Table 1.

Characteristics of included papers. R* retrospective cohort study; P** prospective cohort study. p values*, where provided, are for comparisons between lymphopenic vs non-lymphopenic populations. HR, hazard ratio; OR, odds ratio; LOS, length of stay; IQR, interquartile range; RCT, randomised controlled trial; COPD, chronic obstructive pulmonary disease; UTI, urinary tract infection; CAP, community-acquired pneumonia; RT-PCR, reverse transcription polymerase chain reaction

Study, Year Country Study Period Study Design	Population of Interest and Sample Size (n)	Lymphopenia Definition (109/L)	Lymphopenic Prevalence (n, %)	Lymphopenic Population Characteristics [Age years, mean, SD] [Female n, %] [Co-morbidities n, %]	Timing of ALC	Outcome 1: Infection - cause of admission and/or nosocomial infection (definition) [n, %]	Outcome 2: Mortality [n, %] [OR, 95% Confidence Interval]	Outcome 3: Length of stay (LOS)- hospital or intensive care unit (ICU) [days, mean ± SD]
Andreu-Ballester et al. 2021  [32] Spain, 2 hospitals Jan 2016 to Dec 2019 R*	Patients older than 14 years and emergency and/or elective admission 58260	< 1.0	23892 (41%)	Age 73.5 ± 15.6 [p<0.001]* Female 10,905 (39.4)	Admission and any time during hospital stay	Infection as cause of admission 11016 (46.1)	In-hospital mortality Total deaths n= 3213 (5.5%) of which n=2345 (73%) had lymphopenia during hospital stay (OR 4.2, 3.9-4.6) Lymphopenia on admission 1743 (54.2%) (OR 2.8, 2.5-31)	N/A
Bermejo-Martin et al. 2017 [16] Spain Derivation cohort (DC -multicentre 14 hospitals), January 2012 to June 2015 Validation cohort (VC - single centre) January 2005 to December 2015 R*	Presence of new pulmonary infiltrates on chest X-ray and respiratory signs/symptoms compatible with CAP DC 1550 VC 2846	<0.724 following subsequent AUC analysis (best cut-off value for identifying non-survivors)	DC 520 (33.5) VC 1014 (35.6)	Derivation Cohort Age>65 196 (37.7) Female 178 (34.2) Diabetes 113 (22.2) [p 0.915]* COPD 139 (27.3%) [p 0.854] Cardiac disease 176 (34.2%) [p<0.001] Liver disease 32 (6.3%) [p 0.002] Validation Cohort Age>65 644 (64.5) Female 370 (34.5) Diabetes 224 (22.6) [p 0.949]* COPD 350 (35.7) [p 0.949] Cardiac disease 129 (12.8) [p 0.064] Liver disease 45 (4.5) [p 0.357]	N/A	N/A Septic shock subgroup: DC 36 (6.9) VC 74 (7.5)	30-day mortality Derivation Cohort 41 (7.9) [p<0.001]* OR 1.93 (1.06-3.51) [p 0.031] Validation Cohort 116 (11.4) [p<0.001]* OR 1,86 (1.28-2.71) [p 0.001]	N/A
Campbell et al. 2022 [33] USA, trauma centre hospital July 2009 to May 2018 R*	Traumatic brain injuries (concussion, subarachnoid, subdural, intraventricular, epidural, and intra-parenchymal haemorrhage) or diffuse axonal injury from blunt trauma Exclusion of death within 24 hours and/or bowel perforation on admission 2570	<1.0	946 (36.8)	Age 66.9 ± 23.0 Female 337 (39.9) Diabetes 68 (7.2) [ p 0.238]* COPD 58 (6.1) [ p 0.494]* Heart Failure 77(8.1 ) [ p 0.002]* Hypertension 495 (52.3) [ p <0.001]* Chronic liver disease 13 (1.4) [p 0.077]*	Within 24 hours of admission	Nosocomial Infection including pneumonia, UTI, septicaemia, intra-abdominal abscess and wound infection (n=380) of which 184 (48.4%) lymphopenic Pneumonia 84 (8.9) OR 1.510 (1.081-2.111) [ p 0.016] UTI 85 (9) OR 1.324 (0.960-1.826) [p 0.087]	In-hospital mortality 110 (11.6) [p<0.001]* Lymphopenia associated with increased risk of mortality OR = 1.903 (1.389-2.608) [p<0.001] Lymphopenic patients at higher risk of dying sooner in hospital OR 1.459 ( 1.097 - 1.941) [p 0.009]	Hospital LOS 5.7 ± 5.9 [p<0.001]* ICU LOS 5.1 ±5.2 [p 0.084]*
Carneiro et al. 2021 [17] USA, neurocritical care unit November 2008 to April 2014 R*	Diagnosis of intracranial haemorrhage (including intra-ventricular haemorrhage and both supratentorial and infratentorial locations) on non-contrast CT scan 213	< 1.0 (or <1.1 depending on lab essay internal: validity at time of sample collection)	53 (24.9)	Age 69.0 ± 17.5 [p 0.082]* Female 22 (41.5) Hypertension 44 (83.02) [ p 0.5022]* Diabetes 15 (28.3) [p 0.9802]*	Admission	Nosocomial infection (i.e. 48 hours after admission). Subtypes included pneumonia, UTI, ventriculitis, endocarditis and bacteraemia Nosocomial Infection 23 (43.4) [p 0.037]* OR 2.15 (0.98- 4.73) [p 0.0569] Nosocomial UTI 13 (24.5) [ p 0.0033]* OR 3.66 (1.36, 9.88) [p 0.0104]	In-hospital mortality 18 (34.0) [p 0.0964]*	Hospital LOS 12.1 ± 15.2 [p 0.187]*
Ceccato et al. 2019 [34] Spain, 6 ICUs in a single centre tertiary hospital (medical and surgical patients) 2005 to 2016 P**	≥ 18 years with clinical suspicion of pneumonia 48 h after ICU admission, with or without intubation and mechanical ventilation (IMV) 473	< 0.595	141 (29.8)	Age 67.3 ± 13.5 [p 0.13]* Female 42 (29.8) SOFA score 7 (5-10) Diabetes 40 (28) [p 0.12]* Chronic heart disorders 50 (35) [p 0.67]* COPD 38 (27) [p 0.063]* Chronic liver disease 39 (28) [p 0.002]*	Admission	N/A	28-day mortality 38 (27) [p 0.024]* 90-day mortality 74 (53) [p<0.001]*	N/A
Chung et al. 2015 [35] Taiwan, 2 hospitals October 2010 to January 2012 P**	≥20 years admitted to medical ICUs for severe sepsis or septic shock 92	< 0.5	24 (26.1)	Age 71.1 ± 13.8 [p 0.105]* Female 8 (39.1) SOFA score 11 (6.3-14) APACHE II score 21.5 (16.3-28.5) Congestive heart failure 2 (8.3) [p 1.00]* Diabetes 10 (41.7) [p 0.866]* Cirrhosis 3 (12.5) [p 0.180]*	Admission, day 1 and day 3 bloods	N/A	28-day mortality 13 (52.4)	N/A
Drewry et al. 2014 [15] USA, tertiary hospital January 2010 to July 2012 R*	All adults admitted with sepsis and blood cultures positive for bacteria ± fungal organisms within 5 days of admission 335	<1.2 Severe lymphopenia ALC < 0.6 Moderate lymphopenia ALC 0.7 to 1.1	210 (62.7) Severe 76 Moderate 134	Moderate persistent lymphopenia Age 61.5 ± 16.1 [p 0.07]* Female 64 (47.8) APACHE II 17.6 (5.9) [p 0.002]* Congestive heart failure 37 (31.3) [p 0.59]* Diabetes 44 (32.8) [p 0.02]* Liver disease 26(19.4) [p 0.09]* COPD 42 (31.3) [p 0.21]* Severe persistent lymphopenia Age 65.3 ± 12.5 Female 25(32.9) APACHE II 18.6 (5.8) Congestive heart failure 26 (34.2) Diabetes 30 (39.5) Liver disease 18 (23.7) COPD 33 (43.4)	Day 4 ALC (4 days after blood culture taken)	Nosocomial infection = culture positive infections identified >48 hours after primary bacteraemia and arising from secondary source Moderate lymphopenia 27 (20.1) OR 1.60 (0.83, 3.11) [p 0.16] Severe persistent lymphopenia 19 (25) OR 2.11 (1.02, 4.39) [p 0.04]	28-day mortality 63 (11.0) 1-year mortality 98 (46.7)	Hospital LOS 14.8 ±9.4 [p 0.37]* ICU LOS 4.4 ± 4.3 [p 0.15]*
Imabayashi et al. 2022 [36] University hospital 2012 to 2016 R*	Consecutive patients who underwent spinal surgery. Exclusion of patients treated with unplanned antibiotics (except for prophylactic surgery) 329	≤1	61 (18.5)	Age 72 (15-85) (median, IQR) [ p 0.013]* Female 17 (27.9)	Post operative (day 7)	Surgical site infection (SSI), defined according to criteria of the Centres of Disease Control and Prevention. Diagnosis was made by attending surgeon based on the need for debridement, blood cultures that were positive for infectious agents or draining of surgical wound within 4 weeks 4 (6.56) [p 0.065]* OR 7.54 (1.91-29.83) [p 0.004] Univariate analysis on lymphopenia preoperatively on SSI OR 0 (0.001- 0.002) [p 0.997]	N/A	N/A
Koch et al. 2022 [37] USA, trauma centre hospital May 2009 to December 2018 R*	Adults admitted with Chest Abbreviated Injury Scale (CAIS) ≥2. Exclusion of patients who died within 24 hours of admission, bowel perforation on admission, penetrating trauma and burns 1394	≤1	618 (44.3)	Age 57.4 ± 22.3 [p <0.001]* Female 185 (29.9) Heart failure 37 (6) [p 0.019]*	Within 24 hours of admission	Pneumonia 95 (15.4) [ p 0.317 ]* UTI 60 (9.7) [p 0.453 ]* Wound infection 13 (2.3) [ p 1.00]* Other infection 16 (2.6%) [ p 1.00 ]*	In-hospital mortality 60 (9.7)	Hospital LOS 9.7 ± 7.4 [p<0.001]* OR 1.151 (1.03-1.29] [p 0.017] ICU LOS 5.05 ± 5.20 [p 0.797]*
Mendez et al. 2019 [38] Spain, tertiary hospital Not reported P**	≥18 years admitted with CAP Exclusion of nursing home patients, life expectancy less than 3 months, immunosuppression, and hospital admission for ≥48 hours in the preceding 15 days 217	≤0.724 (based on Bermejo-Martin et al.) Analysis also carried out on ALC ≤1	ALC ≤ 1.0 128 (59.0) ALC ≤ 0.724 85(39.2)	ALC ≤0. 724 Age 72.9 ± 15.1 [p<0.001]* Female 28 (32.9) Diabetes 19 (22.4) [p 0.749]* Heart disease 31 (36.5) [p 0.120]* Liver disease 3 (3.5) [p 0.839]* COPD 27 (31.8) [p 0.010]*	First morning after hospital admission	N/A	N/A	ALC ≤1.0 Hospital LOS 7 ± 2.0 [p 0.0040]* ALC ≤0.724 Hospital LOS 7 ± 3.0 [p 0.176]*
Rubio-Rivas et al. 2015 Spain 2012 to 2013 P**	All consecutive ≥ 75 years admitted for medical conditions 180	<1.1	45 (25)	Age 84.5 ± 5.0 [p 0.312] Female 25 (55.6)	Admission	Infection as cause of admission 1 (2.2)	In hospital mortality 12 (26.7) [p 0.001]* OR 3.9 [p 0.03] CIs not reported 1 year mortality multivariate analysis HR 1.9 [p 0.038] CIs not reported	Hospital LOS 19.9 ± 12.2 [p 0.002]*
Ruiz et al. 2023 [43] Spain, 2 hospitals January 2002 to December 2020 P**	≥18 years admitted with pneumococcal CAP (based on the results of pneumococcal urinary antigen test and/or blood culture) 1173	<1 Severe lymphopenia: ALC below 0.5	686 (58.4) Severe lymphopenia 282 (24)	Mean age not provided Female 259 (37.8) Pneumonia Severity Index (PSI)>3 381 (55.5) [p<0.0001]*	Admission	N/A Septic shock subgroup (based on ALC < 0.5) 66 (23.4) [p<0.001]	In-hospital mortality (severe lymphopenia) 30 (10.6) [p<0.001]	N/A
Vulliamy et al. 2015 UK, district general hospital January 2002 to October 2013 R*	Emergency general surgical patients admitted to ICU with acute intra-abdominal pathology and SOFA score≥5 at time of ICU admission 173	<1 Persistent lymphopenia: ALC below the lower limit of normal (defined as 1-3.0 x 109/L) throughout the 7-day period or until death	61 (35.3) with persistent lymphopenia	Age 72.6 ± 15.2 [p<0.01]* APACHE II 19 (15-23) [p<0.01]*	ALC from ICU admission to day 7 of admission	N/A	In-hospital mortality 39 (64) [p<0.01}* OR 3.36 (1.60-7.04) [p<0.01]	N/A
Wittermans et al. 2022 [41] The Netherlands, multicentre study Post hoc analysis of RCT	Non-ICU hospitalised CAP Exclusion of immunosuppressed patients 354	≤0.71	117 (33.1)	Age 68 ± 15 [p 0.002]* Female 38 (32.5) COPD 19 (16) [p 0.36]* Diabetes 29 (25) [p 0.021]* Congestive heart failure 15 (13) [ p 0.057]* Liver disease 2 (2) [p 0.47]*	ALC on Emergency Department presentation	N/A	30-day mortality 5 (4) [p = 0.37]*	Hospital LOS 5.5 ± 3.4 [p 0.61]*
Zhou et al. 2018 [42] China, 424 hospitals September 2009 to December 2009 P**	RT-PCR positive for influenza A (H1N1) on admission Exclusion of secondary bacterial or fungal infection within 48 hrs of hospitalisation 2146	<0.8	821 (38.3)	N/A	N/A	Nosocomial infection: clinical symptoms/signs of pneumonia or bacteraemia and positive culture of a new pathogen ≥48 hours after admission 148 (65.5) [p<0.001]* OR 1.906 (1.361-2.671) [p <0.001]	N/A	N/A