|Year : 2014 | Volume
| Issue : 3 | Page : 111-118
Acute chest syndrome
Bello Jamoh Yusuf1, Abdullah A Abba2, Mohammed Tasiu2
1 Department of Medicine, Clinical Haemato-Oncology Unit, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Pulmonology Unit, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
|Date of Submission||21-Jul-2014|
|Date of Acceptance||23-Jul-2014|
|Date of Web Publication||17-Aug-2014|
Bello Jamoh Yusuf
Clinical Haemato-Oncology Unit, Department of Medicine, Ahmadu Bello University Teaching Hospital, Zaria
Source of Support: None, Conflict of Interest: None
Sickle cell anaemia - the disease that combines molecular biology, clinical features, biochemistry, pathology, natural selection, population genetics, gene expression and genomics - is the world's most common life threatening monogenic disorder. Acute chest syndrome is a common complication of SCA and it has been identified as the most common cause of mortality in adult patients with SCA. In addition to elaboration of pro-inflammatory cytokines and up-regulation of cellular adhesion molecules, interplay among red cell sequestration, fat embolism and pulmonary infection, which are the pertinent pathophysiological phenomena that operate in a vicious cycle, lead to the clinical features of ACS. Chest infection, usually caused by atypical organisms, is a more common trigger in children, while fat embolism is considered as a more common trigger in adults. More common clinical features are cough, fever and chest pain, although the pattern of these symptoms varies between children and adults cohorts. The operational definition of ACS appears to be a bit loose, making it difficult to categorically distinguish from other differential diagnoses like pneumonia, especially in resource-poor areas. However, when ACS is diagnosed, treatment should be aggressive, addressing analgesia, hydration, the use of broad-spectrum antibiotics, inhaled bronchodilators, anticoagulation and blood transfusion if required. Randomized trials on efficacy of novel agents like statins, glycoprotein IIa/IIIb inhibitors and phospholipase inhibitors are still on-going.
Keywords: Acute chest syndrome, sickle cell disease, review
|How to cite this article:|
Yusuf BJ, Abba AA, Tasiu M. Acute chest syndrome. Sub-Saharan Afr J Med 2014;1:111-8
| Introduction|| |
Following the first documented description of sickle cell disease (SCD) in a Grenadian dental student in Chicago over a century ago (in the year 1910), subsequent studies indicated that the disease was almost confined to people of African ancestry.  Sickle cell anemia (SCA), the world's most common life-threatening monogenic disorder,  is caused by monozygosity for a single β-globin gene mutation (hemoglobin S [HbS]; β6GAG - GTG; Glu - Val; glu6val). This change in Hb causes red blood cell (RBC) deformation, resulting in occlusion of small vessels and local tissue hypoxia and damage, consequently behaving clinically as a multigenic trait with exceptional phenotypic variability. 
Data from WHO revealed that an estimated 20-25 million individuals worldwide, have homozygous SCA, out of which 12-15 million are in sub-Saharan Africa, 5-10 million in India and about 3 million distributed in other parts of the World.  The public health burden of SCD in Africa is massive, considering that about 300,000-400,000 infants are born with major Hb disorders annually,  which includes more than 200,000 cases of SCD.
In Nigeria alone, the frequency of SCA has been estimated at 150,000/year.  There is a paucity of data in Nigeria regarding the financial implications directly attributable to SCA.  However, in the United States where 60,000 people have the disease,  there are approximately 75,000 hospital admissions/year, which result in an estimated annual expenditure of $475 million. 
There is an extremely high prevalence of SCA in Nigeria with associated high case-mortality rate. The WHO has estimated that 24% of Nigerians carry the mutant gene.  According to the Nigeria's Ministry of Health publication, Nigeria ranks the first in the list of sickle cell-endemic countries. 
| Historical perspective|| |
The study of SCD was initiated a century ago, when the Chicago physician, James Herrick, with his intern, Ernest Irons, wrote a case report on a 20-year-old dental student (Walter Clement Noel), who presented with leg ulcers, body pains, anemia, jaundice and fever.  Following blood investigations [Figure 1], Prabhakar reported that "this case is reported because of the unusual blood findings, no duplicate of which I have ever seen described… large number of thin, sickle-shaped, and crescent shaped RBCs." 
|Figure 1: Full blood count result for W.C. Noel, at diagnosis. Source: Sergeant, 2011|
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This patient, Dr. W.C. Noel, eventually graduated from a dental school, returned to Granada and setup a dental practice at St. Georges, died at the age of 32-year from acute chest syndrome (ACS). 
Better understanding of the molecular basis of the disease was provided in 1949, by a protein-chemist, Linus Pauling. He and his postdoctoral student published their work titled "SCA: A molecular disease," which showed that the Hb of SCA patients had a distinct behavior in an electric field. They concluded that a different amino acid sequence might be responsible for such observation.  Two decades later, Ingram  analyzed HbS molecule, sequentially degrading one amino acid at a time and found valine substituting glutamic acid at position 6 of the β-globin chain.
This review focuses on ACS in SCA subjects, not because it was the cause of W.C. Noel's death, but largely because of the diagnostic challenges it presents to physicians practicing in resource-limited areas.
| Geographic distribution of sickle cell disease|| |
The distribution pattern of several specific haplotypes of β-globin suggests the evidence for sickle cell mutations foci, notably in Africa and Asia [Figure 2]. In Equatorial Africa, the mutations appear to have arisen independently on at least 3 or 4 separate zones and subsequently named after the areas where they were first described, hence designated the Senegal, Benin, Bantu, and Cameroon haplotypes.  The Benin and Bantu types have lower HbF levels and, therefore, more severe clinical course. The Asia haplotypes, O-Arab and India (D-Punjab), are generally associated with increased frequencies of α-thalassemia and high levels of HbF, both factors are believed to dampen the severity of the disease.  The spread of sickle cell gene is also present around the Mediterranean - Sicily, Southern Italy, Northern Greece and the South Coast of Turkey - and are all believed to be of the Benin haplotypes and, therefore, of African origin, probably imported via trade routes and the slave trade. 
|Figure 2: Map identifying the three distinct areas in Africa and one in the Arab-India region where the sickle gene is present (dotted lines) and individuals with sickle cell disease (red lines). Source: Stuart, 2004|
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However, SCD is observed, occasionally, among the white population: 10% of patients with HbSS identified by the California newborn screening program are not of African descent. 
| Pathophysiology of Sickle Cell Vaso-Occlusive Crisis|| |
The vaso-occlusion phenomenon in SCA involves a complex pathophysiological process of interplay among several inter cellular, molecular events [Figure 3]. Following exposure to vaso-occlusive rises (VOC) triggers, e.g., infections, trauma, hypoxia, dehydration, there is explosion of downstream processes where soluble and membrane - bound proteins mediate the adherence of sickled red cells (as well as leucocytes and reticulocytes) to the vascular endothelium. These molecular interactions lead to mechanical sequel in the sequence of initiation, propagation and then overt occlusion with consequent clinical features. 
|Figure 3: Endothelial and red cell adhesion molecules in vasocclusion. The top right panel illustrates the role of cell adhesion molecules (TSP=Thrombospondin, vWF=von Willebrand factor, FN=Fibronectin, VCAM=Vascular cell adhesion molecule). Source: Vichinsky, 2007|
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| Pulmonary complications of sickle cell anaemia|| |
Acute and chronic pulmonary complications are the leading cause of death in older patients with SCA.  ACS, recurrent chest infections and pulmonary hypertension are typical of such complications.
| Acute chest syndrome|| |
Acute chest syndrome is defined as a new pulmonary infiltrate on chest X-ray [Figure 4], combined with one or more manifestations such as fever, cough, sputum production, tachypnoea, dyspnoea, or new onset hypoxia.  This operational definition appears vague because there are many conditions that could satisfy it. The illness clinically and radiographically resembles bacterial pneumonia, with fever, leukocytosis, pleuritic chest pain, pleural effusion, and cough.  However, multiple lobe involvement and recurrent infiltrates are common in SCD, and the duration of clinical illness and radiologic clearing of infiltrates are prolonged to 10-12 days. 
|Figure 4: Chest X-ray of a sickle cell anemia patient with acute chest syndrome, revealing multiple pulmonary infiltrates. Source: www. ann-clinmicrob.com|
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In children, lung infections predominate while in adults, pulmonary infarcts, or occasionally pulmonary fat embolism, may be seen.  ACS has been identified as the leading cause of morbidity and mortality in the UK. 
| Epidemiology of acute chest syndrome|| |
Acute chest syndrome is a frequent cause of hospitalization for patients with SCD, second only to painful crisis, and recurrent episodes may cause debilitating chronic pulmonary disease.  It causes approximately 25% of deaths in patients with SCD.  In the cooperative study of sickle cell disease (CSSCD), the death rate in patients with ACS was 1.1% in children and 4.3% in adults.  In another multicenter study in the USA,  the national ACS study group analyzed 671 episodes of ACS in 538 patients, where 13% of patients diagnosed with ACS required mechanical ventilation and 3% died. Patients who were 20-year or more had more severe course than those who were younger, and 46% of patients who had neurological events in addition to ACS had respiratory failure.
In a 5-year study on the impact of seasonal variation of climatic factors on morbidities associated with VOC among patients with SCA in Maiduguri and Kano Teaching Hospitals, Nigeria, Ahmed et al.  found 56 episodes of ACS out of 2652 patients of VOC, giving a proportion of 2.11%. This value is only half of what was reported by the CSSCD. Whether this disparity is due to under-diagnosis, as a result, of poor diagnostic tools, or as a result of the difference in the biology of the disease in a different study populations is not clear.
A prospective, study in Enugu, Nigeria, found the prevalence of hypoxemia to be 23.8% and 13% in SCA patients in VOC and steady state respectively, against 0% observed among normal HbAA controls. 
| Pathogenesis of acute chest syndrome|| |
The ACS has a varied pathogenesis that includes occlusion of the pulmonary vascular bed by sickle erythrocytes, infection, embolized marrow fat, and lung infarction. It often follows a painful event, particularly in adults and although many pathologic processes may coexist establishing a specific cause is often difficult. Infections due to bacteria like Mycoplasma, Chlamydia, Legionella, Streptococcus pneumoniae, Haemophilus influenzae and viruses are more likely in children.  Fat-laden pulmonary macrophages in the airways due to fat embolization from the bone marrow are present in half of the cases. There is a widespread inflammation surrounding the fat embolus, often making these patient present with more 'toxic' features than those with thromboembolism. Hypoxia due to ACS can result in widespread sickling and vaso-occlusion, with the risk of multi-organ failure.
| Pulmonary vascular occlusion|| |
Pulmonary vascular occlusion is thought to be either the primary cause or the final common pathway in the pathogenesis of ACS. Endothelial dysfunction of the pulmonary microvasculature with increased expression of vascular adhesion molecules, increased platelet and plasma coagulation activation, and disordered nitric oxide (NO) metabolism leads to thromboembolism.  Erythrocytes arriving at the lungs are already in a deoxygenated state. In addition, within the pulmonary vasculature, a variety of events trigger additional deoxygenation of HbS leading to HbS polymerization and sickling of the RBC that results in vaso-occlusion, ischemia, and endothelial injury.  Postmortem studies of SCD patients show in situ pulmonary thrombosis, pulmonary infarction, and alveolar wall necrosis.  Furthermore, thin-section of CT scan images obtained during ACS demonstrates pulmonary microvascular occlusion,  and angiographic and nuclear studies document transient perfusion defects. 
Interaction between sickled erythrocytes and microvascular endothelium or the endothelial matrix is mediated through a variety of adhesion proteins [Figure 3], Panel B]. Various adhesion molecules on the sickle reticulocyte include integrin α4β1, CD36, CD47, phosphatidyl serine, basal cell adhesion molecule, Lutheran blood group, and sulfated glycans. Other endothelial cell receptors, such as the integrin αvβ3 and P-selectin, may also play substantial roles. Matrix components participating in adhesion include fibronectin, thrombospondin, von Willebrand factor, and laminin. 
Hemoglobin S polymerization generates reactive oxygen species,  which activate the transcription factor nuclear factor-kappa B,  which in turn up-regulates the expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelium and facilitating the endothelial adhesion of sickle erythrocytes by means of erythrocyte α4β1.  VCAM-1 is also up-regulated by hypoxia and by inflammatory cytokines such as interleukin-1 and tumor necrosis factor-α, both of which are elevated during ACS. 
Other vasoactive substances also mediate the pathogenesis of ACS. Endothelin-1 (ET-1) is a potent vasoconstrictor of the pulmonary vasculature; its levels are increased with hypoxemia.  In patients with SCD, levels of ET-1 are remarkably increased, especially just before and during ACS.  NO, a potent vasodilator, is generated from the amino acid L-arginine by means of NO synthase.  L-arginine levels are low in adults with SCD and decrease during acute pain episodes and in ACS,  whereas NO metabolites are increased, suggesting accelerated metabolism and possible depletion of NO in these acute illnesses. NO is important in counteracting the up-regulation of VCAM-1 and it can reduce cytokine-induced endothelial cell activation by repression of VCAM-1 gene transcription.  Alterations in the balance between ET-1 vasoconstriction and NO vasodilatation can increase capillary transit time and endothelial cell expression of VCAM-1 and finally decrease intrapulmonary flow and increase microvascular erythrocytes sequestration. Isoprostanes also play a role in vaso-constriction.  There is a nine-fold increase in the plasma levels of F2 isoprostanes in patients with SCD during ACS and increased F2 isoprostanes levels have been found to be a marker of oxidative stress in SCA patients with ACS.  Imbalance between vasoconstrictor and vasodilator molecules, increased expression of adhesion molecules, and increased secretion of inflammatory cytokines secondary to infection or other causes lead to prolonged sickle erythrocytes transit time. This leads to sequestration of sickle erythrocytes in pulmonary microvascular circulation and the consequent ischemia. Ischemia further induces endothelial activation, heralding a vicious cycle of adherence, sequestration of sickle erythrocytes, and prolonged ischemia.
| Fat embolism|| |
Embolization of fat is associated with a severe vaso-occlusive pain crisis involving multiple bones, especially the pelvis and femur, which results in infarction of the bone marrow. Godeau et al. demonstrated fat embolism in 12 of 20 adults with ACS. Fat, marrow cells, and even bony spicules are released into the bloodstream owing to bone marrow necrosis and carried to the lung, where they cause severe pulmonary inflammation, vaso-occlusion, hypoxemia, and in most cases, acute pulmonary hypertension.  The enzyme secretory phospholipase A2 converts bone marrow phospholipids to free fatty acids, which initiate an inflammatory response and lung injury. 
| Infection|| |
Patients who have SCD have increased susceptibility to certain infections. This susceptibility appears related to splenic dysfunction, decreased serum opsonic activity, and a relatively poor antibody response to the polysaccharide component of the bacterial capsule. Infection is commonly associated with ACS in children but does not play a major role in adults.  Infectious agents may be either viral or bacterial. The National Acute Chest Syndrome Study Group revealed that Infectious agents associated with ACS in children 9-year of age or younger were viruses (11% of all episodes), Mycoplasma (9%), Chlamydia (9%), and bacteria (4%). In another ACS study, a single infectious agent was identified in 30% of patients.  In these patients, the most common cause of infection was Chlamydia (30%) followed by Mycoplasma (21%), respiratory syncytial virus (10%), Staphylococcus aureus (4%), and S. pneumoniae (3%).
All of the above mechanisms involved in the pathogenesis of ACS operate in a vicious cycle [Figure 5], leading to an explosive development of signs and symptoms attributable to the condition.
|Figure 5: A vicious cycle in the pathogenesis of acute chest syndrome, involving red cell sequestration, fat embolism and pulmonary infection. Source: Gladwin et al., 2008|
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| Clinical features of acute chest syndrome|| |
The clinical features of ACS are diverse and involve interplay among various factors. Notable among these players are the etiological factors of ACS itself, SCD phenotype, environmental factors, age of the individual, co-morbidities and seasonal changes. In most adults with sickle cell anemia, the ACS develops 24-72 h after the onset of severe pain in the arms, legs, or chest. 
Succinct clinical profiles of presenting features of ACS were presented by two major longitudinal studies in African Americans: The CSSCD and National Acute Chest Syndrome Study.
The CSSCD,  perhaps one of the largest studies on SCD, is a 10-year (1979-1988) prospective study of the clinical course of SCD with 3,751 patients at 23 centers, enrolled from birth to 66-year of age and followed for a range of 1-month to 8-year. According to that study, the most common presenting symptoms were fever, cough, and chest pain. The less common symptoms, however, included shortness of breath, wheezing and hemoptysis [Table 1]. These symptoms were age-dependent with fever and cough being more common in young children and the incidence of chest pain, shortness of breath, chills, productive cough, and hemoptysis was more common with increasing age.
|Table 1: Presenting symptoms in patients with ACS, according to cooperative study on SCD |
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The National Acute Chest Syndrome Study  was also in Afro-American. It is a 30-centre study involving 671 episodes of ACS in 538 patients. The major presenting symptoms [Table 2] were similar to what obtains in the CSSCD study.
|Table 2: Presenting symptoms in patients with ACS, according to National ACS study |
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Pulmonary complications of SCD are often accompanied by asthma. Reactive airway disease occurs in 13% or more of patients with the ACS and in up to 53% of children between birth and the age of 9-year.  Some studies suggest that asthma is a risk factor for the ACS and stroke in patients with SCD,  but it still remains uncertain whether there is an increase in the prevalence of asthma among children with SCD in the steady state, as compared with matched controls.  During steady-state SCD, the major abnormality in pulmonary function is a restrictive ventilatory impairment, characterized by mild reduction in total lung capacity, and reduced diffusion capacity for carbon monoxide. 
Social habits like cigarette smoking and environmental factors like seasonal changes were thought of as contributing factors in the development of ACS.
In Northern Nigeria, Ahmad et al.,  in a 6-year prospective study (2005-2007) on seasonal variation of VOC in patients with SCD found that among sickle cell crises of bone pains, ACS, priapism and stroke, the incidence of ACS ranked the second. They also demonstrated that the incidence of ACS was particularly high in 4 consecutive months of October (10.72%), November (14.29%), December (16.07%) and January (12.5%). No other month recorded an incidence above 8%. This period (October to February) is when the region comes under the influence of dry and dusty trans-Saharan tropical continental air mass, referred to as the Harmattan.  It is associated with low atmospheric humidity, increased speeds of wind and dusty haze, which partially blocks the sunrays over northern Nigeria. This results in the fall in average temperatures to as low as 13°C with many daily temperature values reaching as low as 3°C especially in the evenings and night times. 
| Treatment of acute chest syndrome|| |
In most cases, treatment for ACS is largely supportive. Early detection and supportive treatment may limit its severity and prevent death. Treatment includes continuous pulse oximetry and delivery of supplemental oxygen to patients with hypoxemia, adequate pain management, empiric antimicrobial therapy, monitoring of the Hb concentration, blood transfusion, and maintenance of good hydration. 
| Pain management|| |
Adequate pain management is important to prevent hypoventilation. Pain management often requires opioid analgesia, which can produce respiratory depression with its attendant risk of hypoxia and its potential for acceleration of pulmonary vaso-occlusion.  Pleuritic chest pain, because of splinting of the chest wall, may reduce ventilation and may predispose to atelectasis. Nonsteroidal antiinflammatory drugs should be avoided in patients with ACS as they may worsen the features of ACS. Intercostal nerve block with a long-acting local anesthetic like bupivacaine can ameliorate both chest wall pain and splinting and has the additional advantage of reducing the amount of systemic analgesia needed to control pain, reducing the consequent risks of respiratory depression, hypoxia, and atelectasis. This procedure may provide long-term pain relief and can be repeated as needed to control symptoms.  It is important that patients' ambulation be encouraged once adequate pain control is achieved. Mechanical ventilation may be needed for patients with severe disease and acute respiratory distress syndrome. The use of patient-controlled analgesia (PCA) helps to minimize over sedation and hypoventilation but still provides adequate pain control. In one randomized controlled study,  the efficacy of intravenous morphine administration with PCA was compared with continuous infusion (CI) of morphine in patients with SCD during VOC. Patients in the PCA group were found to have significantly lower mean and cumulative morphine consumption when compared with the patients in the CI group.
| Blood transfusion|| |
Patients with ACS hypoxia may have simple or exchange transfusion successfully and achieve rapidly increased oxygenation.  Vichinsky et al.  found the mean partial pressure of arterial oxygen while the patients were breathing room air as 63 mm Hg before transfusion, and it increased to a mean 71 mm Hg after transfusion.  They also found that treatment with phenotypically matched blood transfusion improved outcome, with a 1% rate of alloimmunization. In addition, oxygen saturation was found to have increased from 91% to 94% with transfusion with no clear difference found between red cell exchange and simple transfusion.
The conclusion derived from that study was that red cell exchange transfusions can be life saving and should be carried out in patients who have severe disease, including those with hypoxia despite oxygen therapy, those requiring mechanical ventilation, those with multi lobar processes, especially when a simple red cell transfusion has not improved the patient.
| Antibiotics|| |
Antibiotics are generally given in cases of ACS irrespective of the conceived aetiopathogenesis, although some studies  indicate that the antibiotic treatment may not shorten the clinical course. The antibiotic selection should be made on clinical grounds, considering the changes in microbial flora, as well as sensitivity pattern locally.  An epidemiologic guideline recommends the use third- or fourth-generation cephalosporin and a macrolide,  but the decision should be guided by the prevalence of locally endemic or suspected organisms, and this should be modified as culture results become available. Alternative regimens include a quinolone or a macrolide plus a beta-lactam.  Progression of disease despite transfusions should prompt a reassessment of antibiotic coverage because of the occasional Gram-negative organism and the high frequency of viral agents.
| Inhaled nitric oxide|| |
Inhaled NO increases the oxygen affinity of HbS, thus potentially decreasing sickling of RBCs.  The beneficial effect of inhaled NO was seen in cases of SCD patients with ACS whose clinical courses were complicated by ARDS, hypoxia, and pulmonary hypertension that failed to respond to standard treatments.  However, a multicenter, double-blind, randomized, placebo-controlled clinical trial failed to show any significant difference in time to resolution of the crisis, length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of ACS between the NO and placebo groups. 
| Bronchodilators|| |
As with asthma, patients with ACS often develop wheezing, suggesting airway narrowing of some sort. In fact, bronchial hyper-responsiveness may be a component of the ACS in patients with SCD. In their study, Vitchinsky et al.  found that 20% of patients with ACS, who had bronchodilator therapy had clinical improvement. It then follows that bronchodilators may be useful in the treatment for ACS. They may be given to the patient when wheezing, or airflow obstruction is present, and some researchers recommend their routine use in all patients.  However, there is a paucity of data to assess the benefits and risks of the supplementary use of inhaled bronchodilators to established therapies for SCD patients with ACS.
| Anticoagulation|| |
Subtle thromboses, from multiple etiologies, are common among patients with hemoglobinopathies, notably HbSC and HbSS disease.  Anticoagulants and antiplatelet agents have been studied in patients with SCD with varying results. Heparin has been found to decrease endothelial adhesion of sickled erythrocytes, as well as P-selectin-mediated flow adherence of sickle cells to thrombin-treated human vascular endothelial cells, .  In a randomized, double-blind, placebo-controlled study of patients with SCD during acute pain episodes, treatment with the low molecular weight heparin, Tinzaparin, resulted in a significant reduction in the overall duration of painful crisis, number of days with the most severe pain scores, and duration of hospitalization compared with placebo.  Similarly, the glycoprotein IIb⁄IIIa inhibitor, eptifibatide, was reported to be safe in a pilot study of HbSS patients, with decreases in platelet aggregation and levels of the inflammatory mediator, soluble CD40 ligand.  Anticoagulants are established back bone agents in the management of pulmonary thromboembolism, but whether these agents have specific therapeutic effect in cases of ACS requires further investigations.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]