Lymphopenia Tied to Higher All-Cause Mortality Risk

Marcia Frellick

January 13, 2020

Lymphopenia is linked with a higher risk for both all-cause and cause-specific mortality, a study with more than 100,000 participants found.

The study builds on previous work that has linked lymphopenia with higher risk for cancer, cardiovascular disease, liver disease, and systemic autoimmune disease.

The study by Marie Warny, MD, with the Department of Hematology at Herlev and Gentofte Hospital and Copenhagen University Hospital in Herlev, Denmark, and colleagues was published online January 13 in the Canadian Medical Association Journal.

After adjusting for age and sex, lymphopenia (defined as a lymphocyte count <1.1 × 109/L) was associated with a 63% increase in all-cause mortality (hazard ratio, 1.63) and with a 1.5- to 2.8-fold increased risk of dying from causes such as hematologic and nonhematologic cancer, cardiovascular and respiratory disease, and infections.

Table. Cause-Specific Mortality Risk Linked With Lymphopenia

Cause of Mortality Hazard Ratio 95% Confidence Interval
Nonhematologic cancers 1.67 1.42 – 1.97
Hematologic cancers 2.79 1.82 – 4.28
Cardiovascular disease 1.88 1.61 – 2.20
Respiratory diseases 1.88 1.55 – 2.29
Infectious diseases 1.86 1.53 – 2.25
Other causes 1.50 1.19 – 1.88


The researchers examined and followed 108,135 white, Danish participants in the Copenhagen General Population Study (mean age, 68 years). They concluded that individuals with lymphopenia were at higher risk of dying from any cause, regardless of other risk factors, including age. They note that lymphopenia may be an underrecognized sign of frailty that signals higher risk for death.

The authors say their findings may help predict who might benefit from more surveillance after a blood test indicates lymphopenia. In current practice in Denmark, such patients are not generally referred for further examination because the possible connection with mortality risk has been unclear.

They note, "For all-cause mortality, the highest absolute 2-year risks of death were observed in women (61%) and men (75%) who smoked and were aged 80 years or older with lymphocyte counts less than 0.5 × 109/L."

The authors acknowledge that the study involved only white, Danish participants and that the generalizability of the findings could not therefore be determined.

Findings Similar in US Research

Cardiologist David A. Zidar, MD, PhD, and colleagues had similar results in a related retrospective cohort study in the United States that was published online December 2, 2019, in JAMA Network Open.

He and his colleagues analyzed National Health and Nutrition Examination Survey (NHANES) data from more than 31,000 participants.

Zidar told Medscape Medical News the Danish work "is a terrific confirmatory observation. It is very helpful when independent groups publish using different databases and different patient populations and come to the same general agreement."

The NHANES data are meant to represent the diversity of the United States, and his study controlled for factors that included race and ethnicity, but neither study should be considered definitive, and the conclusions should be tested in other populations, he continued.

"It's increasingly clear that immune function plays a role in a number of different disease arenas," he added.

Zidar is from the Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, in Ohio.

The importance of lymphocyte counts has been underrecognized in medicine; however, "It is more closely linked to mortality than a lot of things we look at," he noted.

Findings from the Danish study and others can help with a precision medicine approach to immune therapies, Zidar said.

"Long term, it's important to dissect which populations of patients might respond preferentially to immune therapies or intensification of preventive therapies. We've lacked an ability to risk-stratify people based upon their immune function," he explained.

The Danish study authors note that in a previous study that involved the same cohort, they determined that lymphopenia was linked with a 1.4-fold higher risk of being admitted to a hospital and a 1.7-fold higher risk for infection-related death.

The project received funding from the European Union's Horizon 2020 research and innovation program. The authors and Zidar have disclosed no relevant financial relationships.

CMAJ. Published online January 13, 2020. Full text

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