CARDIAC MANIFESTATIONS IN DENGUE FEVER

CARDIAC MANIFESTATIONS IN DENGUE FEVER

Dissertation submitted in partial fulfillment of the Requirement for the award of the Degree of

DOCTOR OF MEDICINE

BRANCH I - GENERAL MEDICINE MAY 2020

REG.NO: 201711111

THE TAMILNADU DR.M.G.R. MEDICAL

UNIVERSITY

CERTIFICATE FROM THE DEAN

This is to certify that the dissertation entitled “CARDIAC MANIFESTATIONS IN DENGUE FEVER” is the bonafide work of Dr. KRISHNANANTH. P in partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R Medical University, Chennai, for M.D General Medicine Branch I examination to be held in MAY 2020.

Dr. K. VANITHA., M.D., DCH., The Dean,

Govt Rajaji Hospital &

Madurai Medical College

Madurai.

CERTIFICATE FROM THE HEAD OF THE DEPARTMENT

This is to certify that the dissertation entitled “CARDIAC MANIFESTATIONS IN DENGUE FEVER” is the bonafide work of Dr. KRISHNANANTH. P in partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R Medical University, Chennai, for M.D General Medicine Branch I examination to be held in MAY 2020.

Dr. M. NATARAJAN., M.D., The Professor and HOD,

Department of General Medicine,

Government Rajaji Hospital,

Madurai Medical College,

Madurai .

CERTIFICATE FROM THE GUIDE

This is to certify that the dissertation entitled “CARDIAC MANIFESTATIONS IN DENGUE FEVER” is the bonafide work of Dr. KRISHNANANTH. P in partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R Medical University, Chennai, for M.D General Medicine Branch I examination to be held in MAY 2020.

Dr. DAVID PRADEEP KUMAR., M.D., DGM., MRCP, Professor and Chief,

Department of General Medicine, Government Rajaji Hospital &

Madurai Medical College,

Madurai .

DECLARATION

I, Dr. KRISHNANANTH. P. solemnly declare that, this dissertation

“CARDIAC MANIFESTATIONS IN DENGUE FEVER” is a bonafide record of work done by me at the Department of General Medicine, Govt. Rajaji Hospital, Madurai, under the guidance of Dr. DAVID PRADEEP KUMAR., MD., DGM., MRCP., Professor, Department of General Medicine, Madurai Medical College, Madurai.

This dissertation is submitted to The Tamil Nadu Dr. M.G.R Medical University, Chennai in partial fulfillment of the rules and regulations for the award of Doctor of Medicine (M.D.), General Medicine Branch-I examination to be held in MAY 2020.

Place: Madurai

Date: Dr. KRISHNANANTH. P

ACKNOWLEDGEMENT

I would like to thank Dr. K. VANITHA., M.D, DCH., The Dean, Madurai Medical College, for permitting me to utilize the facilities of Madurai Medical College and Government Rajaji Hospital for this dissertation.

I wish to express my respect and gratitude to our beloved teacher, Prof.

Dr. M. NATARAJAN., M.D., Professor & Head, Department of GeneralMedicine, for his valuable guidance and support during the study period and throughout the

course period.

I would like to express my deep sense of gratitude, and sincere thanks to

our beloved chief, Prof. Dr. DAVID PRADEEP KUMAR., M.D., DGM., MRCP., for his valuable suggestions, guidance and encouragement during the study period and throughout the course period.

I am greatly indebted to our beloved Professors Dr. G.BAGHYALAKSHMI., M.D., Dr. J. SANGUMANI., M.D., Dr. C. DHARMARAJ., M.D., DCH., Dr. S. C.

VIVEKANANTHAN M.D., Dr. K. SENTHIL., M.D., Dr. V.N. ALAGAVENKATESAN.,

M.D., for their valuable suggestions throughout the course of study.

I extend my sincere thanks, Prof. Dr. S.R. VEERAMANI., MD., D.M.,Professor &

Head, Department of Cardiology and Prof. Dr. S. BALASUBRAMANIAN., M.D., D.M., Professor, Department of Cardiology for their constant support, guidance, cooperation to complete this study.

I am extremely grateful to the Assistant Professors of Medicine from our

Unit Dr. N. RAGAVAN., M.D., Dr. K. RAM KUMAR., M.D., and Dr. M.J. SENTHIL KUMAR., M.D., for their valuable comments and suggestions.

I sincerely thank all the staffs of the Department of Medicine and the

Department of Cardiology, for their timely help rendered to me, whenever and wherever needed.

I wish to acknowledge all my postgraduate colleagues, friends and my family members who have directly or indirectly helped me to complete this work with great success.

I thank all the patients who participated in the study for their extreme patience and co-operation without whom this project would have been a distant dream.

Above all, I thank God Almighty, for the Kindness and benevolence showered on me.

CONTENTS

S.NO

CONTENTS

1

INTRODUCTION

10 2

AIM AND OBJECTIVES

13 3

REVIEW OF LITERATURE

14 4

MATERIALS AND METHODS

48 5

RESULTS AND OBSERVATIONS

54 6

DISCUSSION

82 7

LIMITATIONS

85 8

CONCLUSION

86

BIBLIOGRAPHY PROFORMA

ABBREVIATIONS MASTER CHART

ETHICAL COMMITTEE APPROVAL LETTER ANTI PLAGIARISM CERTIFICATE

CARDIAC MANIFESTATIONS IN

DENGUE FEVER

INTRODUCTION

Dengue fever caused by dengue virus is the most important disease transmitted by arthropod vector namely mosquito. The tropical countries of the world are the main regions where the Arboviruses cause serious health problems affecting the community. There are 4 serotypes of dengue virus (DENV 1, DENV 2, DENV 3, DENV 4). They belong to Arbovirus group and come under Flaviviridae family. Infection by these viruses can be transmitted from person to person by mosquitoes. The main vector for dengue virus is Aedes group of mosquitoes. Dengue is gaining importance because of its ability to produce massive epidemic outbreaks. There are evidences stating the endemic viral transmission in many tropical countries throughout the year.

The spectrum of dengue viral infection may vary greatly 1. Dengue fever (DF) - mild self-limiting illness.

2. Dengue hemorrhagic fever (DHF) – fever characterized by bleeding tendencies.

3. Dengue shock syndrome (DSS) – presenting with circulatory collapse.

Majority of the cases of dengue infection are usually mildly symptomatic and self-limiting just like any other minor viral illnesses. The major symptoms experienced by the patients are as nonspecific febrile state, generalized malaise and weakness, headache/ retro orbital pain and back pain. In a group of patients, along with the above symptoms bleeding manifestations like bleeding gums,

hematemesis, melaena, epistaxis occurs thereby causing dengue hemorrhagic fever (DHF). In a further narrowed down group there will be circulatory collapse thereby causing dengue shock syndrome (DSS).

According to the WHO guidelines, all patients come under 3 categories,

 Dengue without warning signs

 Dengue with warning signs

 Severe dengue

This helps in the syndromic management of the dengue epidemic deciding hospitalization and the mode of treatment. Laboratory findings in a case of dengue infection may show leukopenia, thrombocytopenia, elevated liver enzymes. But these observations are nonspecific for dengue infection. Early diagnosis of the illness is mandatory. The most specific method of confirmation of dengue infection is virus isolation. But detection of the antibodies of the class IgM/IgG is a readily available and easy method. The presence of IgM or high levels of IgG in the serum of a suspected patient helps in making a diagnosis.

Detection of NS1 antigen in the serum of a suspected patient helps to arrive at a diagnosis during the earlier days of the illness. The occurrence of bleeding manifestations is attributed to the quantitative and qualitative deficiency of platelets during the course of the illness. Along with that there is a state of increased capillary permeability and leakage of plasma into the extra-vascular

interleukin 8 (IL-8), and other factors. This results in further worsening of the existing capillary leak.

Dengue affecting the heart is postulated as rare. But there are references stating the occurrence of various abnormalities in the ECG recording of such patients. The main observations reported are atrioventricular conduction disturbances including junctional arrhythmia, atrioventricular block and supraventricular arrhythmia. Ventricular dysfunction is usually underdiagnosed in patients which may occur in patients with hemorrhagic fever especially during the acute phase. Although there is rarity of specific cardiac manifestations pertaining to dengue virus infection, there are various findings which have an underlying cardiac cause which may be superficially attributed to the existing shock. Myocarditis is common and is mostly under documented. The issue encountered is rapid decline in the clinical condition of the patient.

On date only a limited number of studies have reported the cardiac abnormalities in dengue virus infection. Hence this study was planned to analyze the cardiac manifestations in dengue virus infection in order to identify subclinical or latent manifestations involving the cardiovascular system.

AIMS AND OBJECTIVES

 The main aim of the study is to assess the prevalence of cardiac abnormalities in dengue affected patients in our hospital.

 The cardiac manifestations including abnormalities in cardiac rhythm (whether transient or long standing), conduction disturbances, arrhythmias, pericardial effusion and myocarditis are taken into account.

 To analyse the correlation between incidence of cardiac manifestations according to the disease severity and durations of illness

REVIEW OF LITERATURE

DENGUE – THE DISEASE

Dengue, otherwise called as ‘break bone fever’ is a fast-emerging viral disease. It has gained wide importance worldwide due to its impending pandemic- prone nature. It is the most important among the arthropod-borne viral diseases worldwide. Among the mosquito-borne viral infections which affect the human population Dengue is the most widely distributed. The disease is caused by 4 serotypes of dengue viruses namely DEN V1, DEN V2, DEN v3, DEN V4.

Among the Arbovirus group they come under the Flaviviridae family which is very much significant in causing diseases in human beings. The global burden of Dengue is mainly due to the geographical distribution, morbidity and mortality of the disease. Globally there is at least a fourfold increase in the disease burden for the past 3 decades. The transmission of the virus from person to person is by Aedes group of mosquitoes.

EPIDEMIOLOGY

The geographical locations which have favourable factors for the multiplication of mosquitoes in turn favours the spread of dengue virus serotypes.

This is the scenario in the tropical and subtropical region where there is an optimal environment for dengue virus transmission by Aedes mosquitoes. The endemic zones for Dengue fall between 30N and 40S which includes the tropical and subtropical regions. In such regions, the virus transmission occurs throughout the year. Additionally, there is a variable seasonal pattern with exaggerated transmission rates especially associated with increase in rainfall. If an area is endemic for more than one serotype of the virus simultaneously, infection with heterogenous types can occur. This results in frequent outbreaks due to sequential epidemics.

Due to the far and wide spread of Aedes mosquitoes in the tropics and subtropics along with an increase in international travel of infected humans, large areas of the world have become vulnerable to dengue virus infection. In dengue endemic regions the incidence of the disease is more common in children between the age of 2 – 15 years. The high severity of the disease is associated with secondary or reinfection, in primary infection in infants less than 1 year of age born to dengue immune mothers.

Dengue risk – A global problem

Dengue along with other arboviruses had a widespread distribution in the tropical and sub-tropical regions for more than 200 years. The likely postulate is that like yellow fever, dengue originated in Africa and spread to the other parts of the world after 1600s. The first described outbreak occurred in Philadelphia, USA in 1780. During the same period a similar outbreak was documented in Spain named ‘break bone fever’. After the Second World War, there was global expansion of the vector Aedes aegypti in Asian and then in America due to increase in trade. Due to subsequent international travel and rapid urbanization the incidence of dengue infection increased dramatically. Further outbreaks were reported in many tropical Asian countries including Vietnam, Singapore, Malaysia, Myanmar and China. This trend continued and at present around 70%

of the global burden of the disease occurs in Asian countries. In the 1997

epidemic in Cuba, it was confirmed that the role of secondary infection, in particular the sequence of DENV1 – DENV2 was a significant risk factor for the occurrence of DHF.

In 2006, the World Health Assembly highlighted dengue as an emerging illness. Since then, there is wide spread of dengue to newer areas. This sudden increase in the number of cases in a public health region which has not experienced the disease preventive measures leads to high morbidity and mortality. Similarly, in endemic areas due to vector expansion (e.g. Other Aedes species like A. albopictus), secondary infection and rapid spread, the morbidity and mortality has been high.

The national scenario in India is different. The first isolation of virus in India was in 1945. Very first evidence of dengue case report was from Vellore district in 1956. In 1963, Calcutta in West Bengal experienced the first outbreak of dengue hemorrhagic fever. Among the 36 states and union territories together, except Lakshadweep, all have reported cases in the last 20 years. The most severe outbreak was in 1996 in Delhi where 423 deaths were reported. In 2006 another outbreak took its toll f 184 deaths with the increase in the incidence of the disease in the last few years. Another epidemic in 2010 reported the highest number of cases in the country. The national guidelines were framed for the clinical management of Dengue fever/hemorrhagic fever/shock syndrome in 2007 and the

Seasonal trend of incidence of Dengue in India

Distribution of Dengue cases in India

Each year, during the month of July to November, which reflects the monsoon period when the country experiences major rainfall there is a rapid rise in the incidence of cases. The peak occurs just after the monsoon and there will be uneven distribution throughout the year reflecting a seasonal pattern. But most of the southern states and the western parts report perennial transmission of the disease.

THE VIRUS

The dengue virus is a member of the genus Flavivirus in Flaviviridae family. It is an RNA virus containing a single stranded RNA and is 30nm in diameter. The 4 serotypes (DENV 1-4) are distinct but closely related. They have antigenic cross-reactivity with each other and along with yellow fever, Japanese encephalitis and West Nile viruses. All evolved independently from ancestral sylvatic viruses. Exact origin remains uncertain. There are numerous genetic variations within each serotype. At present there are 5 genotypes in DENV1, 5 genotypes in DENV2, 4 in DENV3 and 4 in DENV4. Certain subtypes differ in virulence and in their ability to cause severe disease.

Electron microscopic view of Dengue virus

TRANSMISSION

Dengue virus is transmitted from person to person by different species of Aedes mosquito. It is otherwise called as the ‘Tiger mosquito’.

Aedes aegypti – the major vector

There are 2 cycles:

1. Endemic or epidemic cycle existing between humans and peri domestic mosquitoes

2. Sylvatic enzootic cycle between non-human primates and arboreal Aedes species.

Transmission cycle of Dengue virus

The most efficient vector mosquito is Aedes aegypti due to its domestic habits. The female mosquito bites during the daytime. After feeding, the mosquito can transmit the virus from one person to another, either immediately by a change of host or after an incubation period of 8-10 days, during which the virus multiplies in the salivary glands. Once infected the mosquito remains infected for life (30-45 days). Other capable vectors include Aedes albopictus, Aedes polynesiensis and Aedes scutellaris. Each has specific geographical distribution

and are usually a less efficient vector than Aedes aegypti. The epidemiological importance of transovarian transmission has not been established yet. The environmental factors of the geographical location in turn have an impact on the vectors.

PATHOGENESIS

The pathogenesis of severe dengue is due to the immune mediated effects.

This is confirmed by the strong association between the development of severe disease in secondary dengue and by the occurrence of complications during the decline of viremia. Based on the invitro studies in primates, Halstead proposed the ‘antibody-dependent immune mediated enhancement theory’ (ADE). This sequential dengue infection as a risk for the disease severity has been confirmed by numerous studies throughout the world. During the second infection with a different dengue serotype, pre-existing antibody from the first infection fails to neutralize and may instead enhance viral uptake and replication in mononuclear cells. This results in high viral load causing severe dengue infection. Other factors contributing to the severity of the illness include virulent strain of the virus, host factors, extremes of age and other comorbidities.

After an acute infection by a dengue serotype, there is an antibody response to all serotypes. There is a lasting immunity to the homologous serotype of the infecting strain. A heterotypic cross-reactive immunity to all serotypes has been reported for period of 2 months to 1 year following primary infection.

Immunopathogenesis of Dengue virus infection

The decreasing trend of cross-reactive antibody is implicated in the occurrence of severe dengue through ‘antibody dependent enhancement’. This occurs when the antibody acquired from a previous infection fails to neutralize the current antigenic serotype. Instead it accentuates viral uptake into Fcy receptor-bearing cells, particularly monocytes and macrophages. Further works identified that cross-reactive antibodies to the structural precursor membrane protein (prM) formed a major component of ADE and even though high titers of

In secondary dengue infection there is predominant expansion of T cells with low avidity for the current viral serotype and high avidity for the serotype of the previous infection. This skewing of the antigenic response to the previous dengue serotype is called as original antigenic sin. This delays the viral control and contribute to a higher peak viremia and is associated with very severe forms of the disease. There is activation of memory CD4+ and CD8+ T cells, which are sensitized during the previous infection, which leads to further rapid proliferation of these cells and release of proinflammatory cytokines, particularly TNF-α and IFN-γ. In severe dengue infection there is low cytotoxic potential of the T cells which fail to obtain early viral control. Presence of high cytokine-producing cells dominate the immune response with excessive pro-inflammatory cytokines which cause tissue damage and plasma leakage. Other markers linked to the disease severity include activation of IL-6 and soluble IL-2 receptor.

Complement system activation plays a pivotal role in the pathogenesis of dengue. Studies have shown that cross reactive antibodies can activate complement system through the endothelial cell surface. The release of C3a and C5a anaphylatoxins has been implicated with the onset of plasma leakage and progression to shock. High levels of the non-structural protein 1 (NS1) have been linked to the disease severity. A study in Thailand demonstrated that NS1 was able to activate complement which leads on to local and systemic generation of C5a anaphylatoxin and the terminal SC5b-9 complexes. The plasma levels of NS1 and SC5b-9 complexes correlate with the severity of the disease and these

complexes were detected in patients with severe dengue especially in the pleural fluid. In addition, NS1 may play an immune evasion role as it modulates the classical and lectin complement pathways by a reduced functional capacity of C4.

These studies suggest a possible role for complement in the pathogenesis of severe dengue, both through excessive local activation at endothelial surfaces contributing to vascular leakage and immune modulation leading to a higher viremia.

HISTOPATHOLOGY

In experimental studies in monkeys, inoculation of the virus reaches the lymph nodes in the particular region and then disseminates into the reticuloendothelial system, in which there is multiplication and from there it enters the blood stream. Skin lesions in non-fatal, uncomplicated dengue fever cases showed that the abnormality mainly occurred around the small blood vessels and consisted of endothelial swelling, perivascular edema and mononuclear cell infiltration. Petechial lesions showed extensive extravasation of blood without appreciable inflammatory reaction.

Significant changes are found in major organ systems:

 Vascular - vasodilatation, congestion, perivascular hemorrhage and arterial wall edema.

 Proliferation of reticuloendothelial cells along with accelerated phagocytic activity.

 The lymphoid tissues show high activity of the B lymphocyte system with active plasma cell proliferation.

 Liver shows focal necrosis of the hepatic and Kupffer cells, with formation of Councilman-like bodies.

 Cells of the spleen, thymus and lymph nodes, Kupffer cells and sinusoidal lining cells of liver and alveolar lining cells of the lung show the presence

of viral antigen.

PATHOPHYSIOLOGY

Pathophysiology leading to severity of dengue

The hallmarks of severe dengue are plasma leakage and abnormal hemostasis. Clinical evidence supporting plasma leakage includes a rapid rise in hematocrit, hypoproteinemia, pleural effusion and ascites and reduced plasma volume, leading to hemodynamic compromise and hypovolemic shock.

Microvascular leakage has been demonstrated using the noninvasive technique of strain gauge plethysmography. There are age-related changes in microvascular permeability, with children having higher filtration capacity than adults, which would explain why dengue shock syndrome is more common in childhood. The functional increase in vascular permeability is attributed to its transient nature.

The microvascular leak occurs at a time when the viral load is in declining phase and is associated with a more vigorous immune response.

Pathophysiology of Dengue virus infection

Disruption of the glycocalyx layer in the endothelium has been implicated, through immune-mediated mechanisms by the virus or the NS1 antigen adhering to the endothelial layer, thus facilitating immune complex formation and antibody-dependent complement activation causing the endothelial damage and microvascular leakage.

CLINICAL FEATURES

Dengue can present with a varied spectrum of features ranging from a simple febrile illness through a life-threatening shock syndrome. The severe form of the disease shows features of capillary leak.

Warnings of Dengue Fever – WHO guidelines

The natural course of the illness follows 3 phases.

 Febrile phase

 Critical phase

 Convalescent phase FEBRILE PHASE

The onset of fever is associated with a sudden rise in body temperature as high as 40C. This occurs after an incubation period of 5-8 days following a mosquito bite. The symptoms include headache, retro orbital pain, myalgia,

maculopapular type appears over the neck, chest and face and fades off in the later phase. Petechial rashes may appear over the extremities as localized clusters.

Maculopapular rash in Dengue patient

In patients with comorbid illnesses unusual hemorrhagic manifestations may occur. Liver may be enlarged but without jaundice. At times, dermal bleeding, epistaxis, gum bleed or gastrointestinal bleed may occur in the later days of febrile phase. Towards the end of this phase there will be leucopenia which reaches a nadir shortly before the temperature and platelet count drops which marks the beginning of the critical phase.

Skin impression in a patient with Dengue fever

CRITICAL PHASE

During this phase the plasma leakage goes up and high hemoconcentration occurs. There is high chance for the patients to develop hypotension. Plasma leakage and abnormalities in hemostasis may lead on to circulatory shock, aggravated bleeding, fluid collection in the pleural and peritoneal cavities. The skin may become cold and clammy and the pulse pressure becomes narrow. There is a drop in the platelet count and a rise in hematocrit. The clotting profile of the

correlation to the severity of the disease. This persists for 36-48 hours and is associated with high degree of morbidity and mortality. The WHO included the list of warning signs to diagnose the impending clinical deterioration during this phase, so that with aggressive management during these days the mortality of the disease could be reduced.

If not treated meticulously with fluid resuscitation, the patient can go for refractory shock with a thread pulse and hypotension. Prolonged shock in turn lead on to metabolic acidosis, severe bleeding and multiorgan failure leading to grave prognosis.

Clinical features of Dengue categorized based on the severity of illness and WHO criteria for each category

RECOVERY PHASE

In this phase the extravascular fluid lost due to capillary leak starts to be reabsorbed into the vascular compartment with the patient showing signs of

There will be return of appetite, diuresis and hemodynamic stability. WBC count will rise followed by increase in platelets. Hematocrit may drop due to the dilutional effect. So fluid therapy has to be optimized in this phase with close patient monitoring.

Phases of illness in Dengue and the corresponding time frame of manifestations

Dengue - high risk groups

Specific organ damage without shock can occur in many patients especially in endemic areas. These include hepatitis, encephalitis, myocarditis etc.

Expanded Dengue Syndrome

Our study gives emphasis on the cardiac manifestations. These

myocarditis. The case reports were low due to the slow tropism of the virus on the myocardial tissue. In patients receiving prompt treatment if there is no clinical improvement from the critical phase a suspicion of myocarditis can be considered. Although the sinus bradycardia occurring just at the end of the critical phase may seem to be a sign of recovery, this could also be due to the underlying myocarditis. There is high incidence of arrhythmias which might be due to the underlying myocarditis.

The severity of myocarditis may vary from asymptomatic myocarditis causing transient arrhythmias, to refractory cardiac failure due to left ventricular failure. There may be serious rhythm disturbances like complete heart block which can be overlooked during the course of the illness. This may prolong the recovery from the critical phase thereby requiring longer period of intensive monitoring and duration of hospital stay. The cardiac involvement can be picked by sustained ECG changes and elevation of cardiac enzymes. But confirmation could be made only by cardiac Magnetic Resonance Imaging (MRI). More than that the ultimate confirmation is made only by Endomyocardial Biopsy (EMB).

VIROLOGICAL DIAGNOSIS

The diagnosis is mostly based on the clinical signs and symptoms along with history of residence in or travel to endemic/epidemic areas. Diagnosis can be confirmed by serological tests, virus detection by molecular techniques or rarely by virus isolation. But the sensitivity and specificity of each test varies according to the stage of the illness. During the febrile phase of the illness, the most sensitive and specific test is to identify DENV RNA in the blood by RT- PCR technique. The use of this technique is limited because after defervescence there is steep fall in viremia. Serological tests for the detection of IgM and IgM anti dengue antibodies is the next choice. This can be done by ELISA method.

This helps to distinguish between primary and secondary dengue infection. But in the early stage of the illness this lacks sensitivity. IgG testing on the other hand lacks specificity due to cross reactivity to other arboviruses. Also, IgG testing requires paired samples.

The specific test to distinguish dengue from other Flavivirus infections is IgM antibody capture (MAC) – ELISA. This can be done with an acute blood sample with the sensitivity and specificity being 78% and 97% respectively.

There is a rapid increase in the IgG antibody levels in patients with secondary dengue. The demonstration of 4-fold increase in IgG levels in paired sera by hemagglutination inhibition testing can be used as a diagnostic tool for secondary

ELISA assay for dengue NS1 has been recently developed for rapid diagnosis. This has high sensitivity and specificity. The limitation is concurrent humoral immune response and late stage of the disease showing false results.

Rapid card tests are commercially available which are cheaper and provides instant diagnosis with false interpretation as the limitation.

Rapid testing kit for Dengue diagnosis

DIFFERENTIAL DIAGNOSIS

 Chikungunya fever

 Enteric fever

 Malaria

 Pharyngitis

 Tonsillitis

 Leptospirosis

 Influenza

 Scrub typhus

 Epidemic typhus

 Meningococcal infection

 Crimean-Congo hemorrhagic fever

 Ebola hemorrhagic fever

MANAGEMENT

The management starts with early clinical suspicion, diagnosis and treatment without waiting the laboratory diagnosis. This was made possible with the case definition given by WHO. Close monitoring is essential to pick up the warning signs and complications. The mainstay of treatment comprises of judicious fluid resuscitation. The delay in the initiation of treatment is attributed to the worse outcomes. In a case of Dengue, the patient’s outcome could not be predicted based on their initial presentation as there may be a rapid decline at any point of time until the recovery phase establishes. The warning signs arising should be picked up early and treated accordingly.

Initial assessment includes careful history recording and thorough physical examination. Basic investigations like complete blood count including hematocrit and platelets to be done. Further investigations include renal function tests, liver function tests, cardiac enzymes, lactate levels. Imaging studies required include X-ray chest PA view, ultrasonography of the abdomen and 2D echocardiography.

Coagulation profile is to be monitored. Serial monitoring of WBC count, platelets and hematocrit is mandatory to assess the phase of the illness.

Dengue Management - Initial Assessment

Prompt monitoring for identification of any new symptom is important.

This may include occurrence of rash or bleeding tendency or volume overload or shock. Antipyretics may be needed to reduce the temperature. NSAIDs and aspirin should be avoided for the fear of gastritis, gastrointestinal bleeding and Reye syndrome. Oral rehydration therapy is the mainstay of treatment for patients who are on OP basis as well as for IP patients.

Patients who develop warning signs should be hospitalized and should be started on intensive fluid management. Monitoring includes charting of pulse rate and volume, blood pressure, peripheral perfusion, hydration status and urine output. Platelet count and hematocrit should be monitored. The fluid requirement should be calculated based on these measurements. Intravenous fluids should be administered so as to maintain an average urine output of 0.5 ml/kg/hour. The suggested initial rate of fluid replenishment is 5ml/kg/hour which should be gradually decreased as per the clinical response. The use of isotonic fluids should be minimized only for the critical period as there is a risk of volume overload in the recovery phase.

Patients with evidence of severe plasma leakage in the form of hemodynamic compromise/ fluid accumulation/ respiratory distress/ severe bleeding or organ impairment require intensive care and immediate fluid resuscitation. WHO suggests the use of crystalloids at a rate of 5ml/kg/hour with intermittent boluses for patients with compensated shock. Monitoring of the clinical parameters of the patient should be done for every 15 minutes. Once there

is improvement, the rate of fluid infusion is to be gradually reduced. If there is clinical deterioration or a major bleeding is suspected, blood transfusion is to be initiated. Packed cell at a rate of 5-10ml/kg or whole blood at a rate of 10-20ml/kg is required. In severe dengue, there is no evidence supporting the use of platelet transfusion in order to correct severe thrombocytopenia. But in case of massive hemorrhages this may be considered as an option. Patients with hypotensive shock should be vigorously managed with crystalloids or colloids at a rate of 20ml/kg followed by boluses in order to maintain the vital signs stable. Oxygen therapy is mandatory for all shock cases.

The common complication in the treatment of severe dengue is volume overload secondary to fluid therapy. Increased capillary permeability along with the existing degree of myocardial impairment worsens the situation.

The lethal combination of cardiac dysfunction along with plasma loss makes it difficult in calculating the fluid requirement. Therefore, it is important to gradually decrease the fluid replacement by monitoring the vital signs and urine output in order to avoid excess infusion. The replacement of fluid should not be continued beyond 48 hours. If not, this gets reabsorbed in the recovery phase leading to pleural and pericardial effusion, ascites and pulmonary edema in turn leading to respiratory failure.

Step wise management of Dengue

There is no role for antivirals in dengue cases. Also, studies have proved that there is no advantage in using corticosteroids or IVIG in order to reduce the immune reactions.

There are no vaccines available globally for dengue prevention. In May 2019, USFDA approved the use of ‘Dengvaxia’ vaccine, manufactured by Sanofi Pasteur. This vaccine covers all 4 serotypes of dengue virus and is meant for people from the age of 9 years to 45 years. This vaccine though licensed and available in some countries is yet to gain credibility and popularity.

MATERIALS AND METHODS

The study was conducted at the Department of Medicine, Government Rajaji Hospital, Madurai. Our hospital is the major hub of tertiary care for the neighboring 8 districts. During the year 2017-18 when there was a large epidemic outbreak of Dengue fever in Madurai and Tamil Nadu. The timeline of the study was fixed from October 2017 to September 2017.

PLACE OF STUDY:

Department of Medicine, Government Rajaji Hospital and Madurai Medical College, Madurai

TYPE OF STUDY:

Descriptive study

PERIOD OF STUDY:

October 2017 to September 2017 (12 months)

FINANCIAL SUPPORT:

Nil

CONFLICT OF INTEREST:

Nil

SAMPLE SIZE:

200 patients

INCLUSION CRITERIA:

 Age greater than or equal to 18 years.

 Patients admitted for acute febrile illness and those who tested Positive for Dengue IgM antibodies.



EXCLUSION CRITERIA:

 Patients with previous history of any type of cardiac illness.

 Patients with admission ECG suggestive of CAD/MI

 Patients who are on drugs altering the rate and rhythm of the heart e.g. beta blockers, calcium channel blockers, xanthine derivatives, etc.,

 Patients with mixed infections, who had clinical symptoms and laboratory investigations favouring other infections like typhoid, scrub typhus or leptospira.

DATA COLLECTION:

During this Dengue epidemic in Madurai, patients who were admitted with acute febrile illness were taken into consideration. The patients were interviewed with a structured questionnaire for the signs and symptoms of dengue. Among these those who tested positive for Dengue IgM were analysed. Among them, patients who are more than or equal to 18 years of age were included in the study.

Patients who had previous history of heart disease were excluded from the study.

Those who had admission ECG changes suggestive of coronary artery disease were also excluded from the study. Patients who were already taking drugs which alter the rate/rhythm of the heart like betablockers, calcium channel blockers, xanthine derivatives etc., were excluded from the study. 200 consecutive patients who met with the criteria were chosen for the study purpose. Their profile was studied, and patients were grouped under 3 categories, Dengue fever, Dengue Hemorrhagic Fever with the presence of bleeding manifestations and Dengue Shock Syndrome with the presence of shock according to the severity.

Patients with Dengue IgM positivity were classified under 3 major groups based on WHO criteria, Dengue Fever – With/without warning signs, Dengue Hemorrhagic Fever and Dengue Shock Syndrome.

Patients included in the study were followed up from admission till discharge.

Age of the patient and the duration of the illness were taken into consideration.

They were watched for the symptoms of dengue fever, especially the presence of warning signs.

INVESTIGATIONS

 Complete blood count

 Serial Platelet count

 Dengue IgM Antibody

 Blood Glucose – Random

 Renal function test

 Liver function test

 Serial Electrocardiography

 2D Echocardiography

 Cardiac enzymes- CK, CK-MB

The patients were subjected to complete blood count, Dengue IgM, Serial Platelet count monitoring, ECG on admission and follow up on Day 2 and Day 5.

Those who had abnormalities in ECG were subjected to 2D Echocardiography and their levels of Creatinine Kinase Total and MB fraction were measured.

STATISTICAL ANALYSIS

The data collected from the selected patients were recorded in a Master Chart using Microsoft Excel. The analysis of the tabulated data was done by using SPSS 16 software tool. With the help of this software tool, percentages, means, standard deviations and 'p’ values were calculated. For consolidated data Chi Square test was used to test the significance of difference between variables.

Any 'p' value less than 0.05 was considered to denote significant relationship among the tested variables. The age wise and sex wise distribution of the illness were tabulated. The duration of illness in the patients were distributed as 0-2 days, 3-5 days, 6-8 days, 9-11 days and 12 & more days for the study purpose. The platelet count of the patients was tabulated with the class intervals namely,

<10000, 10000-50000, 50000 to 100000 and >100000.

The bleeding tendencies taken into consideration were gum bleeding, epistaxis, purpuric rashes in skin and mucous membranes, hemoptysis, hematemesis, melaena and hematuria. The presence or absence of these symptoms in these patients were recorded. The patients were assessed for the presence of shock by blood pressure monitoring, observations for changes in hematocrit value, presence of third space fluid loss and observations were tabulated. If patients had coexisting bleeding tendencies as well as shock, they were considered under the presence of shock category for statistical purposes.

The most remarkable finding of the ECG of these patients were tabulated on day 1 as well as day 5. ECG changes included sinus tachycardia, sinus bradycardia,

ST-T changes in the form of depression as well as elevation, T inversion, QT prolongation, bundle branch block, ventricular premature complexes, presence of atrioventricular block.

The patients who had abnormalities in ECG were subjected to 2D Echocardiography. Echocardiography findings interpreted included pericardial effusion mild or moderate, global hypokinesia, right ventricular dysfunction, left ventricular dysfunction, diastolic dysfunction and pericarditis. Further the levels of CK and CK-MB were measured in these patients. The correlation of various variables among these were tested by Chi Square test and ‘P’ values calculated.

‘P’ values less than 0.05 were considered clinically significant.

RESULTS AND OBSERVATIONS

In this study of 200 patients conducted at Government Rajaji Hospital, 127 were male and 73 were female. This corresponds to 63.5% of males against 36.5% of females. The incidence in our study is more among the males. This may be attributed to the lot of travel history among the men in the area of the study.

But it may not correlate with the geographical ratios as this study was institution based and not community based.

The lower limit of the age was taken as 18 years, and the oldest was 64 years of age. The mean age of the study group was 34.14. The standard deviation was ±11.82 years. Highest number of patients came under the class interval of 26 – 35 years age group (34.5%) followed by 18 – 25 years age group (25.5%).

The duration of illness of the presenting acute febrile illness is documented for each patient. They were tabulated with the intervals of 0-2 days, 3-5 days, through 12-14 days. The mean of the duration of the illness at the time of presentation in our study was 5.26 days. This indicates a delay in the time of presentation in the patients. Most patients were treated elsewhere for the first two days and then referred to our centre later as our hospital is a tertiary care centre.

Majority of the patients come under the duration of 3-5 days (40.5%) followed by 6-8 days (31%) duration.

The patients in the study group were grouped according to their platelet count at the time of admission. In that, majority of patients (39%) presented with

platelet counts more than 1 lakh cells per cubic mm. Out of 200, 17 patients presented with severe thrombocytopenia of less than 10000 cells per cubic mm.

During the course of the hospital stay the patients were monitored for the presence of bleeding manifestation like skin rashes, epistaxis, gum bleeding, hemoptysis, hematemesis, melaena, hematuria or bleeding PV. Among the 200 patients, 97 patients had bleeding manifestation. The most common form of bleeding occurred in the form of skin bleeding followed by gum bleeding followed by melaena. Most of these patients recovered with aggressive fluid management while a small group required transfusions.

Through the complete duration of illness, the incidence of shock in the study group was recorded. The incidence of shock in our study was 18.5% which is quite high.

Gender Distribution

MALE 63.5%

FEMALE 36.5%

MALE FEMALE

GENDER

DISTRIBUTION

Age Distribution

Age (in Years) No. of patients (n) Percentage (%)

15 - 25 51 25.5

26 - 35 69 34.5

36 - 45 41 20.5

46 - 55 27 13.5

56 - 65 12 6.0

Total 200 100.0

Mean 34.14 -

SD ±11.816 -

Age Distribution

51

69

41

27

12 25.5

34.5

20.5

13.5

6.0

15 - 25 26 - 35 36 - 45 46 - 55 56 - 65

No. of Patients Percentage

AGE DISTRIBUTION

Duration of illness at the time of presentation Duration of illness

(in days) No. of patients (n) Percentage (%)

0 - 2 31 15.5

3 - 5 81 40.5

6 - 8 62 31.0

9 - 11 17 8.5

12 - 14 9 4.5

Total 200 100%

Duration of Illness at the time of presentation

15.5

40.5

31.0

8.5

4.5

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0

0 - 2 3 - 5 6 - 8 9 - 11 12 - 14 PERCENTAGE

DURATION OF ILLNESS

Platelet Count on Day 1

< 10000, 8.5%

10000 - 50000, 24%

50000 - 100000, 28.5%

> 100000, 39%

< 10000 10000 - 50000

50000 - 100000 > 100000

PLATELET COUNT DAY 1

Platelet Count on Day 1 Platelet count

Day 1 No. of patients (n) Percentage (%)

< 10000 17 8.5

10000 - 50000 48 24.0

50000 - 100000 57 28.5

> 100000 78 39.0

Total 200 100.0

Presence of Bleeding

97 103

48.5 51.5

0 20 40 60 80 100 120

Yes No

No. of Patients Percentage

PRESENCE OF BLEEDING

Presence of Shock

18.5%

81.5% Yes

No PRESENCE OF SHOCK

On considering the presence of bleeding and shock the patients were grouped under 3 categories

1. Dengue Fever (DF)

2. Dengue Hemorrhagic Fever (DHF) 3. Dengue Shock Syndrome (DSS)

Patients without bleeding or shock were put under the category of Dengue Fever (DF). Out of 200, 66 patients (33%) neither had bleeding manifestations nor had circulatory shock and were categorized as Dengue Fever (DF). 97 out of 200 patients (48.5%) had some form of bleeding tendencies and were classified under Dengue Hemorrhagic Fever (DHF). 37 patients (18.5%) experienced circulatory shock and were classified as Dengue Shock Syndrome (DHF).

Clinical categories of dengue severity

Dengue Fever 33%

Dengue Hemorrhagic Fever

48.5%

Dengue Shock Syndrome

18.5%

Dengue Fever

Dengue Hemorrhagic Fever Dengue Shock Syndrome

DENGUE SEVERITY

The patients in the study group were subjected to 12 lead ECG recording at the time of admission and during, day 2 of admission and day 5 of admission and the findings were tabulated.

Majority of the patients had normal ECG recording, during admission. Out of 200 patients 143 had normal ECG on the day of admission and 176 had normal ECG on day 5 of hospital stay. 57 patients out of 200 (28.5%) had abnormal ECG on the day of admission. The major finding being Sinus Tachycardia (11.5%) followed by Sinus Bradycardia (6.5%). On day 5 of hospital stay, the positivity of ECG was reduced to 12% with only 24 patients showing ECG abnormalities.

Out of these 24 patients, 9 patients (4.5%) had Sinus Bradycardia and was the most common observation.

Comparison of ECG Findings in Dengue patients on Day 1 & Day 5 Electrocardiography Findings No. of Patients

ECG on Admission

No. of Patients ECG on Day ’5’

Normal ECG 143 176

Sinus Tachycardia 23 4

Sinus Bradycardia 13 9

ST-T Depression 4 2

ST Elevation 7 5

T- Inversion 3 2

Q-T Prolongation 1 -

RBBB 2 1

1^st Degree AV Block 1 -

VPCs 3 1

ECG Abnormalities on Day1 (TOTAL = 57)

1st Degree AV Block, 1

QT Prolongation, 1 RBBB, 2

Sinus Brady, 13

Sinus Tachy, 23 ST Depression, 4

ST Elevation, 7 T Inversion, 3

VPC, 3

1st Degree AV Block QT Prolongation

RBBB Sinus Brady

Sinus Tachy ST Depression

ECG ABNORMALITIES DAY 1 N= 57

ECG Abnormalities on Day 1

ECG Day 1 No. of Patients (n) Percentage (%)

1st Degree AV Block 1 0.5

QT Prolongation 1 0.5

RBBB 2 1.0

Sinus Brady 13 6.5

Sinus Tachy 23 11.5

ST Depression 4 2.0

ST Elevation 7 3.5

T Inversion 3 1.5

VPC 3 1.5

Normal 143 71.5

Total 200 100.0

The patients who had abnormal ECG were then subjected to 2D Echocardiography and their serum levels of Creatinine Kinase Total & MB Fraction were measures. Among th estudy population 31 patients had positive echocardiography findings. The commonest finding noted was mild pericardial effusion which was present in. 17 cases. Moderate pericardial effusion was found in 5 patients, 3 patients had left ventricular dysfunction, 2 patients had right ventricular dysfuntion, 2 had diastolic dysfunction, 1 patient showed global hypokinesia and 1 patient had pericarditis. CPK and CPK MB levels were elevated only in 14 patients among which 8 patients had significant rise of > 400 IU/l.

Echocardiography findings (Total = 31)

Diastolic Dysfunction, 2

Global Hypokinesia, 1

LV Dysfunction, 3

Mild Pericardial Effusion, 17 Moderate

Pericardial Effusion, 5 Pericarditis, 1

RV Dysfunction, 2

Diastolic Dysfunction Global Hypokinesia

LV Dysfunction Mild Pericardial Effusion

Moderate Pericardial Effusion Pericarditis RV Dysfunction

ECHOCARDIOGRAPHY FINDINGS N = 31

Echocardiography findings in Dengue patients

Echocardiography No. of Patients (n) Percentage (%)

Diastolic Dysfunction 2 1.0

Global Hypokinesia 1 0.5

LV Dysfunction 3 1.5

Mild Pericardial Effusion 17 8.5

Moderate Pericardial Effusion 5 2.5

Pericarditis 1 0.5

RV Dysfunction 2 1.0

Nil 169 84.5

Total 200 100.0

Statistical significance was tested against the age of the patient vs the ECG changes by Chi Square test. The p value was > 0.05 (0.596) and hence concluded that the age of the patient was not a statistically significant factor for the occurrence of abnormalities in ECG.

ECG Changes in various age intervals

P value > 0.05 – Not significant

0 5 10 15 20

18-25 Years 26-35 Years 36-45 Years 46-55 Years 56-65 Years

No of Patients

AGE vs ECG ABNORMALITIES

ECG Changes in various age intervals

P value > 0.05 – Not Significant

Age group 1st Degree AV Block QT Prolongation RBBB Sinus Bradycardia Sinus Tachycardia ST Depression ST Elevation T Inversion VPC SUB TOTAL Normal TOTAL

15 - 25 0 1 1 2 4 1 3 2 0 14 37 51

26 - 35 1 0 0 6 7 1 1 1 0 17 52 69

36 - 45 0 0 0 4 5 0 1 0 1 11 30 41

46 - 55 0 0 1 0 4 2 1 0 2 10 17 27

56 - 65 0 0 0 1 3 0 1 0 0 5 7 12

Total 1 1 2 13 23 4 7 3 3 57 143 200

Test of significance was utilized to assess the impact of duration of illness against the ECG findings. There was statistically significant correlation between the duration of illness and the ECG changes. The mean duration of illness in our study group at the time of admission was 5.26 days. This corresponds to the later stage of critical phase or early recovery phase which correlates to high incidence of cardiac manifestations.

Duration of Illness vs ECG abnormalities

P Value < 0.05 - SIGNIFICANT

0 10 20 30 40 50 60 70 80

0 to 2 Days 3 to 5 Days 6 to 8 Days 9 to 11 Days 12 to 14 Days

Abnormal ECG Normal ECG

DURATION OF ILLNESS vs ECG

ECG changes at various durations of illness

P Value < 0.05 - SIGNIFICANT

Duration of the Illness 1st Degree AV Block QT Prolongation RBBB Sinus Brady Sinus Tachy ST Depression ST Elevation T Inversion VPC SUB TOTAL Normal TOTAL

0 - 2 0 0 0 0 1 0 0 0 0 1 30 31

3 - 5 0 0 0 6 4 2 2 0 0 14 67 81

6 - 8 0 0 0 7 11 1 1 3 2 25 37 62

9 - 11 0 0 2 0 5 1 2 0 0 10 7 17

12 - 14 1 1 0 0 2 0 2 0 1 7 2 9

Total 1 1 2 13 23 4 7 3 3 57 143 200

Our study showed statistically significant correlation between the incidence of bleeding manifestations and cardia manifestations in the form of ECG changes. There is high incidence of ECG changes in patients having bleeding tendencies.

Presence of bleeding vs ECG changes

P Value < 0.05 – SIGNIFICANT

Presence of Bleeding 1st Degree AV Block QT Prolongation RBBB Sinus Bradycardia Sinus Tachycardia ST Depression ST Elevation T Inversion VPC SUB TOTAL Normal TOTAL

Yes 1 1 1 8 14 3 6 2 3 39 58 97

No 0 0 1 5 9 1 1 1 0 18 85 103

Total 1 1 2 13 23 4 7 3 3 57 143 200

Presence of bleeding vs ECG changes

P value < 0.05 – SIGNIFICANT

0 2 4 6 8 10 12 14

1st Degree AV Block QT Prolongation RBBB Sinus Brady Sinus Tachy ST Depression ST Elevation T Inversion VPC

1 1 1

8

14

3

6

2

3

0 0

1

5

9

1 1 1

0

Yes No

BLEEDING vs ECG CHANGES