DHF initially manifests as dengue fever and thus patients show fever (< 40°C), headaches and generalized pain as well as rash. This acute phase lasts up to one week and cannot easily be distinguished from other tropical infectious diseases such as malaria, leptospirosis and typhoid as well as viral pathologies. In uncomplicated cases of dengue fever, symptoms diminish after this time.

In contrast, additional symptoms are manifested, fever reappears and the patient's condition deteriorates in cases of DHF. Symptoms indicating circulatory failure caused by plasma leakage, hemoconcentration and edema development can usually be detected in between 24 hours before or after the initial fever peak drops. Patients frequently experience acute abdominal pain before going into shock. Dengue shock syndrome may result from plasma leakage or, less frequently, from hemorrhages and blood loss [7]. Patients suffering from dengue shock syndrome are severely hypotensive (< 20 mm Hg), their pulse is nearly undetectable, they present petechial hemorrhages, perioral cyanosis and tachycardia as well as decreased consciousness. Dengue shock syndrome is associated with a very high mortality if left untreated.

• Easy Bruising

  There is bleeding with easy bruising, blood spots in the skin (petechiae), spitting up blood (hematemesis), blood in the stool (melena), bleeding gums and nosebleeds (epistaxis). Pneumonia and heart inflammation ( myocarditis ) may be present. [medicinenet.com]

  bruising DHF Grade II : Spontaneous bleeding plus the manifestations with Grade I (usually observed in GIT or mucocutaneous DHF Grade III (DSS) : Presence of circulatory failure as evidenced by rapid, weak pulse, narrowing of pulse pressure or hypotension [rnpedia.com]

  bruising) Sometimes, symptoms are mild and can be mistaken for those of the flu or another viral infection. [webmd.com]

  Symptoms of dengue fever may include: Sudden high fever Severe headache Severe joint and muscle pain Rash Nausea and vomiting Pain behind the eyes Dengue hemorrhagic fever may also cause: Unusual bleeding such as bleeding gums or nosebleeds Easy bruising [summitmedicalgroup.com]

  Subtle, minor epithelial hemorrhage, in the form of petechiae, are often found on the lower extremities (but may occur on buccal mucosa, hard and soft palates and or subconjunctivae as well), easy bruising on the skin, or the patient may have a positive [cdc.gov]

• Fever

  We diagnosed dengue hemorrhagic fever during pregnancy with clinical pictures of fever, hemoconcentration and thrombocytopenia with serological proof in all cases. [ncbi.nlm.nih.gov]

• Anemia

  She had no serious complications except for postpartum anemia. The newborn became febrile at the 48th hour of life. He had fever for 2 days, hepatomegaly, thrombocytopenia and a right pleural effusion. [ncbi.nlm.nih.gov]

• Chills

  A 54-year-old man who had fever, chills, bone pain, and skin rash for 4 days was admitted. We diagnosed dengue hemorrhagic fever because of fever, gum bleeding, thrombocytopenia, and hemoconcentration, and confirmed the diagnosis by serology. [ncbi.nlm.nih.gov]

  (classical) (fever) A90 ICD-10-CM Diagnosis Code A90 Dengue fever [classical dengue] 2016 2017 2018 2019 Billable/Specific Code Type 1 Excludes dengue hemorrhagic fever ( A91 ) hemorrhagic A91 Fever (inanition) (of unknown origin) (persistent) (with chills [icd10data.com]

  […] hemorrhage may include: Avoidance of dark colored foods and liquids Client is encouraged to prevent from using sharp- bristled toothbrushes, instead advised to gargle with saline solution Clients are educated not to use hot liquids for alleviation of chills [rnpedia.com]

  Provisional diagnosis: Dengue Fever without Haemorrhage / Classic Dengue Fever Reasons : Fever, chills, headache,Myalgia,Arthralgia No signs of bleeding(Clinical Symptoms) Low platelet, low wbc (Lab Reasons) (according to WHO, Fever plus any 2 clinical [slideshare.net]

• Ecchymosis

  He was febrile with small ecchymosis on arms. Pulse 120/m, respiratory rate 34/m ,BP 98/60 mm Hg. Crackles heard bilaterally. Hb 7.6 gm, hematocrit 24.5%, platelets 30000, WBC 3500 with a normal differential. DHF was suspected. [erj.ersjournals.com]

  Acute Symptoms of Dengue Haemorrhagic Fever • Ecchymosis - Skin discolouration due to internal rupture of blood vessels • Generalised Rashes. • Petechiae – Red spots on the skin caused by breaking of blood capillaries. • The earlier symptoms are worsened [onlymyhealth.com]

• Malaise

  Clinical presentation: Clinically, symptoms start 6 days after infection as malaise and headache, followed by sudden onset of fever, intense backache and generalized pains, mainly in the orbital and periarticular areas. [histopathology-india.net]

  The affected patient might first notice feelings of restlessness, perspiration, low appetite, headache, blood shot eyes and malaise. In severe cases they may also experience bleeding from the nose and gums. [healthguidance.org]

• Respiratory Distress

  A patient of dengue hemorrhagic fever who progressed into acute respiratory distress syndrome (ARDS) is reported. The patient recovered after mechanical ventilation and supportive treatment. [ncbi.nlm.nih.gov]

  Adult respiratory distress syndrome, disseminated intravascular coagulopathy, and multi-organ failure were the most common causes of death despite early hospitalization, intravenous fluid, and blood-product support. [researchonline.lshtm.ac.uk]

  Patient received multiple transfusions & intensive care but developed severe respiratory distress with shock & died 10 days later. [erj.ersjournals.com]

  Severe dengue is a potentially deadly complication due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding, or organ impairment. [who.int]

• Tachycardia

  Patients suffering from dengue shock syndrome are severely hypotensive (< 20 mm Hg), their pulse is nearly undetectable, they present petechial hemorrhages, perioral cyanosis and tachycardia as well as decreased consciousness. [symptoma.com]

  Patients with plasma leak should be monitored for early changes in hemodynamic parameters consistent with compensated shock such as increased heart rate (tachycardia) for age especially in the absence of fever, weak and thready pulse, cool extremities [cdc.gov]

  Admission for intravenous fluid administration is indicated for patients who develop signs of dehydration, such as the following: Tachycardia Prolonged capillary refill time Cool or mottled skin Diminished pulse amplitude Altered mental status Decreased [emedicine.medscape.com]

• Hepatomegaly

  He had fever for 2 days, hepatomegaly, thrombocytopenia and a right pleural effusion. Dengue virus type 1 was detected from his serum by polymerase chain reaction (PCR). [ncbi.nlm.nih.gov]

  Surprisingly, the prevalence of hepatomegaly in DHF patients seems to depend on the specific strain of dengue virus. Distinct serotypes apparently cause different degrees of liver damage. [symptoma.com]

• Myalgia

  CASE PRESENTATION: A 44-year old previously healthy Sinhalese man presented on day 3 of the illness with fever, headache, arthralgia and myalgia and watery loose stools. [ncbi.nlm.nih.gov]

  [Sp. corruption of "dandy" fever] dengue hemorrhagic fever Abbreviation: DHF A grave sequela of dengue, marked by fever, headache, myalgia, arthralgias, rash, spontaneous bleeding, increased blood vessel permeability to proteins, and low platelet counts [medical-dictionary.thefreedictionary.com]

• Arthralgia

  Symptomatically, it is characterized by fever, arthralgia, headache, and rash. Ophthalmic manifestations can involve both the anterior and posterior segment. [ncbi.nlm.nih.gov]

  [Sp. corruption of "dandy" fever] dengue hemorrhagic fever Abbreviation: DHF A grave sequela of dengue, marked by fever, headache, myalgia, arthralgias, rash, spontaneous bleeding, increased blood vessel permeability to proteins, and low platelet counts [medical-dictionary.thefreedictionary.com]

  […] fever, vomiting, a maculopapular rash, liver involvement, and occasionally, a protein-losing shock syndrome. 1 This disease is to be differentiated from dengue fever, a relatively benign disease occurring primarily in adults and manifested by myalgia, arthralgia [pediatrics.aappublications.org]

• Petechiae

  In the course of the co-infection, he developed fever, thrombocytopenia (13,700 cells/mm3), petechia, and hypoalbuminemia, which are compatible with the World Health Organization criteria for a case of dengue hemorrhagic fever. [ncbi.nlm.nih.gov]

  Bleeding will appear as small spots of blood on the skin called ‘petechiae’, with larger patches beneath the surface. [healthguidance.org]

• Skin Rash

  Typical manifestations of dengue like fever, myalgia, arthralgia, headache, vomiting, abdominal pain and skin rash were observed in more than 40 % patients. DHF was observed in 79 (11.8 %) cases. [ncbi.nlm.nih.gov]

  There may be skin rash and lymphadenopathy. [histopathology-india.net]

  Skin rashes, bleeding often in gums and under the skin, and extreme drop in blood pressure are symptoms that distinguishes dengue hemorrhagic fever from dengue fever or the flu. [thrombocyte.com]

• Purpura

  WinRho® SDF is currently licensed to treat immune thrombocytopenia purpura (ITP) in pediatric or adult patients. [bloodjournal.org]

  Dengue is also known as Breakbone Fever, Hemorrhagic Fever, Dandy Fever, Infectious Thrombocytopenic Purpura. Dengue hemorrhagic fever is a fatal manifestation of dengue virus that manifest with bleeding diathesis and hypovolemic shock. [nurseslabs.com]

  A thorough clinical examination and possibly imaging techniques may reveal a bleeding diathesis (petechial bleedings, ecchymoses, purpura, positive tourniquet test ), pleural effusion, ascites, hepatomegaly and a thickened gallbladder wall. [symptoma.com]

  The authors proposed that, as in immune thrombocytopenic purpura from disorders other than dengue, intravenous anti-D produces Fcγ receptor blockade to raise platelet counts. [80] Patients who are resuscitated from shock rapidly recover. [emedicine.medscape.com]

  […] more formal term "bilious remitting fever". [78] The term dengue fever came into general use only after 1828. [77] Other historical terms include "breakheart fever" and "la dengue". [77] Terms for severe disease include "infectious thrombocytopenic purpura [en.wikipedia.org]

• Erythema

  Hemorrhagic erythema on the palms and soles as well as focal petechiae on the hard palate and scleral and conjunctival bleeding were also observed. Hypotension and renal insufficiency developed 1 week after the illness started. [ncbi.nlm.nih.gov]

• Epistaxis

  The initial picture of classical dengue fever was followed by painful liver enlargement, vomiting, hematemesis, epistaxis and diarrhea. [ncbi.nlm.nih.gov]

  There is bleeding with easy bruising, blood spots in the skin (petechiae), spitting up blood (hematemesis), blood in the stool (melena), bleeding gums and nosebleeds (epistaxis). Pneumonia and heart inflammation ( myocarditis ) may be present. [medicinenet.com]

  Other forms of hemorrhage such as epistaxis, gingival bleeding, gastrointestinal bleeding, or urogenital bleeding can also occur, but are rare. Leukopenia is frequently found and may be accompanied by varying degrees of thrombocytopenia. [cdc.gov]

  The case definition for DHF included acute febrile illness; hemorrhagic manifestations (positive tourniquet test, petechiae, epistaxis, gum bleeding or gastrointestinal bleeding); thrombocytopenia (platelet count of 3 ); and plasma leakage evidenced by [journals.plos.org]

• Headache

  He presented with thrombocytopenia and developed severe headache and vomiting. During hospitalization, acromegaly was suspected because of the characteristic disease phenotype. [ncbi.nlm.nih.gov]

• Confusion

  Symptoms of dengue hemorrhagic fever can include abnormal bruising or bleeding, and when severe, can progress to "shock" which has variable symptoms but can include dizziness, chest or severe abdominal pain, or confusion. [zocdoc.com]

  Sorry for any spelling errors, errors or confusions. Please kindly notify me if any at [email protected] Thanks [slideshare.net]

Recommended procedures depend on the condition of the patient upon admission.

During the acute dengue fever-like stage of the disease, alterations detected in laboratory analyses may be less severe than after remission of the initial fever peak.

Hemogram, blood chemistry and coagulation tests should be realized and most frequently show the following alterations:

• Lymphocytosis due to viral infection. Atypical lymphocytes are not uncommon.
• Elevated levels of alanine aminotransferase and aspartate aminotransferase but hypoalbuminemia due to hepatic damage [8].
• Hyponatremia.

Plasma leakage and eventually hemorrhages are often associated with the following pathological findings:

• Lymphopenia and leukopenia [9].
• Elevated hematocrit (>20%) due to plasma leakage and hemoconcentration.
• Thrombocytopenia (<100,000 per μl), low fibrinogen but elevated fibrinolysis products due to disseminated intravascular coagulation.
• Prolonged prothrombin partial thromboplastin and activated partial thromboplastin time.
• Metabolic acidosis.
• Possibly elevation of blood urea nitrogen , but kidney damage is unlikely [10].

These symptoms aggravate upon onset of dengue shock syndrome. For this reason, blood analyses should be repeated at least daily to monitor disease progress or remission and to be able to act as soon as possible when the patient threatens to go into shock. Worse condition justifies an even more frequent evaluation of these parameters.

A thorough clinical examination and possibly imaging techniques may reveal a bleeding diathesis (petechial bleedings, ecchymoses, purpura, positive tourniquet test ), pleural effusion, ascites, hepatomegaly and a thickened gallbladder wall. Ultrasonography is available at most places and provides reliable results [11]. Surprisingly, the prevalence of hepatomegaly in DHF patients seems to depend on the specific strain of dengue virus. Distinct serotypes apparently cause different degrees of liver damage [12].

Because DHF and dengue shock syndrome may be accompanied by life-threatening edema formation and hemorrhages, the patient should be closely monitored and, if necessary, thoroughly examined to determine if those conditions affect vital organs, e.g., in form of cerebral edema or intracranial bleedings.

Hydration, fluid therapy and maintenance of water and electrolyte balances are the mainstays of DHF therapy. Hemodynamic and metabolic parameters have to be constantly monitored in order to be able to react rapidly. Isotonic solutions are usually administered to compensate hemoconcentration. Bicarbonate may be given to correct the acid-base balance. More severe cases of DHF and dengue shock syndrome may require transfusion of blood products.

Non-steroidal anti-inflammatory drugs are not recommended as analgesics and antiphlogistics because they may enhance the patient's bleeding diathesis. Furthermore, they have been associated with the development of Reyes syndrome in children. In order to manage pain and fever, acetaminophen should be administered.

Of note, effectivity of methylprednisolone in dengue shock syndrome has been refuted in a prospective clinical trial [13].

Prognosis is good when adequate treatment is provided during early stages of the disease. DHF, however, is associated with high mortality rates when left untreated or after patients go into shock.

Dengue fever is a tropical infectious disease caused by a positive single-stranded RNA virus pertaining to the family Flaviviridae and the genus Flavivirus. The virus is termed dengue virus.
There are four distinct serotypes of dengue virus that are indicated with numbers one to four. Evolutive studies suggest that all serotypes originate from one common ancestor presumably distributed in primate populations. Nowadays, all four serotypes are transmitted in urban cycles [3]. Dengue virus serotypes present distinct antigenic determinants and may be further subdivided into different genotypes. These virus properties, serotype and genotype, as well as the sequence of infection with different virus strains presumably triggers DHF and determines the severity of the disease.
Dengue virus is transmitted by mosquitos and dengue fever may be contracted in endemic areas. People living in such areas have an increased risk of repeated infection and are therefore more likely to develop DHF [4].

About 40% of the world population live in subtropical and tropical climates and are at constant risk to be infected with dengue fever. Virus and vectors are present on every continent with the exception of Europe and Antarctica. The worldwide incidence of dengue fever has been estimated to range between 50 and 100 million per year, with this figure set to increase in the future. Indeed, case numbers have been increasing 30-fold during the last 50 years. Annually, about half a million individuals develop DHF and about 20.000 deaths occur due to DHF. Mortality is increased in children [5].
About one million cases of dengue fever are registered every year on the American continent. Approximately 2.5% of the affected patients developed DHF. All four serotypes have been detected in the northern countries of South America, with Brazil, Colombia and Venezuela reporting the majority of cases. Increasing case numbers have been registered in the Caribbean. With regards to Asia, most cases of dengue fever and DHF are registered in South-East Asia, particularly in Indonesia. While currently a significant share of cases corresponds to children, the average age at time of infection and mortality are augmenting. Interestingly, in all other continents DHF is equally distributed among all ages. Less reliable data are available regarding the African continent. It is known that many countries located in sub-Saharan Africa and the Arabian subcontinent harbor all subtypes of dengue virus as well as transmitting mosquitos.

The dengue virus replicates inside of different target cells, e.g. in endothelial cells, hepatocytes and cells pertaining to the reticulo-endothelial system. It is not yet known why some patients develop a coagulopathy and present with the more severe clinical picture of DHF after repeated infection with distinct serotypes and genotypes of the virus.

The most characteristic symptom of DHF is plasma leakage that occurs due to increased vascular permeability. This condition causes hemoconcentration as well as edema development. Fragile blood vessels may break and give rise to hemorrhages that become visible in form of petechiae when the skin is affected, but that may also affect the gastrointestinal tract or other organ system. Hemorrhages may become life-threatening, particularly when the patient suffers from disseminated intravascular coagulopathy and subsequent deficiency of thrombocytes and coagulation factors. To date, complex interactions between viruses, the host immune system, its antibodies, inflammatory cells and cytokines is presumed to be responsible for the development of DHF.

As has been mentioned above, viruses also replicate in hepatocytes and reticulo-endothelial cells. This may cause severe hepatic damage. It has been shown that up to 90% of all hepatocytes and Kupffer cells are infected with the viral agent in cases of fatal dengue hepatitis [6]. Of note, only very low levels of pro-inflammatory cytokines could be detected here. Less severe hepatic damage, although not fatal, may aggravate the deficiency of coagulation factors that is initially caused by the above mentioned coagulopathy.

There are no specific measures to avoid contracting dengue fever and subsequently DHF other than avoiding the mosquitos that serve as vectors for the dengue virus.

Travelers can be advised to take preventive measures, to wear adequate clothing that covers arms and legs, to use repellents, to impregnate clothes with repellents and to stay in rooms that dispose of window screens. Sleeping under mosquito nets is recommended but not sufficient because the most of the mosquitos that transmit the virus, the genus Aedes, is active during the day. If possible, journeys should not be realized when large mosquito populations have to be expected, especially during rainy seasons.

However, these recommendations are of limited help to billions of people living in endemic areas. Moreover, many endemic areas correspond to developing countries where large shares of the population do not have access to the required articles. It has repeatedly been tried to eliminate mosquitos from larger areas by spraying whole cities, but these measures have not proven effective. General efforts to eliminate the insects' habitat, to implement hygienic measures, to remove garbage and other reservoirs of stagnant water may be helpful to decrease the incidence of the disease. Water in reservoirs that cannot be eliminated because they are needed by the population should regularly be changed, ideally daily.

Current research focuses on the possibility of biological mosquito control. Predatory copepods may eventually be used in this context [14].

Finally, general measures such as raising the awareness of health care givers and the general public are as necessary as surveillance systems to stop the increasing incidence of dengue fever and DHF.

Dengue hemorrhagic fever (DHF) is a severe complication of dengue fever. The causative agent of the latter, the dengue virus, replicates in endothelial and other types of cells. It is not yet fully understood why some patients suffering from dengue fever develop severe vasculopathies that result in DHF. It has been speculated that repeated infection with distinct serotypes and genotypes of dengue virus predisposes individuals for DHF. Children seem to be more susceptible to DHF [1].

DHF is characterized by plasma leakage due to increased vascular permeability and edema formation. More severe lesions to the endothelial cells may even result in hemorrhages. Hemoconcentration and hemorrhages contribute to circulatory failure and provoke the potentially lethal dengue shock syndrome [2].

Symptoms of DHF usually set in with some delay in relation to acute dengue fever symptoms. During this acute phase, it is difficult to distinguish DHF from uncomplicated dengue fever and even other tropical infectious diseases. About 24 hours after dengue fever-associated fever subsides, DHF patients will start to show signs of hemoconcentration and edema development.

Treatment aims at stabilizing the patient and preventing dengue shock syndrome. Therefore, fluid therapy and correction of electrolyte imbalances are the mainstays of therapy. If adequate treatment is provided, prognosis is good.

Dengue hemorrhagic fever (DHF) is a severe form of dengue fever, an infectious disease transmitted by mosquitos in subtropical and tropical regions. A small share of dengue fever patients develops DHF.

Causes

Patients may develop DHF after repeated infection with distinct types of the dengue virus. It seems the specific types, the sequence of infection as well as the patient's immune system contribute to the development of DHF, but the precise background is not yet completely understood.

In cases of DHF, the inner layer of the blood vessels, called the endothelium, is damaged in the course of the disease. This allows fluids and certain solutes to pass from the vessel into the surrounding tissue. The same condition may also cause an overall bleeding tendency.

Symptoms

Similarly to an uncomplicated case of dengue fever, DHF patients develop fever, headaches and generalized pain as well as rash. The fever usually subsides after a few days, but contrary to the uncomplicated cases, it will return soon after and be accompanied by additional symptoms.

Due to the above mentioned damage to the endothelium, edema may form in different parts of the body, e.g. in the abdomen or around the lungs. Hemorrhages may be recognized as differently sized spots of blood on the skin and an overall tendency to bleed due to minimal traumas.

The cardiovascular system will be lacking those fluids and blood that leave the intravascular space through the damaged endothelium. The body may try to compensate this by increasing the heart rate but may not be able to make up for the severely decreasing blood pressure. At this point, patients may start to sweat but feel cold and clammy and go into shock. If not adequately treated, shock can lead to death.

Diagnosis

Diagnosis is based on clinical examination and laboratory tests. Blood samples are particularly helpful to confirm viral infection and to identify hemoconcentration, electrolyte imbalances and coagulation disorders that result from an increased vascular permeability. Treatment will be adjusted to the results obtained in blood analyses. Therefore, such analyses may not only be realized to verify the diagnosis of DHF, but also to monitor disease progress and recovery after treatment has been started.

Chest X-rays or ultrasound examinations may be conducted to check the condition of the liver and to see if fluids are accumulated in thorax or abdomen.

Treatment

There is no specific treatment against dengue fever or DHF. Thus, any treatment will be symptomatic and focus on compensating for plasma and blood loss. Therefor, isotonic solutions may be administered in mild cases and blood or blood product transfusions may be required in more severe cases. Oxygen might be supplemented to increase the amount of oxygen distributed to the body's tissues and cells.

Additional drugs may be prescribed in order to alleviate pain and fever.

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