Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study.

As recently discussed in the Journal, baricitinib was safe and improved the clinical conditions in 12 patients with mild-moderate Coronavirus Disease 2019 (COVID-19) pneumonia. It is known that severe symptoms of COVID-19 may develop after a median of 8-days from illness-onset, with a median time to Intensive Care Unit (ICU) admission of 5 days from the dyspnea occurrence. Currently, no antiviral therapies or vaccines are available. An uncontrolled immune response is observed and is likely involved in tissues injury. Baricitinib is an anti-Janus kinase inhibitor-1 and −2, and has a dual action on COVID-19 therapy including the inhibition of cytokine release and SARS-CoV-2 endocytosis. Based on this evidence, we conducted an observational, retrospective, longitudinal multicenter-study in consecutive-hospitalized patients with COVID-19 moderate pneumonia to evaluate the 2-week effectiveness and safety of baricitinib combined with antivirals (lopinavir/ritonavir) compared with the standard of care therapy which was hydroxychloroquine and lopinavir/ritonavir. Primary aim was to evaluate the mortality rate; secondary aims were to evaluate the rate of ICU transfer, hospital discharge, improvement of respiratory parameters, adverse events (AEs) occurrence. Moreover, associations between therapy and modification of respiratory parameters and C-Reactive Protein (CRP), interleukin-6 (IL-6), lymphocyte percentage were evaluated.

Clinical charts of patients with moderate COVID-19 pneumonia from 7 Italian hospitals (Hospital of Prato, Hospital of Pistoia, Hospital S.Maria Nuova, Florence, Hospital of Alessandria, Hospital of Fano, Hospital of Pesaro, Hospital of Ariano Irpino (Avellino) were reviewed.

Baricitinib-treated arm included consecutive-hospitalized patients,18 years-older, SARS-CoV-2 naso-pharingeal swab-positive, with a moderate pneumonia characterized by typical symptoms, radiological findings of pneumonia, SpO2 >92% on room air,and PaO2/FiO2 100–300 mmHg, admitted between March 15th-May 5th, 2020. Baricitinib 4 mg/day was provided orally associated with lopinavir/ritonavir tablets 250 mg/bid for 2 weeks.

Control-arm included all consecutive-hospitalized patients from February 20th-March 15th, 2020 with moderate COVID-19 pneumonia, 18 years-older, treated with hydroxychloroquine (HCLR) and lopinavir/ritonavir. Exclusion criteria were: history of thrombophlebitis, latent tuberculosis infection, , HBV or HCV infection, current varicella zoster or bacterial infection, pregnancy, lactation, contraceptive pills intake, previous (last 5 years) or current malignancy, neutrophil count<1.0 × 109/L, lymphocyte count<0.2 × 109/L, platelets count<50 × 109/L, transaminases values 4-fold higher than the upper normal limit. Prophylactic anti-thrombotic therapy with low-weight molecular heparin wasadministered. Patients had supportive therapy (O2 supply, rehydration, diuretics, anti-hypertensive, antibiotics) if needed. Corticosteroids were not allowed. If patients were discharged earlier than 2 weeks, they were requested to continue the ongoing therapy until the scheduled 14-days.

Temperature, respiratory and pulse rate, arterial blood gas analysis, blood pressure, blood cell count, liver and kidney tests function were daily assessed. IL-6 serum levels of (RayBioⓇ Human IL-6 ELISA Kit, RayBiotech Co.,USA) were tested at baseline, week 1 and 2. Since low lymphocyte percentage can predict a poor prognosis, patients were stratified at baseline as: lymphocytes >20%, >5% to <20%, and <5%.

Patients provided a written-informed consent. The off-label use of baricitinib was approved by the Hospital-Committee and Ethical-Committee of Toscana-Region (Code: BARIC-off; 17,261; approval date: May 5th 2020).

Mann-Whitney U test was used to compare quantitative variables; Wilcoxon test for paired data; Chi-squared or Fisher's exact test for categorical variables. A two-tailed p-value <0.05 was considered significant.

At baseline, 113 patients were in the baricitinib-arm, and 78 in the control-arm (Table 1 ). The results indicate that the 2-week case fatality rate was significantly lower in the baricitinib-arm compared with controls [0% (0/113) vs 6.4% (5/78) (p-value: 0.010; 95%CI 0.0000–0.4569)] (Table 2 ). ICU admission was requested in 0.88% (1/113) vs 17.9% (14/78) patients in the baricitinib-arm compared to the control-arm (week 1, p-value: 0.019; 95%CI 0.0092–0.6818), (week 2, p-value: <0.0001; 95%CI 0.0038–0.2624). Discharge rate was significantly higher in the baricitinib-arm at week 1 [9.7% (11/113) vs 1.3% (1/78) (p-value: 0.039; 95%CI: 1.41–90.71)], and at week 2 [77.8% (88/113) vs 12.8% (10/78) (p:<0.0001; 95%CI 10.79–51.74)].

Table 1

Baseline demographic, clinical, and laboratory characteristics of COVID-19 patients treated with lopinavir/ritonavir and either baricitinib or with standard of care therapy.

Feature	BaricitinibCombined with lopinavir/ritonavir treated arm a	HydroxychloroquineCombined with lopinavir/ritonavir treated arm(standard of care-treated arm) b	P value
Patient number, No (%)	113 (100)	78 (100)
Male/female, No (%)	73/40 (64.6/35.4)	46/32 (59/41)	0.524
Age years, median (IQR)	68 (57–76)	63 (55.5–69.5)	0.602
Interval from symptoms onset and therapy starting, days, No	7 (5–10)	6.5 (4–9)	0.915
Cough, No (%)	75/113 (66.4)	53/78 (67.9)	0.943
Dyspnea, No (%)	84/113 (74.3)	58/78 (74.4)	0.869
Sputum production, No (%)	41/113 (36.2)	29/78 (37.2)	0.979
Headache, No (%)	56/113 (49.5)	31/78 (39.7)	0.234
Diarrhea, No (%)	26/113 (23)	11/78 (14.1)	0.179
Ageusia/anosmia, No (%)	44/113 (38.9)	29/78 (37.1)	0.925
Hypertension, No (%)	32/113 (28.3)	21/78 (26.9)	0.962
Diabetes, No (%)	18/113 (15.9)	13/78 (16.6)	0.949
COPD, No (%)	16/113 (14.1)	14/78 (17.9)	0.613
CVD, No (%)	10/113 (8.5)	5/78 (6.4)	0.732
Fever °C, median (IQR)	37.9 (36.7–38.3)	37.8 (37.7–38.7)	0.915
Breath rate n/min, median (IQR),	20 (17–22)	21 (19–24)	0.825
SpO2 (%),median (IQR)	95 (92–98)	93 (92–97)	0.234
PaO2/FiO2, median (IQR)	265.7 (202–330)	267.5 (263.1–301)	0.522
Pulse rate, median (IQR)	80 (70–90)	85 (79–92)	0.129
SBP mm/hg, median (IQR)	125 (112–135)	115 (105–130)	0.121
DBP mm/hg, median (IQR)	70 (65–80)	65 (60–72)	0.232
WBC (x109/l), median (IQR)	6.5 (4.9–8.3)	7.2 (5.8–8.6)	0.708
Neutrophils (x109/l), median (IQR)	4.7 (3.5–6.5)	4.9 (4.4–6.9)	0.911
Lymphocytes (x109/l), median (IQR)	0.93 (0.7–1.2)	0.88 (0.7–0.9)	0.728
Lymphocyte percentage
>20 N (%)	39 (34.5)	24 (30.8)	0.701
>5-<20	70 (61.9)	51 (65.4)	0.740
<5	4 (3.6)	3 (3.8)	0.779
Hemoglobin (g/l), median (IQR)	118 (101–134)	125 (108–133)	0.426
Platelets (x109/l), median (IQR)	213 (167–308)	268 (156–392)	0.234
Alt (u/l), median (IQR)	29 (19–49)	34 (25–52)	0.168
Ast (u/l), median (IQR)	34 (25–51)	40 (34–47)	0.628
Creatinine (mg/dl), median (IQR)	0.9 (0.7–1.1)	1.00 (0.9–1.2)	0.925
Crp (mg/dl), median (IQR)	8.2 (4.1–14.5)	6.3 (2.8–13.6)	0.129
IL-6 (PG/ML), MEDIAN (IQR) c	29.4 (16–45)	32.6 (25–61)	0.225
Procalcitonin (ng/ml), median (IQR)	0.6 (0.3–1.2)	0.9 (0.8–2.1)	0.802
Mews, median (IQR)	1 (0–2)	2 (1–3)	0.225

Abbreviations and symbols: No= number;%= percentage; °C: grade Celsius; min= minute; SpO2= peripheral capillary oxygen saturation; PaO2/FiO2= ratio of arterial oxygen partial pressure to fractional inspired oxygen; SBP= systolic blood pressure; DBP= diastolic blood pressure; WBC= white blood cells; AST= serum glutamic oxaloacetic transaminase; ALT= serum alanine aminotransferase; MEWS= Modified Early Warning Score; IQR: Interquartile range.

Baricitinib-treated arm: Baricitinib-therapy was given 4 mg/day orally combined with lopinavir/ritonavir tablets 250 mg/bid.

Consecutive patients treated with standard of care therapy (hydroxychloroquine 200 mg/bid with lopinavir/ritonavir tablets 250 mg/bi) during the previous weeks before the first baricitnib-treated patient served as controls.

IL-6 values were available in 58 patients of the baricitinib-treated group and in 36 controls.

Table 2

Clinical, laboratory and respiratory parameters of COVID-19 patients after 1- or 2-week treatment in the baricitinib-treated group and in the standard-treated group: comparison within the same treatment group and between the 2 different treatment groups.

	Baricitinibcombined with lopinavir/ritonavir treated arm113 patients				Hydroxychloroquinecombined with lopinavir/ritonavir treated arm(Standard of care-treated arm)78 patients				Baricitinib-based therapy arm vsstandard of care therapy arm
Clinical, laboratory, respiratory parameters	Baseline	Week 1	Week 2	P valueBaseline values vsWeek 1 a orvs Week 2 b values	Baseline	Week 1	Week 2	P valueBaseline values vsWeek 1 a orvs Week 2 b values	P valueWeek 1 aWeek 2 b
Cough, No (%)	75 (66.4)	25 (22.1)	4 (3.5)	0.000 a0.000 b	53 (67.9)	39 (50)	15 (19.2)	0.034 a0.000 b	0.000 a0.014 b
Dyspnea, No (%)	84 (74.3)	20 (1.7)	4 (3.5)	0.000 a0.000 b	58 (74.4)	51 (65.3)	39 (50)	0.295 a0.003 b	0.000 a0.000 b
Sputum production, No (%)	41 (36.2)	15 (13.2)	10 (8.8)	0.000 a0.000 b	29 (37.2)	18 (23)	12 (15.3)	0.081a0.004 b	0.117 a0.246 b
Headache, No (%)	56 (49.5)	12 (10.6)	2 (1.7)	0.000 a0.000 b	31 (39.7)	24 (30.7)	10 (12.8)	0.315 a0.002 b	0.000 a0.005 b
Diarrhea, No (%)	26 (23)	2 (1.7)	0	0.000 a0.000 b	11 (14.1)	1 (1.3)	0	0.007 a0.002 b	0.745 aNA b
Ageusia/Anosmia, No (%)	44 (38.9)	32 (28.3)	24 (21.2)	0.121 a0.006 b	29 (37.1)	25 (32)	19 (24.3)	0.614 a0.118 b	0.694 a0.740 b
Fever °C, median (IQR)	38(37.4–38.2)	36.1(36–36.4)	36(36–36.1)	0.001 a0.001 b	38(37.7–38.7)	37.5(36.5–38.1)	37(36.3–37.4)	0.516 a0.129 b	0.000 a0.000 b
Breath, N/min, median (IQR)	20 (17–22)	18(15–20)	16(14–18)	0.003 a0.002 b	21 (19–24)	19(18–22)	17(16–21.7)	0.083 a0.058 b	0.724 a0.225 b
SpO2%, median (IQR)	95 (92–98)	96(95–98)	97(96–98)	0.191 a0.0018 b	93 (92–97)	93.8(91.8–94.7)	93.6(86.7–94.3)	0.678 a0.715 b	0.000 a0.000 b
PaO2/FiO2 value, median (IQR)	265.7 (202–330)	336.5(245.5–452)	395(320–452.3)	0.0016 a0.0000 b	267.5 (263.1–301)	278.2(258.3–302.4)	293.5(244.2–315.1)	0.514 a0.376 b	0.001 a0.000 b
Pulse rate, No/min. median (IQR)	80 (70–90)	76(68.5–81)	74.5(68–80)	0.433 a0.177 b	85 (79–92)	82.5(76.5–91)	83(77–96.4)	0.433 a0.903 b	0.129 a0.004 b
WBC, x109/L, median (IQR)	6.5 (4.9–8.3)	7.0 (5.7–9.2)	7.0 (5.8–8.6)	0.481 a0.225 b	7.2 (5.8–8.6)	6.9(6.5–7.4)	7.2(6.4–8.6)	0.789 a0.922 b	0.389 a0.533 b
Neutrophils, x109/L, median (IQR)	4.7 (3.5–6.5)	5 (3.3–7)	4.4(3.2–6.9)	0.720 a0.876 b	4.9 (4.4–6.9)	5.4(5.1–6.2)	6.7 (6.3–7.3)	0.054 a0.002 b	0.136 a0.068 b
Lymphocytes, x109/L, median (IQR)	0.93 (0.7–1.2)	1.11 (0.8–1.9)	1.3 (1–2.1)	0.0023 a0.0017 b	0.88 (0.7–0.9)	0.86 (0.5–1)	0.9 (0.69–1.0)	0.524 a0.836 b	0.023 *0.004 †
Lymphocytes, No (%)
>20	39 (34.5)	57 (50.4)	78 (69.0)	0.022 a0.000 b	24 (30.8)	32 (41.0)	35 (44.9)	0.243 a0.099 b	0.256 a0.001 b
>5-<20	70 (61.9)	49 (43.4)	28 (24.8)	0.008 a0.000 b	51 (65.4)	39 (50.0)	35 (44.9)	0.075 a0.016 b	0.449 a0.006 b
<5	4 (3.6)	7 (6.2)	7 (6.2)	0.536 a0.536 b	3 (3.8)	7 (9.0)	8 (10.2)	0.327 a0.211 b	0.658 a0.452 b
Hb, g/L, median (IQR)	118 (101–134)	120(106–112)	125(118–131)	0.234 a0.129 b	125 (108–133)	122(112–125.2)	124(114–128)	0.812 a0.534 b	0.925 a0.746 b
Platelets, Nox109/L, median (IQR)	213 (167–308)	347(265–426)	284(205–419)	0.121 a0.189 b	268 (156–392)	328 (321–461)	359(316–423)	0.268 a0.189 b	0.786 a0.144 b
ALT, U/L, median (IQR)	29 (19–49)	45 (29–68)(43.2–57.2)	45 (26.7–71(43–83.7)	0.065 a0.076 b	34 (25–52)	57.5(38–69.4)	54.8(39.5–54.5)	0.049 a0.057 b	0.533 a0.144 b
AST, U/L, median (IQR)	34 (25–51)	36(25–49.2)	30(23–43.5)	0.965 a0.764 b	40 (34–47)	46.5(41.7–52.5)	48.5(42–55.8)	0.624 a0.019 b	0.076 a0.129 b
Creatinine, mg/dl, median (IQR)	0.9 (0.7–1.1)	0.86(0.69–1.0)	0.88(0.7–1.0)	0.969 a0.934 b	1.00 (0.9–1.2)	1.0(0.9–1.1)	1.1(1–1.2)	0.956 a0.783 b	0.433 a0.246 b
CRP, mg/dlmedian (IQR)	8.2 (4.1–14.5)	0.96(0.51–2.28)	0.3(0.13–0.88)	0.000 a0.000 b	6.3 (2.8–13.6)	5.4(2.8–8.9)	4.6(2.3–6.4)	0.871 a0.433 b	0.003 a0.000 b
IL-6 (pg/ml), median (IQR) c	29.4 (16–45)	5 (2–9)	2.3 (0–4.2	0.0001 a0.0001 b	32.6 (25–61)	29.3 (23–35.2)	16.3 (12–20.5)	0.189 a0.087 b	0.001 a0.000 b
Procalcitonin, ng/ml, median (IQR)	0.6 (0.3–1.2)	0.9(0.6–1.4)	0.8 (0.6–1.8)	0.625 a0.567 b	0.9 (0.8–2.1)	1.3(0.7–1.9)	1.2(0.8–1.4)	0.278 a0.124 b	0.276 a0.146 b
MEWS, median (IQR)	1 (0–2)	01(0–0)	0(0–0)	0.000 a0.000 b	2 (1–3)	1(1–2)	1(0–2)	0.643 a0.184 b	0.004 a0.012 b
ICU transfer, No (%)	0	1 (0.88) d	0 (0)	0.000 aNA b	0	6 (7.7)	14 (17.9)	0.037 a0.000 b	0.019 a0.000 b
Discharged,No (%)	0	11 (9.7)	88 (77.8)	0.002 a0.000 b	0	1 (1.3)	10 (12.8)	1.000 a0.003 b	0.039 a0.000 b
Positive RT-PCR swabs at discharge, No (%) e			11 (12.5)	NA			4 (40)	NA	0.043
Deaths,No (%)	0	0	0	NA	0	2 (2.6)	5 (6.4)	0.477 *0.069 †	0.323 a0.010 b

Abbreviations and symbols: No: number;%: percentage; °C: grade Celsius; min: minute; SpO2: peripheral capillary oxygen saturation; PaO2/FiO2: ratio of arterial oxygen partial pressure to fractional inspired oxygen; SBP: systolic blood pressure; DBP: diastolic blood pressure; WBC: white blood cells; AST: serum glutamic oxaloacetic transaminase; ALT: serum alanine aminotransferase; IU: international unit; MEWS: Modified Early Warning Score; IQR: Interquartile range. Statistical analysis was performed using the Wilcoxon test (for paired comparisons) or the Mann-Whitney test. P value was considered significant if <0.05.

Differences between the values at baseline and after 1 week.

Differences between the values at baseline and after 2 weeks. Standard of care therapy-treated group: COVID-19 patients under standard respiratory therapy and lopinavir/ritonavir and hydroxychloroquine treatment that were admitted in the hospital the week before starting the therapy with baricitinib and lopinavir/ritonavir.

IL-6 values were available in 58 patients of the baricitinib-treated group and in 36 controls.

This patient required intubation 2 days after baricitinib starting; she remained 2 day in ICU and then she prosecuted the drug. She was discharged 2 days after the treatment completion with baricitinib.

RT-PCR= real time Reverse Transcription-Polymerase Chain Reaction.

Except ageusia/anosmia, all clinical, laboratory and respiratory functions significantly improved at week 1. SpO2 significantly improved at week 2 (p-value: 0.0018); PaO2/FiO2 significantly improved at weeks 1 and 2 compared with baseline-values (p-value: 0.0016 and <0.0001, respectively). Significant differences resulted from the comparison between the baricitinib-arm and the control-group (SpO2, week 1 p-value: <0.0001; week 2 p-value: <0.0001; PaO2/FiO2, week 1 p-value: 0.001; week 2 p-value: <0.0001). CRP and IL-6 levels significantly decreased in the baricitinib-arm (CRP at week 1, p-value: 0.003; at week 2, p-value: <0.0001; IL-6 at week 1, p-value: 0.001; at week 2, p-value: <0.0001). Lymphocytes significantly increased in the baricitinib-arm, with the exception of patients with a baseline proportions-value <5% (Table 2).

At discharge, the proportion of patients [positive to viral naso-pharingeal swabs was significantly lower [12.5% (11/88)] in the baricitinib-arm compared to the control-arm [40% (4/10)] (p-value: 0.043; 95%CI 0.06044–0.7737).

Seven AEs, not requiring the therapy discontinuation, were recorded in the baricitinib-arm, including transaminase increase in 4 (3.5%) patients, epistaxis due to heparin overdose in 1 patient, urinary infection in 1 patient, and oral candidiasis in 1 patient.

The results of the present observational, retrospective, longitudinal, multicenter-study in 113 consecutive-hospitalized patients with moderate pneumonia confirm the effectiveness and safety of baricitinib in patients with moderate COVID-19 pneumonia previously reported. Baricitinib-therapy was started in the early phase of COVID-19 disease (median: 7-days from symptoms onset), and the early treatment and the rapid action of the drug may explain the low number of ICU admissions and deaths. The importance of early starting COVID-19 therapies is highlighted in trials of tociluzimab showing a higher efficacy to reduce ICU admission if administered during the initial phase of pneumonia. ,

Interestingly, a significant reduction of positive naso-pharingeal swabs was observed in the baricitinib-arm at discharge, with only 12.5% positive-swabs compared to 40% in the control-group, confirming the anti-inflammatory and anti-viral effects of the baricitinib recently described in 4 patients.

The short-term administration of the drug compared to the long-term treatment in rheumatoid arthritis, may probably explain the absence of serious AEs.

In conclusion, baricitinib is a promising and safe therapy in patients with moderate COVID-19 pneumonia. A randomized clinical trial is needed to confirm our findings.

Declaration of Competing Interest

All Authors have nothing to disclose.