. Morbus Alzheimer, Multiple
Sclerosis, Depressions, Fibromyalgia, Chronic Fatigue
Syndrome (CFS), , heart attacks, apoplectic stroke,
arteriosclerosis, Autism, Parkinsonism, Rheumatoid Arthritis
Risk factors: immune suppression (children/older people)
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Chlamydia pneumoniae: Diagnosis
Cellular activity test:
Chlamydia pneumoniae Elispot-LTT (Lymphocytes
transformation test)
Antibodies for Chlamydia pneumoniae-IgA and Chlamydia
pneumoniae-IgG: indirect detection
PCR of Chlamydia pneumoniae in sputum/pharyngeal secretion:
direct detection
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Mycoplasma infection
Bacteria: Mycoplasma pneumoniae/fermentans
(gram-positive, intracellular)
Transmission: airborne infection (aerogen),
human to human
Symptoms: tiredness (100%), fever, joint pain,
swelling of joints, muscle pain, headache,
insomnia, anxiety, emotional lability, lack of
concentration, alertness and memory,
confusion, Autism
Risk factors: immune suppression (children/older
people), Chronic Fatigue Syndrome (CFS), „Gulf
War I syndrome“
17
Mycoplasma: Diagnosis
Antibodies: Mycoplasma pneumoniae-IgM, Mycoplasma
pneumoniae-IgA and Mycoplasma pneumoniae-IgG: indirect
detection
Bacterial culture
PCR of Mycoplasma pneumoniae in sputum/secretion: direct
detection
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Case report 1: General informations
Male
Born 05/06/1971: 39 years
Outdoor activities: cycling
Tick bite: August 2008 on the right upper leg
No „bulls eye rash“
First symptoms: May 2009
Physical capacity June 2010: 70 %
Mental capacity June 2010: 80 %
No treatment yet
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Case report 1: Neuropsychiatric Symptoms
All
symptoms started in May 2009:
Bad temper, loss of realitiy, attacks of loss of control
Fear, anxiety, panic attacks
Restlessness, listlessness, agitation, apathie
Drowsiness, need to lay down or to sit, feeling of being
„beside yourself“
Impaired/change/clouding of consciousness
Difficulty in concentration, reading difficulties, mental
block
Problems in absorbing new informations
Dizziness, vertigo, balance/movement disturbance
Speech disorders, slip of the tongue, wrong words or
pronunciation, difficulties in talking
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Case report 1: Neuropsychiatric symptoms
Mood swings, depression, excitability, nervousness
More afflicted by stress than others, increased crying,
reduced self-esteem
Forgetfulnes, bad short-term memory, less attention
Confusion, concentration difficulties
Difficulties in remembering names or word, problems in
finding the right words
Rage attacks, outburst of fury
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Case report 1: Laboratory test results
22
Male
Born 08/01/1982: 28 years
Living place: Amsterdam/Netherlands
Outdoor activities: Jogging
Animal contact: Dog
Tick bite: During July-October 2009
„Bulls eye rash“: Beginning of October 2009 kneeregion, 14 days doxycyline afterwards
First symptoms: October 2009
Loss of weight during infection: - 22 lb
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All
symptoms started in October 2009:
Loss of room-to-room memory, drowsiness, need to lay
down or to sit, feeling of being „beside yourself“
Disorientation, confusion, feeling of getting lost
block
pronunciation, difficulties in talking and writing, mixing up
letters or figures
24
reduced self-esteem
In November 2009 one time extremely epilepsy, cramp
attacks or spasm
25
26
Male
Born 05/13/1974: 36 years
Living place: Stockholm/Sweden
Outdoor activities: Soccer
Animal contact: cats, dogs
Tick bite: around the year 2000
Big „Bulls eye rash“ on the back around the year 2000,
no treatment till now
First symptoms: 2002
Loss of weight during infection: - 66 lb
27
Symptoms started in the year 2002 :
In 2002 two times extremely epilepsy, cramp attacks or
spasm
block
pronunciation, difficulties in talkingMood swings,
depression, excitability, nervousness
28
reduced self-esteem
Symptoms started in the year 2005:
Aggressiveness, bad temper, loss of realitiy, change of
personality, rage attacks, outburst of fury
pronunciation, difficulties in talking or writing, mixing up
letters or figures
29
30
31
Male
Born 02/09/1965: 45 years
Living place: Abu Dhabi/UAE
Outdoor activities: 1983-84 camping Greece and Africa
Animal contact: dogs
Tick bite: August 1983 Greece
„Bulls eye rash“: September 1983, no treatment
afterwards
First symptom: 1983
Diagnosed with fibromyalgia in 2004 and RA 2008
2003 for 2 week tyhpoid infection
32
Symptoms started in the year 1983 :
For 6 months extremely psychosis
All symptoms started in the year 2003:
personality
Panic attacks (2003-2004)
Impaired/change/clouding of consciousness (in 2003)
33
block
pronunciation, difficulties in talking or writing, mixing up
letters and figures
reduced self-esteem
34
35
36
Male
Born 12/18/1966: 43 years
Living place: La Chapelk/France
Outdoor activities: Soccer
Animal contact: cats, dogs
Tick bite: unknown
„Bulls eye rash“: unknown
First symptoms: September 2001
Loss of weight last 6 months: - 22 lb
37
All symptoms started in September 2001:
personality
block
Cramp attacks or spasm
38
Psychosis, hallucinations, paranoia, delusions, bipolar
disorder
pronunciation, difficulties in talking and writing, mixing
up letters or figures
reduced self-esteem
39
40
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Case report 6: “Mixed dementia”
65-year old patient with ataxia in walking, fatigue, loss of memory
and concentration, depressions, increasing disorientation,
hypertension, panic attacks, helplessness, change of character since
2003. Patient remembers several tick bites before the start of the
illness.
Feb. 3rd, 2005: University Hospital Munich: “Mixed dementia” with no
findings in spinal fluid - “Exclusion of Neuroborreliosis”
Nov. 11th, 2006: Appointment at Borreliose Centrum Augsburg:
Borrelia IgG-/IgM-specific antibodies detectable
Elispot-LTT positive (Borrelia fully antigen: SI 3)
Dec. 2006 / Jan. 2007: Treatment for 10 weeks with oral antibiotic
therapy: Cefuroxim, Clarythromycin and Metronidazol in a row
42
Case report 6: “Mixed dementia”
April 2nd, 2007 Next consultation at BCA: increasing autonomy,
significant improvement in ataxia und movement disorders, no
panic attacks anymore
June 6th, 2007 Next consultation at BCA: condition remains stable,
following treatment for 12 weeks with oral Donta treatment
scheme (Clarythromycin und Hydroxychloroquin)
Nov. 11th, 2007: Next consultation at BCA:
Borrelia serology IgG-/IgM- antibodies unchanged
Borrelia Elispot-LTT negative (SI <2)!
Patient is healed!
Correct diagnosis: Chronic Neuroborreliosis with dementialike symptoms
43
Correlation of modern laboratory tests for Borrelia
burgdorferi and Chlamydia pneumoniae
Borrelia burgdorferi
Chlamydia pneumoniae
IgG / IgM
LTT
CD57
ChlP IgG
ChlP IgA
LTT
positive
22 = 44%
21 = 42%
27 = 56%
27 = 54%
26 = 52%
15 = 50%
negative
20 = 40%
12 = 24%
21 = 44%
20 = 40%
20 = 40%
10 = 33%
borderline
8 = 16%
17 = 34%
3 = 6%
4 = 8%
5 = 17%
no value = 2
no value = 20
44
Summary of new study
Sensitivities in our study (n=50):
- Chl. Pneumoniae-IgA: 60 %
- Chl. Pneumoniae-IgG: 60 %
- Chl. Pneumoniae-Elispot-LTT: 67 %
All 3 tests together: 78 %
- Borrelia-Elispot-LTT 76 %
- Borrelia-IgG/IgM-immunoblot: 60 %
- CD57-count: 56 %
All 3 tests together: 90 %
45
Conclusions
86% of patients with chronic Lyme disease are coinfected with
Chlamydia pneumoniae („multiple infections“), many
patients are coinfected by other bacteria/viruses like Babesia,
Coxsackie-Virus
Borrelia- or Chlamydia pneumoniae-neuropychiatric symptoms
are not high-specific („Overlapping symptoms“)
„Staging“ of Lyme disease and coinfections should be done by
modern laboratory tests like Elispot-LTT and CD57-count
before any antibiotic or other therapeutical decision
Modern laboratory tests like the more sensitive Borreliaimmunoblot (Not ELISA!), Chlamydia-IgA/IgG-ELISA, CD57count, Elispot-LTT Borrelia/Chlamydia should be done in a
„test-package“ in neuropsychiatric disorders
Many infected patients develop autoimmune disorders like
Antinuclear antibodies
In each neuropsychiatric disorder should be asked for Borrelia,
Chlamydia and other TBD (Exposure for ticks? Tick-bites?)
46
Infectolab
Laboratory for Lyme disease and co-infections
Thank you very much for
your attention !
See you at the 2nd European Annual ILADS meeting
27./28. May 2011 in Augsburg city !
Specialist for laboratory medicine
Morellstrasse 33
86159 Augsburg (Germany)
Tel. +49 (821) 455471-0
www.borreliosecentrum.de
www.infectolab.de
service@borreliosecentrum.de
47

Laboratory Aspects of Neuropsychiatric Disorders in Lyme and

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