Review of Respiratory Medicine - Volumen 22, Número 3 - September 2022

Original Articles

Compassionate-Use Ruxolitinib for Covid-19 Compared to Treatment with Chloroquines. Report on 100 cases at the Hospital de Especialidades Portoviejo, Ecuador

Ruxolitinib como uso compasivo para la Covid-19 frente al tratamiento con cloroquinas: Reporte de 100 casos en el Hospital de Especialidades Portoviejo – Ecuador

ABSTRACT

The group with compassionate use of ruxolitinib for Covid-19 showed improved chest images and a larger number of discharged patients, compared to group 1 (chloro­quines and azithromycin), with a decrease in inflammatory markers. There is one arti­cle that described a case which refractory to anti-IL6 therapy but responded to Jak-Stat inhibition with ruxolitinib.¹ The most common comorbidity in both groups was arterial hypertension, followed by diabetes type 2; group 1 showed a larger number of patients without comorbidities (18 patients).

The number of male patients with the disease caused by SARS-CoV2 was larger in group 1, with 31 males (62.0%), compared to a total of 19 females (38.0%), whereas in group 2, 25.0% were males, and 25.0% females. The severity of Covid-19 was defined as moderate: adolescent or adult with clinical signs of pneumonia (fever, cough, dys­pnea, tachypnea), particularly SpO2 ≥ 90% on ambient air; and severe: adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnea, tachypnea) plus some of the following: respiratory rate > 30 breaths/min, severe respiratory distress or SpO2 < 90% on ambient air.²

The acute respiratory distress syndrome (ARDS) in both groups had an average ratio of pressure arterial oxygen and fraction of inspired oxygen (PaFi) of 135.3 mmHg in the ruxolitinib group versus 138.9 mmHg in the control group.

Efficacy was defined as: decrease in inflammatory markers, gasometric improvement in the PaFi, lower oxygen requirement, lower number of patients with severe symptoms admitted to the Intensive Care Unit, proof of the drug’s safety 10 days after use, and detailed number of discharged patients.

Key words: Coronavirus Infection; Cytokines; Respiratory Distress Syndrome, Adult; SARS-CoV2; Chloroquines

RESUMEN

El uso compasivo de ruxolitinib en la covid-19 demostró una mejoría en las imágenes de tórax y mayor número de altas en el grupo que lo usó vs. el grupo 1 (cloroquinas y azitromicina), con descenso de los marcadores inflamatorios. Existe un artículo que señaló que un caso que fue refractario a la terapia anti-IL6, pero respondió a la inhibi­ción de Jak-Stat con ruxolitinib.¹ La comorbilidad más frecuente en ambos grupos fue la hipertensión arterial, seguida por la diabetes tipo 2; el grupo 1 presentó un mayor número de pacientes que no presentaban comorbilidades (18 pacientes).

El número de hombres con enfermedad por SARS-CoV2 fue mayor en el grupo 1, con 31 hombres (62,0%) frente un total de 19 mujeres (38,0%), mientras que, en el grupo 2, el 25,0% eran hombres y mujeres, el 25,0%. La gravedad de la covid-19 fue definida como moderada: adolescente o adulto con signos clínicos de neumonía (fiebre, tos, disnea, taquipnea), en particular SpO2 ≥ 90% con aire ambiente; y grave: adolescente o adulto con signos clínicos de neumonía (fiebre, tos, disnea, taquipnea) más alguno de los siguientes: frecuencia respiratoria > 30 inspiraciones/min, dificultad respiratoria grave o SpO2 < 90% con aire ambiente.²

El síndrome de dificultad respiratoria aguda (SDRA) en ambos grupos fue de un pro­medio de relación entre la presión arterial de oxígeno y la fracción inspirada de oxí­geno (PaFi) en el grupo ruxolitinib 135,3 mmHg vs. Grupo control PaFi 138,9 mmHg.

Se definió la eficacia por descenso de los marcadores inflamatorios, mejoría gasomé­trica de la PaFi, menor requerimiento de oxígeno, disminución del ingreso a unidad de cuidados intensivos de los pacientes con sintomatología grave, demostración de la seguridad del fármaco en los 10 días posteriores a su uso y detallado del número de casos con alta médica.

Palabras clave: Ruxolitinib; Infecciones por coronavirus; Citocinas; Síndrome de Dificultad Respiratoria del Adulto; SARS-CoV2; Cloroquinas

INTRODUCTION

The Covid-19 pandemic presented approximately 10 874 146 million cases and around 521 355 deaths on a worldwide level.³

In Ecuador, the rate was 147 033 cases confirmed by RT-PCR (reverse transcription-polymerase chain reaction), with more than 10 800 deaths.⁴

The city of Guayaquil was one of the most af­fected areas, with the largest number of confirmed cases (17 973); whereas in the Manabí province, 10 151 cases confirmed with swab PCR tests have been reported up to now.⁵

The Intensive Care Units around the country collapsed during the first four weeks. There was a group of patients who couldn’t have access to a ventilator. The mortality rate was 7%.

The Hospital de Especialidades Portoviejo re­ceived during the first 6 months more than 12 000 cases of suspected Covid-19 based on clinical and epidemiological criteria and chest imaging, with 491 deaths from SARS-CoV-2; and the highest mortality rate occurred in the Intensive Care Unit (48.8%) (Table 1).

In view of the severity of this disease, the Pulmonology and Infectology Service of the Hos­pital de Especialidades Portoviejo, based on poor pharmacological and therapeutic evidence about the Covid-19 pandemic, created a protocol for the compassionate use of medication with ruxolitinib. It was used in SARS-CoV-2 cases with increased in­flammatory markers (Ldh [lactate dehydrogenase], ferritin, D-dimer, IL6) and those with more than 50% of radiologic involvement in chest images, at the IIB stage of the disease with hypoxemia. The hypothesis included the fact that the use of rux­olitinib could provide a benefit, because it reduces the cytokine levels, and so it could reduce the number of patients admitted to the Critical Care Units with moderate and severe acute respiratory distress syndrome; this would cause radiological improvement and faster lymphocyte recovery.⁶

Secondary hemophagocytic lymphohistiocy­tosis (sHLH) is a hyperinflammatory syndrome secondary to several triggers, including sepsis, characterized by strong increase in cytokines with multi-organ failure and a very high mortality rate.⁷

Ruxolitinib reduces the spleen volume and circulating levels of proinflammatory interleu­kins, particularly IL-6 and TNF-alpha.⁸ Recently, preliminary data from 7 patients with sHLH who were treated with ruxolitinib 15 mg (twice a day) showed promising results regarding global sur­vival, and improvement has been observed in the inflammatory markers such as ferritin and soluble IL-2 receptor.⁹

MATERIALS AND METHODS

Patients were studied from April 2020 to June 2020 at the Hospital de Especialidades Portoviejo.

Inclusion criteria

Patients who met the following criteria:

• High suspicion and diagnosis of Covid-19.

• Chest X-ray and tomographies showing more than 50% of radiologic involvement.

• PaFi ≤ 250 mmHg.

• Rapidly worsening respiratory failure requiring invasive ventilation.

• Increase in any of the systemic inflammatory response in­dicators: LDH 300 U/L, ferritin 1000 ng/mL, D-dimer 1500 ng/mL.

• SpO2 ≤ 93%.

Exclusion criteria

• Patients diagnosed with Covid-19 plus chronic renal failure with clearance of less than 30 mL/h.

• Infectious diseases, such as tuberculosis, HIV.

• Hypersensitivity to the active principle.

• Pregnant women.

• Patients who weigh less than 50 kg.

• Platelets <50,000 cells/mmc.

• Hemoglobin < 8 g/dL.

• Neutrophils < 500 cells/mmc.

• Sepsis documented by pathogens other than SARS-CoV2.

• Patients who didn’t sign consent to the use of ruxolitinib.

DATA ANALYSIS

In the analysis of the information gathered from the medi­cal records of Covid patients, we applied the quantitative paradigm through the use of descriptive statistics and the creation of contingency tables, absolute and relative frequencies, and the calculation of mean values, standard deviation and minimum and maximum values. Inferential statistics is also applied to support the research hypothesis through student-t techniques for independent samples and chi square test, as applicable, depending on the type of variable. For data processing we used the program Excel for windows and the statistical program SPSS, version 21.

Treatment as compassionate use

Patients were randomly selected; 1:1 ratio. They were divided in two groups, 50 patients each, with a total of 100 patients diagnosed with Covid-19 through PCR: group 1 received 250 mg chloroquine phosphate every 12 h, for 7 days; group 2 received 5 mg ruxolitinib, twice a day, for 10 days. Also, systemic corticoids were used during 3 days, plus general measures (Figure 1).

We performed daily electrocardiogram control and sus­pended medication in patients with prolonged QT interval ≥ 500 ms.

RESULTS

This study intends to compare the use of two types of treatment in patients admitted to the Hospital Especialidades Portoviejo, Ecuador, an institution in the province of Manabí with the sentinel sur­veillance system for cases of SARS-CoV-2. Group 1 includes patients who receive chloroquine + azithromycin; and in group 2 patients receive ruxolitinib + methylprednisolone.

Table 2 shows the clinical aspects of the cases according to the treatment group. One of the variables is “age”, where patients aged 60 or older predominate in both groups (62% in group 1 and 58% in group 2). Mean age was 60.9 ± 10.7 years and 62.2 ± 12.7 years, respectively.

Regarding sex, males predominate in group 1 (62%), and account for 50% in group 2.

The degree of severity that is most frequently presented is “severe” (70.0% in group 1 and 78.0% in group 2). With regard to comorbidities, the presence of an underlying disease (40% in group 1 vs. 34% in group 2), or two or more associated diseases (22% in both groups) predominate in both groups. The most frequently found conditions were: hypertension (22% vs. 16%), hypertension and diabetes (12% vs. 14%), and diabetes (8% vs. 2%), group 1 vs. group 2, respectively.

Table 3 shows some of the clinical parameters used for the Covid diagnosis protocol. SaO₂ was measured upon admission, and similar mean val­ues were observed in both groups (82.94 ± 12.2 in group 1, and 84.12 ± 8.6 in group 2). Also, upon admission, we carried out chest X-ray or lung tomography in patients who were able to move in order to observe the percentage of involvement of the pulmonary parenchyma, and found 51.55 ± 11.9 in group 1, and 54.4 ± 12.7 in group 2. Then, 72% of the patients underwent a control chest X-ray, and a lower percentage of involvement was found in patients treated with ruxolitinib + methylprednisolone (79.1 ± 30.3 in group 2). An assay conducted in China showed significant improvement in the chest computed tomographies of 43 patients who received ruxolitinib.¹⁰

In order to show the differences between the groups regarding the percentages of lung involve­ment through imaging, we applied the student-t for independent samples. The results showed that there weren’t any statistical differences between the groups in relation to the percentage of lung involvement (p > 0.05; at 95% CI).

Adverse effects

Group 1: chloroquines + azithromycin: 4 out of 50 patients had prolonged QT interval, so treatment with chloroquines was suspended. Those patients, who were older than 70 years, died on days 7, 8 and 10 of hospitalization. On day 4 of hospitalization, another patient showed lower gastrointestinal bleeding; it is worth mentioning that the patient had arterial hypertension, diabetes mellitus and nephrectomy due to clear cell cancer. Four patients had sudden death on days 6 and 7 of hospitaliza­tion.

Group 2: ruxolitinib + methylprednisolone: 1 out of 50 patients died on day 5 due to a stroke. The other symptoms presented by 4 patients were mild, such as cephalea, insomnia and nervousness on days 1 to 3 of hospitalization; we couldn’t de­termine if those symptoms were characteristic of the ongoing disease.