Current best evidence for clinical care (more info)
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.
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This is an interesting idea (especially given the emphasis on immune suppression in other treatments), but nothing which will change practice, yet. Further research is needed.
Well done study and analysis.
Interesting results but preliminary/hypothesis-generating for now. This would not influence practice unless it can be repeated in a larger population with demonstrated effect on patient-important outcomes.
This is not surprising, but it is important to realize that this approach may not be efficacious. It may also reflect a simplistic view of using immune responses.
This is a Phase 2 trial, so not ready for clinical use.
Good early data!
I have rated this highly (R=6; N=6) for a respiratory audience as it describes an intervention that shows (with important caveats) less mortality and less progression to a critical condition in patients with Covid-19. It also highlights the confusion that arises when a difference in primary outcome measure is not reached (in this case a soft one: days to clinical improvement) while differences in hard (but secondary) outcomes such as mortality are reached. One of the difficulties interpreting these results is that the patients and staff were not blinded to the intervention. The improvement in mortality and progression to critical condition look too good to be true. The result of this trial seems to me to demand follow-up with a blinded trial to test the hypothesis that rhGCSF influences the clinical course of Covid-19 in a meaningful way (i.e., less death, less need for invasive respiratory support).