Chronic Lyme Disease – A French Epidemiological Study

Thank you, and thanks to the organisers of this interesting meeting. I’m glad to be here, it’s an honour and a pleasure to be asked to speak. Please excuse my English mistakes!

I’ll speak about the first epidemiological study in France. France has come to the study of tick-borne disease very late. Difficult to do studies especially with any hospital or university team. I am from Professor Peronne’s team.
We received a lot of patients with Tick Borne Disease (TBD) or chronic TBD, suffering for more than one year, and rejected by GPs and by hospital staff. These patients, need help and they need global examination. We first decided that to better understand the symptoms, to do a descriptive, epidemiological study about this strange, emerging infectious disease.
I think now this morning was very intersting but we can’t speak only about Lyme Disease, we should speak about Tick-Borne Disease or Tick-Transmitted Infections, and with this new word, we can then advance /understand more about the epidemiological, pathological and treatment about this difficult disease.

In France Tick-Borne Disease is often misdiagnosed. The course of the illness is highly variable from one case to another, especially due to immunity variations (in the patients) or Co-infections which were often not searched for.

This is the first results of our cohort of more than 170 patients I think. We don’t know how to see every patient and our delays are very, very long. Especially because there is no other University team in France which accepts to do more than one serology and one consultation. This is the first results of a group, the team, Professor Peronne’s team in the Raymond Poincare University Hospital, a group of Assistance Publique Hospitaux de Paris. Our work supported by Institute Pasteur, department for epidemiological analysis.
We are now trying to find a good laboratory to have good PCR tests.

These are the first results about the first hundred patients who came in the unit.
We analysed only those patients who came three times.
First time and first description for Inclusion (in the study).
They were seen again at three months and then again at six month and their visit made only with at least one follow-up visit at month 3 or month 6.

Sex ratio 0.35. Mean age 45 years old.
Between males and females there is no difference.
And they are included since 1999 and we took one patient from in the unit since 1995.
So it’s a global, prospective study, if very scientific and rigorous, we can take first patient who was followed since 1995.

Tick Bite History:

If looking for Tick-Bite History – interesting because now a cohort of 87 patients have tick bite history. With the tick or with other insect or with something they can’t describe. We have to be conscious about (the fact that) often people have tick-bite history, and often have Erythema migrans (Em or Ecm) without remembrance of tick bite history. People have tick bite history, Em and have negative serology. Everything is considered not to reject these patients but try more arguments to speak about Tick-Transmitted Infectious disease. You can see that people, often describe more that one bite of tick and perhaps more insects.

Lyme Serology:

Lyme serology - (Elisa and Western blot) – it’s not a good test especially for the inclusion of patients, now most people know serology especially Elisa and Western Blot, this is not good for diagnosis. Even if we do serology study.
History 2% positive and 98% none. Elisa is not a good test for diagnosis.
In future this will be a difficulty, especially if in future (there are) more clinical trials. We need to find different arguments to include patients in clinical trials. It’s absolutely sure that we can’t use Lyme serology.

Antibiotics:

This is a description of history of antibiotics.
Before inclusion a lot of patients had received more than 3 or 4 courses of antibiotics. They come with a long history of treatment, they came after 1,2,3,5,10 years of suffering and we included all these patients with one bi-antibiotic therapy for more than one month each time and we gave them two or three courses during the follow up study.

So, if we try to study antibiotic history before Inclusion:
65% had received antibiotics, especially Amoxycillin or Ceftriaxone or Doxycycline. A few had had clarithromycin or another treatment.

At inclusion, we tried to be quite simple.
We essentially used two antibiotics - Amoxycillin (at high doses 6x a day) and Doxycycline or an association of Doxycycline and Amoxycillin together. Why (this way)? Now, we try both, and other regimes but, at this time, originally in 1999, we tried to be in accordance to official recommendations and if you see in the official recommended treatments, these two antibiotics have authorisation for Lyme Disease.

At first follow-up - a lot of patients were still treated by Amoxycillin (46%) or Doxycycline (33%) and 21% had both Amoxycillin and Doxycycline.

At second follow-up – 76 patients were under Amoxycillin and more patients retreated with association of Doxycycline and Amoxycillin.

Symptoms:

If we try to describe the symptoms at inclusion you can see it is very large, that’s why we have to try to classify symptoms to help patients and to help GPs. You can see endocrine abnormalities, gastro-intestinal symptoms, muscle pain, neurologic or neuropsychiatric symptoms, cardiac and respiratory symptoms, cutaneous symptoms and global symptoms. Global and neuropsychiatric symtoms were diagnosed a lot as hysteria. A lot came to see us with this diagnosis.

Hormonal abnormalities at Inclusion, not very described, but it is a very important problem, galactorrhoea or dysmenorrhoea. Our cohort of 100 patients, 6 or 7 patients had dysthyridia, with auto-immune antibodies at a very, very high level. An important problem I think needs study. We had 3 or 4 cases of hyperthyridia.

Here you have Gastro-intestinal symptoms: transit problems, gastralgia – and perhaps more painful in women.
Muscular symptoms: More than two thirds of the patients have myalgia and that explains the diagnosis of Fibromyalgia.
Neurological and psychological symptoms: Concentration troubles, hypersomnia or difficulty sleeping, memory troubles, mood troubles, sexual dysfunction and depression which needs often treatment or has a history of treatment.
Cardiac and respiratory symptoms: As you know Lyme Disease is a cause of carditis and we have to be aware about it. Palpitations or conduction troubles and we can describe high level blocks of the 2^nd or 3^rd degree, hypertension, recent trouble of cold, chills and all respiratory symptoms, dyspnoea especially ‘effort dyspnoea’, which is quite frequent.

Cutaneous symptoms at Inclusion: A good point is that the site of the bite remains painful. After this loss of hair is quite frequent. History of Erythema migrans or something like it. Migratory erythema or history of Em. 53% had Em history and16% had Em observed at Inclusion.

General symptoms at Inclusion: Of course, fatigue very frequent at 83%.
Interesting that 36% of our cohort had fever – a good argument for co-infection actually.
Weight disturbance either up or down.
Adenopathy.

Articular symptoms: Arthritis. Recurrent arthritis, painful arthralgia, hard to make the difference. You see a rheumatologic description of Lyme Disease here is very frequent in our cohort, over 80% have an arthritis.

Neurological symptoms: Most frequent that is not described much but is very frequent is ‘hearing trouble’ -irritation. Trouble to speak or write. Facial palsies and other cranial nerve palsy. Temporo-spatial disorientation – not dementia, difficult to find the date (?time) exactly and position in space. Patients have a very interesting symptom – which is dysaesthesia, especially painful dysaesthesia, especially a warm sensation or sensation of burning, or hot water on the hand or legs. Headaches, visual dysfunction and you call migralgia is very frequent and difficulty to walk and sometimes faults (with walking.)

Symptom Evolution:

Evolution of classes of symptoms during study:
All classes of symptoms decrease under treatment, quite a surprising result. Most impressive result is about the global manifestations. Patients have less fatigue, less fever.
Cutaneous symptoms are also quite an impressive result – they are quite disappearing.
But what is obvious - is the difficulty to treat all the neurological symptoms. It is quite obvious because of the length of the disease and difficulty of the antibiotic to go through the CNS and, of course, nerve has delayed repair - more than a month, perhaps years.

What we did we numbered all classes of symptoms
At inclusion 82% of the population had more than four classes of symptoms.
And under treatment it was decreasing especially at month 3 and stable after that.
It was a good way. To see decreasing global symptoms under treatment.
If you look for Em – at Inclusion 53% had objective Em (history).
At first visit 16% had it. At 3 months and 6 months – a very few had it. Quite interesting – it is not a Herxheimer Reaction but Em appears first days under treatment. It is quite a good sign to look for. If we see the Herxheimer (Jarisch-Herxheimer Reaction), some people had it before Inclusion and only 4% of the cohort have Herxheimer at month 3.
But as you know the Herxheimer is a short and brutal reaction – it is a good sign in the first two days under treatment. I think we have to explain to the patient and it is a good sign of Tick-Borne Disease - this very brutal reaction and general global reaction at first hours under treatment.

Evaluation of ‘Chronic Lyme’ probability.

Classifying these Treatments: How to classify these treatments?
Because in France patients are put quite quickly in the psychiatric classification and patients can go under psychiatric classification. So we try to give arguments to come(bring these cases) back to the medical staff.
So we try to use the New England Journal of Medicine classification.
Its not perfect but it was published in July 2001 and uses some good arguments.

(Scoring system for patient’s symptoms and signs)
Erythema migrans (Em) = 5 points (objective).
History of serology – Borrelia in count 5 points (quite different of serology now) but if positive shows patient has been in contact with Borrelia.
History of Tick Bite - 3 points.
Clinical presentation 2 or 1 point. .

So you classify patients in three groups:
Low probability equal to or less than 4 points, (which does not mean you don’t have Lyme disease). Perhaps the patient was not aware about Em or no serology.
Medium probability - up to 9 points.
High probability - over 10 points. (Patients generally have tick-bite history with one serology and objective Em).

Lyme Probability Distribution:

Low, Medium and High probability.
Quite new that we try to look for probability during the study.
So we have more patients evolving and changing class under treatment.
At Inclusion Visit, 2/3 (67%) patients have a high probability, 27% have medium probability and only 6% low probability.
We maybe have recruitment bias because we only have ‘very difficult’ patients and when they come often very evocative story of tick-borne disease. Surprising these patients became less symptomatic – so they lost 2 or 3 points, so global increasing, it’s a global good result, they seem to be less ‘Lyme Disease’ because they have evolved a little.
Principal effect between inclusion and three months. Very important the first response to treatment.

Clinical Evolution:

A few have no evolution, absolutely none.
A very few went worse and the majority have partial or very good recovery and here – a difficult group - some have a cyclic evolution. Maybe there is cystic Borrelia or something else?
This means they are going very well and then they relapse – it should be carefully studied.

Survey at 6 months:
64 patients came for their visit and we can study for these 64 patients the probability.
We had a lot of medium and high probability patients.
The same evolution is observed with less clinical picture evocating Lyme Disease after 3 months and with stability between 3 and 6 months.

Objective Symptoms – can be described by a doctor. (documented).
Conduction troubles
Dysthyridia
Galactorrhoea
Temporo-spatial disorientation
Arthritis
Hypertension
Facial Palsy
Dysaesthesia
Rapid or slow heartbeat.

So it is going better in evolution – especially for dizzyness, or carditis, or even for facial palsy (no more facial palsy), after nervous deficiency, adenopathy and fever. Fever decreases under antibiotic treatment.
More difficult for vision troubles or for headaches which are neurological Lyme or neurological symptoms. And can see no more Erythema migrans (Em) after three months evolution.

Subjective Symptoms:
Depression
Pain
Sexual dysfunction
Pelvic Pain
Respiratory
Immune disorder
Flu-like illness

We can see a global recovery especially for dyspnoea or for myalgia and muscular symptoms. All CNS lesions are very long to recover. You can see Myalgia, Mood troubles, walking troubles, difficulty in sleeping, much better, for arthritis for example. Here Concentration troubles or memory troubles. Here we have: Arthritis pain, myalgia, headaches, arthralgia, dysaesthesia and fatigue – (last two symptoms are difficult to treat.)

Evolution of all classes of symptoms:

During study and six months follow-up:
Neurological symptoms – difficult to disappear. Global symptoms better, articular symptoms better too, no muscular, Cardio-respiratory and GI, but global and neuropsychiatric symptoms - seems to be more difficult.
So, if we keep the global classification system:
At Inclusion, 83% then have more than 4 classes of symptoms. At three months, now only 39% with four classes and only 31% after 6 months.

Low Probability of Chronic Lyme at Inclusion:
Not a lot of evolution in this group – a short group. Good response to cutaneous and articular symptoms. Perhaps it’s not Lyme disease (in these patients) but something else?
But much better probability to see evolution between Inclusion and month 3.

Medium Probability group:
Quite a lot better, especially articular and cutaneous symptoms but not for neurological and global symptoms. Good response of muscular symptoms, in this group of 16 patients and it is rather increasing. Have a good response to treatment because only 31% patients (of a cohort of 16) have still four classes at 6 months.

High Probability Group at Inclusion:
A good response for cutaneous, articular, global and muscular symptoms. 43 patients followed for 6 months in this group. You can see (classification of all organ dysfunction) during study at Inclusion, month 3 and month 6 and we can see a global recovery.

Evolution of Objective symptoms:

On this graph the three groups had variable evolution
At Inclusion, Month Three and Month Six.
(We) described with statistical analysis:
First for all groups (in red) – there is a statistically significant difference between Inclusion and month Three and still significant difference between month Three and month Six.
For the low probability (purple) – there is no difference – so this group does not respond to therapy.
For the medium probability (red) – there is a difference between Inclusion and Month three and Month three and Month six.
For the high probability (blue) – patients very significantly decrease in number of symptoms (three down to less than1.5 during first three months treatment.) And after that it is quite stable. Very interesting, because in High probability group often - all decrease can be obtained within first 3 months. The more impressive response.

Same results in all (low, medium and high) probability groups:
And see here very significant difference between Inclusion and Three months regarding the number of classes of symptoms.

Evolution of Subjective and Objective symptoms:

Same results. Good response for subjective symptoms between Inclusion and month Three and you have - quite difference between all groups.
Low probability – no statistically significant difference and no significant difference in Medium Probability. And very significant difference even for subjective symptoms in high probability group – between Inclusion and month Three, so on this graph shows the Evolution of objective and subjective symptoms in the three groups. Low Probability have quite good response, Medium Probability - good response and very good response in High Probability group even for objective symptoms.

Global Patient’s Clinical Evolution:

As I said, no worsening – but a few had an absence of response.
Three groups with partial or good recovery and a lot of Cyclic Evolution especially after 6 months to a year evolution.
Follow-up + 6 months, then come back to see you and have often Cyclic evolution.
Low probability group - quite good response in first three months, better at 6 months, but 20% have cyclic evolution, even after more than 6 months.
Evolution in the Medium Probability group – people better or significantly better, but if keep them for more than 6 months they are 66% (2/3) in a Cyclic evolution, sometimes they are well and other times they have a ‘crisis’.
High probability group – 65% make quite a good recovery , 21% in a Cyclic evolution after more than 6 months follow up.
Exacerbation Frequencies:
Quite different from Herxheimers. Herxheimer is at early evolution of treatment, exacerbations often observed after more than 2 – 3- -4 weeks after treatment (and) good global evolution of objective and subjective symptoms. Sometimes there is an articular crisis or a myalgia crisis under treatment. A lot of this exacerbation of symptoms under treatment in the High and Medium Probability groups, so better (?) you keep symptoms even under antibiotic.
A lot of patients had more than one course of antibiotics. We gave two antibiotics for more than one month, but 90% people in the High Probability group needed more than one course of treatment.

To conclude:

This is a descriptive, epidemiological study of only one hundred patients.
We can say the best response is observed in the High Probability group of chronic Lyme Disease or chronic Tick-Borne Disease. Statistically significant decrease in number of symptoms and global clinical improvement at 3m, 6m and one year. The main question now is ‘Does Lyme Disease really exist?’ I think ‘yes’ but not all French doctors agree.

Many patients have objective and subjective symptoms, a few months or even years after Tick Bite infection and they require attention and complete clinical, radiological and biological examinations.

What causes Lyme Disease or chronic Lyme Disease (cLD) or Post TBI?
In post Lyme or cTBI there are a lot of co-infections. We must search for Co-infections especially in cLD after one year of evolution. We have a lot of autoimmune disturbance and we have a lot of multifactorial explanations, sometimes with the hidden and sometimes with other disease. Studies urgently needed especially prospective studies and therapy trials/studies and therapeutic treatment. And we must change our words and speak about Tick-transmitted disease and multiple infections or co-infections.
TTI or TBD better because LD is not a good word and doctors don’t want to hear about it. We need new laboratory examinations and the presentation of
Dr. Mordechai (this morning) was very interesting for me because I think if we have PCR good laboratory tests, I think doctors will change if we have these. (Especially CSF examination or cutaneous puncture or synovial puncture). Because if (now) you say to a doctor I have ‘chronic Lyme Disease’ there is no proof, and he doesn’t want to hear about it. If you say I have had a lumbar puncture and CSF tested and my PCR is positive and what is your answer - he is obliged to have a good answer. What we try to do for these difficult patients to have each time a CSF, good result to PCR (send maybe New Jersey).

We have to explore immune abnormalities especially lymphocytes and CD57s and perhaps metabolism cytokines 11,17, 2 must be analysed.
And we must create a good victim’s network. I think you have a good victim’s network.

We must make a good medical network because we are quite alone. We have to organise quite quickly a randomised, double blind, controlled trial to these chronic Lyme victims. Thank you very much.