COVID-19 is a deadly pulmonary disease with peculiar characteristics, which include variable clinical course and thrombophilia. A thorough understanding of the pathological correlates of the disease ...is still missing.
Here we report the systematic analysis of 41 consecutive post-mortem samples from individuals who died of COVID-19. Histological analysis is complemented by immunohistochemistry for cellular and viral antigens and the detection of viral genomes by in situ RNA hybridization.
COVID-19 is characterized by extensive alveolar damage (41/41 of patients) and thrombosis of the lung micro- and macro-vasculature (29/41, 71%). Thrombi were in different stages of organization, consistent with their local origin. Pneumocytes and endothelial cells contained viral RNA even at the later stages of the disease. An additional feature was the common presence of a large number of dysmorphic pneumocytes, often forming syncytial elements (36/41, 87%). Despite occasional detection of virus-positive cells, no overt signs of viral infection were detected in other organs, which showed non-specific alterations.
COVID-19 is a unique disease characterized by extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, along with the presence of infected cell syncytia. Several of COVID-19 features might be consequent to the persistence of virus-infected cells for the duration of the disease.
This work was supported by a King's Together Rapid COVID-19 Call grant from King's College London. MG is supported by the European Research Council (ERC) Advanced Grant 787971 “CuRE” and by Programme Grant RG/19/11/34633 from the British Heart Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite treatment being in line with current guidelines, mortality remains high in those ...with septic shock. Intravenous immunoglobulins represent a promising therapy to modulate both the pro- and anti-inflammatory processes and can contribute to the elimination of pathogens. In this context, there is evidence of the benefits of immunoglobulin M (IgM)- and immunoglobulin A (IgA)-enriched immunoglobulin therapy for sepsis. This manuscript aims to summarize current relevant data to provide expert opinions on best practice for the use of an IgM- and IgA-enriched immunoglobulin (Pentaglobin) in adult patients with sepsis.
Main text
Sepsis patients with hyperinflammation and patients with immunosuppression may benefit most from treatment with IgM- and IgA-enriched immunoglobulin (Pentaglobin). Patients with hyperinflammation present with phenotypes that manifest throughout the body, whilst the clinical characteristics of immunosuppression are less clear. Potential biomarkers for hyperinflammation include elevated procalcitonin, interleukin-6, endotoxin activity and C-reactive protein, although thresholds for these are not well-defined. Convenient biomarkers for identifying patients in a stage of immune-paralysis are still matter of debate, though human leukocyte antigen–antigen D related expression on monocytes, lymphocyte count and viral reactivation have been proposed. The timing of treatment is potentially more critical for treatment efficacy in patients with hyperinflammation compared with patients who are in an immunosuppressed stage. Due to the lack of evidence, definitive dosage recommendations for either population cannot be made, though we suggest that patients with hyperinflammation should receive an initial bolus at a rate of up to 0.6 mL (30 mg)/kg/h for 6 h followed by a continuous maintenance rate of 0.2 mL (10 mg)/kg/hour for ≥ 72 h (total dose ≥ 0.9 g/kg). For immunosuppressed patients, dosage is more conservative (0.2 mL 10 mg/kg/h) for ≥ 72 h, without an initial bolus (total dose ≥ 0.72 g/kg).
Conclusions
Two distinct populations that may benefit most from Pentaglobin therapy are described in this review. However, further clinical evidence is required to strengthen support for the recommendations given here regarding timing, duration and dosage of treatment.
Even in the absence of strong indications deriving from clinical studies, the removal of mediators is increasingly used in septic shock and in other clinical conditions characterized by a ...hyperinflammatory response. Despite the different underlying mechanisms of action, they are collectively indicated as blood purification techniques. Their main categories include blood- and plasma processing procedures, which can run in a stand-alone mode or, more commonly, in association with a renal replacement treatment. The different techniques and principles of function, the clinical evidence derived from multiple clinical investigations, and the possible side effects are reviewed and discussed along with the persisting uncertainties about their precise role in the therapeutic armamentarium of these syndromes.
Polyclonal Intravenous Immunoglobulins (IvIg) are often administered to critically ill patients more as an act of faith than on the basis of relevant clinical studies. This particularly applies to ...the treatment of sepsis and septic shock because the current guidelines recommend against their use despite many investigations that have demonstrated their beneficial effects in different subsets of patients. The biology, mechanisms of action, and clinical experience related to the administration of IvIg are reviewed, which aim to give a more in-depth understanding of their properties in order to clarify their possible indications in sepsis and septic shock patients.
The extracorporeal elimination of a pathogen or damage-associated molecular pattern via blood purification techniques is increasingly being used in patients with septic shock and other clinical ...conditions characterized by a life-threatening inflammatory response. The removal of these substances can be accomoplished by means of ultrafiltration or hemoadsorption. Independently from the blood putification technique used, they could also affect the clearance of antibacterial and antifungal agents with a potentially significant clinical impact. In our review, we describe the basic principles of ultrafiltration and hemoadsorption, the available devices for this latter and the existing experimental and clinical studies; the final paragraph is dedicated to practical considerations that can help clinicians to consider the clearance of antibiotics and antifungals attributable to these techniques to minimize the risk of a iatrogenic underdosage.
Pneumomediastinum is a rare complication of acute respiratory distress syndrome (ARDS), when air leaks into the mediastinum. An increased pneumomediastinum incidence, of up to 5–13%, was reported ...during the coronavirus disease 2019 (COVID-19) pandemic 1, 2 and even occurred spontaneously without a history of mechanical ventilation 3, similarly to the previous severe acute respiratory syndrome (SARS)-1 4. Almost half of the 30 consecutive COVID-19 patients who had prolonged invasive mechanical ventilation had full-thickness tracheal lesions and pneumomediastinum 5. Although pronation and high positive end-expiratory pressure levels were presumed to be the putative causes of pneumomediastinum 5, the mechanism of this COVID-19 complication remains unknown. We hypothesise that sonic hedgehog (SHH) and Wnt5a signalling, crucial pathways in tracheal morphogenesis, and repair/regeneration of cartilage lesions in adulthood 6, 7, could play a role in pneumomediastinum-related COVID-19 tracheal lesions.
Pneumomediastinum is a rare complication of ARDS but is more common during #COVID19. The fibrous hyaline degeneration of the tracheal rings seen in this autoptic series is an original observation that has not been previously described in COVID-19 patients.
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Definitive data on the incidence rate of ventilator-associated pneumonia (VAP) in COVID-19 are still lacking, ranging from 29 to 58%. To date, most of the existing literature refers to patients who ...are not subjected to VAP prevention with selective decontamination of the digestive tract (SDD). We retrospectively collected data on all COVID-19 patients admitted to our ICU during the second phase of the pandemic with the aim of assessing the occurrence of VAP and the related mortality at 30 days and comparing our findings with the available literature. Of 213 patients, only 74 were eligible for the analysis. An incidence of 6.90 VAP per 1000 days of mechanical ventilation was detected. Apart from a smoking habit (0% vs. 10%, p < 0.005) and diabetes (14% vs. 54%, p = 0.026), patients who developed VAP did not differ significantly from those who did not regarding comorbidities, steroid use, and the severity of COVID-19. VAP were predominantly caused by mono-microbial Gram-negative or fungal infections. Mortality was significantly higher in those who developed VAP (86 vs. 33%, p = 0.002). Our evidence aligned with the available literature in assuming a possible role of SDD in reducing the incidence of VAP in COVID-19 patients, with a possible impact on related mortality and costs.
The Waterhouse-Friderichsen syndrome represents a critical condition characterized by a septic shock associated with a disseminated intravascular coagulation causing the plugging of the microvascular ...network virtually all organs and systems, including the skin, the kidneys, the liver, and adrenal glands; the mortality rate is elevated, and survivors often must undergo multiple limb amputations. Here, we describe the uncommon case of an asplenic patient who developed this syndrome after a superficial wound caused by a dog bite causing an initial infection due to
Capnocytophaga canimorsus
that is part of the normal oral microbiome of pets. The clinical and pathological findings and the current and future therapeutic options are reviewed and discussed.
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IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
During bronchoscopy hypoxemia is commonly found and oxygen supply can be delivered by interfaces fed with high gas flows. Recently, the high-flow nasal cannula (HFNC) has been introduced for oxygen ...therapy in adults, but they have not been used so far during bronchoscopy in adults. Forty-five patients were randomly assigned to 3 groups receiving oxygen: 40 L/min through a Venturi mask (V40, N=15), nasal cannula (N40, N=15), and 60 L/min through a nasal cannula (N60, N=15) during bronchoscopy. Gas exchange and circulatory variables were sampled before (FiO2 = 0.21), at the end of bronchoscopy (FiO2 = 0.5), and thereafter (V40, FiO2 = 0.35). In 8 healthy volunteers oxygen was randomly delivered according to V40, N40, and N60 settings, and airway pressure was measured. At the end of bronchoscopy, N60 presented higher PaO2, PaO2/FiO2, and SpO2 than V40 and N40 that did not differ between them. In the volunteers (N60) median airway pressure amounted to 3.6 cmH2O. Under a flow rate of 40 L/min both the Venturi mask and HFNC behaved similarly, but nasal cannula associated with a 60 L/min flow produced the better results, thus indicating its use in mild respiratory dysfunctions.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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