Dengue/DHF

Regional Guidelines on Dengue/DHF Prevention and Control ( Regional Publication 29/1999 )

Clinical Manifestations and Diagnosis

3.1 Clinical Presentation

Dengue virus infection may be asymptomatic or may cause undifferentiated febrile illness (viral syndrome), dengue fever (DF), or dengue haemorrhagic fever (DHF) including dengue shock syndrome (DSS). Infection with one dengue serotype gives lifelong immunity to that particular serotype, but there is no cross-protection for the other serotypes. The clinical presentation depends on age, immune status of the host, and the virus strain (Box 9).

1.      Undifferentiated fever: Infants, children and some adults who have been infected with dengue virus for the first time (i.e. primary dengue infection) will develop a simple fever

indistinguishable from other viral infections. Maculopapular rashes may accompany the fever or may appear during defervescence.

2.      Dengue fever: Dengue fever is most common in older children and adults. It is generally an acute biphasic fever with headache, myalgias, arthralgias, rashes and leucopenia. Although DF is commonly benign, it may be an incapacitating disease with severe muscle and joint pain (break-bone fever), particularly in adults, and occasionally with unusual haemorrhage. In dengue endemic areas, DF seldom occurs among indigenous people.

3.      Dengue haemorrhagic fever: Dengue haemorrhagic fever is most common in children less than 15 years of age, but it also occurs in adults. DHF is characterized by the acute onset of fever and associated non-specific constitutional signs and symptoms. There is a haemorrhagic diathesis and a tendency to develop fatal shock (dengue shock syndrome). Abnormal haemostasis and plasma leakage are the main patho-physiological changes, with thrombocytopenia and haemoconcentration presenting as constant findings. Although DHF occurs most commonly in children who have experienced secondary dengue infection, it has also been documented in primary infections. 

     Dengue fever

Clinical Symptoms

After an average incubation period of 4-6 days (range 3-14 days), various non-specific, undifferentiated prodomes, such as headache, backache and general malaise may develop. Typically, the onset of DF in adults is sudden, with a sharp rise in temperature occasionally accompanied by chillis, and is invariably associated with severe headache and flushed face⁽¹²⁾. Within 24 hours there may be retro-orbital pain, particularly on eye movement or eye pressure, photophobia, backache and pain in the muscles and joints/bones of the extremities. The other common symptoms include anorexia and altered taste sensation, constipation, colicky pain and abdominal tenderness, dragging pains in the inguinal region, sore throat, and general depression. These symptoms vary in severity and usually persist for several days.

Fever: The body temperature is usually between 39^oC and 40^oC, and the fever may be biphasic, lasting 5-7 days.

Rash: Diffuse flushing or fleeting pinpoint eruptions may be observed on the face, neck and chest during the first half of the febrile period, and a conspicuous rash that may be maculopapular or scarlatiniform appears on approximately the third or fourth day. Towards the end of the febrile period or immediately after defervescence, the generalized rash fades and localized clusters of petechiae may appear over the dorsum of the feet, on the legs, and on the hands andarms. This confluent petechial rash is characterized by scattered, pale, round areas of normal skin. Occasionally the rash is accompanied by itching.

Skin Haemorrhage: A positive tourinquet test and/or petechiae.

Course: The relative duration and severity of DF varies between individuals in a given epidemic, as well as from one epidemic to another. Convalescence may be short and uneventful, but may also often be prolonged. In adults it sometimes lasts for several weeks and may be accompanied by pronounced asthenia and depression. Bradycardia is common during convalescene. Haemorrhagic complications, such as epistaxis, gingival bleeding, gastrointestinal bleeding, haematuria and hypermenorrhoea, may accompany epidemics of DF. Severe bleeding has occasionally caused deaths in some epidemics. Dengue fever with haemorrhagic manifestations must be differentiated from dengue haemorrhagic fever.

Clinical Laboratory Findings

The laboratory findings during an acute DF episode of illness are as follows:

     Total WBC is usually normal at the onset of fever; then leucopenia develops and lasts throughout the febrile period.

     Platelet counts are usually normal, as are other components of the blood clotting mechanism. However, thrombocytopenia is common in some epidemics.

     Serum biochemistry and enzymes are usually normal, but liver enzyme levels may be elevated.

Differential Diagnosis: The differential diagnoses associated with DF include a wide variety of viral (including chikungunya), bacterial, rickettsial and parasitic infections that produce a similar syndrome. It is impossible to diagnose mild dengue infection clinically, particularly when there are only sporadic cases. A definitive diagnosis is confirmed by virus isolation and/or serology.

Dengue haemorrhagic fever and dengue shock syndrome

Typical cases of DHF are characterized by high fever, haemorrhagic phenomena, hepatomegaly, and often circulatory failure^(12,13). Moderate to marked thrombocytopenia with concurrent haemoconcentration are distinctive clinical laboratory findings. The major pathophysiologic changes that determine the severity of the disease in DHF and differentiate it from DF are abnormal haemostasis and leakage of plasma as manifested by thrombocytopenia and rising haematocrit.

DHF commonly begins with a sudden rise in temperature which is accompanied by facial flush and other non-specific constitutional symptoms resembling dengue fever, such as anorexia, vomiting, headache, and muscle or joint pains (Table 2)⁽¹⁴⁾.

Some DHF patients complain of sore throat, and an injected pharynx may be found on examination. Epigastric discomfort, tenderness at the right costal margin, and generalized abdominal pain are common. The temperature is typically high and in most cases continues for two to seven days, then falls to a normal or subnormal level. Occasionally the temperature may be as high as 40^oC, and febrile convulsions may occur.

The most common haemorrhagic phenomenon is a positive tourniquet test. Easy bruising and bleeding at venipuncture sites are present in most cases. Fine petechiae scattered on the extremities, axillae, face and soft palate may be seen during the early febrile phase. A confluent petechial rash with characteristic small, round areas of normal skin is sometimes seen in convalescence after the temperature has returned to normal. A maculopapular or rubella-type rash may be observed early or late in the disease. Epistaxis and gum bleeding are less common. Mild gastrointestinal haemorrhage is occasionally observed. Haematuria is rarely observed.

Table 2. Non-specific constitutional symptoms observed in haemorrhagic fever patients
with dengue and chikungunya virus infection^a

The liver is usually palpable early in the febrile phase, varying from just palpable to 2-4 cm below the right costal margin. Liver size is not correlated with disease severity, but hepatomegaly is more frequent in shock cases. The liver is tender, but jaundice is not usually observed, even in patients with an enlarged, tender liver. In some epidemics, hepatomegaly is not a consistent finding. Splenomegaly is rarely observed in infants under six months, however, the spleen is sometimes prominent on X-ray examination. Chest X-rays show/reveal pleural effusion, mostly on the right side, as a constant finding. The extent of pleural effusion is positively correlated with disease serverity.

In mild or moderate cases, all signs and symptoms abate after the fever subsides. Fever lysis may be accompanied by profuse sweating and mild changes in pulse rate and blood pressure, together with coolness of the extremities and skin congestion. These changes reflect mild and transient circulatory disturbances as a result of some degree of plasma leakage. Patients usually recover either spontaneously or after fluid and electrolyte therapy.

In severe cases, the patient’s condition suddenly deteriorates a few days after onset of fever. At the time of or shortly after the temperature drop, between three and seven days after the onset, there are signs of circulatory failure: the skin becomes cool, blotchy and congested, circumoral cyanosis is frequently observed, and the pulse becomes weak and rapid. Although some patients may appear lethargic, they become restless and then rapidly go into a critical stage of shock. Acute abdominal pain is a frequent complaint shortly before the onset of shock.

The early stage of shock is characterized by a rapid and weak pulse with narrowing of the pulse pressure £ 20 mmHg, with a minimal difference between systolic and diastolic blood pressure levels, e.g (100/90) or hypotension, with cold clammy skin and restlessness. Patients in shock are in danger of dieing if they do not promptly get appropriate treatment. Patients may pass into a stage of profound shock with blood pressure and/or pulse becoming imperceptible. Most patients remain conscious almost to the terminal stage. Shock lasts for a short time; the patient may die within 12 to 24 hours, or recover rapidly following appropriate volume-replacement therapy. Alternatively, uncorrected shock may give rise to a more complicated course with metabolic acidosis, severe bleeding from the gastrointestinal tract as well as from various other organs, and a poor prognosis. Patients with intracranial haemorrhage may have convulsions and go into coma. Encephalopathy may occur in association with metabolic and electrolyte disturbances.

Convalescence in DHF with or without shock is short and uneventful. Even in cases with profound shock, once the shock is overcome, the surviving patients recover within two to three days. The return of appetite is a good prognostic sign. Common findings in convalescence include sinus bradycardia or arrythmia and the characteristic dengue confluent petechial rash as described for DF.

3.2 Pathogenesis and Pathophysiology

The pathogenesis of DHF is not fully understood, but two main pathophysiologic changes occur:

     Increased vascular permeability resulting in plasma leakage, hypovolaemia and shock. DHF appears unique in that there is selective leakage of plasma into the pleural and peritoneal cavities and the period of leakage is short (24-48 hours).

Abnormal haemostasis due to vasculopathy, thrombocytopenia and coagulopathy, leading to various haemorrhagic manifestations.

Activation of the complement system is a constant finding in patients with DHF. Levels of C3 and C5 are depressed, and C3a and C5a are elevated. The mechanisms of complement activation are not known. The presence of immune complexes has been reported in DHF cases, however, the contribution of antigen-antibody complexes to complement activation in patients with DHF has not been demonstrated.

It has been hypothesized that the severity of DHF compared with DF is explained by the enhancement of virus multiplication in macrophages by heterotypic antibodies resulting from a previous dengue infection. There is evidence, however, that viral factors and a cell-mediated immune response are also involved in the pathogenesis of DHF.

3.3 Clinical Laboratory Findings of DHF

The laboratory findings in DHF are as follows:

     The WBC may be normal, but leucopenia is common initially, with neutrophils predominating. Towards the end of the febrile phase there is a drop in the total number of white cells as well as in the number of polymorphonuclear cells. A relative lymphocytosis with more than 15% atypical lymphocytes is commonly observed towards the end of the febrile phase (critical stage) and at the early stage of shock.

     Thrombocytopenia and haemo-concentration are constant findings in DHF. A drop in platelet count to below 100,000/mm3 is usually found between the third and eighth days of illness. A rise in haematocrit occurs in all DHF cases, particularly in shock cases. Haemo-concentration with haematocrit increased by 20% or more is considered objective evidence of increased vascular permeability and leakage of plasma. It should be noted that the level of haematocrit may be affected by early volume replacement and by bleeding.

     A transient mild albuminuria is sometimes observed.

     Occult blood is often found in the stool.

     In most cases, assays of coagulation and fibrinolytic factors show reductions in fibrinogen, prothrombin, factor VIII, factor XII, and antithrombin III. A reduction in antiplasmin (plasmin inhibitor) has been noted in some cases. In severe cases with marked liver dysfunction, reduction is observed in the vitamin K-dependent prothrombin family, such as factors V, VII, IX and X.

     Partial thromboplastin time and prothrombin time are prolonged in about one-half and one-third of DHF cases respectively. Thrombin time is also prolonged in severe cases.

     Serum complement levels are reduced.

     Other common findings are hypoproteinemia, hyponatremia, and mildly elevated serum aspartate aminotransferase levels. Metabolic acidosis is frequently found in cases with prolonged shock. Blood urea nitrogen is elevated in the terminal stage of cases with prolonged shock.

3.4  Criteria for Clinical Diagnosis of DHF/DSS

     Fever: acute onset, high and continuous, lasting 2 to 7 days.

     Any of the following haemorrhagic manifestations (including at least a positive tourniquet test* ): petechiae, purpura, ecchymosis, epistaxis, gum bleeding, and haematemesis and/or melena.

     Enlargement of the liver (hepatomegaly) is observed at some stage of the illness in 90-98% of Thai children, but its frequency may be variable in other countries.

     Shock, manifested by rapid and weak pulse with narrowing of the pulse pressure (20mm Hg or less), or hypotension, with the presence of cold, clammy skin and restlessness.

 The tourniquet test is performed by inflating a blood pressure cuff to a point midway between the systolic and diastolic pressures for five minutes. The test is considered positive when 10 or more petechiae per 2.5 cm2 (1 square inch) are observed. In DHF the test usually gives a definite positive result with 20 petechiae or more. The test may be negative or only mildly positive during the phase of profound shock. It usually becomes positive, sometimes strongly positive, if it is conducted after recovery from shock.

Laboratory Findings:

     Thrombocytopenia (100,000/mm3 or less).*

     Haemoconcentration; haematocrit increased by 20% or more.``

The first two clinical criteria, plus thrombocytopenia and haemoconcentration or a rising haematocrit, are sufficient to establish a clinical diagnosis of DHF. Pleural effusion (seen on chest X-ray) and/or hypoalbuminaemia provide supporting evidence of plasma leakage. This is particularly useful in those patients who are anaemic and/or having severe haemorrhage. In cases with shock, a high haematocrit and marked thrombocytopenia support the diagnosis of DHF/DSS.

The physical and laboratory findings associated with the various grades of severity of DHF are shown in Box 10 (see section 3.5 for a description of the DHF severity grades).

* Direct count using a phase-contrast microscope (normal 200,000-500,000/mm3). In practice, for outpatients, an approximate count from a peripheral blood smear is acceptable. In normal persons, 4-10 platelets per oil-immersion field (the average observed from 10 fields is recommended) indicate an adequate platelet count. An average of 2-3 platelets per oil-immersion field or less is considered low (less than 100,000/mm3).

3.5 Grading the Severity of Dengue Haemorrhagic Fever

The severity of DHF is classified into four grades^(12,13) (Box 11).

The presence of thrombocytopenia with concurrent haemoconcentration differentiates Grade I and Grade II DHF from dengue fever.

Grading the severity of the disease has been found clinically and epidemiologically useful in DHF epidemics in children in the South-East Asia, Western Pacific, and American Regions of WHO. Experiences in Cuba, Puerto Rico and Venezuela suggest that this classification is also useful for adults.

3.5  Differential Diagnosis of DHF

Early in the febrile phase, the differential diagnoses associated with DHF include a wide spectrum of viral, bacterial, and protozoal infections. Diseases such as leptospirosis, malaria, infectious hepatitis, chikungunya, meningococcaemia, rubella and influenza should be considered. The presence of marked thrombocytopenia with concurrent haemoconcentration differentiates DHF/DSS from other diseases. In patients with severe bleeding, evidence of pleural effusion and/or hypoproteinemia indicates plasma leakage. A normal erythrosedimentation rate in DHF/DSS helps to differentiate this disease from bacterial infection and septic shock.

3.7 Complications and Unusual Manifestations of DF/DHF in Childhood

Encephalitic signs such as convulsion and coma are rare in DHF. They may, however, occur as a complication in cases of prolonged shock with severe bleeding in various organs including the brain. Water intoxication, as a result of inappropriate use of hypotonic solution to treat DHF patients with hyponatraemia, is a relatively common iatrogenic complication that leads to encephalopathy. A subtle form of seizure is occasionally observed in infants under one year of age during the febrile phase and, in some cases, is considered to be febrile convulsions since the cerebrospinal fluid is normal. Subdural effusions have been observed in some cases.

In recent years there has been an increasing number of reports of DF or DHF with unusual manifestations. Unusual central nervous system manifestations, including convulsions, spasticity, change in consciousness and transient paresis, have been observed. Some of these cases may have encephalopathy as a complication of DHF with severe disseminated intravascular coagulation that may lead to focal occlusion or haemorrhage.

Fatal cases with encephalitic manifes-tations have been reported in Indonesia, Malaysia, Myanmar, India and Puerto Rico. However, in most cases there have been no autopsies to rule out bleeding or occlusion of the blood vessels. Although limited, there is some evidence that, on rare occasions, dengue viruses may cross the blood-brain barrier and infect the CNS. Further studies are needed to identify the factors contributing to these unusual manifestations. Attention should be given to the study of underlying host factors such as convulsive disorders and concurrent diseases.

Encephalopathy associated with acute liver failure is commonly observed and renal failure usually occurs at the terminal stage. Liver enzymes are markedly elevated in these cases, with serum aspartate aminotransferase about 2-3 times higher than serum alanine aminotransferase.

Other rarely observed, unusual manifes-tations of DF/DHF include acute renal failure and haemolytic uraemic syndrome. Some of these cases have been observed in patients with underlying host factors (e.g. G6P deficiency and haemoglobinopathy) that lead to intravascular haemolysis. Dual infections with other endemic diseases, such as leptospirosis, viral hepatitis B, and melioidosis, have been reported in cases with unusual manifestations.

3.8 Clinical Manifestations of DF/DHF in Adults

Cuba’s experience in 1981, with 130 adult cases (26 with fatal outcome), showed that the infection was usually manifested by the clinical symptoms of dengue fever (high fever, nausea/vomiting, retro-orbital headache, myalgias and asthenia), regardless of whether the patient had a fatal outcome or not. Less frequently, patients demonstrated thrombocytopenia and haemorrhagic manifestations, the most common of which were skin haemorrhages, menorrhagia, and haematemesis. Overt shock in adults was less frequently observed than in children, but was severe when it did occur. It was found mostly in white adults with a history of bronchial asthma and other chronic diseases. In one series of 1,000 adult cases studied in Cuba, the persons who were severely ill usually showed thrombocytopenia and haemoconcentration. In five cases with hypovolemic shock not associated with haemorrhage, the disease responded, as in children, to vigorous fluid replacement⁽¹⁵⁾. In the 1986 Puerto Rico outbreak, DHF with overt shock in adults was not rare, but did occur less frequently than in children⁽¹⁶⁾. Similar observations were reported in the recent outbreak in New Delhi, India in 1996⁽¹⁷⁾.