Perpetually Positive: Post-COVID Interstitial Lung Disease in an Immunocompromised Patient With Diffuse Large B-cell Lymphoma.

As more patients recover from COVID-19 infection, long-term complications are beginning to arise. Our case report will explore a debilitating long-term complication, Post-COVID Interstitial Lung Disease (PC-ILD). We will introduce a patient who developed PC-ILD in the setting of diffuse large B-cell lymphoma, outlining a difficult hospital course, including a positive COVID-19 polymerase chain reaction (PCR) for more than 3 months. We will then discuss the human body's physiological response to the virus and how our patient was not able to adequately mount an immune response. Finally, the pathophysiology of PC-ILD will be explored and correlated with the patient's subsequent computed tomographic images obtained over a 3-month period. The difficult hospital course and complex medical decision-making outlined in this case report serve as a reminder for health care providers to maintain vigilance in protecting our most vulnerable patient population from such a devastating disease process.

Diffuse interstitial pneumonia-like/macrophage activation syndrome-like changes in patients with COVID-19 correlate with length of illness.

OBJECTIVES: Assess the pathologic changes in the lungs of COVID-19 decedents and correlate these changes with demographic data, clinical course, therapies, and duration of illness. METHODS: Lungs of 12 consecutive COVID-19 decedents consented for autopsy were evaluated for gross and histopathologic abnormalities. A complete Ghon "en block" dissection was performed on all cases; lung weights and gross characteristics recorded. Immunohistochemical studies were performed to characterize lymphocytic infiltrates and to assess SARS-CoV-2 capsid protein. RESULTS: Two distinct patterns of pulmonary involvement were identified. Three of 12 cases demonstrated a predominance of acute alveolar damage (DAD) while 9 of 12 cases demonstrated a marked increase in intra-alveolar macrophages in a fashion resembling desquamative interstitial pneumonia or macrophage activation syndrome (DIP/MAS). Two patterns were correlated solely with a statistically significant difference in the duration of illness. The group exhibiting DAD had duration of illness of 5.7 days while the group with DIP/MAS had duration of illness of 21.5 days (t-test p = 0.014). CONCLUSIONS: The pulmonary pathology of COVID-19 patients demonstrates a biphasic pattern, an acute phase demonstrating DAD changes while the patients with a more prolonged course exhibit a different pattern that resembles DIP/MAS-like pattern. The potential mechanisms and clinical significance are discussed.

Interstitial lung opacities in patients with severe COVID-19 pneumonia by bedside high-resolution ultrasound in association to CO2 retention.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause acute respiratory distress syndrome (ARDS). OBJECTIVE: This single centre cross-section study aimed to grade the severity of pneumonia by bed-side lung ultrasound (LUS). METHODS: A scoring system discriminates 5 levels of lung opacities: A-lines (0 points),≥3 B-line (1 point), coalescent B-lines (2 points), marked pleural disruptions (3 points), consolidations (4 points). LUS (convex 1-5 MHz probe) was performed at 6 defined regions for each hemithorax either in supine or prone position. A lung aeration score (LAS, maximum 4 points) was allocated for each patient by calculating the arithmetic mean of the examined lung areas. Score levels were correlated with ventilation parameters and laboratory markers. RESULTS: LAS of 20 patients with ARDS reached from 2.58 to 3.83 and was highest in the lateral right lobe (Mean 3.67). Ferritin levels (Mean 1885µg/l; r = 0.467; p = 0.051) showed moderate correlation in spearman roh calculation. PaCO2 level (Mean 46.75 mmHg; r = 0.632; p = 0.005) correlated significantly with LAS, while duration of ventilation, Horovitz index, CRP, LDH and IL-6 did not. CONCUSIONS: The proposed LAS describes severity of lung opacities in COVID-19 patients and correlates with CO2 retention in patients with ARDS.

Short-Term Consequences of SARS-CoV-2-Related Pneumonia: A Follow Up Study.

The aim of the study was to assess the short-term consequences of SARS-CoV-2-related pneumonia, also in relation to radiologic/laboratory/clinical indices of risk at baseline. This prospective follow-up cohort study included 94 patients with confirmed COVID-19 admitted to a medical ward at the Montichiari Hospital, Brescia, Italy from February 28th to April 30th, 2020. Patients had COVID-19 related pneumonia with respiratory failure. Ninety-four patients out of 193 survivors accepted to be re-evaluated after discharge, on average after 4 months. In » of the patients an evidence of pulmonary fibrosis was detected, as indicated by an altered diffusing capacity of the lung for carbon monoxide (DLCO); in 6-7% of patients the alteration was classified as of moderate/severe degree. We also evaluated quality of life thorough a structured questionnaire: 52% of the patients still lamented fatigue, 36% effort dyspnea, 10% anorexia, 14% dysgeusia or anosmia, 31% insomnia and 21% anxiety. Finally, we evaluated three prognostic indices (the Brixia radiologic score, the Charlson Comorbidity Index and the 4C mortality score) in terms of prediction of the clinical consequences of the disease. All of them significantly predicted the extent of short-term lung involvement. In conclusion, our study demonstrated that SARS-CoV-2-related pneumonia is associated to relevant short-term clinical consequences, both in terms of persistence of symptoms and in terms of impairment of DLCO (indicator of a possible development of pulmonary fibrosis); some severity indices of the disease may predict short-term clinical outcome. Further studies are needed to ascertain whether such manifestations may persist long-term.

Patent foramen ovale revealed by COVID-19 pneumonia.

BACKGROUND: Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by dyspnoea (platypnea) and arterial desaturation in the upright position resolved in the supine position (orthodeoxia). Intracardiac shunt, pulmonary ventilation-perfusion mismatch and others intrapulmonary abnormalities are involved. CASE PRESENTATION: We report a case of POS associated with two pathophysiological issues: one, cardiac POS caused by a patent foramen ovale (PFO) and second, pulmonary POS due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interstitial pneumonia. POS has resolved after recovery of coronavirus disease 2019 (COVID-19) pneumonia. CONCLUSIONS: Right-to-left interatrial shunt and intrapulmonary shunt caused by SARS-CoV-2 pneumonia contributed to refractory hypoxemia and POS. Therefore, in case of COVID-19 patient with unexplained POS, the existence of PFO must be investigated.

The immune response to SARS-CoV-2 and COVID-19 immunopathology - Current perspectives.

SARS-CoV-2 is a new beta coronavirus, similar to SARS-CoV-1, that emerged at the end of 2019 in the Hubei province of China. It is responsible for coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization on March 11, 2020. The ability to gain quick control of the pandemic has been hampered by a lack of detailed knowledge about SARS-CoV-2-host interactions, mainly in relation to viral biology and host immune response. The rapid clinical course seen in COVID-19 indicates that infection control in asymptomatic patients or patients with mild disease is probably due to the innate immune response, as, considering that SARS-CoV-2 is new to humans, an effective adaptive response would not be expected to occur until approximately 2-3 weeks after contact with the virus. Antiviral innate immunity has humoral components (complement and coagulation-fibrinolysis systems, soluble proteins that recognize glycans on cell surface, interferons, chemokines, and naturally occurring antibodies) and cellular components (natural killer cells and other innate lymphocytes). Failure of this system would pave the way for uncontrolled viral replication in the airways and the mounting of an adaptive immune response, potentially amplified by an inflammatory cascade. Severe COVID-19 appears to be due not only to viral infection but also to a dysregulated immune and inflammatory response. In this paper, the authors review the most recent publications on the immunobiology of SARS-CoV-2, virus interactions with target cells, and host immune responses, and highlight possible associations between deficient innate and acquired immune responses and disease progression and mortality. Immunotherapeutic strategies targeting both the virus and dysfunctional immune responses are also addressed.

Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry.

Anti-Melanoma Differentiation-Associated gene 5 (MDA-5) Dermatomyositis (MDA5, DM) is a recently identified subtype of myositis characteristically associated with Rapidly Progressive Interstitial Lung Disease (RP-ILD) and unique cutaneous features. We reviewed PubMed, SCOPUS and Web of Science databases and selected 87 relevant articles after screening 1485 search results, aiming to gain a better understanding of the pathophysiology, clinical features, diagnosis, and treatment approaches of anti-MDA-5 DM described in the literature. The etiopathogenesis is speculatively linked to an unidentified viral trigger on the background of genetic predisposition culminating in an acquired type I interferonopathy. The clinical phenotype is highly varied in different ethnicities, with new clinical features having been recently described, expanding the spectrum of cases that should raise the suspicion of anti-MDA-5 DM. Unfortunately, the diagnosis is frequently missed despite excessive mortality, calling for wider awareness of suspect symptoms. RP ILD is the major determinant of survival, treatment being largely based on observational studies with recent insights into aggressive combined immunosuppression at the outset.

Clinical characteristics of COVID-19 in patients with preexisting ILD: A retrospective study in a single center in Wuhan, China.

Since the outbreak of 2019 novel coronavirus (SARS-CoV-2) pneumonia, many patients with underlying disease, such as interstitial lung disease (ILD), were admitted to Tongji hospital in Wuhan, China. To date, no data have ever been reported to reflect the clinical features of Corona Virus Disease 2019 (COVID-19) among these patients with preexisting ILD. We analyzed the incidence and severity of COVID-19 patients with ILD among 3201 COVID-19 inpatients, and compared two independent cohorts of COVID-19 patients with pre-existing ILD (n = 28) and non-ILD COVID-19 patients (n = 130). Among those 3201 COVID-19 inpatients, 28 of whom were COVID-19 with ILD (0.88%). Fever was the predominant symptom both in COVID-19 with ILD (81.54%) and non-ILD COVID-19 patients (72.22%). However, COVID-19 patients with ILD were more likely to have cough, sputum, fatigue, dyspnea, and diarrhea. A very significantly higher number of neutrophils, monocytes, interleukin (IL)-8, IL-10, IL-1ß, and D-Dimer was characterized in COVID-19 with ILD as compared to those of non-ILD COVID-19 patients. Furthermore, logistic regression models showed neutrophils counts, proinflammatory cytokines (tumor necrosis factor-alpha, IL6, IL1ß, IL2R), and coagulation dysfunction biomarkers (D-Dimer, PT, Fbg) were significantly associated with the poor clinical outcomes of COVID-19. ILD patients could be less vulnerable to SARS-CoV-2. However, ILD patients tend to severity condition after being infected with SARS-CoV-2. The prognosis of COVID-19 patients with per-existing ILD is significantly worse than that of non-ILD patients. And more, aggravated inflammatory responses and coagulation dysfunction appear to be the critical mechanisms in the COVID-19 patients with ILD.

Therapeutic effects of adenosine in high flow 21% oxygen aereosol in patients with Covid19-pneumonia.

BACKGROUND: SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. PATIENTS AND TREATMENT: Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests. RESULTS: The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group. CONCLUSION: Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials.

[Expert recommendations for the diagnosis and treatment of interstitial lung disease caused by novel coronavirus pneumonia].

COVID-19 is an acute infectious disease caused by a newly discovered coronavirus (SARS-CoV2). COVID-19 may manifest bilateral interstitial pneumonia on imaging. About 30%-60% of patients present varying degrees of interstitial changes, while most patients have a good prognosis. Since there's little practical instruct on treating interstitial lung disease (ILD) caused by COVID-19, we present this file as references for all the colleagues fighting with this disease. The primary findings on CT are bilateral, peripheral ground-glass opacities (GGO) and consolidation. Inter-/intra-lobular septal thickening are also common. Subpleural lines and traction bronchiectasis can be seen in some cases which indicate the presence of interstitial fibrosis. Images of severe cases are similar with those in advanced stage of nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP). COVID-19 could present the typical two phases of diffuse alveolar damage: acute and proliferative phase on pathology. Massive pulmonary interstitial fibrosis may also be present. HRCT is the best radiological approach for the diagnosis and differential diagnosis of COVID-19, and to assess the presence of ILD. Periodical CT following-up is recommended for patients who present interstitial manifestations. Biomarkers such as KL-6, SP-D, RAGE may also helpful on evaluating the severity of interstitial fibrosis and therapeutic response. We do not suggest applying pulmonary function tests and 6-minute walking test on patients in active stage of the disease. The primary treatments in acute phase are antiviral therapy and supportive treatment. We do not suggest routine use of corticosteroids, while on patients with excessive activation of inflammatory response or rapid progression of lung lesions, a low to medium dosage of corticosteroids could be applied for a short course. Pirfenidone and Nintedanib are encouraged to apply on patients in reparative phase with evidence of progressing fibrosis. Low to medium dosage of corticosteroids is also feasible on patients with NSIP or OP manifestation in this phase, with a relatively longer course. Chinese traditional medicine and rehabilitation medicine may also helpful. Lung transplant surgery is an option for severe pulmonary fibrosis patients. Patients should receive CT following-up after be discharged from hospital, especially those whose pulmonary exudation is not well absorbed. We suggest a routine following-up on month 1, 4 and 10 after discharging, and an extended period for those who have developed irreversible interstitial fibrosis.

Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.

The Potential for Remotely Mentored Patient-Performed Home Self-Monitoring for New Onset Alveolar-Interstitial Lung Disease.

Purpose: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is an acute respiratory illness. Although most infected persons are asymptomatic or have only mild symptoms, some patients progress to devastating disease; such progression is difficult to predict or identify in a timely manner. COVID-19 patients who do not require hospitalization can self-isolate at home. Calls from one disease epicenter identify the need for homebased isolation with telemedicine surveillance to monitor for impending deterioration. Methodology: Although the dominant approach for these asymptomatic/paucisymptomatic patients is to monitor oxygen saturation, we suggest additionally considering the potential merits and utility of home-based imaging. Chest computed tomography is clearly impractical, but ultrasound has shown comparable sensitivity for lung involvement, with major advantages of short and simple procedures, low cost, and excellent repeatability. Thoracic ultrasound may thus allow remotely identifying the development of pneumonitis at an early stage of illness and potentially averting the risk of insidious deterioration to severe pneumonia and critical illness while in home isolation. Conclusions: Lung sonography can be easily performed by motivated nonmedical caregivers when directed and supervised in real time by experts. Remote mentors could thus efficiently monitor, counsel, and triage multiple home-based patients from their "control center." Authors believe that this approach deserves further attention and study to reduce delays and failures in timely hospitalization of home-isolated patients.

Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques.

Coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. It is unclear whether convalescing patients have a risk of reinfection. We generated a rhesus macaque model of SARS-CoV-2 infection that was characterized by interstitial pneumonia and systemic viral dissemination mainly in the respiratory and gastrointestinal tracts. Rhesus macaques reinfected with the identical SARS-CoV-2 strain during the early recovery phase of the initial SARS-CoV-2 infection did not show detectable viral dissemination, clinical manifestations of viral disease, or histopathological changes. Comparing the humoral and cellular immunity between primary infection and rechallenge revealed notably enhanced neutralizing antibody and immune responses. Our results suggest that primary SARS-CoV-2 exposure protects against subsequent reinfection in rhesus macaques.

Some pathological observations on the naturally infected dromedary camels (Camelus dromedarius) with the Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia 2018-2019.

Background: The natural MERS-CoV infection in dromedary camels is understudied. Recent experimental studies showed no obvious clinical signs in the infected dromedary camels.Aim: To study the pathological changes associated with natural MERS-CoV infection in dromedary camels.Methods: Tissues from three MERS-CoV positive animals as well as two negative animals were collected and examined for the presence of pathological changes. The screening of the animals was carried out first by the rapid agglutination test and then confirmed by the RT-PCR. The selected animals ranged from six to twelve months in age. The sensitivity of the latter technique was much higher in the detection of MERS-CoV than the Rapid test (14 out of 75 animals positive or 18% versus 31 out of 75 positive or 41%).Results: MERS-CoV induced marked desquamation of the respiratory epithelium accompanied by lamina propria and submucosal mononuclear cells infiltration, epithelial hyperplasia in the respiratory tract, and interstitial pneumonia. Ciliary cell loss was seen in the trachea and turbinate. In addition, degeneration of glomerular capillaries with the complete destruction of glomerular tufts that were replaced with fibrinous exudate in renal corpuscles in the renal cortex were noticed. Expression of the MERS-CoV-S1 and MERS-CoV-N proteins was revealed in respiratory tract, and kidneys.Conclusion: To our knowledge, this is the first study describing the pathological changes of MERS-CoV infection in dromedary camels under natural conditions. In contrast to experimental infection in case of spontaneous infection interstitial pneumonea is evident at least in some affected animals.

Lung ultrasound for the identification of COVID-19 pneumonia.

The SARS-CoV-2 infection has as a clinical manifestation the disease known as COVID-19. Although knowledge of the nature of the disease is dynamic, with dozens of scientific articles being published every day about new features of COVID-19, the typical presentation is that of interstitial pneumonia. Despite the large amount of information that has been developed in recent weeks, it has been estimated that this disease can have up to 72% underdiagnosis, which requires clinical tools that are simple, easily accessible, and increase the detection of cases in a feasible way and that yield information with prognostic value. Given this need, some proposals have emerged to be able to diagnose, monitor and respond to the treatment of patients with COVID-19, such as pulmonary ultrasound (USP). It is worth mentioning that the USP has proven to be an efficient and easily reproducible technique for diagnosing heart failure and pleuro-pulmonary pathologies, especially in critically ill patients. Evidence of the usefulness of USP in COVID-19 is still scarce, although preliminary, it seems to be a sensitive technique whose findings have a high gold standard. In this brief review we will emphasize its technical aspects, the advantages and disadvantages, and finally a proposal for the approach in this type of patient.

La infección por SARS-CoV-2 tiene como manifestación clínica la enfermedad conocida como COVID-19. Si bien el conocimiento de la naturaleza de la enfermedad es dinámico, publicándose cada día decenas de artículos científicos sobre nuevas características de COVID-19, la presentación típica es la de neumonía intersticial. A pesar de la gran cantidad de información que se ha desarrollado en las últimas semanas, se ha estimado que esta enfermedad puede llegar a tener hasta un 72% de infradiagnóstico, por lo que se requieren herramientas clínicas que sean simples, de fácil acceso, que incrementen la detección de casos de forma factible y que arrojen información con valor pronóstico. Ante esta necesidad, han surgido algunas propuestas para poder realizar el diagnóstico, seguimiento y respuesta al tratamiento de los pacientes con COVID-19, tales como el ultrasonido pulmonar (USP). Cabe mencionar que el USP ha probado ser una técnica eficiente y de fácil reproducibilidad para diagnosticar insuficiencia cardiaca y patologías pleuro-pulmonares, sobre todo en pacientes críticamente enfermos. La evidencia de la utilidad de USP en COVID-19 es aún escasa, aunque de forma preliminar, parece ser una técnica sensible cuyos hallazgos tienen una elevada gold-standard. En esta breve revisión haremos énfasis en sus aspectos técnicos, las ventajas y desventajas, y por último una propuesta para el abordaje en este tipo de pacientes.