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

Incidence of ARDS in Covid Patients

• A meta-analysis which included 50,466 COVID-19 cases described an ARDS incidence of 14.8% (95% CI: 4.6-29.6).

Age

• Covid-19 affects all age groups

• In a retrospective cohort study of 201 hospitalised patients with confirmed COVID-19 pneumonia, 84 (41.8%) developed ARDS. The median age of ARDS patients was 58.5 years, compared with 48 years for non-ARDS patients. They calculated being aged 65 years or over was associated with a 3.26 increased risk of ARDS (95% CI 2.08-5.11 p<0.001) compared to the under 65s. They also found that patients who developed ARDS and were aged 65 years or over had a 6.17 increased risk of death (95% CI, 3.26-11.67; P<0.001) compared to ARDS patients under 65.

Gender

• Some case studies report that men are more commonly affected by ARDS than women.
• In the public data set, the number of men who died from COVID-19 is 2.4 times that of women (70.3 vs. 29.7%, P = 0.016).

Race

• A large study in the United States reported that that African Americans were at a higher risk of ARDS than white individuals.\

Risk Factors

Increase Risk of developing ARDS in relation to Comorbidities

• Older age (≥65 years old)
• High fever (≥39 °C)
• Comorbidities (eg, hypertension, diabetes)
• Neutrophilia
• Lymphocytopenia (as well as lower CD3 and CD4 T-cell counts)
• Elevated end-organ related indices (eg, AST, urea, LDH)
• Elevated inflammation-related indices (high-sensitivity C-reactive protein and serum ferritin)
• Elevated coagulation function–related indicators (PT and D-dimer)

Reported hazard ratio for risk developing ARDS in relation to selected laboratory results

	Hazard Ratio	95% CI interval	P-value
Higher LDH	1.40	1.44-1.79	<0.001
Higher D-Dimer	1.03	1.01-1.04	<0.001
Higher Neutrophils	1.14	1.09-119	<0.001

Natural History, Complications and Prognosis

The natural history of ARDS is hallmarked by three histopathological phases—exudative, proliferative, and fibrotic phase—each correlated to distinctive clinical manifestations.

Exudative Phase

• • he exudative phase typically encompasses the first 5 to 7 days of illness after exposure to one or more precipitation factors.
  • Histopathologically, loss of integrity of the alveolar barrier results in the influx of proteinaceous fluid into the air place, and formation of the hyaline membrane. Pulmonary edema and atelectasis with reduced pulmonary compliance ensue, leading to the development of pulmonary shunt and hypoxemia.
  • In this phase, patients experience respiratory symptoms including dyspnea, tachypnea, and increased work of breathing that eventually result in respiratory failure requiring ventilator support. If left untreated, approximately 70% of patients with ARDS may progress to mortality.Among non-survivors, approximately 50% patients die within a week of the onset with exudative change as the predominant histopathological feature

Proliferative Phase

• • The proliferative phase generally lasts from day 7 to day 21.
  • Histopathologically, reparative processes take place in the injured alveoli, including organization of exudates, a shift to lymphocyte-predominant infiltrates, and proliferation of type II pneumocytes.
  • In this phase, patients may recover from acute respiratory distress despite the persistence of residual symptoms. Patients who do not recover during this phase develop progressive lung injury and early changes of fibrosis.

Fibrotic Phase

• The fibrotic phase occurs 3 to 4 weeks following the initial pulmonary insult.
• Histopathologically, extensive fibrosis is prominent in the alveolar interstitium and duct, with disruption of acinar architecture and emphysema-like changes.
• The evidence for pulmonary fibrosis on biopsy is associated with increased mortality.

Complications

Complications may include the following:

• • Lungs: barotrauma (volutrauma), pulmonary embolism (PE), pulmonary fibrosis, ventilator-associated pneumonia (VAP)
  • Gastrointestinal: bleeding (ulcer), dysmotility, pneumoperitoneum, bacterial translocation
  • Neurological: hypoxic brain damage
  • Cardiac: abnormal heart rhythms, myocardial dysfunction
  • Kidney: acute kidney failure, positive fluid balance
  • Mechanical: vascular injury, pneumothorax (by placing pulmonary artery catheter), tracheal injury/stenosis (result of intubation and/or irritation by endotracheal tube)
  • Nutritional: malnutrition (catabolic state), electrolyte abnormalities Other complications that are typically associated with ARDS include:
  • Atelectasis: small air pockets within the lung collapse
  • Complications that arise from treatment in a hospital: blood clots formed by lying down for long periods of time, weakness in muscles that are used for breathing, stress ulcers, and even depression or other mental illnesses.
  • Failure of multiple organs
  • Pulmonary hypertension or increase in blood pressure in the main artery from the heart to the lungs. This complication typically occurs due to the restriction of the blood vessel due to inflammation of the mechanical ventilation

Prognosis

• The overall prognosis of ARDS is poor, with mortality rates of approximately 40%. Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important sequelae of ARDS.

Diagnosis

Diagnostic Criteria

COVID-19 ARDS is diagnosed when someone with confirmed COVID-19 infection meets the Berlin 2012 ARDS diagnostic criteria of:

1. acute hypoxemic respiratory failure,
2. presentation within 1 week of worsening respiratory symptoms;
3. bilateral airspace disease on chest x-ray, computed tomography, or ultrasound that is not fully explained by effusions, lobar or lung collapse, or nodules;
4. and cardiac failure is not the primary cause of acute hypoxemic respiratory failure.

Symtoms

Patient will present with the following symptoms.

• fever (85-90%)
• cough (65-70%)
• disturbed taste and/or smell (40-50%)
• fatigue (35-40%)
• sputum production (30-35%)
• shortness of breath (15-20%)

Physical Examination

Vital Signs[edit | edit source]

• The presence of the following signs of shock or infection on physical examination is highly suggestive of ARDS:
  • Temperature (Temp, T): Hyperpyrexia ≥ 38°C or 100.4°F) or low temperature < 36°C or 96.8°F.
  • Blood pressure (BP): inappropriately low, with a low mean arterial pressure (MAP).
  • Heart rate (HR): rapid (tachycardia > 100 beats/minute), normal, or slow (bradycardia <60 beats/minute).
  • Respiratory rate (RR): Tachypnea > 20 breaths/minute or bradypnea <12 breaths/minute.
  • Peripheral capillary oxygen saturation (SpO₂): low (< 90% on ambient air or a fraction of inspired oxygen, (FIO₂) of 21% at sea level).

Skin[edit | edit source]

• Cyanosis due to poor oxygenation.
• Pallor due to poor perfusion.

Lungs[edit | edit source]

• Tachypnea
• Dyspnea
• Coarse breath sounds, rhonchi, crackles, or decreased breath sounds

Heart[edit | edit source]

• Tachycardia or bradycardia on heart auscultation.

Extremities[edit | edit source]

• Cyanosis
• Cool extremities or reduced peripheral pulses due to poor perfusion.

Laboratory Findings

• • In the early stage of the disease, a normal or decreased total white blood cell count (WBC) and a decreased lymphocyte count can be demonstrated. Interestingly, lymphopenia appears to be a negative prognostic factor.
  • Increased values of liver enzymes, lactate dehydrogenase (LDH), muscle enzymes, and C-reactive protein can be detected.
  • Unless a bacterial overlap, a normal procalcitonin value is found.
  • The elevated neutrophil-to-lymphocyte ratio (NLR), derived NLR ratio (d-NLR) [neutrophil count divided by the result of WBC count minus neutrophil count], and platelet-to-lymphocyte ratio, can be the expression of the inflammatory storm The correction of these indices is an expression of a favorable trend.
  • increased prothrombin time (PT)
  • Increased  D-dimer
  • In critical patients, D-dimer value is increased, blood lymphocytes decreased persistently, and laboratory alterations of multiorgan imbalance (high amylase, coagulation disorders, etc.) are found.

Imaging

The radiology of ARDS is distinctive, yet COVID‐19 pneumonia appears to have unique features. This likely results from the co‐occurrence of viral pneumonia and ARDS, and allows radiologists to be fairly specific in diagnosing COVID‐19 pneumonia. The most discriminating features for COVID‐19 pneumonia in China compared with viral pneumonia in the United States included a peripheral distribution of opacification (80% v 57%; P  < 0.001), frosted glass opacities (91% v 68%; P  < 0.001), and vascular thickening or enlargement (58% v 22%; P < 0.001).

Chest-X ray

• Chest radiographs may be normal in early/mild disease. In those COVID-19 cases requiring hospitalization, 69% had an abnormal chest radiograph at the initial time of admission, and 80% had radiographic abnormalities sometime during hospitalization. Findings are most extensive about 10-12 days after symptom onset.

On Chest X-ray following findings can be seen.

• Ground-glass opacification and consolidation
• Early findings on the chest radiograph include normal or diffuse alveolar opacities (consolidation), which are often bilateral and which obscure the pulmonary vascular markings.
• Later, these opacities progress to more extensive consolidation that is diffuse, and they are often asymmetrical.

Bilateral alveolar consolidation with panlobar change, with typical radiological findings of ARDS. Source: Dr. Edgar Lorente

Chest CT Scan

• Chest CT scan shows characteristic ground-glass opacities (GCO). This indicates the presence of exudate in the bronchoalveolar airspace.
• Lung biopsy shows fibrin deposition.

Multifocal ground glass, mainly in the periphery of both lungs. Source: Dr. Elshan Abdullayev

Treatment

Medical Therapy

Fluid and electrolytes management

• Studies have shown that in ARDS, conservative fluid management may help patients by reducing edema formation.
• Conservative fluid management with buffered or non-buffered crystalloid is recommended for ARDS patients.
• The conservative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay. However, its effect on mortality remains uncertain.

Corticosteroids

• Recent studies have shown that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients.
• In England, a non-peer-reviewed randomized trial was issued as a press release which suggested that dexamethasone has a potential survival benefit in hospitalized COVID-19 patients requiring oxygen.
• The Society of Critical Care Medicine (SCCM) provided a weak conditional recommendation in the favor of glucocorticoids in patients with COVID-19 who have severe ARDS with a partial arterial pressure of oxygen/fraction of inspired oxygen PaO2:FiO2] <100 mmHg). This recommendation suggests benefit in patients with moderate to severe ARDS which is refractory to low tidal volume ventilation.

Mechanical Ventilation

• Mechanical ventilation along with supportive therapies are the mainstay of treatment of ARDS.
• Invasive mechanical ventilation (ie, ventilation via an endotracheal tube or tracheostomy with breaths delivered by a mechanical ventilator) is preferred for patients with ARDS, particularly those with moderate or severe ARDS (ie, arterial oxygen tension/fraction of inspired oxygen PaO2/FiO2 ≤200 mmHg on positive end-expiratory pressure (PEEP) ≥5 cm H2O).
• It is recommended to use low tidal volume ventilation (LTVV) with 4 to 8 mL/kg predicted body weight [PBW]. Several meta-analyses and randomized trials that report a mortality benefit from LTVV in patients with ARDS.
• The aim is to maintain oxygen saturation between 90% to 96%. The severe hypoxemia of the COVID-19 ARDS best responds when Positive end-expiratory pressure (PEEP) is high with Pplat ≤30 cm H2O. It is beneficial if the physician starts with higher than usual levels of PEEP (10 to 15 cm H2O).

Anticoagulant or thrombolytic therapy

• Fibrinolytic drugs such as tissue-type plasminogen activator (tPA) degrade pre-existing fibrin in the lungs.
• Nebulizer plasminogen activators may provide more targeted therapy to degrade fibrin and improving oxygenation in critically ill patients. It is in Phase II of the clinical trial.

Prevention

Primary Prevention

• The best way to prevent being infected by COVID-19 is to avoid being exposed to this virus by adopting the following practices for infection control:
  • Often wash hands with soap and water for at least 20 seconds.
  • Use an alcohol-based hand sanitizer containing at least 60% alcohol in case soap and water are not available.
  • Avoid touching the eyes, nose, and mouth without washing hands.
  • Avoid being in close contact with people sick with COVID-19 infection.
  • Stay home while being symptomatic to prevent spread to others.
  • Cover mouth while coughing or sneezing with a tissue paper, and then throw the tissue in the trash.
  • Clean and disinfect the objects and surfaces which are touched frequently.
• There is currently no vaccine available to prevent COVID-19.

Secondary Prevention

• The secondary prevention measures of Coronavirus disease 2019 (COVID-19) constitute protective measures to make sure that an infected individual does not transfer the disease to others by maintaining self-isolation at home or designated quarantine facilities.
• The ARDS patients have an increased risk of hospital-associated venous thromboembolism (VTE).
• Due to this reason, it is advised to take low molecular weight heparin (LMWH) prophylactically in patients who do not have the contraindications. Studies have shown that the heparin, either unfractionated or LMWH, can also reduce inflammatory biomarkers hence could help in reducing the inflammation.

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