Visceral Fat Inflammation and Fat Embolism are associated with Lung's Lipidic Hyaline Membranes in COVID-19 patients

Background: Visceral obesity is a critical determinant of severe coronavirus disease-2019 (COVID-19). Methods: In this study, we performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissues (VAT), lungs and livers of 19 COVID-19 and 23 non-COVID-19 subjects. Results: Although there were no between-groups differences in body-mass-index and adipocytes size, higher prevalence of CD68+ macrophages in COVID-19 subjects VAT was detected (p=0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution employing Oil-Red-O staining (ORO). Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19 individuals (p<0.001). Notably, signs of fat embolism were more prevalent among obese (p=0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication, exacerbated by SARS-CoV2 infection. Importantly, all infected subjects lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control with non-COVID-19 pneumonia. Conclusions: This study describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in obese SARS-CoV2-infected-subjects.

Weak giants

Nearly 2% of all pregnancies nowadays are complicated by maternal pregestational or gestational diabetes. Long before diabetic fetopathy was acknowledged, macrosomia was dreaded by obstetricians because of the trauma risk and the need for mutilating operations. Diabetic fetopathy was described and maternal glucosuria quantified by Henrich Bennewitz in 1824. However, most authors ignored his findings and well into the 20th century, series of ‘giant babies’ were published without even mentioning diabetes mellitus. When insulin became available in 1923, maternal but not fetal mortality decreased. In 1952, Priscilla White classified six forms of maternal diabetes during pregnancy and reported an overall intrauterine, intrapartum, and neonatal death rate of 45%. But not all those infants died from macrosomia-associated traumatism and birth asphyxia: the main finding in the deceased infants was pulmonary hyaline membranes, demonstrated by Louis Gluck in 1973 to result from retarded surfactant maturation in diabetic fetuses.

Covid-19 Interstitial Pneumonia: Histological and Immunohistochemical Features on Cryobiopsies

Background: The pathogenetic steps leading to Covid-19 interstitial pneumonia remain to be clarified. Most postmortem studies to date reveal diffuse alveolar damage as the most relevant histologic pattern. Antemortem lung biopsy may however provide more precise data regarding the earlier stages of the disease, providing a basis for novel treatment approaches. Objectives: To ascertain the morphological and immunohistochemical features of lung samples obtained in patients with moderate Covid-19 pneumonia. Methods: Transbronchial lung cryobiopsy was carried out in 12 Covid-19 patients within 20 days of symptom onset. Results: Histopathologic changes included spots of patchy acute lung injury with alveolar type II cell hyperplasia, with no evidence of hyaline membranes. Strong nuclear expression of phosphorylated STAT3 was observed in >50% of AECII. Interalveolar capillaries showed enlarged lumen and were in part arranged in superposed rows. Pulmonary venules were characterized by luminal enlargement, thickened walls, and perivascular CD4+ T-cell infiltration. A strong nuclear expression of phosphorylated STAT3, associated with PD-L1 and IDO expression, was observed in endothelial cells of venules and interstitial capillaries. Alveolar spaces macrophages exhibited a peculiar phenotype (CD68, CD11c, CD14, CD205, CD206, CD123/IL3AR, and PD-L1). Conclusions: Morphologically distinct features were identified in early stages of Covid-19 pneumonia, with epithelial and endothelial cell abnormalities different from either classical interstitial lung diseases or diffuse alveolar damage. Alveolar type II cell hyperplasia was a prominent event in the majority of cases. Inflammatory cells expressed peculiar phenotypes. No evidence of hyaline membranes and endothelial changes characterized by IDO expression might in part explain the compliance and the characteristic pulmonary vasoplegia observed in less-advanced Covid-19 pneumonia.

Accelerated hyaluronan concentration as the primary driver of morbidity and mortality in high-risk COVID-19 patients: with therapeutic introduction of an oral hyaluronan inhibitor in the prevention of “Induced Hyaluronan Storm” Syndrome

To date, the fundamental drivers of the morbidity and mortality in COVID-19 remain uncertain. Clinicians worldwide appear to be at a loss to know how to prevent and treat the severe respiratory distress in these patients effectively. Consequently, the fundamental mechanisms leading to death in high-risk patients need to be discovered and addressed with urgency. The post-mortem autopsy remains an essential part of both discovering the cause of death in a particular individual, but also in advancing the science and treatment of disease, especially in the case of novel pathogens such as SARS-CoV-2[2]. The goal of an autopsy is to discover the cause of death (COD) using a macro/microscopic investigation. Because lung weight is often affected by the cause of death and the last breath occurs very near if not now of death, the evaluation of the lungs is one of the starting points of any COD investigation[3]. A comprehensive search was performed to systematically review all reported autopsy findings in COVID-19 patients with respect to lung weights and histologic findings. We then compared these findings with the results of a targeted literature review of hyaluronan in relationship to acute respiratory distress syndrome (ARDS). In total, data from 38 autopsies were identified. From this group, 36 autopsies of COVID-19 patients were selected for detailed review and statistical analysis. The average lung weight of those who were determined to have died as a result of SARS-CoV-2 was 1994g approximately 3.7 times the normal lung weight. Hyaline membranes were consistently identified on histologic sections. A review of the literature reveals that markedly elevated lung weights and hyaline membranes and have been associated with the pathophysiology of ARDS since 1967. However, the key role key of hyaluronan in driving the morbidity and mortality of the condition has heretofore not been fully recognized. We propose that the induced hyaluronan storm syndrome or IHS, is the model that best addresses the heretofore perplexing respiratory failure that is the proximal cause of death. An aggressive research effort should be undertaken to discover why the majority of individuals who are exposed to the virus are minimally symptomatic, while a minority of high-risk individuals rapidly progress to respiratory failure and death.

Acute Respiratory Distress Syndrome in Preterm Newborns (Morphological Study)

The aim of the study is to provide a rationale for the morphological diagnostic criteria of respiratory distress syndrome (RDS) and acute respiratory distress syndrome of the newborn (ARDSN) in extremely preterm newborn infants.Materials and methods. Autopsy protocols of 31 newborns were studied. The average gestational age of children was 28.9±5.3 weeks, body weight at birth was 1404±945 grams. Fifty eight percent of newborns in the sample had extremely low body weight (ELBW). At birth, all newborns were found to have severe asphyxia, and the median score on the Apgar scale at the 1st minute of life was 3 [2; 5] points. In all cases there was an unfavorable course of the disease. The median life span was 72 [22; 181] hours.The results of the study. The study revealed two variants of hyaline membrane formation in preterm newborns with acute respiratory failure. Hyaline membranes in the lungs were found in 93.5% of newborns, in 51.6% of cases there was ARDSN due to the primary surfactant deficiency, in 41.9% of children ARDS was due to immature lung being exposed to various direct and indirect damaging factors. In all cases a distinct morphological pattern in newborns with the hyaline membranes was identified: immaturity and antenatal damage to air-blood barrier, pneumonia, microaspiration, ischemia of the lungs.Conclusion. Acute respiratory distress syndrome is typical for 41.9% of extremely preterm infants, its development is favored by exposure of immature lungs to direct (congenital pneumonia, amniotic fluid aspiration) and indirect (severe perinatal hypoxia with ischemia, shock, hemorrhagic syndrome) damaging factors. Morphological signs of ARDS were most often found in newborns with congenital pneumonia, asphyxia, neonatal aspiration of amniotic fluid.

Pulmonary Pathology of Early Phase SARS-COV-2 Pneumonia

There is currently a lack of pathologic data on the SARS-CoV-2 pneumonia, or COVID-19, from autopsy or biopsy. Two patients who recently underwent lung lobectomies for adenocarcinoma were retrospectively found to have had COVID-19 at the time of surgery. These two cases thus provide important first opportunities to study the pathology of COVID-19. Pathologic examinations revealed that, apart from the tumors, the lungs of both patients exhibited edema, proteinaceous exudate with globules, focal hyperplasia of pneumocytes with only patchy inflammatory cellular infiltration, and multinucleated giant cells. Hyaline membranes were not prominent. Since both patients did not exhibit symptoms of pneumonia at the time of surgery, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia.

Differential Diagnosis of Congenital Pneumonia in Newborns with Low and Extremely Low Body Weight (Morphological Study)

The purpose of the study is a comprehensive assessment of morphological changes in the placenta and lungs to detect early signs of congenital pneumonia in extremely premature infants.Materials and methods. Protocols of post-mortem examinations of 23 preterm newborns died from severe respiratory failure were analyzed. The average gestational age of the newborns was 26.4±2.7 weeks and the body weight at birth was 972.4±355.8 grams. In the sample, 78.3% of infants had an extremely low birth weight (ELBW). At birth, all newborns presented severe asphyxia. Newborn underwent several types of respiratory therapy since birth: Mechanical ventilation was performed in 65.2% of newborns since their birth, non-invasive ventilation was performed in 26.1% of cases, and 8.7% of patients underwent oxygenotherapy through a facial mask. In all cases, there was an unfavorable course of the neonatal period, a progressive deterioration of newborns' condition, and a lethal outcome. A comprehensive histological examination of the placenta and the lungs of deceased premature newborn infants was performed.Results. Congenital infections of different localizations remain the leading cause of death.Congenital pneumonia and generalized infections are clinically manifested at birth by severe perinatal hypoxia and respiratory failure. In the case of congenital pneumonia, the morphological patterns are polymorphic and characterize the severity of lung damage. For some newborns, these patterns include accumulation of exudates and fibrin, segmented leukocytes, fragments of basophilic coccal microflora, and a large number of colony forming bacilli, and desquamated alveolocytes with a deformed nucleus are visualized in the deformed lumen of the alveoli and bronchi. Diffuse lymphoid-leukocyte infiltration in the septa and respiratory parts of the lungs are typical for other infants. Histological examination find lumpy or lamellar eosinophilic hyaline membranes in alveoli in specimens from these newborns. Diffuse, focal or confluent segmentonuclear infiltration in various lung structures is commonly combined with hyaline membranes of various localizations and sizes. Hyaline membranes were detected in 93.5% of cases.Conclusion. Very early preterm delivery is associated with intrauterine pneumonia and systemic infection in extremely premature infants. Early clinical and laboratory signs of intrauterine infectious lung include severe perinatal hypoxia, very low Apgar score and laboratory test findings (hypoxaemia and decompensated metabolic lactate acidosis) that are resistant to standard resuscitation measures. Hypoxemia and decompensated metabolic acidosis persisting during the first hours of postnatal life indicate the severity of intrauterine lung damage and require a rapid change of treatment aimed at normalization of lung function, prevention of complications in the respiratory system, hemostasis and central nervous system. Clinicians should be better informed about the features of early postnatal adaptation of extremely premature infants with congenital pneumonia to provide appropriate treatment.

RESPIRATORY DISTRESS SYNDROME

Respiratory Distress Syndrome (RDS) is due to immaturity of the lungs, primarily the surfactant synthesising system; hence, the risk of RDS is inversely proportional to gestational age. The incidence of RDS has been reduced by the routine use of both antenatal corticosteroids and postnatal surfactant, but still approximately one per cent of babies develop RDS. Hyaline membranes, formed from plasma proteins which have leaked onto the lung surface through damaged capillaries and endothelial cells, line the terminal airways. Hence, RDS has also been called hyaline membrane disease, but RDS is the preferred name as the presence of hyaline membranes can only be confirmed histologically. The aim of this review is to emphasize the pathophysiology of RDS and the clinical presentation and relevance of diagnostic techniques in the current population of very prematurely born infants, highlighting the differential diagnosis. In addition, the evidence base for prophylactic and management strategies including whether new therapies and techniques of respiratory support have positively impacted on outcomes are discussed. The mortality and long term morbidity associated with very premature birth are described. Our increasing understanding that the so-called new bronchopulmonary dysplasia (BPD) and associated chronic adverse respiratory outcomes in such infants can reflect antenatal events resulting in abnormal lung growth is highlighted.