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XI. PATHOPHYSIOLOGY Medical Diagnosis
T/C Dengue Hemorrhagic Fever/ Pleural Effusion, T/C Liver Pathology

Definition
Dengue Hemorrhagic Fever - is a severe, potentially deadly infection spread by certain species of mosquitoes (Aedes aegypti). Pleural Effusion - is excess fluid that accumulates in the pleural cavity, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during inhalation. Liver Pathology – a condition characterized by any liver diseases or condition

Schematic Diagram
Predisposing Geographical area – tropical islands in the Pacific (Philippines) and Asia

Precipitating Environmental conditions (open spaces with water pots, and plants) Immunocompromise Mosquito carrying dengue virus Soldier Sweaty skin

Aedes aegypti (dengue virus carrier): 812 days of viral replication on mosquitos’ salivary glands Bite from mosquito (Portal of Entry in the Skin) Allowing dengue virus to be inoculated towards the circulation/blood (Incubation Period: 3-14 days) Redness & itchiness in the area

Virus disseminated rapidly into the blood and stimulates WBCs including B lymphocytes that produces and secretes immunoglobulins (antibodies), and monocytes/macrophges, neutrophils Diagnostic: Hematology : Decreased Monocytes: 4%(8-14%) Decreased Neutrophils: 49%(50-70%) Antibodies attach to the viral antigens, and then monocytes/macrophages will perform phagocytosis through Fc receptor (FcR) within the cells and dengue virus replicates in the cells Recognition of dengue viral antigen on infected monocyte by cytotoxic T cells Release of cytokines which consist of vasoactive agents such as interleukins, tumor necrosis factor, urokinase and platelet activating factors which stimulates WBCs and pyrogen release Signs/ symptoms: Febrile: 38.6C Diaphoresis, warm skin, flushed; headache of 3/10 pain scale; whitish spots; body weakness

Diagnostic: Hematology : Increased WBC: 12,900/cumm (5,000- 10,000/cumm) Increased Lymphocytes: 49% (2040%)

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Entry to the spleen, and liver

Entry to the bone marrow

Dengue Fever

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Diagnostic: Ultrasound: minimal hepatospleno megaly Blood Chemistry: SGOT: 558.0 U/L(Up to 46)

Virus ultimately targets liver and spleen parenchymal cells where infection produces apoptosis/cell death

Cellular direct destruction and infection of red bone marrow precursor cells as well as immunological shortened platelet survival causing platelet lyses

Hepatosplenomeg aly
Signs/ symptoms: >Abdominal pain with 5/10 pain scale as verbalized.

Thrombocytop enia Dengue Hemorrhagic Fever
Increase number and size of the pores in the capillaries which leads to a leakage of fluid from the blood to the interstitial fluid (capillary leakage) of the different

Diagnostic: Hematology : Decreased Platelet: 68,000/cumm Signs/ symptoms: Red sclera in both eyes Petechiae Signs/ symptoms: +1 Bipedal edema; weak bounding pulse

Signs/ symptoms: Profuse non-productive cough with white sputum with blood spots noted; shallow & rapid respirations of 35cpm; crackles/rales Diagnostic: Ultrasound: Conclusion: Minimal bilateral pleural effusion.

Pleural effusion

Ascite s

Signs/ symptoms: Abdominal distention with abdominal girth of 93cm (36.6 inches); hypoactive bowel sounds of 2/min Diagnostic: Ultrasound: Conclusion: Moderate ascites

Complications: Intense bleeding Pulmonary Edema Shock White-patho red-meds green s/sblue-dignosticorange-interventions Very low blood pressure broken red-complications, broken green early signs Liver cirrhosis Death PATHOPHYSIOLOGY Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes: dengue virus 1 (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3),

Recovery

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and dengue virus 4 (DENV-4). Genetic studies of sylvatic strains suggest that the 4 viruses evolved from a common ancestor in primate populations approximately 1000 years ago and that all 4 viruses separately emerged into a human urban transmission cycle 500 years ago in either Asia or Africa. Albert Sabin speciated these viruses in 1944. Each serotype is known to have several different genotypes. Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can eventually be infected by all 4 serotypes. Several serotypes can be in circulation during an epidemic. Dengue viruses are transmitted by the bite of an infected Aedes (subgenus Stegomyia) mosquito. Globally, A aegypti is the predominant highly efficient mosquito vector for dengue infection, but A albopictus and other Aedes species can also transmit dengue with varying degrees of efficiency. Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite and are easily disturbed during a blood meal, causing them to move on to finish a meal on another individual, making them efficient vectors. Entire families who develop infection within a 24- to 36-hour period, presumably from the bites of a single infected vector, are not unusual. Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 8-12 days of viral replication in the mosquito's salivary glands (extrinsic incubation period). The mosquito remains infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of dengue virus in mosquitoes has been documented.9 The eggs of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C. Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 d) while viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells, result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections. Following incubation, a 5- to 7-day acute febrile illness ensues. Recovery is usually complete by 7-10 days. Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to seventh day of illness, approximately at the time of defervescence. The major pathophysiological abnormalities caused by dengue hemorrhagic fever and dengue shock syndrome include the rapid onset of plasma leakage, altered hemostasis, and damage to the liver, resulting in severe fluid losses and bleeding. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding. Liver damage manifests as increases in levels of alanine aminotransferase and aspartate aminotransferase, low albumin levels, and deranged coagulationparameters(PT,PTT). In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2). This is similar to that seen with fatal yellow fever and Ebola infections. Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior infection with one or more dengue serotypes. In individuals with low levels of neutralizing antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage and monocyte Fc receptors, have been proposed to result in increased viral entry and replication and increased cytokine production and complement activation. This phenomenon is called antibody-dependent enhancement. Some researchers suggest T-cell immunopathology may play a role, with increased T-cell activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days following fever onset during symptomatic secondary dengue infections. The activation of cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has been correlated with disease severity. Cuban studies have shown that stored serum sample analysis demonstrated progressive loss of cross-reactive neutralizing antibodies to DENV-2 as the interval since DENV-1 infection increased. In addition, certain dengue strains, particularly those of DENV-2, have been proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.  DIAGNOSTIC EXAMINATION  Hemoconcentration – more than 20% increase from the baseline Hct;  Thrombocytopenia – less than 100,000/mm3;  Chest X-ray – presence of pleural and pericardial effusion;  Bleeding parameters (BT, CT, PT, or aPTT)

Laboratory Studies

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• Complete blood cell count findings include the following: o Leukopenia, often with lymphopenia, is observed near the end of the febrile phase of illness. Lymphocytosis, with atypical lymphocytes, commonly develops before defervescence or shock. A recent systematic review found that patients with dengue had significantly lower total WBC, neutrophil, and platelet counts than patients with other febrile illnesses in dengue-endemic populations. o o A hematocrit level rise of greater than 20% is a sign of hemoconcentration and precedes shock. The hematocrit level should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever and every 3-4 hours in severe cases of dengue hemorrhagic fever or dengue shock syndrome. o o Thrombocytopenia has been demonstrated in up to 50% of dengue fever cases. Platelet counts of less than 100,000 cells/μL are seen in dengue hemorrhagic fever or dengue shock syndrome and occur before defervescence and the onset of shock. The platelet count should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever. Basic metabolic panel findings include the following: o Hyponatremia is the most common electrolyte abnormality in patients with dengue hemorrhagic fever or dengue shock syndrome. o Metabolic acidosis is observed in those with shock and must be corrected rapidly. o Elevated BUN levels are observed in those with shock. Acute kidney injury is uncommon. Liver injury panel findings include the following: o Transaminase levels may be mildly elevated into the several thousands in patients with dengue hemorrhagic fever who have acute hepatitis. o Low albumin levels are a sign of hemoconcentration. Coagulation studies may help to guide therapy in patients with severe hemorrhagic manifestations. Findings are as follows: o Prothrombin time is prolonged. o Activated partial thromboplastin time is prolonged. o Low fibrinogen and elevated fibrin degradation product levels are signs of disseminated intravascular coagulation. Typing and crossmatching of blood should be performed in cases of severe dengue hemorrhagic fever or dengue shock syndrome because blood products may be required. Serum specimens should be sent to the laboratory for serodiagnosis, PCR, and viral isolation. Because the signs and symptoms of dengue fever are nonspecific, attempting laboratory confirmation of dengue infection is important. Serodiagnosis is made based on a rise in antibody titer in paired IgG or IgM specimens. Results vary depending on whether the infection is primary or secondary. o The IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) has become the most widely used assay, although other tests, including complement fixation (CF), neutralization test (NT), hemagglutination inhibition (HI), and IgG ELISA are also used. o A recent European study found that, if only a single serum sample is available, a single positive result on ELISA (PanBio IgM or IgG) was found to have a high rate of false positivity and should be confirmed using a second more specific diagnostic technique. o In order to provide a more rapid reliable diagnosis, clinically available PCR studies are being developed. Cultures of blood, urine, CSF, and other body fluids should be performed as necessary to exclude or confirm other potential causes of the patient's condition. o

Imaging Studies • • Chest radiography: Right-sided pleural effusion is typical. Bilateral pleural effusions are common in patients with dengue shock syndrome. Serial ultrasonography o Ultrasonography is a potentially timely, cost-effective, and easily used modality in the evaluation of potential dengue hemorrhagic fever. Positive and reliable ultrasonographic findings include fluid in the chest and abdominal cavities, pericardial effusion, and a thickened gallbladder wall. Thickening of the gallbladder wall may presage clinically significant vascular permeability. The utility of previous studies was limited because of the use of single studies for evaluation. However, a recent study involving 158 patients examined the role of daily serial ultrasonographic examinations of the thorax and abdomen in the evaluation of patients with suspected dengue hemorrhagic fever.. Plasma leakage was detected in some patients within 3 days of fever onset. Pleural effusion was the most common sign. Based on ultrasonographic findings, dengue hemorrhagic fever was predicted in 12 patients before hemoconcentration criteria had been met

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