Immune monitoring of interleukin-7 compassionate use in a critically ill COVID-19 patient

Abstract

One of the immune characteristics of coronavirus disease 2019 (COVID-19) is a massive fall in lymphocyte count in which magnitude associates with mortality. 1,2 Recent monitoring of COVID-19 intensive care units (ICU) patients confirmed the profound lymphopenia and its remarkable stability over time. 3,4 While most immunomodulation approaches proposed so far in COVID-19 focused on inhibiting inflammatory cytokine response; mounting evidence indicates that this viral-induced defective lymphocyte response may play a central role in COVID-19 pathophysiology. 5 Interestingly, recombinant human interleukin-7 (IL-7) therapy, known to efficiently restore lymphocyte count in several viral infections was safely administered in septic shock patients 6 who present with similar lymphocyte alterations as observed in COVID-19. 3 We report here the case of a 74-year-old patient without any comorbidity. He was admitted to our university hospital ICU (Hospices Civils de Lyon, France) for COVID-19 ARDS requiring high flow oxygen. ICU admission (thereafter corresponding to day 0) occurred 9 days after first symptom onset. SARS-COV-2 PCR was positive (nasal swab) and CT scan was highly suspect of severe COVID-19. He was intubated 24 h after admission and ventilation was set according to guidelines for ARDS including prone positioning. PEEP was around 8-10 cm H 2 O for the whole ICU stay. Antibiotics were initiated at admission until bacterial samples were negative. On day 10, as the patient was still presenting with severe ARDS without any infection criteria, steroids were initiated at 1 mg/kg/day (equivalent prednisolone) but stopped 5 days later (i.e., day 15) due to ventilator associated pneumonia (VAP, Morganella morganii and Aspergillus fumigatus were identified in BALF). Antibiotics and antifungal therapies were started immediately. At day 20, an additional VAP was suspected (without any bacterial documentation) treated with meropenem. After admission, SARS-CoV-2 PCR remained positive at D10 and D16. From day 0 to day 24, the patient remained deeply lymphopenic and presented with markedly decreased monocytic expression of HLA-DR (Fig. 1) reflecting deep immunocompromised state. Therefore, at day 24, while the patient did not show any improvement in pulmonary function, presented with several intercurrent infections, absence of negativation of SARS-CoV-2 PCR, and marked and persisting lymphopenia, compassionate use of IL-7 was initiated in order to improve immunity and consequently allow viral clearance. After inaugural injection

The signal pathways and treatment of cytokine storm in COVID-19

“…Thus, the authors prospectively proposed that earlier administration of IL-7 may have indicated better clinical outcomes. 222 In a case series from St. Luc University Hospital, Brussels, Belgium, the authors showed that patients in the IL-7 treatment group seemed to have higher levels of lymphocyte counts than those in the control group, without aggravated inflammation and pulmonary injury. 223 Unfortunately, the absence of detailed phenotypic or functional studies on lymphocytes weakens the reliability of these studies.…”

Monocyte HLA‐DR Measurement by Flow Cytometry in COVID‐19 Patients: An Interim Review

“…In some studies, the lowest mHLA‐DR expression levels (<4,000 AB/C) were observed in patients who died. Interestingly, mHLA‐DR expression has been used for the monitoring of a critically ill COVID‐19 patient who received compassionate rhIL‐7 therapy (31). After more than 3 weeks in ICU and several episodes of recurrent infections along with constant SARS‐CoV‐2 positive PCR, mHLA‐DR expression was <4,000 AB/C.…”

“…After more than 3 weeks in ICU and several episodes of recurrent infections along with constant SARS‐CoV‐2 positive PCR, mHLA‐DR expression was <4,000 AB/C. After initiation of the drug, mHLA‐DR expression rapidly normalized (31). In addition, although these did not report data as AB/C, two other studies are of note: Hue et al reported a decreased mHLA‐DR in patients with COVID ARDS compared with healthy controls, but this was not as low as that found in bacterial ARDS.…”

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

“…In a case study conducted by Monneret et al (301), compassionate administration of IL-7 to a patient with severe COVID-19 significantly improved total lymphocyte count and HLA-DR expression in circulating monocytes four days after administration of the first dose. The patient also showed a significant improvement in lung involvement and negative viral load.…”