Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19. We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001). In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.

Colorectal cancer is not one disease but rather a collection of neoplastic diseases. Due to heterogeneity in the disease biology, therapy response, and prognosis, extensive disease stratification is required. Therefore, TNM stage, microsatellite status, tumor grade, lymphovascular invasion, and other parameters are assessed in the pathology report to indicate the extent and prognosis of the disease. The mutation status of KRAS, BRAF, and NRAS is also investigated in a metastatic context to predict the response to anti-EGFR therapy. Recently, 4 distinct molecular subtypes of colorectal cancer have been described that have both prognostic and therapeutic relevance. In addition, characterization of the inflammatory infiltrate revealed major differences in the amount and location of inflammatory cells in distinct colorectal tumor types. Together, all of these parameters help to stratify patients into different therapeutic and prognostic subgroups. However, this stratification is not unambiguous since tumors often display intratumoral heterogeneity, whereby several subpopulations within one tumor show differences in morphology, inflammatory infiltrate, mutational status, or gene expression profile. This article gives an overview of all of the current known data with regard to tumor heterogeneity at both inter- and intratumoral levels.

Primary graft dysfunction (PGD) is the clinical syndrome of acute lung injury after lung transplantation (LTx). However, PGD is an umbrella term that encompasses the ongoing pathophysiological and -biological mechanisms occurring in the lung grafts. Therefore, we aim to provide a focused review on the clinical, physiological, radiological, histological and cellular level of PGD. PGD is graded based on hypoxemia and chest X-ray (CXR) infiltrates. High-grade PGD is associated with inferior outcome after LTx. Lung edema is the main characteristic of PGD and alters pulmonary compliance, gas exchange and circulation. A conventional CXR provides a rough estimate of lung edema, while a chest computed tomography (CT) results in a more in-depth analysis. Macroscopically, interstitial and alveolar edema can be distinguished below the visceral lung surface. On the histological level, PGD correlates to a pattern of diffuse alveolar damage (DAD). At the cellular level, ischemia-reperfusion injury (IRI) is the main trigger for the disruption of the endothelial-epithelial alveolar barrier and inflammatory cascade. The multilevel approach integrating all PGD-related aspects results in a better understanding of acute lung failure after LTx, providing novel insights for future therapies.

Background Detailed data on post‐operative death in lung transplant (LTx) recipients are lacking. Therefore, we investigated all deaths after LTx in a large, single‐centre, 25‐year follow‐up, cohort. Methods Prevalence, time, place and cause of death (COD) were retrospectively analysed for all patients undergoing primary LTx between July 1991 and December 2015 in our centre. Results Over subsequent years, post‐operative survival significantly improved, with proportionally more patients surviving to one year post‐LTx (p<0.0001). A total of 347 (38.9%) LTx recipients died, of which 53.6% expired within 3 years post‐LTx (median time to death 910 (236‐2447) days). Autopsy was performed in 34.8% of deaths. COD included CLAD in 27.1% (BOS 63.8% vs. RAS 36.2%); infection (26.5%); malignancy (15.6%); postoperative complication (11.2%); cardiovascular disease (4.6%); or other causes (6.9%). In 8.1% no clear COD could be determined. COD significantly differed between the various LTx indications (p=0.047). With longer follow‐up, infection becomes a less prevalent COD, but CLAD and malignancies a more important COD. The majority of patients died on the intensive care unit (40.6%) or hospital ward (29.1%), but place of death varied depending on the underlying COD. Conclusion The current study provides insights in the post‐operative deaths of LTx recipients.

Long-term survival after lung transplantation (LTx) is hampered by development of chronic lung allograft dysfunction (CLAD).Pseudomonas aeruginosais an established risk factor for CLAD. Therefore, we investigated the effect ofP. aeruginosaeradication on CLAD-free and graft survival.Patients who underwent first LTx between July, 1991, and February, 2016, and were free from CLAD, were retrospectively classified according toP. aeruginosapresence in respiratory samples between September, 2011, and September, 2016.P. aeruginosa-positive patients were subsequently stratified according to success ofP. aeruginosaeradication following targeted antibiotic treatment. CLAD-free and graft survival were compared betweenP. aeruginosa-positive andP. aeruginosa-negative patients; and between patients with or without successfulP. aeruginosaeradication. In addition, pulmonary function was assessed during the first year followingP. aeruginosaisolation in both groups.CLAD-free survival ofP. aeruginosa-negative patients (n=443) was longer compared withP. aeruginosa-positive patients (n=95) (p=0.045). Graft survival ofP. aeruginosa-negative patients (n=443, 82%) was better compared withP. aeruginosa-positive patients (n=95, 18%) (p<0.0001). Similarly,P. aeruginosa-eradicated patients demonstrated longer CLAD-free and graft survival compared with patients with persistentP. aeruginosa. Pulmonary function was higher in successfullyP. aeruginosa-eradicated patients compared with unsuccessfully eradicated patients (p=0.035).P. aeruginosaeradication after LTx improves CLAD-free and graft survival and maintains pulmonary function. Therefore, earlyP. aeruginosadetection and eradication should be pursued.