Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context.

The pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. In this Series paper, we review the clinical and methodological heterogeneity of studies of IL-6 receptor antagonists, and consider how this heterogeneity might have influenced reported treatment effects. Timing from clinical presentation to treatment, severity of illness, and concomitant use of corticosteroids are among the factors that might have contributed to apparently inconsistent results. With an understanding of the sources of variability in these trials, available evidence could be applied to guide clinical decision making and to inform the enrichment of future studies.

Fluorescent microangiography (FMA): an improved tool to visualize the pulmonary microvasculature.

Visualization of the complex lung microvasculature and resolution of its three-dimensional architecture remains a difficult experimental challenge. We present a novel fluorescent microscopy technique to visualize both the normal and diseased pulmonary microvasculature. Physiologically relevant pulmonary perfusion conditions were applied using a low-viscosity perfusate infused under continuous airway ventilation. Intensely fluorescent polystyrene microspheres, confined to the vascular space, were imaged through confocal optical sectioning of 200 microm-thick lung sections. We applied this technique to rat lungs and the markedly enhanced depth of field in projected images allowed us to follow vascular branching patterns in both normal lungs and lungs from animals with experimentally induced pulmonary arterial hypertension. In addition, this method allowed complementary immunostaining and identification of cellular components surrounding the blood vessels. Fluorescent microangiography is a widely applicable and quantitative tool for the study of vascular changes in animal models of pulmonary disease.

Increased expression of nitric oxide synthase in human lung transplants after nitric oxide inhalation.

BACKGROUND: The effects of the ischemia-reperfusion process of organ transplantation on nitric oxide (NO) synthase (NOS) in humans are unknown. The effects of NO inhalation on endogenous NOS expression and activity are controversial. The authors hypothesized that NO inhalation may affect ischemia-reperfusion-induced alterations of the endogenous NOS system. METHODS: The authors performed lung biopsy on patients in a randomized phase II clinical trial of NO inhalation during lung transplantation. After lung implantation, 20 ppm of NO or placebo gas was administered 10 min after the start of reperfusion. Lung tissues were collected from 20 patients (NO, n=9; placebo, n=11) after cold and warm ischemia, 1 hr and 2 hr after reperfusion. The protein levels of NOS isoforms were analyzed by Western blotting and the total NOS activity was measured. RESULTS: The protein levels of inducible NOS did not change significantly in either of the groups. In contrast, during the 2-hr reperfusion period, constitutive NOS (neuronal NOS [nNOS] and endothelial NOS) tended to decrease in the placebo group, but gradually increased in the NO group. After 2 hr of reperfusion, the nNOS protein in the NO group was significantly higher than that in the placebo group (P <0.05). However, the total NOS activity remained at low levels in both groups. CONCLUSIONS: NO inhalation-induced increase of constitutive NOS proteins indicates the interaction between inhaled NO molecules and lung tissues. However, the activity of these newly synthesized NOS proteins remains suppressed during the ischemia-reperfusion period of lung transplantation.

A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation.

Inhalation of nitric oxide (NO) has been advocated as a method to prevent ischemia-reperfusion injury after lung transplantation. We enrolled 84 patients into a concealed, randomized, placebo-controlled trial to evaluate the effect of inhaled NO (20 ppm NO or nitrogen) initiated 10 minutes after reperfusion on outcomes after lung transplantation. The groups (n = 42) were balanced with respect to age, sex, lung disease, procedure, and total ischemic times. PaO2/FIO2 ratios were similar on admission to the intensive care unit (ICU) (NO 361 +/- 134; control patients 357 +/- 132), and over the duration of the study. There were no differences in hemodynamics between the two groups. Severe reperfusion injury (PaO2/FIO2 < 150) was present at the time of admission to the ICU in 14.6% NO patients versus 9.5% of control patients (p = 0.48). The groups had similar median times to first successful trial of unassisted breathing (25 vs. 27 hours; p = 0.76), successful extubation (32 vs. 34 hours; p = 0.65), ICU discharge (3.0 days for both groups), and hospital discharge (27 vs. 29 days; p = 0.563). Five NO versus six control patients died during their hospital stay. Adjusting for age, sex, lung disease etiology, presence of pulmonary hypertension, and total ischemic time did not alter these results. In conclusion, we did not detect a significant effect of inhaled NO administered 10 minutes after reperfusion on physiologic variables or outcomes in lung transplant patients.

Bronchogenic carcinoma after solid organ transplantation.

BACKGROUND: This study assesses the risk of bronchogenic carcinoma after solid organ transplantation. Although the overall incidence of malignancy is increased after solid organ transplantation, the risk of bronchogenic carcinoma in the transplant population has not been systematically studied. METHODS: Among a cohort of 3,374 patients transplanted in our institution between 1985 and 2000 (1,735 kidney recipients, 930 liver, 313 heart, and 396 lung recipients), 9 patients (0.3%) had a bronchogenic carcinoma develop. Lung carcinoma occurred in 3 kidney recipients, 3 liver recipients, 2 heart recipients, and 1 lung recipient. RESULTS: Time to diagnosis after the transplant procedure ranged from 9 to 126 months (mean, 63 months). Aside from the lung transplant candidate, all recipients had a smoking history. Seven patients underwent thoracotomy and 6 had a complete resection. Tumors were classified as stage IA (n = 1), IB (n = 2), IIB (n = 2), IIIA (n = 2), IIIB (n = 1), and IV (n = 1). Genotyping demonstrated that the carcinoma arising in the lung transplant recipient originated from the donor and may have been transmitted at the time of transplantation. Two patients were alive without recurrence 21 and 42 months after the operation. CONCLUSIONS: The risk of bronchogenic carcinoma is low and occurs mainly in recipients with a smoking history. However, bronchogenic carcinoma can also be transmitted from donor lungs at the time of transplantation. Hence careful examination of chest roentgenograms, and computed tomographic chest scan if available, as well as meticulous assessment of the lung, and biopsy of any suspicious lesions, are important to limit the risk of lung cancer transmission, especially with the liberalization of donor criteria.

Prognostic significance of thymomas in patients with myasthenia gravis.

BACKGROUND: The presence of thymoma may be a negative prognostic factor with respect to the outcome of myasthenia gravis (MG). METHODS: Of 122 consecutive patients with MG undergoing thymectomy between August 1994 and September 2000, 37 had a thymoma. Postoperative radiation was administered to all patients with stage II thymoma and higher. To determine differences in presentation and outcome, thymoma patients were compared with patients with atrophic (n = 49) or hyperplastic (n = 36) thymus gland on final pathology. RESULTS: Thymoma patients were significantly older (52 +/- 14 vs 36 +/- 15 years, p < 0.0001) and included a significantly higher proportion of males (54% vs 28%, p = 0.006) than patients without thymoma. However, the preoperative Osserman grade and the duration of symptoms before surgery were not significantly different between groups. Mean follow-up after thymectomy was not significantly different between patients with or without thymoma (32 +/- 23 vs 37 +/- 19 months, respectively, p = 0.3). At last follow-up, the proportion of asymptomatic patients (63% vs 70%, respectively, p = 0.5) and the mean Osserman grade (0.6 +/- 0.9 vs 0.5 +/- 0.9, respectively, p = 0.6) were similar in both groups. In addition, the rate of complete remission reached 36% at 5 years in patients with or without thymoma (p = 0.8). CONCLUSIONS: Although myasthenic patients with thymoma are significantly older and include a greater proportion of males, the overall outcome, including the rate of complete remission, was similar between patients with or without thymoma. Therefore, the presence of a thymoma should not necessarily be viewed as a negative prognostic factor regarding recovery from myasthenia gravis.

Heart-lung or lung transplantation for Eisenmenger syndrome.

BACKGROUND: The optimal therapy for end-stage Eisenmenger syndrome (ES) is unknown. We analyzed the United Network for Organ Sharing/International Society for Heart and Lung Transplantation Joint Thoracic Registry to determine predictors of survival. METHODS: Univariate analysis was performed using Kaplan-Meier survival curves. Groups were compared using the log-rank test. Multivariate analysis was performed using a proportional hazards model. RESULTS: There were 605 transplants performed between 1988 and 1998. The causes of ES included atrial septal defect (ASD) in 171, ventricular septal defect (VSD) in 164, multiple congenital anomalies (MCA) in 68 and patent ductus arteriosus (PDA) in 32. Procedures included 430 heart-lung (HLT), 106 bilateral lung, and 69 single lung transplants (LT). Survival after HLT was better than after LT on univariate analysis (p = 0.002). For HLT, survival at 30 days and 1 year was 80.7% and 70.1% compared with 68% and 55.2% for LT. Diagnosis was also a significant predictor of survival (p = 0.011), being best for VSD and MCA (1-year survival 71.4% and 77.6%). There was a highly significant benefit of HLT over LT for VSD patients (p = 0.0001). Diagnosis, the combination of diagnosis and procedure, recipient age, recipient gender, donor age, ischemic time and recipient status were significant in a multivariate model. Multivariate analysis confirmed the superior prognosis of patients with VSD or MCA (p = 0.007 and p = 0.022, respectively) and suggested that the adverse effect of LT was predominately in patients with VSD (risk ratio 1.817, p = 0.035). CONCLUSIONS: This analysis suggests that ES recipients are not a homogeneous group. Patients with VSD and MCA have the best prognosis. HLT appears to offer a survival benefit for patients with ES secondary to VSD and should be re-considered as the operation of choice.

Transplant immunosuppression enhances efficiency of adenoviral-mediated gene retransfection: inhibition of interferon-gamma and immunoglobin G.

BACKGROUND: Transplant immunosuppression regimen facilitates successful adenovirus-mediated gene transfection and retransfection in the rat lung. Herein, we investigated the effect of this strategy on circulating cytokines and antiadenoviral immunoglobin G antibody. METHODS: Male Lewis rats were transfected with 1 x 10(9) pfu/mL of E1-deleted Ad5CMVLacZ vector transtracheally. Rats were randomly assigned to receive daily intraperitoneal triple immunosuppression regimen consisting of cyclosporine (15 mg/kg per day), azathioprine (6 mg/kg per day), and methylprednisolone (2.5 mg/kg per day), or normal saline solution. Retransfection was performed 35 days later to all nonimmunosuppressed animals, whereas immunosuppressed rats were further randomized to receive retransfection or phosphate-buffered saline. Animals were sacrificed on days 1, 2, 7, 35, 42, and 49 after the initial transfection. Beta-galactosidase activity was measured on lung homogenates. Interferon-gamma, tumor necrosis factor-alpha, and antiadenoviral immunoglobin G were measured from the serum. RESULTS: Enhanced and prolonged transgene expression was observed in immunosuppressed animals, especially after retransfection. Concentrations of serum tumor necrosis factor-alpha in both groups were less than 12 pg/mL throughout the study. A significant increase in serum interferon-gamma levels was observed in nonimmunosuppressed animals after retransfection; this was not seen in the immunosuppressed animals. Serum antiadenoviral immunoglobin G titers in both groups were sharply elevated on day 1, and declined to basal levels by day 7, reflecting a preexisting level of humoral immunity to adenovirus. The titer in nonimmunosuppressed rats was significantly increased after retransfection, but remained at very low level in immunosuppressed animals. CONCLUSIONS: Inhibition of interferon-gamma and antiadenoviral immunoglobin G production by triple immunosuppressants may be part of the mechanisms that lead to enhanced and prolonged transgene expression after retransfection.

Marginal donor lungs: a reassessment.

OBJECTIVE: Lung transplantation is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use marginal or extended donors after reports suggesting equivalent outcomes with no additional risk. As our use of extended donor lungs increased and our recipient selection criteria expanded, we believed it was appropriate to reevaluate outcomes with extended donor lungs compared with outcomes with standard donor lungs and recipients outside of the currently accepted guidelines. METHODS: We performed a retrospective review of 128 consecutive lung or heart-lung transplants from January 1, 1997, to June 30, 2000. The primary endpoint was 30-day mortality. Donors were considered extended if any one of the following criteria were met: age greater than 55 years, smoking longer than 20 pack-years, presence of chest radiographic film infiltrate, PO (2) of less than 300 mm Hg, or purulent secretions on bronchoscopy. Guideline and nonguideline recipients were defined on the basis of previously published criteria. RESULTS: Of a total of 123 donors, 63 (51%) were extended. Forty-eight donors failed 1 criterion, 10 failed 2 criteria, and 5 failed 3 criteria. One hundred twenty-eight transplants were performed. The 30-day mortality for the standard donor group was 4 (6.2%) of 65 versus 11 (17.5%) of 63 for the extended donor group (P =.047). CONCLUSIONS: Although many extended donor lungs will result in acceptable postoperative function, caution needs to be exercised in the uses of certain extended donor lungs because there seems to be an increased early mortality rate in that group of recipients. Nonguideline recipients appear to have acceptable early mortality, except when they received extended donor lungs.