COVID-19 in Children: Molecular Profile and Pathological Features.

Although the World Health Organization has declared the end of the COVID-19 pandemic, doctors continue to register new cases of the disease among both adults and children. Unfortunately, the course of COVID-19 in children can have a severe form, with death being a potential outcome. The absence of published works discussing the pathological morphology of COVID-19 in children prevents the objective analysis of the disease's pathogenesis, including among the adult population. In this vein, the objective of our study is to identify the morphological features of the lungs' involvement and evaluate virus-host interactions in the case of COVID-19 in patients at a pediatric medical practice. We present the results of the study of the lungs of three children who died due to COVID-19, highlighting the predominant involvement of their respiratory organs at different stages of the disease (5, 21, and 50 days). This article presents data obtained from histopathological and immunohistochemical investigations, taking into account the results of clinical and laboratory indicators and intravital and postmortem SARS-CoV-2 PCR investigations. The common finding of all of the examined COVID-19 cases is the involvement of the endothelium in microcirculation vessels, which are considered to be a primary target of various pathogenic influencing factors. We also discuss both the significance of apoptosis as a result of virus-host interactions and the most likely cause of endothelium cell destruction. The results of this study could be useful for the development of endothelium-protective therapy to prevent the progression of disseminated intravascular coagulation syndrome.

Trehalose 6,6-Dimycolate from Mycobacterium tuberculosis Induces Hypercoagulation.

Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 µg of i.p. TDM in light mineral oil (TDM-IP). At day 7, another injection of 10 µg of i.v. TDM in oil/water emulsion was given (TDM-IV). The i.p./i.v. TDM (TDM-IVIP) group was compared with mice injected once with i.v. or i.p. TDM. The responses to TDM-IP, TDM-IV, or TDM-IPIV were consistent between mouse strains. Mice that received TDM-IV and TDM-IPIV had inflammatory pathologic findings with increases in inflammatory and T-cell cytokines, and the TDM-IPIV group had further enhancement of IL-10 and granulocyte-macrophage colony-stimulating factor. The TDM-IPIV group had increased CD4(+) T cells in lung tissue, significantly increased coagulation, decreased clot formation time, and increased maximum clot firmness. Masson's trichrome staining revealed increased deposition of collagen in the occluded vasculature. TDM-IPIV promotes a hypercoagulopathy state, independent of inflammation. This new model argues that TDM is sufficient to generate the hypercoagulopathy observed in patients with TB.

Morphoproteomics Identifies the Foamy Alveolar Macrophage as an M2 Phenotype with PD-L1 Expression in the Early Lesion of Post-Primary Tuberculosis: Implications for Host Immune Surveillance and Therapy.

Post-primary tuberculosis (TB) disease is characterized by paucibacillary necrosis of the early lesion, tuberculous pneumonia, in the adult human lung. The mechanism is speculated to be a strong localized delayed type hypersensitive response (DTH). However, up to this date, no one has been able to identify the source of the large accumulation of MTB antigens required for the DTH response. Although it is known and accepted that the pathogen, Mycobacterium tuberculosis (MTB), significantly affects macrophage function and activity, few studies have focused on macrophages at the site of the early lesion of developing post-primary MTB in human lungs. In vitro studies have examined the effect of MTB on skewing the macrophage phenotype, specifically the dynamic of the M1 and M2 differentiation. Additionally, it is also well documented that MTB infection induces macrophages to become foamy, accumulating host, and potentially MTB, lipids in the cytoplasm. The foamy macrophage is necessary for prolonging MTB survival in the infected lung. Using autopsy derived lung samples from untreated TB diseased individuals, this report, by applying morphoproteomics, demonstrates that the alveolar macrophages present in the early lesion of TB are primarily of the M2 phenotype. The M2 foamy alveolar macrophages (FAM) are also loaded with MTB antigens by immunohistochemistry and are paucibacillary. Moreover, the M2 alveolar macrophages predominately express PD-L1, leading to suppression of PD-1+ lymphocytes and host immunosurveillance. These morphoproteomic analyses indicate that early lesion of MTB in the adult human lung leads to a skewed M2 foamy alveolar macrophage phenotype that creates a protective microenvironment that accumulates high concentrations of MTB antigens, which when released can lead to necrosis and eventual cavitation.

Morphological and Immunohistochemical Features of Placental Damage in Cases of Perinatal Death: Institutional Experience with Emphasis on Viral Etiology.

OBJECTIVE: Intrauterine hypoxia/asphyxia is not the cause, but a consequence of different pathological conditions that requires a more detailed study of the morphogenesis of perinatal death. METHODS: Structural changes in placentas of intrauterine fetal demise (IUFD) in different stages of intrauterine period and placentas in early neonatal death were reviewed and compared. Control group was composed of term placentas without evidence of perinatal asphyxia or other neonatal abnormalities. Immunohistochemical investigation was performed by antibodies to Herpes simplex virus (HSV), Cytomegalovirus (CMV), and tumor necrosis factor (TNF). Morphometric analysis was performed using the Pannoramic Midi II histoscanner of "3DHISTECH" company. RESULTS: The histologic examination of placentas revealed differences between IUFD and early neonatal death. Predominant localization of HSV and CMV antigens was noted in the walls of capillaries and in placental villous stroma in absolute majority of IUFD and early neonatal death cases; importantly, colocalization of TNF, HSV, and CMV antigens was also detected in cases of IUFD and early neonatal period. CONCLUSION: Damage of placental vessels due to the influence of pathogenic factors (virus antigens, TNF) can cause acute or chronic intrauterine fetus hypoxia which is a leading pathogenetic factor of perinatal death.

Morphological manifestations of the atypical mycobacteriosis caused by nontuberculous mycobacteria in the HIV infected patients.

Infection with atypical mycobacteria (MAC) is a well-known complication of AIDS that typically occurs only in people with advanced immunodeficiency. We studied tissues from 13 patients with HIV and atypical mycobacterial infection who died in St Petersburg Russia from 2009-2012. Three patterns of disease were identified that suggest effects of host resistance. The first pattern was in people paucibacillary disease. They had positive blood cultures and histologic changes consistent with mycobacterial infection, but no stainable acid fast bacilli (AFB). The second group had disseminated infection in many organs including the lungs with extensive necrosis with many AFB. Finally, the third group had massive infection of many organs, but not the lungs, and only minimal necrosis. These observations suggest significant heterogeneity in atypical mycobacterial infections.