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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 Precipitating

Environmental conditions (open spaces with water
Predisposing pots, and plants)
Geographical area – tropical islands in the Immunocompromise
Pacific (Philippines) and Asia Mosquito carrying dengue virus
Soldier
Sweaty skin

Aedes aegypti (dengue virus carrier): 8-

12 days of viral replication on mosquitos’
salivary glands

Bite from mosquito (Portal of Entry in Redness & itchiness in

the Skin) the area

Allowing dengue virus to be inoculated

towards the circulation/blood (Incubation
Period: 3-14 days)
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Virus disseminated rapidly into the blood Diagnostic:
and stimulates WBCs including B Hematology :
lymphocytes that produces and secretes Increased WBC:
immunoglobulins (antibodies), and 12,900/cumm
monocytes/macrophges, neutrophils (5,000- 10,000/cumm)
Diagnostic: Increased
Hematology : Lymphocytes: 49% (20-
Decreased Antibodies attach to the viral 40%)
Monocytes: antigens, and then
4%(8-14%) monocytes/macrophages will
Decreased perform phagocytosis through Fc
Neutrophils: receptor (FcR) within the cells and
49%(50-70%) Entry to the Entry to the
dengue virus replicates in the cells
spleen, and bone marrow
liver
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, Dengue
flushed; headache of
3/10 pain scale; whitish Fever
spots; body weakness
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Virus ultimately targets liver Cellular direct destruction and

and spleen parenchymal cells infection of red bone marrow
Diagnostic:
Ultrasound: where infection produces precursor cells as well as Diagnostic:
minimal apoptosis/cell death immunological shortened platelet Hematology :
hepatospleno survival causing platelet lyses Decreased
megaly Platelet:
Blood Chemistry: Hepatosplenomeg 68,000/cumm
Thrombocytop
SGOT: 558.0 aly
U/L(Up to 46) enia Signs/
symptoms:
Signs/ symptoms: Dengue Hemorrhagic Red sclera in
>Abdominal pain
with 5/10 pain
Fever both eyes
Petechiae
scale as
verbalized. Increase number and size of
Signs/
the pores in the capillaries
symptoms:
which leads to a leakage of +1 Bipedal
fluid from the blood to the edema; weak
interstitial fluid (capillary bounding pulse
Signs/ symptoms:
leakage) of the different
Profuse non-productive
cough with white
sputum with blood Signs/ symptoms:
spots noted; shallow & Abdominal distention
rapid respirations of Pleural Ascite with abdominal girth of
35cpm; crackles/rales effusion s 93cm (36.6 inches);
hypoactive bowel
sounds of 2/min
Diagnostic:
Ultrasound: Diagnostic:
Conclusion: Ultrasound:
Minimal bilateral Conclusion:
pleural effusion. Recovery
Complications: Moderate
Intense bleeding ascites
Pulmonary Edema
White-patho red-meds green s/sblue-dignosticorange-interventions Shock
Very low blood
broken red-complications, broken green early signs pressure
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),

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
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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

• 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 recent European study found that, if only a single serum sample is
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.
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o 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.
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.
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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