Abstract
Objective
The aim of this study was to determine the prevalence of persistent lymphopaenia, defined as an absolute lymphocyte count (ALC) < 1.0 × 109/L on both the first and second intensive care unit (ICU) days in patients with sepsis and the association of persistent lymphopaenia with advanced organ support.
Design, setting, and participants
A prospective, multicentre, binational point prevalence study of adult patients treated in participating ICUs in June 2023 was conducted.
Main outcome measures
Main outcome measures included prevalence of persistent lymphopaenia in patients with sepsis versus those without sepsis, hospital and ICU mortality, length of stay, and organ support patterns.
Results
Among 829 adult patients in 59 ICUs, 307 (37%) had persistent lymphopaenia, and 338 (40.8%) met sepsis criteria. Persistent lymphopaenia was associated with greater illness severity (mean Acute Physiology and Chronic Health Evaluation II score: 19.4 vs. 16.8, p < 0.001). Persistent lymphopaenia was more common in patients with sepsis than in those without sepsis (44.7% vs. 31.8%, p < 0.001); this difference remained after adjusting for predefined covariates (odds ratio: 1.51, 95% confidence interval: 1.12–2.03, p = 0.008). For patients with sepsis and persistent lymphopaenia, there was a 6% increase in mortality compared to those without lymphopaenia, although this did not reach statistical significance. For patients without sepsis, hospital length of stay was 16.5 days in those who had persistent lymphopaenia versus 14.4 days in those without persistent lymphopaenia (95% confidence interval: 0.5–3.7, p = 0.01).
Conclusion
Persistent lymphopaenia is common in critically ill patients, particularly those with sepsis. Future prospective and interventional investigations are required to clarify the clinical significance of persistent lymphopaenia in critically ill adults and its potential as a therapeutic target.
Keywords: Lymphocyte, Sepsis, Immunosuppression, Mortality
1. Introduction
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.1 The Global Burden of Disease 2021 Global Sepsis Collaborators estimated that sepsis accounted for approximately 21.4 million deaths worldwide, representing 31.5% of total global deaths.2 The Australian Commission Sepsis Epidemiology Report (2025) reported 84,000 public hospital separations with sepsis in 2022–2023, with one in seven sepsis cases resulting in death.3 Among survivors in high-income countries, the hospital readmission rate approaches 41%, highlighting the substantial societal and healthcare burden of sepsis.4
Sepsis-associated immune dysfunction is commonly linked to the development of an immunosuppressive phenotype.5 Lymphopaenia, a pathological reduction in circulating lymphocytes, including adaptive immune T and B lymphocytes as well as innate natural killer cells, represents a key feature of this immunosuppressive state.6 Persistent lymphopaenia has been associated with increased mortality across critically ill patient populations,7 including sepsis,8,9 and trauma.10,11 Furthermore, persistent lymphopaenia is also associated with increased burden of invasive treatment modalities, including mechanical ventilation, vasoactive drug use, and renal replacement therapy (RRT).7 Consequently, there is growing interest in whether treating lymphopaenia may improve health-related outcomes in critically ill patients with and without sepsis.12,13
At the onset of sepsis, lymphocyte count can decrease due to increased expression of inhibitory checkpoint receptors on T cells, including programmed death 1 (PD-1),14 accompanied by a reduction in interleukin-7 (IL-7) receptor expression.15 The combination of T-cell exhaustion and impaired cytokine responsiveness 16 fosters a phenotype in which apoptosis outweighs proliferation. Timely restoration of immune balance has been associated with improved outcomes.17 Additionally, immunosuppressive therapies, including corticosteroids, may contribute to persistent lymphopaenia.18 To further characterise the prevalence and clinical significance of lymphopaenia among critically ill adults in Australasia, we conducted a point prevalence study. Our primary objective was to determine the proportion of critically ill adults with sepsis admitted to Australasian intensive care units (ICUs) who exhibited persistent lymphopaenia, defined as an absolute lymphocyte count (ALC) below 1.0 × 109/L on the first 2 days of ICU admission. A secondary objective was to describe patterns of organ support in patients who had exhibited persistent lymphopaenia with sepsis, compared to those without sepsis.
2. Methods
2.1. Study setting and population
This was a prospective, multicentre, point prevalence study of ICU patients. Data collection was coordinated through the Point Prevalence Program (PPP) of the Australian and New Zealand Intensive Care Society Clinical Trials Group and The George Institute for Global Health. Participating ICUs could choose to participate on one of 2 days in June 2023, with data collected for 24 h on the study day and follow-up conducted at 28 days after the study day.
Data were collected across 59 ICUs. The ICU level reported is based on the College of Intensive Care Medicine of Australia and New Zealand minimum standards for ICUs. The document describes a level III ICU as a tertiary referral unit.19 Study data were collected and managed using Research Electronic Data Capture (Vanderbilt University, Nashville, United States of America [USA]) tools hosted at The George Institute for Global Health.20,21 Collected data included full blood count, Acute Physiology and Chronic Health Evaluation (APACHE) III score,22 and outcome data. Demographic data included age and sex.
We used APACHE III admission diagnostic codes to identify patients admitted to the ICU with infection, and the Sequential Organ Failure Assessment score23 of two or more to indicate qualifying organ dysfunction.7
Patients were excluded if they were younger than 18 years or had a diagnosis of leukaemia, lymphoma, or non-corticosteroid-related immunodeficiency, including human immunodeficiency virus/acquired immuneodeficiency syndrome.
2.2. Variable of interest
In this study, the variable of interest is persistent lymphopaenia, defined as an ALC < 1.0 × 109/L on both the first and second days following ICU admission.
2.3. Outcomes
The primary outcome was the prevalence of persistent lymphopaenia in our cohort of critically ill adults with and without sepsis.
The secondary outcomes included:
-
•
ICU mortality
-
•
Hospital mortality
-
•
Treatment with mechanical ventilation
-
•
Treatment with inotropes or vasopressors
-
•
Initiation of new RRT
-
•
Length of hospital stay
-
•
Length of ICU stay
Secondary outcomes were categorised in two populations: (i) patients with sepsis and (ii) patients without sepsis.
All secondary outcomes were collected at the end of day 28.
2.4. Statistical analysis
Baseline characteristics were described according to the presence of lymphopaenia. Categorical variables were summarised as frequencies and percentages (%), and continuous variables as means and standard deviations.
The primary outcome (presence of lymphopaenia) was analysed using a generalised mixed model with sepsis status as a fixed effect and study site as a random effect. The effect of sepsis was reported as an odds ratio (OR) with a 95% confidence interval (CI) and corresponding p value. As a sensitivity analysis, the primary outcome was reanalysed with adjustment for type of admission (surgical vs. nonsurgical).
Secondary outcomes were analysed using logistic (for binary outcomes) and linear (for continuous outcomes) mixed models, with persistent lymphopaenia as a fixed effect and study site as a random effect. The effect of persistent lymphopaenia was reported as an OR or mean difference for categorical and continuous variables, respectively, with 95% CIs and p values. As a sensitivity analysis, secondary outcomes we reanalysed using an alternative ALC threshold <0.75 × 109/L to define persistent severe lymphopaenia, consistent with the criteria described by Adigbli et al. (2023),7 in place of the primary threshold of 1.0 × 109/L.
For both primary and secondary outcomes, sensitivity analyses were performed adjusting for age, sex, APACHE III score, and the presence of chronic health points greater than 0.
Statistical significance for all analyses was determined using 2-sided type-I error α = 0.05. Analyses were performed using R software (R Core Team, Vienna, Austria), version 4.5.1. The PPP has ethical approval from the Sydney Local Health District Ethics Review Committee (reference no.s: X18-0511 and 2019/ETH07327).
3. Results
Fifty-nine ICUs participated in the PPP on 6th and 21st June 2023. The characteristics of the participating sites are presented in Table 1. Admission source data were missing for one patient. After exclusion of 95 patients due to missing ALC values, the total sample size was 829 patients. The mean age was 60.5 (standard deviation: 16.5) years; 42% of participants were female patients.
Table 1.
Site characteristics.
| Characteristic | Total sites, n |
|---|---|
| Country | |
| Australia | 48 |
| New Zealand | 11 |
| ICU level | |
| Level III | 41 |
| Level II | 17 |
| Level I | 0 |
| Location | |
| Metropolitan | 53 |
| Regional or remote | 6 |
| Sector | |
| Public | 50 |
| Private | 5 |
| Combined | 4 |
Level I provides basic multisystem life support for up to 24 h, including mechanical ventilation and simple cardiovascular monitoring.
Level II provides complex multisystem life support for several days, including mechanical ventilation, extracorporeal renal support, and invasive cardiovascular monitoring.
Level III provides complex multisystem life support for an indefinite period and functions as a tertiary referral service with the laboratory and clinical infrastructure necessary to support this role.
The Modified Monash (MM) Model is used to define a location as metropolitan, regional or remote. The scale measures remoteness and population size on a scale of MM categories MM 1 to MM 7.
Metropolitan (MM 1).
Regional: Remote (MM 2 – MM 7).
Of the 829 participants with an ALC measurement, 307 (37.0%) had an ALC < 1.0 × 109/L on both the first and second day of ICU admission, meeting the prespecified definition of persistent lymphopaenia. A total of 338 participants (40.8%) met the criteria for sepsis, which was more common in those with persistent lymphopaenia (Table 2). Participants with persistent lymphopaenia were older than those without persistent lymphopaenia (mean age: 64.3 years vs. 58.2 years). The mean APACHE II score was higher among participants with persistent lymphopaenia (19.4 vs. 16.8). Similarly, participants with persistent lymphopaenia had more chronic health points, as assessed by the APACHE III score, than those without persistent lymphopaenia (34.5 % vs. 19.3%); sepsis was more common in those with persistent lymphopaenia (49.2% vs. 35.8%) (Table 2).
Table 2.
Baseline characteristics.
| ALC < 1.0 × 109/L n = 307 | ALC ≥ 1.0 × 109/L n = 522 | Overall n = 829 | |
|---|---|---|---|
| Characteristic | Mean (SD) or n/N (%) | Mean (SD) or n/N (%) | Mean (SD) or n/N (%) |
| Age, years | 64.3 (15.2) | 58.2 (16.8) | 60.5 (16.5) |
| Female sex | 136/307 (44.3) | 212/522 (40.6) | 348/829 (42.0) |
| BMI, kg/m2 | 29.4 (9.7) | 30.4 (10.8) | 30.1 (10.5) |
| APACHE II score | 19.4 (7.6) | 16.8 (7.1) | 17.8 (7.4) |
| Total SOFA score | 8.8 (4.1) | 8.1 (4.1) | 8.4 (4.1) |
| Comorbidity (APACHE III chronic health points) | 106/307 (34.5) | 101/522 (19.3) | 207/829 (25.0) |
| Sepsis | 151/307 (49.2) | 187/522 (35.8) | 338/829 (40.8) |
| Mean ALC day 1, × 109/L | 0.5 (0.2) | 1.7 (2.0) | 1.3 (1.7) |
| Mean ALC day 2, ×109/L | 0.5 (0.2) | 1.7 (1.9) | 1.3 (1.6) |
| ICU admission source n/N (%) | |||
| Elective surgery | 38/306 (12.4) | 97/522 (18.6) | 135/828 (16.3) |
| Emergency surgery | 44/306 (14.4) | 77/522 (14.8) | 121/828 (14.6) |
| Emergency department | 104/306 (34.0) | 175/522 (33.5) | 279/828 (33.7) |
| Hospital ward | 65/306 (21.2) | 98/522 (18.8) | 163/828 (19.7) |
| Transfer from another hospital (except another ICU) | 37/306 (12.1) | 35/522 (6.7) | 72/828 (8.7) |
| Transfer from another ICU | 18/306 (5.9) | 40/522 (7.7) | 58/828 (7.0) |
| Primary non-operative ICU diagnosis n/N (%) | |||
| Respiratory | 69/218 (31.7) | 69/342 (20.2) | 138/560 (24.6) |
| Cardiovascular | 33/218 (15.1) | 69/342 (20.2) | 102/560 (18.2) |
| Infection | 54/218 (24.8) | 41/342 (12.0) | 95/560 (17.0) |
| Neurological | 20/218 (9.2) | 63/342 (18.4) | 83/560 (14.8) |
| Musculoskeletal | 9/218 (4.1) | 32/342 (9.4) | 41/560 (7.3) |
| Endocrine/metabolic | 7/218 (3.2) | 29/342 (8.5) | 36/560 (6.4) |
| Gastrointestinal/hepatic | 13/218 (6.0) | 22/342 (6.4) | 35/560 (6.3) |
| Renal/urological | 8/218 (3.7) | 10/342 (2.9) | 18/560 (3.2) |
| Malignancy/haematological | 5/218 (2.3) | 4/342 (1.2) | 9/560 (1.6) |
| Other | 0/218 (0.0) | 3/342 (0.9) | 3/560 (0.5) |
| Primary operative ICU diagnosis n/N (%) | |||
| Cardiac | 19/89 (21.3) | 60/180 (33.3) | 79/269 (29.4) |
| Gastrointestinal/hepatic | 26/89 (29.2) | 29/180 (16.1) | 55/269 (20.4) |
| Trauma/musculoskeletal/skin | 13/89 (14.6) | 32/180 (17.8) | 45/269 (16.7) |
| Neurosurgical | 17/89 (19.1) | 24/180 (13.3) | 41/269 (15.2) |
| Respiratory | 10/89 (11.2) | 11/180 (6.1) | 21/269 (7.8) |
| Vascular | 1/89 (1.1) | 10/180 (5.6) | 11/269 (4.1) |
| Renal/urological | 0/89 (0.0) | 9/180 (5.0) | 9/269 (3.3) |
| Gynaecological | 2/89 (2.2) | 2/180 (1.1) | 4/269 (1.5) |
| Endocrine/metabolic | 1/89 (1.1) | 3/180 (1.7) | 4/269 (1.5) |
ALC = absolute lymphocyte count; APACHE = Acute Physiology and Chronic Health Evaluation; BMI = body mass index; ICU = intensive care unit; SD = standard deviation; SOFA = Sequential Organ Failure Assessment.
3.1. Primary outcome
The prevalence of persistent lymphopaenia was higher among participants with sepsis than among those without, 151 of 338 (44.7%) versus 156 of 491 (31.8%), adjusted OR: 1.74 (95% CI: 1.30–2.33, p < 0.001) (Table 3 and Fig. 1).
Table 3.
Primary outcome: prevalence of persistent lymphopenia in patients with and without sepsis.
| Outcome: Persistent lymphopenia | Sepsis |
OR (95% CI) | p value | |
|---|---|---|---|---|
| Yes | No | |||
| n/N (%) | ||||
| Unadjusted analysis1 | 151/338 (44.7) | 156/491 (31.8) | 1.74 (1.30, 2.33) | <0.001 |
| Adjusted analysis2 | 151/338 (44.7) | 156/491 (31.8) | 1.51 (1.12, 2.03) | 0.008 |
ALC = absolute lymphocyte count; APACHE = Acute Physiology and Chronic Health Evaluation; CI = confidence interval; OR = odds ratio; persistent lymphopenia (ALC < 1.0 × 109/L).
Univariate logistic mixed model including site as a random effect.
Multivariate logistic mixed model including age, sex, APACHE II score, and presence of comorbidity (APACHE III chronic health points) as adjusted variables, and site as a random effect.
Fig. 1.
Absolute lymphocyte count (ALC) on days 1 and 2 of ICU admission, stratified by sepsis status. ALC = absolute lymphocyte count; CI = confidence interval; MD = mean difference.
3.2. Secondary outcomes
3.2.1. Patients with sepsis
The secondary outcomes have been reported in patients with sepsis; the results are presented in Table 4.
Table 4.
Secondary outcomes for patients with sepsis by persistent lymphopenia status (ALC < 1.0 × 109/L vs. ≥ 1.0 × 109/L).
| Outcome | ALC < 1.0 n = 151 | ALC ≥ 1.0 n = 187 | Unadjusteda |
Adjustedb |
||
|---|---|---|---|---|---|---|
| MD/OR (95% CI) | p value | MD/OR (95% CI) | p value | |||
| Binary outcomes, n/N (%) | ||||||
| Hospital mortality | 30/151 (19.9) | 26/187 (13.9) | 1.54 (0.86, 2.73) | 0.144 | 1.07 (0.57, 2.01) | 0.83 |
| ICU mortality | 19/151 (12.6) | 20/187 (10.7) | 1.20 (0.62, 2.34) | 0.590 | 0.80 (0.38, 1.67) | 0.55 |
| Mechanical ventilation | 78/151 (51.7) | 104/187 (55.6) | 0.86 (0.54, 1.37) | 0.536 | 0.99 (0.59, 1.67) | 0.98 |
| Inotropes or vasopressors | 116/151 (76.8) | 131/187 (70.1) | 1.44 (0.87, 2.39) | 0.156 | 1.41 (0.82, 2.42) | 0.21 |
| New renal replacement therapy | 20/151 (13.2) | 18/187 (9.6) | 1.48 (0.74, 2.98) | 0.269 | 1.39 (0.63, 3.06) | 0.41 |
| Continuous outcomes, mean (SD) | ||||||
| Length of hospital stay, days | 17.0 (8.0) | 16.7 (8.3) | 0.3 (−1.3, 2.0) | 0.684 | 0.6 (−1.2, 2.3) | 0.53 |
| Length of ICU stay, days | 11.6 (7.8) | 12.3 (8.9) | −0.4 (−2.2, 1.4) | 0.646 | −0.2 (−2.0, 1.6) | 0.86 |
ALC = absolute lymphocyte count; APACHE = Acute Physiology and Chronic Health Evaluation; CI = confidence interval; ICU = intensive care unit; MD = mean difference; OR = odds ratio; SD = standard deviation; persistent lymphopaenia (ALC < 1.0 × 109/L); nonpersistent lymphopaenia (ALC ≥ 1.0 × 109/L).
Univariate logistic or linear mixed model including site as a random effect.
Multivariate logistic or linear mixed model including age, sex, APACHE II score, and comorbidity (APACHE III chronic health points) as adjusted variables, and site as a random effect.
Treatment with invasive mechanical ventilation was provided to 78 of 151 (51.7%) patients with persistent lymphopaenia and 104 of 187 (55.6%) of those without persistent lymphopaenia (OR = 0.86; 95% CI: 0.54–1.37; p = 0.54).
Treatment with vasopressors and/or inotropes occurred in 116 of 151 (76.8%) of patients with persistent lymphopaenia, and 131 of 187 (70.1%) of those without persistent lymphopaenia (OR = 1.44; 95% CI: 0.87–2.39; p = 0.16).
Commencement of RRT occurred in 20 of 151 (13.2%) of patients with persistent lymphopaenia compared to 18 of 187 (9.6%) of those without persistent lymphopaenia (OR = 1.48; 95% CI: 0.74–2.98; p = 0.27).
For continuous secondary outcomes, the mean ICU length of stay was 0.4 days shorter (95% CI = −2.2 to 1.4; p = 0.65). The mean hospital length of stay was 0.3 days longer for patients with persistent lymphopaenia than for those without persistent lymphopaenia (95% CI = −1.3 to 2.0; p = 0.68).
ICU mortality was there in 19 of 151 (12.6%) of those with persistent lymphopaenia compared to 20 of 187 (10.7%) of those without persistent lymphopaenia (OR = 1.20; 95% CI, 0.62–2.34; p = 0.59).
In patients with sepsis, hospital mortality was there in 30 of 151 (19.9%) of those with persistent lymphopaenia, compared to 26 of 187 (13.9%) of those without persistent lymphopaenia (OR = 1.54; 95% CI: 0.86–2.73; p = 0.14), this difference was attenuated by adjustment for prespecified covariates (OR = 1.07; 95% CI: 0.57–2.01; p = 0.83).
3.2.2. Patients without sepsis
The secondary outcomes are reported for patients without sepsis, the results are presented in Table 5.
Table 5.
Secondary outcomes for patients without sepsis, by persistent lymphopenia status (ALC < 1.0 × 109/L vs. ≥ 1.0 × 109/L).
| Outcome | ALC < 1.0 n = 156 | ALC ≥1.0 n = 335 | Unadjusteda |
Adjustedb |
||
|---|---|---|---|---|---|---|
| MD/OR (95% CI) | p value | MD/OR (95% CI) | p value | |||
| Binary outcomes, n/N (%) | ||||||
| Hospital mortality | 20/156 (12.8) | 44/335 (13.1) | 0.96 (0.54, 1.71) | 0.900 | 0.77 (0.41, 1.45) | 0.41 |
| ICU mortality | 15/156 (9.6) | 31/335 (9.3) | 1.04 (0.55, 1.99) | 0.898 | 0.93 (0.46, 1.91) | 0.85 |
| Mechanical ventilation | 75/156 (48.1) | 162/335 (48.4) | 0.99 (0.66, 1.49) | 0.951 | 1.06 (0.65, 1.72) | 0.81 |
| Inotropes or vasopressors | 85/156 (54.5) | 198/335 (59.1) | 0.83 (0.56, 1.23) | 0.345 | 0.73 (0.47, 1.12) | 0.15 |
| New renal replacement therapy | 8/156 (5.1) | 21/335 (6.3) | 0.82 (0.35, 1.91) | 0.641 | 0.67 (0.27, 1.65) | 0.38 |
| Continuous outcomes, mean (SD) | ||||||
| Length of hospital stay, days | 16.5 (9.1) | 14.4 (8.2) | 2.1 (0.5, 3.7) | 0.010 | 2.1 (0.5, 3.8) | 0.01 |
| Length of ICU stay, days | 10.4 (8.6) | 9.7 (8.4) | 0.8 (−0.8, 2.4) | 0.309 | 1.0 (−0.6, 2.6) | 0.22 |
ALC = absolute lymphocyte count; APACHE = Acute Physiology and Chronic Health Evaluation; CI = confidence interval; ICU = intensive care unit; MD = mean difference; OR = odds ratio; SD = standard deviation. Persistent lymphopaenia (ALC < 1.0 × 109/L); nonpersistent lymphopaenia (ALC ≥ 1.0 × 109/L).
Univariate logistic or linear mixed model including site as a random effect.
Multivariate logistic or linear mixed model including age, sex, APACHE II score, and comorbidity (APACHE III chronic health points) as adjusted variables, and site as a random effect.
Treatment with mechanical ventilation was provided to 75 of 156 (48.1%) of patients with persistent lymphopaenia compared to 162 of 335 (48.4%) of those without persistent lymphopaenia (OR = 0.99; 95% CI = 0.66–1.49; p = 0.95).
Treatment with vasopressors and/or inotropes occurred in 85 of 156 (54.5%) of patients with persistent lymphopaenia, compared to 198 of 335 (59.1%) of those without persistent lymphopaenia (OR = 0.83; 95% CI = 0.56–1.23; p = 0.35).
Initiation of RRT occurred in 8 of 156 (5.1%) of patients with persistent lymphopaenia compared to 21 of 335 (6.3%) of patients without persistent lymphopaenia (OR = 0.82; 95% CI = 0.35–1.91; p = 0.64).
For continuous secondary outcomes, the mean hospital length of stay was 2.1 days longer in patients with persistent lymphopaenia than in those without persistent lymphopaenia (95% CI = 0.5 to 3.7; p = 0.01). The mean ICU length of stay was 0.8 days longer (95% CI = −0.8 to 2.4; p = 0.31).
ICU mortality was 15 of 156 (9.6%) in patients with persistent lymphopaenia, compared to 31 of 335 (9.3%) in those without persistent lymphopaenia (OR = 1.04) (95% CI = 0.55–1.99; p = 0.90).
In patients without sepsis and with persistent lymphopaenia, hospital mortality was 20 of 156 (12.8%), compared to 44 of 335 (13.1%) in those without persistent lymphopaenia (OR = 0.96; 95% CI = 0.54–1.71; p = 0.90).
3.3. Sensitivity analysis
In the primary adjusted model, patients with sepsis had significantly higher odds of persistent lymphopaenia than those without (44.7% vs. 31.8%; adjusted OR: 1.51; 95% CI: 1.12–2.03; p = 0.008). This association was robust to further adjustment for operative versus non-operative status in a sensitivity analysis (adjusted OR: 1.49; 95% CI: 1.10–2.02; p = 0.01) (Table S1).
In an adjusted analysis, patients who received steroids had over three times the odds of persistent lymphopaenia compared to those who did not (60.5% vs. 32.5%; adjusted OR = 3.19; 95% CI: 1.95–5.21; p < 0.001) (Table S2).
In patients with sepsis, secondary outcomes were analysed using an ALC threshold <0.75 × 109/L to define severe persistent lymphopaenia. These results are presented in Table 6.
Table 6.
Sensitivity analysis: Secondary outcomes for patients with sepsis, by persistent lymphopenia status (ALC < 0.75 × 109/L vs. ≥ 0.75 × 109/L).
| Outcome | ALC < 0.75 n = 104 | ALC ≥ 0.75 n = 239 | Unadjusteda |
Adjustedb |
||
|---|---|---|---|---|---|---|
| MD/OR (95% CI) | p value | MD/OR (95% CI) | p value | |||
| Binary outcomes, n/N (%) | ||||||
| Hospital mortality | 25/104 (24.0) | 33/239 (13.8) | 1.98 (1.11, 3.53) | 0.022 | 1.47 (0.79, 2.76) | 0.22 |
| ICU mortality | 16/104 (15.4) | 25/239 (10.5) | 1.56 (0.79, 3.06) | 0.199 | 1.10 (0.53, 2.29) | 0.80 |
| Mechanical ventilation | 53/104 (51.0) | 131/239 (54.8) | 0.84 (0.51, 1.38) | 0.489 | 0.94 (0.53, 1.66) | 0.83 |
| Inotropes or vasopressors | 84/104 (80.8) | 166/239 (69.5) | 1.86 (1.05, 3.29) | 0.033 | 1.90 (1.03, 3.50) | 0.04 |
| New renal replacement therapy | 17/104 (16.3) | 21/239 (8.8) | 2.11 (1.04, 4.29) | 0.039 | 2.08 (0.94, 4.60) | 0.07 |
| Continuous outcomes, mean (SD) | ||||||
| Length of hospital stay, days | 17.5 (8.2) | 16.5 (8.1) | 0.8 (−1.0, 2.6) | 0.379 | 1.2 (−0.7, 3.0) | 0.22 |
| Length of ICU stay, days | 12.0 (8.0) | 12.0 (8.6) | 0.0 (−1.9, 1.9) | 0.975 | 0.1 (−1.8, 2.0) | 0.91 |
ALC = absolute lymphocyte count; APACHE = Acute Physiology and Chronic Health Evaluation; CI = confidence interval; ICU = intensive care unit; MD = mean difference; OR = odds ratio; SD = standard deviation. Persistent lymphopaenia (ALC < 1.0 × 109/L); nonpersistent lymphopaenia (ALC ≥ 1.0 × 109/L).
Univariate logistic or linear mixed model including site as a random effect.
Multivariate logistic or linear mixed model including age, sex, APACHE II score, and comorbidity (APACHE III chronic health points) as adjusted variables, and site as a random effect.
Treatment with mechanical ventilation did not differ between patients with severe persistent lymphopaenia and those with an ALC > 0.75 × 109/L (OR = 0.84; 95% CI = 0.51–1.38; p = 0.50).
Patients with severe persistent lymphopaenia were more likely to require treatment with vasopressors and/or inotropes compared to those with an ALC > 0.75 × 109/L (OR = 1.86; 95% CI = 1.05–3.29; p = 0.03).
Patients with severe persistent lymphopaenia required more RRT initiation compared to those with ALC > 0.75 × 109/L (OR = 2.11; 95% CI = 1.04–4.29; p = 0.04).
For continuous secondary outcomes, the mean hospital length of stay was 0.8 days longer in patients with severe persistent lymphopaenia than in those without (95% CI = −1.0 to 2.6; p = 0.38). There was no difference in mean ICU length of stay (95% CI = −1.9 to 1.9; p = 0.98).
ICU mortality was 16 of 104 (15.4%) in patients with severe persistent lymphopaenia, compared to 25 of 239 (10.5%) of those with an ALC > 0.75 × 109/L (OR = 1.56; 95% CI = 0.79–3.06; p = 0.20).
Hospital mortality was 25 of 104 (24.0%) in patients with severe persistent lymphopaenia, compared to 33 of 239 (13.8%) in those with an ALC > 0.75 × 109/L (OR = 1.98 95% CI = 1.11–3.53; p = 0.02).
4. Discussion
In this multicentre point prevalence study of critically ill patients, persistent lymphopaenia was common and more frequent among patients with sepsis than among those without. A sensitivity analysis indicated that surgical status did not account for the observed association. Among patients with sepsis and persistent lymphopaenia, we observed a 6% higher hospital mortality than among those without persistent lymphopaenia. This was despite a lower likelihood of receiving treatment with mechanical ventilation, a similar rate of vasopressor/inotropic support, and a slightly higher rate of commencing RRT. These differences failed to reach statistical significance, suggesting in this cohort of patients, early lymphopaenia may reflect underlying disease burden rather than a direct association with mortality and burden of organ support.
The higher prevalence of persistent lymphopaenia in patients with sepsis aligns with established evidence that sepsis induces profound immune dysregulation, characterised by accelerated lymphocyte apoptosis, impaired proliferative capacity, and functional exhaustion.9,24 Prior longitudinal studies have demonstrated that persistent lymphopaenia predicts ICU-acquired infection and late mortality.8,25 However, our point prevalence design, limited to the first 48 h of ICU admission, likely captured only an early and likely transient immunological state. Emerging evidence also suggests that temporal ALC trajectories and patterns of immune recovery may offer stronger prognostic value than early absolute counts alone.26,27
Patients with persistent lymphopaenia were older, more severely ill, and more likely to have sepsis, consistent with previous studies.28 Although multivariable adjustment reduced these effects, residual confounding from unmeasured factors such as frailty, immunosuppressant exposure, or haemodilution cannot be excluded. The exploratory signal between “severe” lymphopaenia and greater vasopressor or renal support may reflect dose–response pathophysiology7 but should be regarded as hypothesis-generating given the multiple comparisons and wide CIs.
Our findings align with prior reports that persistent lymphopaenia is common in critical illness,11,29 particularly in patients with sepsis,8,9,30 and add to previous reports from more geographically limited cohorts.7 They also demonstrate a trend linking persistent lymphopaenia in patients with sepsis to mortality. The attenuation of this signal following sensitivity analyses indicates that in older, sicker, or more comorbid patients, the impact persistent lymphopaenia is reduced. In comparison to previous data, the failure to reach statistical significance probably reflects differences in sample size, exposure definition, timing, and analytical approach. While ALC is readily available, its utility for early risk stratification based on single early (day 1 and 2) measurements appears limited. Persistent lymphopaenia is independently associated with the mortality;7,8 it is readily recognisable and measurable through serial blood counts; and it arises the possibility through mechanisms, such as accelerated apoptosis,27,31 that there may be potential therapeutic targets. For example, interleukin-7 is being investigated as a potential therapeutic target.9,32 It therefore meets the three attributes required for a treatable trait: first, clinical relevance; second, recognisability and measurability; and third, treatability.33 Persistent lymphopaenia is particularly interesting given it is defined by a single discrete measurable feature. Persistent lymphopaenia is thus a strong candidate treatable trait. Future research should focus on longitudinal assessment of lymphocyte trajectories, detailed lymphocyte subset phenotyping, and carefully selected clinical trials to determine whether targeting persistent lymphopaenia can improve outcomes in critically ill populations.
This study has several notable strengths. It uses a well-established PPP with broad representation of ICUs, and its binational design enhances the generalisability of the findings across comparable jurisdictions. The PPP serves as a recognised repository of binational ICU admission and hospital outcomes, providing credibility for the data source. There are few missing data points, and haematological measurements were conducted by nationally accredited laboratories, assuring the reliability and accuracy of the results.
Limitations of this study include the point prevalence design, which precluded assessment of lymphocyte recovery or incident infection, potential survivor and selection biases, and limited data on immunosuppressant use or lymphocyte subsets.34,35 Additionally, the study lacked data on the source of sepsis, and whether lymphopaenia predicted readmissions for sepsis and longer-term outcomes.
5. Conclusion
Within Australasian ICUs, persistent lymphopaenia is a common finding in critically ill adults, particularly in those with sepsis, where it is associated with greater illness severity. In patients with sepsis, there was an association between persistent lymphopaenia and mortality, though this did not reach statistical significance. Importantly, advancing age, severity of illness, and comorbidities attenuate this association.
Declaration of generative AI and AI-assisted technologies in the manuscript preparation process
During the preparation of this work, the author(s) used Claude (Anthropic, San Francisco, CA, USA) for assistance with formatting. The author(s) reviewed and edited the output as needed and take full responsibility for the content of the published article.
CRediT authorship contribution statement
Adigbli, Devaux, Knowles, Hardie, Gianacas, Venkatesh, Hammond, Finfer: Concept and design. Adigbli, Devaux, Hardie, Gianacas, Venkatesh, Hammond, Finfer: Acquisition, analysis, or interpretation of data. Adigbli, Devaux, Finfer: Drafting of the manuscript. Adigbli, Devaux, Knowles, Hardie, Gianacas, Venkatesh, Hammond, Finfer: Critical revision of the manuscript for important intellectual content. Devaux: Statistical analysis. The authors were responsible for the study design, data collection, data analysis, data interpretation, and writing of the manuscript.
Conflict of interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Simon Finfer reports a relationship with RevImmune Inc. that includes consulting or advisory. Naomi Hammond reports a relationship with RevImmune Inc. that includes consulting or advisory. Balasubramanian Venkatesh reports a relationship with RevImmune Inc that includes consulting or advisory. Simon Finfer reports a relationship with NeoImmuneTech, Inc. that includes consulting or advisory. Naomi Hammond reports a relationship with NeoImmuneTech, Inc. that includes consulting or advisory. Balasubramanian Venkatesh reports a relationship with NeoImmuneTech, Inc. that includes consulting or advisory and Baxter that includes funding grants. Naomi Hammond reports a relationship with Baxter that includes funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors thank all the contributing sites, the research nurses, and research coordinators at these sites (Appendix A).
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ccrj.2026.100222.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
References
- 1.Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gray A.P., Chung E., Hsu R.L., Araki D.T., Gershberg Hayoon A., Davis Weaver N., et al. Global, regional, and national sepsis incidence and mortality, 1990–2021: a systematic analysis. Lancet Global Health. 2025;13(12):e2013–e2026. doi: 10.1016/S2214-109X(25)00356-0. [DOI] [PubMed] [Google Scholar]
- 3.Care ACoSaQiH . 2025. National sepsis program extension epidemiology report. [Google Scholar]
- 4.Prescott H.C., Langa K.M., Liu V., Escobar G.J., Iwashyna T.J. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med. 2014;190(1):62–69. doi: 10.1164/rccm.201403-0471OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Stortz J.A., Murphy T.J., Raymond S.L., Mira J.C., Ungaro R., Dirain M.L., et al. Evidence for persistent immune suppression in patients who develop chronic critical illness after sepsis. Shock. 2018;49(3):249–258. doi: 10.1097/SHK.0000000000000981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Petramala L., Milito C., Sarlo F., Servello A., Circosta F., Marino L., et al. Clinical impact of transient lymphopenia. Clin Exp Med. 2024;24(1):77. doi: 10.1007/s10238-024-01340-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Adigbli D., Liu R., Meyer J., Cohen J., Di Tanna G.L., Gianacas C., et al. Early persistent lymphopenia and risk of death in critically ill patients with and without sepsis. Shock. 2023;10:1097. doi: 10.1097/SHK.0000000000002284. [DOI] [PubMed] [Google Scholar]
- 8.Drewry A.M., Samra N., Skrupky L.P., Fuller B.M., Compton S.M., Hotchkiss R.S. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42(5):383–391. doi: 10.1097/SHK.0000000000000234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Francois B., Jeannet R., Daix T., Walton A.H., Shotwell M.S., Unsinger J., et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3(5) doi: 10.1172/jci.insight.98960. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cheadle W.G., Pemberton R.M., Robinson D., Livingston D.H., Rodriguez J.L., Polk H.C., Jr. Lymphocyte subset responses to trauma and sepsis. J Trauma. 1993;35(6):844–849. doi: 10.1097/00005373-199312000-00007. [DOI] [PubMed] [Google Scholar]
- 11.Heffernan D.S., Monaghan S.F., Thakkar R.K., Machan J.T., Cioffi W.G., Ayala A. Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit Care. 2012;16(1):R12. doi: 10.1186/cc11157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Harel A., Horng S., Gustafson T., Ramineni A., Farber R.S., Fabian M. Successful treatment of progressive multifocal leukoencephalopathy with recombinant interleukin-7 and maraviroc in a patient with idiopathic CD4 lymphocytopenia. J Neurovirol. 2018;24(5):652–655. doi: 10.1007/s13365-018-0657-x. [DOI] [PubMed] [Google Scholar]
- 13.Terrazzini N., Mantegani P., Kern F., Fortis C., Mondino A., Caserta S. Interleukin-7 unveils pathogen-specific T cells by enhancing antigen-recall responses. J Infect Dis. 2018;217(12):1997–2007. doi: 10.1093/infdis/jiy096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Rienzo M., Skirecki T., Monneret G., Timsit J.-F. Immune checkpoint inhibitors for the treatment of sepsis: insights from preclinical and clinical development. Expert Opin Invest Drugs. 2022;31(9):885–894. doi: 10.1080/13543784.2022.2102477. [DOI] [PubMed] [Google Scholar]
- 15.Boomer J.S., Shuherk-Shaffer J., Hotchkiss R.S., Green J.M. A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit Care. 2012;16(3) doi: 10.1186/cc11404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Boomer J.S., To K., Chang K.C., Takasu O., Osborne D.F., Walton A.H., et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594–2605. doi: 10.1001/jama.2011.1829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ryan T., Coakley J.D., Martin-Loeches I. Defects in innate and adaptive immunity in patients with sepsis and health care associated infection. Ann Transl Med. 2017;5(22):447. doi: 10.21037/atm.2017.09.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Marté J.L., Toney N.J., Cordes L., Schlom J., Donahue R.N., Gulley J.L. Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management. J ImmunoTher Cancer. 2020;8(2) doi: 10.1136/jitc-2020-001019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zealand CoICMoAaN . 2016. IC-1 document: minimum standards for intensive care units; pp. 1–15. [Google Scholar]
- 20.Harris P.A., Taylor R., Thielke R., Payne J., Gonzalez N., Conde J.G. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Harris P.A., Taylor R., Minor B.L., Elliott V., Fernandez M., O'Neal L., et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95 doi: 10.1016/j.jbi.2019.103208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Knaus W.A., Wagner D.P., Draper E.A., Zimmerman J.E., Bergner M., Bastos P.G., et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100(6):1619–1636. doi: 10.1378/chest.100.6.1619. [DOI] [PubMed] [Google Scholar]
- 23.Vincent J.L., Moreno R., Takala J., Willatts S., De Mendonça A., Bruining H., et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–710. doi: 10.1007/BF01709751. [DOI] [PubMed] [Google Scholar]
- 24.Hotchkiss R.S., Monneret G., Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–874. doi: 10.1038/nri3552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Zeng C., Li X., Lu Z., Mu G., Deng Y. Predictive value of soluble programmed cell death ligand-1 in the progression of septic patients to chronic critical illness in the intensive care unit: a prospective observational clinical study. Shock. 2023;60(2):163–171. doi: 10.1097/SHK.0000000000002156. [DOI] [PubMed] [Google Scholar]
- 26.Reichardt L.-M., Hindelang B., Süberkrüb L., Hamberger K.L., Graw J.A., Schuetze K., et al. Absolute lymphocyte count trajectory predicts clinical outcome in severely injured patients. Eur J Trauma Emerg Surg. 2025;51(1):190. doi: 10.1007/s00068-025-02864-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Wang Z., Zhang W., Chen L., Lu X., Tu Y. Lymphopenia in sepsis: a narrative review. Crit Care. 2024;28(1):315. doi: 10.1186/s13054-024-05099-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chung K.-P., Chang H.-T., Lo S.-C., Chang L.-Y., Lin S.-Y., Cheng A., et al. Severe lymphopenia is associated with elevated plasma Interleukin-15 levels and increased mortality during severe sepsis. Shock. 2015;43(6):569–575. doi: 10.1097/SHK.0000000000000347. [DOI] [PubMed] [Google Scholar]
- 29.Campbell B., Budreau D., Williams-Perez S., Chakravarty S., Galet C., McGonagill P. Admission lymphopenia predicts infectious complications and mortality in traumatic brain injury victims. Shock. 2022;57(2):189–198. doi: 10.1097/SHK.0000000000001872. [DOI] [PubMed] [Google Scholar]
- 30.Jiang J., Du H., Su Y., Li X., Zhang J., Chen M., et al. Nonviral infection-related lymphocytopenia for the prediction of adult sepsis and its persistence indicates a higher mortality. Medicine (Baltimore) 2019;98(29) doi: 10.1097/MD.0000000000016535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Hotchkiss R.S., Osmon S.B., Chang K.C., Wagner T.H., Coopersmith C.M., Karl I.E. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol. 2005;174(8):5110–5118. doi: 10.4049/jimmunol.174.8.5110. [DOI] [PubMed] [Google Scholar]
- 32.Daix T., Mathonnet A., Brakenridge S., Dequin P.F., Mira J.P., Berbille F., et al. Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial. Ann Intensive Care. 2023;13(1):17. doi: 10.1186/s13613-023-01109-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Agusti A., Bel E., Thomas M., Vogelmeier C., Brusselle G., Holgate S., et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J. 2016;47(2):410–419. doi: 10.1183/13993003.01359-2015. [DOI] [PubMed] [Google Scholar]
- 34.Boomer J.S., To K., Chang K.C., Takasu O., Osborne D.F., Walton A.H., et al. Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure. JAMA. 2011;306(23):2594–2605. doi: 10.1001/jama.2011.1829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ward P.A. Immunosuppression in sepsis. JAMA. 2011;306(23):2618–2619. doi: 10.1001/jama.2011.1831. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.