Haematology in dengue and dengue haemorrhagic fever.

Dengue fever (DF) and dengue haemorrhagic fever (DHF) are caused by the dengue virus. The major pathophysiological hallmark that distinguishes DHF from DF is plasma leakage as a result of increased vascular permeability. Following this leakage, hypovolaemic shock occurs as a consequence of a critical plasma volume loss. Constant haematological abnormalities occurring in DHF and frequently include bone marrow suppression, leucopenia and thrombocytopenia. An enhanced immune response of the host to a secondary DV infection is a feature of DHF and leads to many consequences. These are immune complex formation, complement activation, increased histamine release and a massive release of many cytokines into the circulation, leading to shock, vasculopathy, thrombopathy and disseminated intravascular coagulation (DIC).The mechanisms underlying the bleeding in DHF are multiple. These are vasculopathy, thrombopathy and DIC. Thrombopathy consists of thrombocytopenia and platelet dysfunction. DIC is prominent in patients with shock. The most severe DIC and massive bleeding are the result of prolonged shock and cause a fatal outcome. The mechanisms of thrombopathy and DIC and the proper management of DHF are reviewed and discussed.     

Endotoxin and dengue haemorrhagic fever

Limulus amoebocyte lysate test (LALT) was used to detect endotoxin-like substances in the plasma of 57 patients with dengue haemorrhagic fever and dengue shock syndrome (DHF/DSS), four patients with dengue fever and 20 control patients with other diseases. The LALT positivity rates in DHF/DSS and dengue fever patients were 43.9 and 25 per cent respectively, whereas all control patients were negative (p less than 0.0025). LALT positivity was highest on 5th and 6th days of admission with positive rates of 46 and 50 per cent respectively whereas the positive rates in those admitted on fourth and seventh days of admission were 29 and 33 per cent respectively. A follow-up in LALT positive patients showed a decline in the positive rates after admission. LALT positivity was observed in 48.8 per cent of DHF/DSS patients with shock and in 26.6 per cent of patients without shock.     

Hemostatic derangement in dengue haemorrhagic fever

Forty children, aged 1/2-14 years, with serologically proven dengue haemorrhagic fever were daily studied for hemostatic tests. There were 4, 20 and 16 cases of grade I, II III respectively. Hemostatic derangements in DHF is a multifactorial mechanism. Vasculopathy, thrombocytopenia, platelet dysfunction were found in most cases. Mild to moderate degree of prothrombin complex deficiency was observed in 15% and 50% of grade II and grade III respectively while laboratory evidence of consumptive coagulopathy was noted in 30% of shock cases and 10% of non-shock cases. Hypofibrinogenemia and increased PTT are commonly seen in grade III reflect the presence of stimulation of intrinsic coagulation pathway probably from immunologic reaction. Frank DIC is very rarely observed. FDP is slightly increased but not as high as in classical DIC. Further study on the role of platelet-endothelial interaction should be elucidated including the efficient management to stop bleeding in severe shock cases.     

Vectors of dengue fever/dengue haemorrhagic fever with advances in their control

The most important vector of dengue in the Western Pacific Region is Ae. aegypti. On some occasions, Ae. albopictus, Ae. polynesiensis and several other species of the Ae. scutellaris complex have been suspected vectors in localities where Ae. aegypti was not found. Long-term vector control by the use of insecticides has been expensive and difficult to achieve. However, spray equipment and ULV insecticides have been obtained in many places for emergency use during outbreaks, and Abate larviciding also has been used in high-risk localities to help prevent outbreaks. Obtaining greater community participation supported by intensified health education and other acceptable measures is considered an important approach for achieving improved long-term control. Developing an acceptable and effective cover for domestic water storage containers is also recognized as a potentially important tool for suppressing vector populations.     

Epidemiological aspects of an outbreak of dengue fever/dengue haemorrhagic fever in Singapore

A nation-wide outbreak of 260 cases of DF/DHF with 1 death occurred in Singapore from Apr-Sept 1986. The outbreak originated from 3 separate foci of transmission at the western, south-eastern and north-eastern parts of the island and then spread to other dengue receptive urban and suburban areas. The morbidity rate was highest in young male Chinese adults between 15 and 24 years of age. The outbreak was rapidly brought under control through destruction of adult Aedes mosquitoes, surveys and source reduction of larval breeding habitats, health education and to a certain extent law enforcement. The Aedes population was high in the main foci of transmission although the overall house index was only 1.1. Other factors which could have precipitated the outbreak included waning herd immunity of the human population and continuous introduction of dengue virus into the country.     

Bleeding manifestations of dengue haemorrhagic fever in Malaysia

Analysis of the bleeding manifestations of 130 cases of dengue haemorrhagic fever admitted into the Children's ward of the General Hospital, Kuala Lumpur from May 1973 to September 1978 has been done. Petechial skin rash, epistaxis and gum bleeding were seen most commonly in mild and moderately severe cases. However, blood stained gastric aspirates, and severe haematemesis were seen in severe or very severe cases. Though with better vector control and preventive measures, a marked reduction in the incidence of the cases has been noted, severe cases were seen with symptoms of shock and gastrointestinal bleeding. These symptoms carried a bad prognosis. Among 15 children that died 10 had gastrointestinal bleeding and 2 had a disseminated intravascular coagulation defect. Lymphocytosis with atypical lymphocytes, low platelet count, low reticulocyte count and raised packed cell volume were the main haematological features seen in all these cases. All these features reverted to normal within a week. Mild evidence of disseminated intravascular coagulation was seen in a number of cases, but severe features were seen only in four. Two cases improved as a result of heparin therapy.     

Complement and dengue haemorrhagic fever/shock syndrome

The complement system is activated in DHF/DSS. The peak of activation and the presence of C3a and C5a anaphylatoxins coincided with the onset of shock and leakage. The levels of C3a correlated well with disease severity. This indicated an important role of the complement system in the pathogenesis of shock. Circulating immune complexes as assayed by two standard techniques were not detected in the majority of patients, and if detected were found in small amount. The role of circulating immune complexes in the activation of complement in DHF/DSS needs to be reinvestigated, and other possible mechanisms leading to complement activation should be sought.     

Immunological changes and recovery in patients with dengue haemorrhagic fever

In studying the immunological changes in dengue haemorrhagic fever, three phases of investigations had been carried out. During the earlier phase of investigation, significant immunological findings were obtained, namely the elevation of immunoglobulins, activation of complements, formation of circulating-immune-complexes and diminished number of T lymphocytes. The changes tended to recover during the convalescent phase. During the second phase of investigation, the extended studies revealed further confirmation of T cell impairment during the acute phase which tended to recover during the convalescent phase. Elevated number of Fc-receptor- and C3-receptor-bearing cells was also observed in some patients, variedly occurred during the acute or the convalescent phase. Elevated number of B cells was only found in small proportion. Significantly high number of activated RNA-rich lymphocytes was found in almost the half of patients. The virus-lymphocyte interaction has been demonstrated by the detection of viral antigen on the surface of lymphocytes in a proportion of patients. The circulating-immune-complexes was shown to contain viral (DEN-1) antigen. During the third phase of investigation, the impairment of T cells was further analyzed on their regulatory T populations. Impairment of total T lymphocytes, helper-T and suppressor-T was detected during the acute phase and tended to recover during the convalescent phase. The reversed changes occurred on B cells, The immunological changes and recovery are considered to be related to the stimulatory and suppressive effects of the dengue virus and regulatory mechanism.     

Age-adjusted dengue haemorrhagic fever morbidity in Thailand 1983-1987

Age-adjusted morbidity rates of Dengue Haemorrhagic Fever in Thailand during the period 1983-1987 were analysed. The 1983 data were used as standard baseline rates. The age-adjusted rates showed increasing trend in the disease morbidity, i.e., 60.2, 138.2, 159.6, 55.2 and 344.7 (per 100,000 capita) respectively. These rates were consistently higher than the crude rates. The Standardised Morbidity Ratios (SMRs) as compared with the baseline 1983 were 1.00, 2.30, 2.65, 0.92 and 5.73 respectively. Regional comparisons revealed annual increases in Bangkok areas, other Central provinces, the North and the Northeast with fluctuations observed in the South. The epidemic was most of the time higher in the Central provinces other than Bangkok areas. The authors suggest that age-adjusted rates (or possibly sex) should be applied in the study of DHF morbidity data, since there were discrepancies in the age distribution among different regions of the country.     

Slow improvement of clinically-diagnosed dengue haemorrhagic fever case fatality rates

Dengue haemorrhagic fever (DHF) is recognized as a leading cause of hospitalization and death among children in many Southeast Asian countries. This study reviews the case fatality rates of DHF cases admitted to a referral hospital in Cebu (Philippines) over the past 5 years. Information on patients 14 years old or younger admitted from 1 January 1997 to 31 December 2001 with the final clinical diagnosis of DHF was collated and analysed. Case fatality rates were compared before and after a standardized management protocol was implemented by the healthcare staff and after introduction of revisions to that protocol. The case fatality rate during the 2-year periods prior and after introduction of the management protocol decreased significantly from 197/2644 (7.45%) to 39/1182 (3.30%) (P < 0.01). Following the introduction of revisions to the protocol, the case fatality was reduced even further to 52/1697 (3.06%) (P = 0.7). In this government hospital the introduction of a standardized management protocol for DHF was associated with a significant improvement in the case fatality rate of hospitalized children with clinically diagnosed DHF. However, compared with reports from hospitals in other dengue-endemic countries, the improvement has been slow. Possible ways to decrease fatality rates further have been identified.     

Clinical and biochemical profile of dengue haemorrhagic fever in children in Delhi

The clinical and biochemical profile of dengue haemorrhagic fever (DHF) varies from epidemic to epidemic. We studied children hospitalized with DHF from September 2003 to December 2003. All were diagnosed, managed and monitored according to a standard protocol. Of the 34 who fulfilled the World Health Organization criteria of DHF, 22 (64.6%) were male. All patients presented with fever and hepatomegaly. Examination also revealed splenomegaly in 11 (32.4%), ascites in 6 (17.6%) and pleural effusion in 3 (8.8%). Common bleeding manifestations were positive tourniquet test in 22 (64.7%) and epistaxis in eight (23.5%). Most children had a platelet count of between 20,000/mm(3) and 50,000/mm(3) (56%). Bleeding manifestations were not related to platelet count (P > 0.05). Serum glutamic pyruvic transaminase (SGPT) >40 IU/L was seen in 22 (64.6%) patients, alkaline phosphate (ALP) >400 IU/L in 12 (35.3%) and serum bilirubin >1 mg% in 3 (8.8%). IgM dengue serology was positive in 68.5% cases. There was no significant difference in liver function tests with age or sex (P > 0.05). Clinical features of DHF varied from the previous epidemic. Hepatic dysfunction with increased levels of serum enzymes was common in DHF.