Effect of Recombinant Human Granulocyte Colony-Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia: A Randomized Clinical Trial

JAMA Intern Med. 2021 Jan 1;181(1):71-78. doi: 10.1001/jamainternmed.2020.5503.

Abstract

Importance: Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19).

Objective: To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19.

Design, setting and participants: Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per μL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing.

Exposures: Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 μg/kg, subcutaneously at days 0-2).

Main outcomes and measures: The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score.

Results: Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, -13%; 95%CI, -21.4% to -5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/μL vs usual care group median of 620/μL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group.

Conclusion and relevance: In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted.

Trial registration: Chinese Clinical Trial Registry: ChiCTR2000030007.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Adult
  • Anti-Bacterial Agents / therapeutic use
  • Antiviral Agents / therapeutic use
  • B-Lymphocytes
  • CD4 Lymphocyte Count
  • COVID-19 / blood
  • COVID-19 / complications
  • COVID-19 / physiopathology
  • COVID-19 Drug Treatment*
  • China
  • Disease Progression
  • Female
  • Granulocyte Colony-Stimulating Factor / therapeutic use*
  • Hematologic Agents / therapeutic use*
  • Hospital Mortality*
  • Humans
  • Killer Cells, Natural
  • Leukocyte Count
  • Lymphocyte Count
  • Lymphopenia / blood
  • Lymphopenia / complications
  • Lymphopenia / drug therapy*
  • Male
  • Middle Aged
  • Mortality
  • Noninvasive Ventilation
  • Oxygen Inhalation Therapy
  • Recombinant Proteins
  • Respiratory Distress Syndrome / physiopathology
  • Respiratory Insufficiency / physiopathology
  • SARS-CoV-2
  • Sepsis / physiopathology
  • Shock, Septic / physiopathology
  • Time Factors

Substances

  • Adrenal Cortex Hormones
  • Anti-Bacterial Agents
  • Antiviral Agents
  • Hematologic Agents
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor