Sandbox:Usman Shah

Historical Perspective

• On 31 December 2019, the World Health Organization (WHO) was formally notified about a cluster of cases of pneumonia in Wuhan City.
• Ten days later, WHO was aware of 282 confirmed cases, of which four were in Japan, South Korea and Thailand
• The virus responsible was isolated on 7 January and its genome shared on 12 January.The cause of the severe acute respiratory syndrome that became known as COVID‐19 was a novel coronavirus, SARS‐CoV‐2
• ARDS is one of the most important causes of hospital and ICU admission due to COVID.
• Many autopsies studies reported ARDS to be the cause of death in patients dying due to respiratory complications of COVID.

• As of July 19 2020 the number of total cases worldwide are 14,043,176 including 597,583 deaths, reported to WHO.

Classification

Authors in a case report highlighted the nonuniformity of patients with COVID-19-associated ARDS and proposed the existence of two primary phenotypes:

• Type L (low values of elastance, pulmonary ventilation/ perfusion ratio, lung weight, and recruitability).
• Type H (high values of elastance, right-to-left shunt, lung weight, and recruitability), more consistent with typical severe ARDS.

ARDS is divided into three categories based on oxygenation index (PaO2/FiO2) on PEEP ≥ 5 cmH2O:

• mild (200 mmHg ≤ PaO2/FiO2 < 300 mmHg),
• mild-moderate (100 mmHg ≤ PaO2/FiO2 < 200 mmHg), and
• moderate-severe (PaO2/FiO2 < 100 mmHg).

Pathophysiology

• The SARS-CoV-2 virus, like the closely-related MERS and SARS coronaviruses, effects its cellular entry via attachment of its virion spike protein (a.k.a. S protein) to the angiotensin-converting enzyme 2 (ACE2) receptor.
• This receptor is commonly found on alveolar cells of the lung epithelium.It suggested that injury to the alveolar epithelial cells was the main cause of COVID-19-related ARDS.
• Cellular infection and viral replication cause activation of the inflammasome in the host cell, leading to the release of pro-inflammatory cytokines and cell death by pyroptosis with ensuing release of a damage-associated molecular pattern, further amplifying the inflammatory response.
• The cytokine storm and the deadly uncontrolled systemic inflammatory response resulting from the release of large amounts of proinflammatory cytokines including interferons and interleukins and, chemokines by immune effector cells resulting in acute inflammation within the alveolar space. The exudate containing plasma proteins, including albumin, fibrinogen, proinflammatory cytokines and coagulation factors will increase alveolar-capillary permeability and decrease the normal gas exchange and plasma proteins, including albumin, fibrinogen, proinflammatory cytokines and coagulation factors.
• In line with this, recent studies have shown that patients with COVID-19 have high levels of inflammatory cytokines, such as interleukin (IL)-1β, IL-2, IL-6 IL-7, IL-8, IL-9, IL-10, IL-18, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, fibroblast growth factor, macrophage inflammatory protein 1, compared to healthy individuals.
• Circulating levels of IL-6, IL-10, and TNF-α also correlated with illness severity as they were significantly higher in intensive care unit (ICU) patients compared to mild/moderate cases. In particular, IL-6 may suppress normal T-cell activation and TNF-α can promote T-cell apoptosis via interacting with its receptor TNF receptor 1, and their upregulation may in part contribute to lymphocytopenia, a feature often encountered in COVID-19, with a more pronounced decline in severe cases
• IL-6 is not the only protagonist on the scene. It was proved, for instance, that the binding of SARS-CoV-2 to the Toll-Like Receptor (TLR) induces the release of pro-IL-1β which is cleaved into the active mature IL-1β mediating lung inflammation, until fibrosis.
• This inflammatory process leads to the fibrin deposition in the air spaces and lung parenchyma and contributes to hyaline-membrane formation and subsequent alveolar fibrosis.
• Patients infected with COVID‐19 also exhibit coagulation abnormalities.This procoagulant pattern can lead to acute respiratory distress syndrome

Differentiating COVID-associated ARDS from other Diseases

• Large observational studies suggest that patients with COVID-19-associated ARDS have similar respiratory system mechanics to patients with ARDS from other causes and that, for most patients, COVID-19-associated ARDS is, in the end, ARDS. However, lung compliance might be relatively normal in some COVID-19-related ARDS patients who met ARDS Berlin criteria. This was obviously inconsistent with ARDS caused by other factors. In addition, the lung compliance was relatively high in some COVID-19-related ARDS patients, which was inconsistent with the severity of hypoxemia.
• COVID-19 associated ARDS can be differentiated from H1N1 another very common cause ARDS caused by a viral infection
• Compared with H1N1 patients, patients with COVID-19-induced ARDS had lower severity of illness scores at presentation and lower SOFA score-adjusted mortality.Ground-glass opacities was more common in patients with COVID-19 than in patients with H1N1
• Pulmonary thrombosis is also associated with COVID-19 related ARDS.
• And most importantly Positive SARS-CoV-2 infection on PCR.

Epidemiology and Demographics

Covid19 healthcare worker. [1]

Classification of Waldenstrom macroglobulinemia (WM) and Related Disorders

Criteria	Symptomatic WM	Asymptomatic WM	IgM-Related Disorders	MGUS
IgM monoclonal protein	+	+	+	+
Bone marrow infiltration	+	+	-	-
Symptoms attributable to IgM	+	-	+	-
Symptoms attributable to tumor infiltration	+	-	-	-

Infra-Hisian Block Microchapters
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
Treatment
Prevention
Differentiating Infra-Hisian Block from other Diseases