Observational study on off-label use of tocilizumab in patients with severe COVID-19.

BACKGROUND: In December 2019 a novel coronavirus designated SARS-CoV-2 was identified, and the disease COVID-19 has caused many deaths. SARS-CoV-2 infection has been associated with the development of cytokine storm (including interleukin 6 (IL-6)), which can cause lung damage and lack of oxygen. Tocilizumab (TCZ) inhibits ligand binding to the IL-6 receptor and may be a potential treatment for the hyperinflammation symptoms of COVID-19. However, data regarding the efficacy of TCZ in COVID-19 are lacking. The rapid spread of the pandemic in France, especially in the Paris region, constrained us to the off-label use of TCZ in patients with severe clinical conditions. METHODS: A single-centre observational cohort study of 44 patients infected with COVID-19 was carried out between 6 April and 21 April 2020 in Groupe Hospitalier Intercommunal Le Raincy-Montfermeil (GHILRM). Twenty-two patients diagnosed with COVID-19 were treated with TCZ and were compared with 22 patients not treated with TCZ matched for age, gender and length of hospital stay for COVID-19. Respiratory rate and oxygen supplementation as well as laboratory parameters (such as C-reactive protein (CRP), aspartate aminotransferase and alanine aminotransferase) were collected at baseline and during 14 days of follow-up. Our primary objective was to assess the efficacy of TCZ on respiratory clinical conditions. FINDINGS: The average respiratory rate was lower in the TCZ group than in the control group (21.5 vs 25.5 breaths/min at day 14, 95% CI -7.5 to -0.4; p=0.03). Treated patients tended to be intubated less during the course of the disease (2/22 vs 6/22, 95% CI -0.4 to 0.1; p=0.12). In each group, 10 patients no longer required oxygen therapy. We found a significant decrease in CRP in treated patients on day 7 (p=0.04). TCZ caused cytolysis in more than half (14/22) of the patients but without clinical impact. INTERPRETATION: There was a significant difference in the respiratory rate on day 14 of follow-up, with a greater decrease observed in the treated group. Fewer patients required mechanical ventilation in the TCZ group, especially among patients with more extensive CT lung damage, than in the control group. The same number of patients were weaned off oxygen on day 14 in the two groups, while the patients in the TCZ group had more severe impairment at inclusion. We consider that TCZ showed significant control of the biological inflammatory syndrome, suggesting that it may limit the effect of the cytokine storm. Our study seems to indicate the efficacy of TCZ, particularly in patients with severe initial pulmonary impairment. Selecting the best candidates and the best timing for TCZ therapy needs to be determined in randomised clinical trials.

The impact of medication review with version 2 STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment) criteria in a French nursing home: a 3-month follow-up study.

BACKGROUND: Improving medication appropriateness is a priority of French national campaigns in nursing homes. A pilot study was conducted to evaluate the impact of a medication review in a French nursing home with a 3-month follow up. METHOD: A medication review was conducted in 2015 using version 2 STOPP and START criteria. The number and type of drugs meeting a STOPP that were reintroduced and the number and type of drug meeting a START that were stopped during follow up were measured. An expert committee adjudicated whether 3-month hospitalizations and deaths were related to medication review. The impact of medication review on the cost related to drug consumption was calculated for 3 months. RESULTS: The 52 residents (age 84 ± 9 years, 83% female) fulfilled, on average, 2 ± 1.4 of the STOPP criteria and 0.7 ± 0.6 of the START criteria. A total of 101 drugs were stopped and 34 drugs were started. Five deaths occurred during follow up and were judged as not related to medication review. Five drugs stopped were reintroduced in five residents for a rebound effect or a symptom occurrence and one resident had stopped a START medication (aspirin) for a minor adverse drug reaction. At 3 months, a gain of 20.21 ± 31.34 euros per resident was observed. CONCLUSION: The medication review using version 2 STOPP and START criteria and involving the physician in charge seems useful for detecting and correcting inappropriate prescribing in a nursing home.

[Impact of Geriatric Drug Guidelines on the Quality Requirement of Elderly Patients]. / Impact d'un livret thérapeutique sur la qualité des prescriptions médicamenteuses des résidents d'EHPAD.

OBJECTIVE: Elderly with several pathologies are usually treated with many drugs, and are exposed to a majored risk of drug-induced adverse effects. A network of local nursing homes (EHPAD) in the south Seine-Saint-Denis area (France) created a geriatric drug guidelines to improve the quality of the drugs prescriptions. This study assesses the conformity of prescriptions in elderly patients prior and after the distribution of the booklet. METHODS: This before and after design study focused on the drug prescriptions for patients in eight EHPAD followed for two randomly given days in 2012 (n = 503) and 2013 (n = 334). The geriatric drug guidelines included a list of medicines suitable for the elderly (conformity list) and recommendations for prescription and monitoring. Data collection was conducted from medical records and interviews with coordinators doctors and nursing staff in nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: Median age, weight and creatinine level were respectively 88 years, 61.0 kg, and 74.9 µmol/L (prior) and 88 years, 59.6 kg, and 77.0 µmol/L (after). Median times of latest serum creatinine dosage were 112 days (prior) and 108 days (after). The median number of prescribed drugs was 8 per resident during the two period of study. The conformity rate of prescription was better prior the distribution of the guidelines, respectively 87.5% and 80.0% (p<10⁻³). The average formal quality score was better after the distribution of the booklet increasing form 4.23 to 4.40 points (p<10⁻4). For high risk inducing drugs, monitoring was prescribed in 34.2% (prior) and 32.4% (after). CONCLUSIONS: This study shows that the drug geriatric guidelines does not improve prescription conformity and monitoring for high risk drugs, but it does significantly improve the median formal quality score.

[Medical treatment of the elderly in residential care: a multicenter cross-sectional study]. / Prescriptions médicamenteuses chez les personnes âgées en EHPAD: une étude transversale multicentrique.

OBJECTIVE: To retrospectively assess the quality of prescriptions in elderly patients prior the distribution of guidelines for geriatric drug prescriptions. METHODS: A cross-sectional study was conducted for one day in 2012 to investigate the quality of the prescriptions in 495 residents of 8 nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: The median number of prescribed drugs was 8,5 per resident. Over a total of 4311 prescribed drugs, the average quality score was 4,96 ± 0,45; 4,54 ± 0,70 in computerized orders and 3,4 ± 1,02 in handwritten orders. Among 939 drugs considered as at high risk of inducing serious adverse reactions, monitoring was prescribed 154 times only (16,4%). CONCLUSIONS: A lack of drug monitoring was highlighted, especially for high risk drugs. The quality of prescription may be improved by the use of computerized orders.

[Frequency and type of adverse drug reactions in two Seine-Saint-Denis departments of pneumology]. / Estimation de l'incidence des événements iatrogènes médicamenteux dans les services de pneumologie de deux hôpitaux de Seine-Saint-Denis.

The aim of this study was to explore the frequency and type of adverse drug reactions between January and June 2001 in hospitalised patients. A prospective study was conducted in two pneumology departments of public hospitals in the Seine-Saint-Denis area. Adverse drug reactions were collected by hospital pharmacists after spontaneous notification by nurses and physicians, except for deliberate drug overdose. The drugs implicated, causality and the severity of each adverse drug reaction were analysed. The mean age of patients was 69 +/- 15 years (63% male and 37% female). The total sample comprised 1598 patients. During the period of the study, 190 patients experienced at least one adverse drug reaction. This amounts to a prevalence of 12% (95% confidence interval [95% CI: 7.4-16.6%). The percentage of severe adverse effects was 28.4% (95% CI: 25.1-31.6%) and adverse reactions were rated avoidable in 35.8% of cases (95% CI: 32.3-39.3%). Antibiotics (23%), corticosteroids (15%), analgesics (13%) and anticoagulants (9%) were the drugs most frequently implicated in adverse effects. Preventable adverse drug events were more serious than non-preventable adverse events (p = 0.001). With regard to the level of severity, antibiotics, corticosteroids and bronchodilators were associated with a low severity level, whereas anticoagulants and antineoplastics were associated with a high severity level.

Pharmacokinetics of teicoplanin during plasma exchange.

OBJECTIVE: To study the elimination of teicoplanin during plasma exchange, a procedure currently used to treat a variety of disorders involving immune complexes. Teicoplanin is a glycopeptide antibiotic that exhibits a long terminal half-life (100-150 h) and is highly bound to plasma proteins (unbound fraction (fu)=0.2). METHODS: Twelve adults with systemic polyarteritis nodosa, cryoglobulinemia-induced vasculitis or dysglobulinemic neuropathy undergoing plasma exchange were studied. Each patient received intravenous teicoplanin, 6 mg/kg body weight, immediately before plasma exchange. Plasma was assayed for teicoplanin by high pressure liquid chromatography. RESULTS: A high level of protein binding of teicoplanin was measured within this patient population (98%). The mean quantity of teicoplanin eliminated (+/-SD) was 74.6+/-34.6 mg. The mean drug fraction eliminated by plasma exchange (+/-SD) was 19.5+/-5.6%. Mean fu value as determined by ultrafiltration (+/-SD) was 2.2+/-1.7%. CONCLUSIONS: These results show that plasma exchange influences teicoplanin pharmacokinetics, with a clinically significant quantity being eliminated. If trough teicoplanin concentrations of around 10 mg/L are desired, it is recommended that teicoplanin dosage be supplemented or given after plasma exchange.