Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease, 2021, Morizot et al

[Sly Saint]

Abstract
Introduction: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. Patients often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk is the development of lymphoma in some cases. To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry.

Material and methods: An anonymous questionnaire following the recommendations of the Institute of Medicine/National Academy of Medicine for screening of the new SEID criteria was created in French and mailed to 50 patients.

Results: Thirty-nine (78%) contacted patients responded. The studied population was mainly constituted of women (90%) with an average age of 50 (18–59) years. Smoking was a constant factor in all patients. A total of 28/39 (72%) respondents met the SEID symptoms criteria. Severe chronic fatigue for more than 6 months was noted in 36/39 cases (92%). Unrefreshing sleep, post-exertional malaise, cognitive impairment, and orthostatic intolerance were described in 30/39 (77%), 32/39 (82%), 28/39 (72%), and 27/39 (69%) cases, respectively. Pain (arthralgia, myalgia, headache) was present in 26/39 (67%) cases.

The most prominent SEID symptoms were fatigue, followed by post-exercise discomfort and cognitive difficulties. The most disabling symptom was non-restorative sleep, followed by pain. An inflammatory and/or autoimmune context was noted in 13 patients (33%), and these comorbidities could have favored the deterioration of the general condition. Three patients also presented with fibromyalgia. However, 3 patients did not mention any complaints.

Conclusion: This survey indicated that patients with PPBL most often initially presented with disabling chronic fatigue, chronic pain, and other symptoms suggestive of SEID but requiring more studies to confirm it. Education of medical staff about the symptoms of PPBL should be encouraged to better assess this peculiar condition.

https://www.mdpi.com/2077-0383/10/15/3374

 

[Snow Leopard]

This either suggests common pathology, or a lack of specificity of the SEID criteria, or poor operationalisation of the SEID criteria.

 

[Peter T]

Given for ME, and therefor presumably for SEID too, onset is associated with a variety of triggers is PPBL just another such trigger? Might it turn out that ME and/or SEID is more common in other conditions than previously recognised?

(Have any studies been done on the overlap between SEID and the various ME diagnostic criteria? Until we have agreed diagnostic biomarkers much of this type of discussion will be semantic quibbling.)

For me the presence of PEM in conditions demonstrably distinct to SEID or ME is potentially exciting, as, though we lose it as unique diagnostic factor, it may lead us to a better understanding of the underlying biological mechanism(s). Also given the current limited development of criteria to objectively measure PEM we can not exclude the possibility of it arising from diverse causes.

Further whilst we have different researchers defining PEM variously as increased fatiguability in response to a single activity episode that bares little relationship to what is understood by many ME patients contrasted with others looking at two day exercise tests, which is more likely to reflect the subjective ME patient experience, interpreting research results is potentially problematic.

[added - this study is based on assessment of SEID using a questionnaire, with PEM identified from the answers to four questions. Have not yet located a link to the text of the questionnaire.]

 

[cassava7]

Interesting to see a study from De Korwin's group. While he has taken a step back from CFS-related activities -- he is the former president of the French CFS association (ASFC) --, he continues to see CFS patients in his internal medicine department at the university hospital of Nancy. It should be noted that he believes in a biopsychosocial etiology to ME/CFS, and unfortunately prescribes graded exercise therapy to some patients.

The questionnaire in this study was designed in 2016 after the SEID criteria were published, with input from the ASFC. I will try to obtain it and translate it into English.

 

[Mithriel]

Unless their PEM included feeling fine then suddenly collapsing and realising they did too much 3 days ago they do not have a similarity to ME.

"Experts" took the exhaustion and sudden episodes of disabling fatigue (paralysis like in many cases) and shoehorned it into chronic fatigue and said our symptoms were just like everyone else's. Now they are taking PEM and shoehorning it into feeling bad after exercising - and are they including lifting a glass of water as exercise? - then being amazed at how similar we are to other illnesses.

If you ignore all the ways our symptoms differ from the experience of other people then you are bound to make everything seem similar.

 

[Ravn]

This either suggests common pathology, or a lack of specificity of the SEID criteria, or poor operationalisation of the SEID criteria.

Have only read the abstract but poor operationalisation seems to be the most likely explanation here. Alternatively this is spectacularly poor wording:

post-exercise discomfort

 

[Hoopoe]

The PEM related questions lack specificity:

After sustained physical or intellectual activity, or prolonged standing:
“I feel crashed, relapsed or collapsed”
“I feel mentally worn out after light effort”
“I feel physically emptied after moderate exertion”
“The more effort my activities require me to put, the more I pay the price in return”

 

[alex3619]

Unless their PEM included feeling fine then suddenly collapsing and realising they did too much 3 days ago they do not have a similarity to ME.

I am not convinced that any survey questions can come close to operationalizing a definition of PEM. Objective tests are needed, including studies on ME patients for those tests. So far the only one that comes close is the 2 day CPET and it has problems including it is difficult to do in large studies.

 

[Hutan]

The delay between the fatigue onset and the diagnosis was substantial, with an average of 4 years, PPBL diagnosis being always made after fatigue occurrence.

The fatigue predates the PPBL diagnosis.

Despite my initial reaction to the abstract, the study seems well-intentioned. It appears that these people with PPBL have been having their symptoms (which do seem to be ME/CFS-like) dismissed or given little recognition by doctors. So, this study aimed to acknowledge them.

The clinical picture seems to be a muddle of overlapping conditions, for example:

When focusing on the single fatigue item, out of the 19 patients with highly disabling fatigue, 14 had antinuclear antibodies and 3 had clinical autoimmune disease. Though pains are not included in SEID criteria, patients reporting pain had a more severe SEID and positive biological investigations for autoimmunity.

Two patients presented with psoriasis and 12 (31%) presented with autoimmune disease: 4 patients with an inflammatory rheumatologic disease (2 rheumatoid arthritis, 2 ankylosing spondylitis), 4 with auto-immune thyroiditis, 1 with type 1 diabetes, 1 with primary biliary cholangitis, 1 with Crohn’s disease, and 1 with Sjögren’s syndrome. Thirteen (34%) patients had positive laboratory test for dysimmunity.

The result, along with the uncertainty about what participants in this study understood about PEM, is, for me, that it is a bit hard to know what to think.

To conclude, this study identified key complaints often reported by patients with PPBL. Nearly three-quarters of the subjects met the SEID criteria characterized by an original questionnaire. Most patients experienced chronic fatigue with a substantial impairment, unrefreshing sleep, PEM, cognitive disorders, and OI that always preceded biological PPBL diagnosis. These symptoms and widespread pains were the most severe and persistent problems in the previous six months, overlapping with the SEID criteria since initial presentation. It would be interesting to confirm these results with a similar survey in a larger worldwide cohort. To clarify the controversial relationship between these two entities, we also plan to conduct the reverse screening for binucleated lymphocytes in patients with ME/CFS according to the SEID criteria.

Good that they are going to screen people with ME/CFS for binucleate lymphocytes.

It sounds as though this PPBL is something to find out more about. Perhaps it is a condition that is often misdiagnosed as ME/CFS, perhaps PPBL is part of a spectrum of related disorders, perhaps it offers a clue about the pathology of ME/CFS?

I wonder if PPBL was involved in some of the seeming reductions in symptoms that Fluge and Mella observe when treating people for lymphoma?

 

[Jonathan Edwards]

I think there may be a major spurious element to this. PPBL seems really just to mean people with rather high B cell counts, and B cell counts are known to vary greatly without it mattering. Maybe starting off with 'patients' with PBBL is a self-fulfilling move. What if we change the definition a bit:

Introduction: People wit purplish-blue locks, i.e. people who like to dye their hair bluish, (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. When these people feel unwell and present as 'patients' without any other obvious reason for being ill than PBBL they often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk might be the development of blue fingernail in some cases (although we don't have any data). To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry.

If you take any group of people who feel ill and therefore present as 'patients' without any definable cause then the chances are their symptoms will be vaguely like ME.

And of course people with ME who happen to fall into this category will be included and will very much seem to have ME.

 

[Hutan]

PPBL seems really just to mean people with rather high B cell counts

Yeah, I don't know how unusual the symptoms are. It does sound a bit poorly defined.

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare disorder, which mostly affects middle-aged women and is associated with smoking.1 It is characterized by the persistent expansion of CD27+IgM+IgD+ B cells, the presence of circulating binucleated lymphocytes and increased IgM serum levels.1, 2, 3 Furthermore, PPBL is associated with HLA-DRB1*07 carriership and a supernumerary isochromosome +i(3q) in a small proportion of lymphocytes.

from https://www.nature.com/articles/leu201477

 

[Jonathan Edwards]

It does sound a bit poorly defined.

Yes, I did see the reference to Dr7 and the isochromosome which may make it worth considering an entity of genuine interest. Maybe having a lot of confused lymphocytes is one way in to ME. But ti sounded as if most people with PPBL were pretty well.

There may be a clue here but the study looks vey much at risk of what I might call ascertainment bias- for various reasons.

 

[Hutan]

https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-015-1742-3
Persistent polyclonal binucleated B-cell lymphocytosis and MECOM gene amplification
This study suggests PPBL is not just higher than normal levels of lymphocytes - only 69% of the 150 diagnosed patients had elevated lymphocyte numbers:

PPBL was diagnosed in 150 untreated patients, whose main characteristics are described in Table 1. Sixty-nine percent of cases showed an absolute lymphocytosis >4 × 109/L, with a mean percentage of binucleate lymphocytes at 3.9 %

With only around 4% of lymphocytes being binucleate, perhaps it is something that could be missed if it wasn't specifically looked for?

This paper suggests that having binucleate lymphocytes is not a common thing - being present just in PPBL, people with MS being treated with a specific drug, and people exposed to ionising radiation.

But it sounded as if most people with PPBL were pretty well.

I think that idea is what the paper that is the subject of this thread was trying to disagree with - it is saying that actually these people aren't at all well; their reports of symptoms have not been given enough weight.

All but two patients with PPBL suffered from a progressive long-lasting fatigue.
Nearly half the patients felt “crashed, relapsed, or collapsed” more than half the time. In addition, 75% of the respondents felt significantly more “mentally tired after the slightest effort”. Thirty-two (82%) patients highlighted severe fatigue after mild exertion.

 

[Jonathan Edwards]

All but two patients with PPBL suffered from a progressive long-lasting fatigue.

Yes, but well people with PPBL probably mostly never get diagnosed and people with more specific symptoms may well get them attributed to something else. I am not saying that is the whole story but working from a register rather than doing an epidemiological study is always liable to throw up ascertainment biases.

I guess maybe what might be more useful would be to compare with other conditions. Chronic lymphatic leukaemia, for instance, is often associated with fatigue but not with the clinical picture of ME.


We also come back to the fact that diagnostic criteria are rarely relevant to making a clinical diagnosis. Making a clinical diagnosis depends on huge numbers of inferences from combinations of facts. We forget how complex our recognition mechanisms are. Diagnostic criteria are only ever crude pigeonholing tools for research and admin purposes.

 

[Mithriel]

When the report came out that defined SEID it was a major disappointment. ME is a serious life changing disease where there is an abnormal response to exertion but that abnormality shows itself by varying symptoms. Why did they think it was so necessary to only have 3 symptoms?

Fatigue is so commonplace in disease that it can almost be taken for granted so it is not useful in specifying any one in particular.

Unrefreshing sleep is not universal in ME. Sleep problems actually are near universal but they take many forms.

Unrefreshing sleep is often twisted to mean feeling just as bad in the morning as when you went to bed. That is a way of saying that recovery from exertion in ME is delayed beyond normal as seen in CPET testing.

So, basically, one of 3 criteria has to be taken apart to get a meaning that is relevant to ME.

Then there is PEM. Snappy but so complicated to define that on this forum we have been trying for years to convey what it means. PEM, a short phrase which needs a book to explain what it means.

What it comes down to is that anyone who wants to say someone has SEID can make them fit.

 

[Milo]

What has it got to do with smoking though?

how many of us living with ME have chronic, sustained, out of range lymphocytosis?

 

[Jonathan Edwards]

What has it got to do with smoking though?

That just seems to be an observation on this pattern of B cell increase. Smoking is the most important environmental causal factor for rheumatoid arthritis so we know it does things to B cells.

how many of us living with ME have chronic, sustained, out of range lymphocytosis?

B cell counts in ME have a normal range in samples of about 50 cases but PPBL is said to be rare. What is not entirely clear is how it is defined.

 

[Milo]

Smoking is the most important environmental causal factor for rheumatoid arthritis so we know it does things to B cells

I did not know that, but of course smoking is really bad for anybody, we have known that for decades now. And of course, never smokers, and minimally exposed patients with RA have gotten RA.

i struggle with ‘causal factor’- can we say for sure that smoking is the cause, or is it linked, or confounding variable? The link from smoking with RA would certainly be weaker than lung cancer and emphysema, no?

 

[Jonathan Edwards]

i struggle with ‘causal factor’- can we say for sure that smoking is the cause, or is it linked, or confounding variable? The link from smoking with RA would certainly be weaker than lung cancer and emphysema, no?

I think the causal role of smoking in RA is pretty well established and it is not small, even if not as dramatic as lung cancer. I think there is a specific link between smoking, antibodies to citrullinated peptides and HLA DR4. It looks as if cigarette smoke contains innate chemical danger signals (seems unsurprising) and RA is to do with dysregulation of innate signals that control antibody production.

Also, in the 1970s and 1980s, when smoking in women was probably at its height, vascular complications of RA like leg ulcers more or less exclusively occurred in smokers. We don't see those now.

 

[Trish]

That's fascinating, I didn't know that. Can you estimate what proportion of people with RA have smoking as the causal factor? And are there other known causal factors?