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.