What is a safe lymphocyte count; 500, 800 or 1000/mm3?
In your peripheral blood, you have circulating leukocytes or white blood cells which help fight infections. When you get your blood results back you often get told your total white cell count or WCC. However, the WCC is a composite and includes different populations of cells. The white cells can be divided into the lymphocyte and non-lymphocyte populations. The non-lymphocyte population or the innate (hard-wired) immune cells are often referred to as polymorphs (neutrophils, eosinophils and basophils) and monocytes (circulating macrophage precursors).
When it comes to lymphocytes we divide them into so-called B-cells and T-cells. B-cells come from the bone marrow; yes B is for Bone. In contrast, T-cells from the thymus; T is for Thymus, which is sweetbread if you like eating offal.
B-cells are specialised cells that use antibodies to recognise infections or cancers. On the other hand, T-cells use T-cell receptors for identifying infections or cancers. There are two broad categories of T-cells. CD4+ T-cells that generally react to foreign protein (generally infections) and cancer proteins (onco-antigens) that circulate outside of cells (extracellular antigens). In contrast, the CD8 pathway is for recognising foreign proteins that are expressed inside cells such as viruses. The CD4 cells tend to orchestrate an immune response and help other cells clear the infection; for example, the stimulate B-cells to make antibodies and produce molecules that attract macrophages to the site of inflammation. A small population of CD4 cells cab cytotoxic and kill target cells directly by producing proteins that kill the target cell.
In comparison, CD8 cells are much more sensitive to being activated and typically do their own killing; this is why a subset of them are called cytotoxic T-lymphocytes (CTLs). CTLs are like military commandos; they survey the body and if they identify a cell that is infected with a virus they kill it there and then. This is why CD8 CTLs are so important in fighting viral infections such as COVID-19.
In a routine blood count, we don’t get back detailed numbers of the lymphocyte subpopulations we simply get the absolute lymphocyte count (ALC), which includes both the B-cells and T-cells.
So what is a normal lymphocyte count?
There are different ways of defining a normal laboratory range in medicine. The most popular way is to take thousands of healthy volunteers of all ages and sexes and measure their ALC and then work out the normal range using the 2.5th and 97.5th percentile on the assumption that 2.5% of the population has abnormally low counts and 2.5% have abnormally high counts. If you do this then you get a different normal range for different populations; for example in the large Danish study below the normal range for Danish people, using this method is defined as 1.1–3.7×109/L or 1100 – 3700/mm3.
To simplify and standardise things the WHO (World Health Organisation) has defined the lower limit of normal as 1.0×109/L or 1000/mm3. This is not necessarily correct because at a population level people with an ALC of 1000/mm3 are at a greater risk of having an infection and dying than someone with an ALC higher than this. What I am trying to say is that the so-called ‘normal’ cutoffs are not black and white boundaries and that the risk of infections is affected by many other factors, in particular age and comorbidities.
For example, the older you get the greater the proportion of your lymphocytes in your peripheral blood become dedicated to fighting latent or dormant viruses such as cytomegalovirus (CMV) and Epstein-Bar virus (EBV). This means older people have less naive lymphocytes to fight new infections. So a younger person with an ALC of 1000/mm3 may have 10-20% of the peripheral T-cells dedicated to controlling CMV and EBV and someone over the age of 70 may be using 60-70% of their T-cells to keep CMV and EBV controlled. When the latter happens we refer to the T-cell repertoire (variability of all the T-cell clones) as being restricted and is indicative of immunosenescence, i.e. the majority of peripheral T-cell clones can’t be used for anything else other than controlling CMV and EBV. This may explain why an older age is such an important risk factor for developing severe COVID-19.
The WHO has also created grades of lymphopaenia based on the ALC:
- Grade 0 >= 1000/mm3
- Grade 1 = 800-999/mm3
- Grade 2 = 500-799/mm3
- Grade 3 = 200-499/mm3
- Grade 4 < 200/mm3
I know that a lot of you are confused because some neurologists are saying that you are at high risk of severe COVID-19 if your ALC is less than 1000/mm3, others like me are saying that you are only at increased risk if your counts are less than 800/mm3 and still others who are saying that you should only worry if your ALC is less than 500/mm3.
Apologies, about the confusion, but as with most things in medicine nothing is certain or definitive; it is a soft call and advice also needs to be pragmatic and generalisable to the wider MS population.
For example, if you are treated with alemtuzumab your counts may never get above 1000/mm3 before the next course. It is clear that the infection risk post-alemtuzumab drops quite precipitously after 3-6 months when most patients have ALC above 500/mm3. So should we use 500/mm3 then as the safe limit? I say no because most of the patients in the alemtuzumab trials were young and had no comorbidities. Therefore, this advice does not take into account immunosenescence and other factors. So then why not recommend 1000/mm3? I personally think this is too conservative and means people will be hyper-cautious when they don’t necessarily have to be.
To try and explain the subtleties to you I have hacked the data from the large Danish study below to show that infection risk increases linearly below an ALC of ~1700/mm3. Even at a WHO grade zero or ‘normal’, there is a 26% higher risk of infection, at Grade 2 (800/mm3 cut-off) there is a 44% increase in risk and with Grade 3 (500/mm3) it starts to increase rapidly (+76%).
I hope you now understand the complexities about setting a normal lymphocyte range and advice about what is safe. Since I was taught how to use azathioprine, one of the original immunosuppressants, I have always used 800/mm3 as my target cut-off for pragmatic reasons. I think the evidence supports this position, but I am sure many of my critics will have other opinions.
What COVID-19 is teaching me is that the MS community is not comfortable with uncertainty, but as we live in an uncertain world you are going to have to adapt to conflicting advice. Until data emerges we have only opinions, this is just one opinion, which may differ from the opinion you were given last week.
Warny et al. Lymphopenia and Risk of Infection and Infection-Related Death in 98,344 Individuals From a Prospective Danish Population-Based Study. PLoS Med, 15 (11), e1002685 2018 Nov 1 eCollection Nov 2018.
Background: Neutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We, therefore, tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population.
Methods and findings: Of the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1-3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28-1.56) for any infection, 1.31 (1.14-1.52) for pneumonia, 1.44 (1.15-1.79) for skin infection, 1.26 (1.02-1.56) for urinary tract infection, 1.51 (1.21-1.89) for sepsis, 1.38 (1.01-1.88) for diarrheal disease, 2.15 (1.16-3.98) for endocarditis, and 2.26 (1.21-4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37-2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68.
Conclusions: Lymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data.
CoI: multiple
As a grade 2 Lymphopaenia (0.6) patient following second year of Cladribine treatment last July, should I have received a letter indicating that I’m in the ‘extremely vulnerable’ category?
Yes, based on the NHSE and PHE guidelines. But no based on the ABN guidelines. You are now outside the at-risk period post-cladribine (6-months) and hence your immune system has recovered sufficiently to deal with viral infections.
Thankyou. Take care.
So having read this and trying to understand the complexity of ALC, I have come to the conclusion that with a lymphocyte count of 0.20 I’m at very high risk of contracting Covid-19 at this time!? Having finished Cladribine year 1 on the 21st February 2020, how long do I have take extra stringent measures to prevent contracting Covid-19, is this likely to be beyond the 12 weeks? I seem to one of only a few with an extremely low lymphocyte count, so looking for advice! My consultant is; D Paling.
Regards Gill
Did you start at year 0 or 1 so have you finished first cycle or second cycle, if it is your first cycle the second cycle will be delayed. Low lymphocytes occur rarely but does happen. The risk of contracting COVID may not be based on your lymphocyte level, it is perhaps based on your avoidance to infection. Hand washing and social distancing can help you do this. I hope will let you know. Anti-virals are being trialled as are vaccines.
Below 200 you are at risk of opportunistic infections, I.e. CMV, pneumocystis, VZV, HSV as well.
I will comment on this next time I do a Q&A session on the COVID-19 & MS microsite.
First of all, I really appreciate you replying to my query – thank you.
In reply to your question I have completed both doses in year 1 and not due to start year 2 until January 2021.
Regards Gill
Thank u Prof G so much for answering this question I asked a number of times but always got non committal answer. If others like me are relaxed in taking risks and not always following guidelines to prevent infection. At least those below the borderline will take appropriate action knowing at least they are vulnerable. Hopefully saving lives. Even though my count has flat lined at 1.4 still not taking risks. But i suspect I’ve had it already!
Thanks Prof. G – the most informative post (or article) I have read in quite a while and one with special relevance to me, as it is to those who have commented before me.
One thing I note on my regular post DMT blood tests is that lymphocyte count varies over time, for me going from grade 0 to 2 over the course of 3 months approximately 10 months after my last treatment. Can you or one of your colleagues elaborate what kind of range in variation one might expect and how fast changes happen? When should we be consdered and contact our consultants or practitioners? Are the measures accurate or would this vary if you did another test a few hours later? I’d assume variation has multiple causes such as response to DMT’s, fighting viruses and illness, or even level of hydration so it’ll rarely be possible to say why a particular change may occur.
A bit more information please!
The test or assay for doing a FBC (full blood count), WCC (white cell count) and ALC (absolute lymphocyte count) has a day-to-day variation of about 5-10%. So a count of 2000, if repeated could be anything from 1800 to 2200. This is why we rarely make decisions on one reading and often request a second assay.
Similarly of the blood tube is not processed quickly the cells can breakdown and/or clump and give a false positive low reading.
Infections and medications, in particularly steroids, can raise or lower the ALC.
What would you expect a lower end lymphocyte count be after 3 months of 1mg Mayzent? I fell from 2.69 to .38. Thank you for the daily posts!
In mice and rats the S1P1 compounds work with a day or two
thank you, this is interesting and you are correct it has been confusing.
On a practical level should grade 2 people be classed as extremely vulnerable? I am prepared to be isolated for 12 weeks but wonder if it is excessive. I do not feel as though I am as at as much risk as the people in the extremely vulnerable group who are shielded.
All is uncertain but I have to make a decision and just need some guidance. But even if shielded at some point I have to come out and then I’ll just be hit with it. Guess the hope is that the NHS will be over the worst by mid-June.
Keep safe all PwMS and all healthcare workers
Re: “… should grade 2 people be classed as extremely vulnerable?”
Only if they have other identifiable risk factors, i.e. greater than 60 years of age, are smokers, have asthma or other lung diseases, are obese, have hypertension or other cardiac disorders.
thank you!
>60 with controlled hypertension but healthy apart from my MS.
This is very helpful for me to make my decisions.
All best wishes to the team and many thanks
I will answer this question on my COVID-19 & MS microsite in more detail later.
Informative article . I am 39 years old . I regularly go for blood checkups ( sometimes twice in a year) My lymphocytes were 39.1 % in 2017 and in 2018 it increased 44 % and in 2019 it was 45 % and now in this month ( Nov 2020) It increased to 47.2 %. . My initial reports says ” mild relative lymphocytosis” and now they marked it as ” relative lymphocytosis”. What could be the cause . I dint have any symptoms ( I got tingling on face from last couple of days. Is this something to do with it? ) .
Hi
I have been on Tecfidera for 7+ years now. My lymphocytes pre-MS were 1.5 to 2.5. After 12mo taking Tefidera they have dropped to between as low as .4 and high as .8 and remained in this range for 6+ years. I have two friends who are also on Tecfidera and they are both at average 1.5 – everyone is different. My Neuro told me I was what is considered super-performer on the drug. Meaning it really works to reduce my WC counts. However with COVID I have been reading that lymphocyte counts are very important and they drop considerable in attempts to recover from it. This worries me should I catch it. We have been checking my blood every 3 months. My current TLC in Dec was 0.6. (prior 0.7, 0.6 , 0.4) After research I believe I am a grade 2, I am 48 and considered obese at BMI of 34% with no other factors. Would this be considered high risk of COVID? I am so considering reducing my Tecfidera to 1 – 240 mg pill a day instead of 2, in hopes that it might start to bring up my TLC. Thoughts? Or I am even considering going off it all together for a different treatment. My Nuero just keeps saying as long at it is not below 0.5, I am fine. BUT as you mentioned it is all opinion. I feel even at 0.6 I am at heightened risk and with the research I done recently – they are finding out that with COVID Lymphocytes play a very important role in recovery.
Thanks!
Shay