Dengue medical disease, study understand

Dengue

1. Dengue

2. 1 . Epidemiology of dengue : What is dengue ? Dengue is an acute febrile illness caused by dengue viruses that belong to the flavivirus group . There are 4 types of dengue viruses [ designated as Den 1, Den 2 , Den 3 , Den 4 ] that can be identified by serological or PCR techniques . 3.2 million cases of dengue have been reported to WHO in 2015 . However there is huge under-reporting of dengue cases . It is estimated that India itself could be having 22-44 million dengue infections yearly [ almost 282-1000 times higher than that reported to National Vector Borne Disease Control Programme ] . Dengue is predominantly in tropical countries of Asia , followed by Latin America and Africa .

3. Contd. Dengue cases have now been reported in Europe, USA and Hawaii also . Aedes albopictus , a second mosquito that transmits dengue virus has spread to Europe and can survive in cooler temperate regions of Europe .

4. 2. Transmission of Dengue: Dengue is spread by the bite of female aedes aegypti and Ae . Albopictus mosquitoes . When the mosquito bites an infected patient with dengue , the virus that the mosquito acquires travels from the gut to the salivary glands . This transmission from gut to salivary glands is temperature controlled and rapid in warm climates . Thus dengue tends to occur in the tronical regions and during the rainy season . Incubation period = 4 – 10 days Ae . Aegypti is a highly domesticated mosquito . It bies more than one host to complete one blood meal and thus it needs more han one feed for the complrtion of the onotropic cycle .

5. Contd. Therefore , it can cause multiple cases and the clustering of dengue cases in cities . Ae . albopictus partly invades peripheral areas of urban cities and feeds on both humans and animals . These mosquitoes breed on clean stored water and are day time feeders with pea bitin periods early in the morning and in the evening before dusk . Though there are 4 serotypes of dengue virus , each serotype has various genotype . With passage of time , a perticular genotype of any serotype virus may die out due to presence of protective antibodies in majority of the population but a new mutation may lead formation of new genotypes and serotypes leading to continued transmission .

6. Contd. The following individuals are at a higher risk of getting dengue: Genetic and Race : Asians inspite of exposure to all 4 types of viruses have genetic protection against clinical dengue . Sex : the male : female incidence of dengue is 2 : 1 , Females tend to have a more severe disease as compared to men . Age : around 7% in children between 5 – 9 years of age but case fatality rate is highest in children . Prevalence : by 1 year of age , 40% of children have presence of dengue antibodies and by 10 years of age , 90% of children have been exposed to dengue virus .

7. Contd. Nutrition : it has been found that malnourished children are relatively protected against severe dengue whereas well – nourished children are more prone to severe dengue . This may be due to the fact that severe dengue is an immunologically mediated phenomenon and children with protein energy malnutrition have a poor immune response to infection .

8. 3 . Pathogenesis of Dengue Mechanism of severe dengue : Infection with one serotype of dengue produces life-long immunity against that serotype but only partial protection against other serotypes . Temporary cross-protection is induced to the other serotypes [heterotypic protection ] , lastly 2 yrs on average . It is well accepted that following waning of cross-neutralizing antibodies , severe illness is more likely to occure with second dengue virus infection than with the first dengue virus infection . Thus infection with second , third or possibly fourth different serotype occure . Dengue infection is unique in a way as infection with a second serotype leads to a more severe disease .

9. Contd. This occurs due to cross-reacting antibody mediated phenomenon as it is thought that antibodies formed in the first infection form an immune complex on exposer with the second virus during the next infection affectin macrophages leading to antibody dependent enhancement and release of cytokines leading to capillary leas due to increase in capillary permeability . This immune enhancement carries the potential risk of precipitating serious manifestations like dengue hemorrhagic fever [ DHF ] or dengue shock syndrome [ DSS ] during secondary infection y a different serotype . Following recovery from a second infection , broadly newtralizing antibodies are induced [ multitypic protection] , such that severe disease with susequent infections is considerd rare .

10. Contd. Worldwide , twelve sequences of 2 dengue infection have been documented of which , the following sequential order of dengue infection can lead to dengue hemorrhagic fever . DEN 1 followed by DEN 2 DEN 2 followed by DEN 1 DEN 3 followed by DEN 2 DEN 4 followed by DEN 2 DEN 1 followed by DEN 3 DEN 2 followed by DEN 3 DEN 2 followed by DEN 4 Infection with DEN 2 is the severest whereas DEN 1 and DEN 4 lead to mild disease while infection with DEN 3 leads to hepatitis and hepatic encephalopathy . Disturbance in the endothelial glycocalyx layer and heparan sulfate[ natural anticoagulant ]in dengue leads to capillary leaks and bleeding manifestations .

11. Cause of thrombocytopenia in dengue ? Two mechanisms have been suggested that could be responsible for dengue induced thrombocytopenia ; 1.impaired thrombopoiesis 2.peripheral platelet destruction 1.Impaird thrombopoiesis – it is reduce megakaryocytes at the onset of infection , which is normal at the time of clinical recovery . This effect could be due to a direct effect of the virus on the megakaryocytes , or an effect on the stromal cells which are responsible for tha release of cytokines and control of megakaryopoisis . It is indicated altered proliferative capacity . Inhibition of differentiation and megakaryocyocytic progenitor apoptosis, mechanism of thrombocytopenia .

12. 2. Increased peripheral platelet destruction- It is by the dengue virus , it could be due to an autoimmune reaction . where antibodies produced by the host against the virus bring about activation and destruction of platelets . Platelets may also show an increased reaction with leucocytes and endothelial cells , leading to their destruction. Platelet dysfunction due to abnormal activation and inhibition of platelet aggregation in dengue patients maY also be responsible for the destruction . Recent studies indicate a direct infection of the platelets by the dengue virus . Increased levels of mediators like tumor necrosis factor alfa and interleukin1B are associated with the thrombocytopenia .

13. Clinical presentations - Dengue virus infections are asymtomatic . For clinical cases Incubatuon period – is usually 4 – 7 days , but can be in the range 3 – 14 days . Sudden onset of fever accompanied by headache , retro – orbital pain , generalized myalgia and arthralia , flushing of the face , anorexia , abdominal pain and nausea . Rash is frequently seen on the trunk , on the medial aspect of the arms and thighs , and plantar and palmar surfaces and can be macular , maculopapular , morbilliform , scarlatiniform or petechial .

14. How to differentiate dengue from other fevers that cause thrombocytopenia ? Severe dengue often mimics other hemorrhagic fevers such as malaria , leptospirosis and thus it is essential to differentiate between these conditions while treating dengue . Severe dengue presents with fever , thrombocytopenia , bleeding manifestations ,vomiting , elevated liver transaminases coagulopathy and serosal fluid accumulaion . However , a way to differentiate from malaria would be to look at hemoglobin and hematocrit . In dengue , there would be high hemoglobin [ or normal heamoglobin if baseline there is anemia ] whereas in malaria, hemoglobin would be low due to hemolysis . To differentiate dengue and leptospirosis one should check serum creatinine . Renal failure is a common feature of leptospirosis unlike that in dengue .

15. Clinical types of undifferentiated fever , dengue fever [DF] , dengue heamorrhagic fever [DHF] , and dengue shoc syndrome [DSS] . In clinical practice it is very difficult to classify patients into these groups . Undifferentiate fever was similar to any other viral fever . DF- It is presented with acute biphasic fever with myagia , arthralgia , headach ,rash and leukopenia and occasionally with unusual hemorrhage along with thrombocytopenia . DHF-it is characterized by acute fever withnon - specific constitutional symptoms and signs of hemorrhagic diathesis, vascular leak and hrombocytopenia . DSS-DHF with shock was labelled as DSS .

16. Thus from clinical management ,WHO has nw classified dengue into three phases as follows ; Febrile phase : it lasts 2-7 days . It is characterized by facial flushing , skin erythema , generalized body ache , myalgia , arthralgia , retro-orbital eye pain , photophobia , headach , hepatomegaly and leukopenia with/without petechiae . Critical phase :it lasts for 24-48 hours . Fever disappears , however , leukopenia , thrombocytopenia , increasing hematocrit , capillary leaks , and serositis may be seen which may progress to shock and DIC . This is the phase when fluid replacement therapy is required to prevent hypoperfusion of the vital organs . Recovery phase :it lasts 48-72 hours . There is resorption of extravascular compartment fluid . Hematocrit falls and leucopenia recovers . Pulmonary edema or CCF will occure if excessive intravenous fluid are given during critical period .

17. What is the natural course of dengue infection ? Primary dengue = it behaves as any undifferentiated viral fever and Is self limiting . = patients present with fever of 2 to 7 days along with headache ,rash , retro-orbital pain , myalgia / arthralgia and even leukopenia and petechiae . Secondary dengue = incubation period is usually of 5 days . followed by fever which lasts for 5-7 days and with defervescence of fever, hemorrhagic manifestation takes place . The plasma leaks usually peaks Around 24 hours after defervescence of fever and lasts for next 48-72 hours followed by the resorption phase where fluid that has accumulated in the third spaces re-enters the intravascular compartment. In this phase , if child is still continued on fluid support,volume overload maytake place leading to pulmonary edema.

18. Thus during the plasma leak phase,one needs to monitor for hypovolemia and during the resorptive phase , one needs to monitor for fluid overloaded . Thrombocytopenia starts usually with onset of fever and persists into the resorptive phase and usually resolves by day 10-12 of illness . Incubation period= day 1-5 Fever= day 5-12 Capillary leaks= day 12-15 Thrombocytopenia= day 5-15 Resorpive phase= day 15-17

19. When to suspect severe dengue? Severe dengue is considerd if there is; Severe plasma leaage that leads to shock and/or fluid accumulation with respiratory distress . Severe bleeding . Severe organ impairment [ liver enzymes greater than 1000 IU/L, impaired consciousness or involvement of heart or other organs .] Few patients may have multi-system organ dysfunction in form of fulminant hepatitis , renal failur , ARDS and encephalopathy . With livercell failure ,mortality is almost 50 % and with multi system organ failure , mortality reaches almost 90 %

20. Warning signs = it occur 3-7 days after the first symptoms in conjunction with a decrease in temperature [below 38 degree c/100 f] and include as follows ; Severe abd . Pain , persistant vomiting , rapid breathing , bleeding gums , fatigue , restlessness , clinically fluid accumulation and blood in vomit . Labotary wise there will be rising hematocrit with rapid fall in platelet count . These patients may require hospitalization . - Dengue could also present in different forms such as brainstem encephalitis , guillain barre syndrome [GBS] , myositis , liver disease and even myocarditis without having bleeding manifestations or shock .

21. Bacterial co-infections: it has been observed that about 5.5 % of the patients with dengue demonstrate bacteremia . As for the pathogenes isolated from blood , majority of the bacteria are normally found in the intestinal tract. Most of the bacteria invade the bloodstream from the intestinal lumen of the patients because dengue viruses infections may lead to disintegration of intestinal mucosal barrier , resulting in creation of a portal of entry for pathogens that normally inhabit the intestinal tract . Micro-organisms that have been identified as occuring simultaneously with dengue virus infections are E.coli,salmonella,streptococcus pneumoniae,mycobacterium tb,mycoplasm Pneumo.,shigellasonnei,lebsiella,enterococcus faecallis,maraxella lacunata,staphylococcus aureus,rosemonas,hemophilus influenza,candida tropicalis and herpes viruses .

22. Diagnosis of dengue Laboratory diagnosis is not necessary for clinical management of dengue . In first 5 days of fever , tests that can be done are RT PCR , NS1 antigen . After 5 days of fever , dengue IgM becomes positive . In a primary infection , viremia develops from 1-2 days before the onset of fever until 4-5 days after . The advantage of doing a PCR test is that all 4 serotypes can be identified and the test is highly sensitive and specific . Dengue NS1 antigen has nearly 100% specificity and sensitivity for primary dengue in the first 4days is 90%and for secondary dengue 70%

23. Anti-dengue IgM specific antibodies can be detected 3-6 days after fever onset . Low levels of IgM are still detectable around one to three months after fever . Dengue –specific IgG slowly increases becoming elevated at days 9-10 .low IgG levels persists for decades, an indication of a past dengue infection . In secondary infection , there is rapid and higher increase of anti-dengue specific IgG antibodies and slower and lower levels of IgM . High IgG levels remain for 30-40 days .

24. Tests for dianosis of dengue: Time of testing Tests that can be done 1 – 5 days of fever RT PCR NS 1 Antigen Acute sera for IgG and IgM Then collecting convalescent sera after 15 – 21 days After 5 days of fever IgM Convalescent sera after 15-21 days

25. Interpretation of NS 1 and dengue serology NS 1 antigen early IgM IgG INTERPRETATION Positive Negative Negative Early [ less than 4 days ] Negative/ positive Positive Negative primary Negative Positive Positive low titres Current / recent Negative / positive Positive Positive high titres secondary Negative Positive Positive high titres secondary Negative Negative Positive low titres Past infection

26. Treatment There is no specific antiviral therapy and treatment is only supportive , fever is treated with pcm [not more than 3-4 times in 24 hrs ] Do not give aspirin , ibuprofen or other non-steroidal anti-inflammatory agents [NSAIDs] or intramuscular injections,as these aggravate gastrities or bleeding . Fluid therapy – During the critical phase , careful watch should be kept for hypovolemia and shock . Prolonged capillary refill time and narrow pulse pressure may be early signs of hypovolemia . Hypotension is a late sign to develop .

27. Contd. Monitorin urine output and hematocrit can aid in decision regarding fluid therapy. Decreasing urine output and increasing hematocrit suggest fluid delpletion . The fluids to be given should be isotonic normal saline [0.9%NS] or Ringer’s lactate or Hartmann’s solution[mixture of NACL+KCL+CACL] and the rate of infusion should be adjusted as per severity of the leak . Too rapid intravenous infusion increases capillary hydrostatic pressure which increases the efflux of fluids over leaky capillaries . Hypotonic fluids should be avoided as they tend to leak even more in the third spaces .

28. Contd. Also remember that though the child has hypovolemia due to fluid losses , all the fluid is still in the body and there are no external losses as seen in diarrhea . Thus total amount of fluids should not be very high as during the recovery phase , all these extra fluids will be reabsorbed in the circulation and if very large amount of fluid has been iven initially ,then the chances of pulmonary edema increases . Urine output is a good measure to determine amount of fluids to be given . Urine output should be maintain at 0.5-1ml/kg/hr, the goal of fluid resuscitation is to maintain perfusion to vital organs during the critical phase which may be 48-72 hrs .

29. Contd. Hence , ensuring just adequate urine output and and good capillary refill time may be enough measures to achieve perfusion to vital organs even if blood pressure remains in the low normal range . Do not try to achieve blood pressure in the 50 th – 90 th centile as that will require more fluid resuscitation and problems during the resorptive phase . In patients in group b, fluids should be given starting at 5-7 ml/kg/hr for 1-2 hrs in patients with hypovolemia and can be increased or decreased depending upon the clinical response. Fluids can then be reduced to 3-5ml/kg/hr for 2-4 hrs , and then reduced to 2-3 ml/kg/hr or less according to the clinical response. Total duration of fluid therapy is 24-48 hours .

30. Contd. If the child does not seem to be improving and is developing sins of pulmonary edema then ventilation and inotropic support may be required . Platelet transfusion is not required if the child is not havin significant bleed . In case of significant bleed , both fresh frozen plasma and platelet transfusion should be given . Papaya leaf extract to increase the pletelet count : A study has reported membrane stabilizing properties of c. papaya leaf extracts in in vitro studies . The study found that c. papaya l. leaf extracts inhibited heat induced and hypotonicity induced hemolysis of erythrocytes obtained from both healthy individuals and individuals with dengue infection ; the effect was observed at the lower concentrations of the extracts .

31. Contd. Thus , the extract are likely to possess membrane stabilizing properties and protect blood cells against stress induced destruction . This property may be useful in patients with dengue infection where the leaf extract could possibly prevent platelet lysis . The authors postulate that this effect could be due to the presence of flavonoids and other phenolic compounds in the papaya leaves . However , no toxic effect has been noted with varied doses .

32. Dengue vaccine In late 2015 and early 2016 ,the first dengue vaccine , dengvaxia [CYD-TDV] by sanofi pasteur . Dengue vaccine is now available and recommended for use in individuals between 9 – 45 years of age staying in the endemic areas . CYD-TDV is a prophylactic , tetravalent , live attenuated viral vaccine .it has 4 attenuated recombinant viruse representing serotypes 1,2,3 and 4 . it is available in a single dosevial or multi –dose [5-dose] vial.it is a freeze-dried product to be reconstituted before injection with either a sterile solution of 0.4 %sodium chloride for the single dose presentation , or a sterile solution of 0.9% sodium chloride for 5-dose presentation . It is given in 3 doses subcutaneously at 6 months interval .

33. Contd. It helps prevent virologically – confirmed dengue illness of any serotype in about 60% of individuals . In those who get dengue , it helps to protect against severe forms of dengue and decreases the hospitalization rates of dengue . Vaccine efficacy is higher in individuals who are seropositive prior to the vaccination . An increased risk of hospitalized dengue is seen in children 2-5 yrs post this vaccine and hence is not used is

34. contraindication Individuals with a history of severe allergic reaction to previous dengue vaccine . Individuals with congenital or aquired immune deficiency . Pregnant or breast feeding women .