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CORRELATION OF HEPATIC DYSFUNCTION AND OUTCOME IN CHILDREN ADMITTED WITH FEVER WITH

THROMBOCYTOPENIA DISSERTATION SUBMITTED

In partial fulfillment of the requirement for the degree of (Branch VII) M. D. (PAEDIATRIC MEDICINE)

REGISTER NO. 201717352 of

THE TAMIL NADU DR. M. G. R MEDICAL UNIVERSITY CHENNAI- 600032

DEPARTMENT OF PAEDIATRIC MEDICINE TIRUNELVELI MEDICAL COLLEGE

TIRUNELVELI- 11 MAY 2020

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BONAFIDE CERTIFICATE

This is to certify that the dissertation entitled “CORRELATION OF HEPATIC DYSFUNCTION AND OUTCOME IN CHILDREN ADMITTED WITH FEVER WITH THROMBOCYTOPENIA” submitted byDr.J.EDWIN MICHAEL, to the Tamilnadu Dr. M.G.R Medical University, Chennai, in partial fulfillment of the requirement for the award of M.D. Degree Branch – VII (Pediatric Medicine) is a bonafide research work carried out by her under direct supervision & guidance.

Professor & Head of the Department,

Department of Pediatric Medicine Tirunelveli Medical College,

Tirunelveli.

Unit Chief,

Department of Pediatric Medicine Tirunelveli Medical College,

Tirunelveli.

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CERTIFICATE

This is to certify that the Dissertation “CORRELATION OF HEPATIC DYSFUNCTION AND OUTCOME IN CHILDREN ADMITTED WITH FEVER WITH THROMBOCYTOPENIA” presented herein by Dr.J.EDWIN MICHAEL is an original work done in the Department of Pediatric Medicine, Tirunelveli Medical College Hospital, Tirunelveli for the award of Degree of M.D. (Branch VII) Pediatric Medicine. Under my guidance and supervision during the academic period of 2016 -2019.

The DEAN

Tirunelveli Medical College, Tirunelveli - 627011.

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DECLARATION

I solemnly declare that the dissertation titled “CORRELATION OF HEPATIC DYSFUNCTION AND OUTCOME IN CHILDREN ADMITTED WITH FEVER WITH THROMBOCYTOPENIA” is done by me at Tirunelveli Medical College Hospital, Tirunelveli Under the guidance and supervision of Prof. Dr.T.R.R. Ananthy Shri M.D., the dissertation is submitted to The Tamilnadu Dr. M.G.R. Medical University towards the partial fulfilment of requirements for the award of M.D. Degree (Branch VII) in Pediatric Medicine.

Place: Tirunelveli Date:

Dr.J.EDWIN MICHAEL, Postgraduate Student, Register No. 201717352 M.D Pediatric Medicine, Department of Pediatric Medicine,

Tirunelveli Medical College Tirunelveli.

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ACKNOWLEDGEMENT

I wish to express my heartfelt gratitude to our Dean Prof. Dr. S. M.

Kannan M.S.,Mch., Tirunelveli medical college for allowing me to do the study in this institution.

I would like to express my humble thanks to our professor and Head of the Department Prof. Dr. C. Krishnamoorthy M.D., Department of paediatrics.

I express my sincere thanks to my renowned teacher and my guide Dr. T.

R. R. Ananthy shri M.D., Professor, Department of paediatrics, Tirunelveli Medical college for her guidance, Valuble suggestions and constant encouragement throughout the study.

I express my sincere thanks to my professors Dr. Baskar, Dr.

Padmanaban, Dr. Venkat subramanyan, For their constant support, encouragement and suggestions which helped me greatly to expedite this dissertation.

I am greatly obliged to Dr. Kavitha, Dr. Vanitha, Dr. Syed Ibrahim Shah, Dr. Naresh, Assistant professor, Department of paediatrics for their valuble suggestions in preparing this dissertation.

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CERTIFICATE – II

This is to certify that this dissertation work title “CORRELATION OF HEPATIC DYSFUNCTION AND OUTCOME IN CHILDREN ADMITTED WITH FEVER WITH THROMBOCYTOPENIA” of the candidate Dr.J.EDWIN MICHAEL, with registration Number 201717352 for the award of M.D. Degree in the branch of PAEDIATRIC MEDICINE (VII). I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion page and result shows 21 percentage of plagiarism in the dissertation.

Guide & Supervisor sign with Seal.

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CONTENTS

SL.NO TITLE PAGE NO

1. INTRODUCTION 1

2. REVIEW OF LITERATURE 2

3. STUDY JUSTIFICATION 36

4. AIM OF THE STUDY 37

5. MATERIALS AND METHODS 38

6. RESULTS 42

7. DISCUSSION 74

8. CONCLUSION 78

9. BIBLIOGRAPHY

10. ANNEXURE

PROFORMA CONSENT FORM MASTER CHART

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INTRODUCTION

The number of patients with fever with thrombocytopenia are increasing now a days. The increase in the number of cases is mainly due to increasing infections in the recent period. The patients who have severe thrombocytopenia, have more chances of bleeding manifestation, they have high mortality. Normal haemostasis and in thrombosis are maintained by platelets. Bleeding due to thrombocytopenia manifests as skin and mucous membrane bleeds. The dangerous event to bother in thrombocytopenia is intracranial haemorrhage. The most common causes of thrombocytopenia are dengue fever, chickugunya, and scrub typhus, leptospirosis, malaria and typhoid.

The most common case seen during winter season in OPD is fever with thrombocytopenia. Some of the patients with fever with thrombocytopenia develops multiorgan dysfunction, these patients are the candidates for ICU admission. They have high morbidity and mortality

The most common organ involved in cases of fever with thrombocytopenia is liver. This study was undertaken to evaluate the prognostic value of liver function test in determining the outcome in cases admitted with fever with thrombocytopenia.

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REVIEW OF LITERATURE

FEVER WITH THROMBOCYTOPENIA

The platelets normally present in the circulation for 7-10 days, most of the platelets are seen in circulation other are seen in spleen. It is estimated that normal platelet count is 80,000 to 4,50,000 in the first week of life. Then the platelet count increases to 150,000 to 400,000/mm3. So the thrombocytopenia can be defined as <80,000 cells/mm3 in first week of life, after first week of life thrombocytopenia is defined as platelets <150,000/mm3. Thrombocytopenia can occur due several reasons. Some infections have effect on the general hematopoiesis and having its effects more on platelets. Many infections cause immune mediated destruction of platelets (e.g., Rubella, EBV infection, Hepatitis B and C , Cytomegaloviurs, and HIV infection) and subacute bacterial infections(e.g.,Syphilis, leptospirosis, and Endocarditis). Some viral infection produce autoantibodies, these autoantibodies produce immune mediated destruction of platelets. ITP presents in a healthy child with mucous membrane bleed and skin bleed due to profound thrombocytopenia. Many bacterial and viral infections cause disseminated intravascular coagulation due to profound thrombocytopenia. Infections caused by Plasmodium, Anaplasma and

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Ehrlichia, Ricketsiae and commonly lead to thrombocytopenia. Shiga like toxin of E.coli and neuraminidase enzyme of pneumococci cause microangiopathic thrombosis and thrombocytopenia, usually the main cause of Hemolytic Uremic syndrome . Mild thrombocytopenia of platelet count beteen 80,0001,50,000/mm3 is seen in some systemic viral illness which is due to bone marrow suppression and destruction of platelets in the peripheral circulation.

Causes of Thrombocytopenia in Children

Decreased Production

Damaged, suppressed, or refractory marrow (infection, drugs, chemicals, radiation)

Replaced marrow (malignant disease, myelofibrosis) Congenital, hereditary disorders

Ineffective thrombocytopoiesis (cobalamin, folate deficiency;

dysplastic hematopoiesis) Aplastic anemia

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Abnormal Distribution

Hypersplenism (congestive or infiltrative) Immune-Mediated Destruction

Idiopathic thrombocytopenic purpura

Drugs (sulfa, ampicillin, rifampin, quinine, and multiple nonantimicrobial agents)

Malignant diseases Vaccines

Infection ( Subacute endocarditis, Hepatitis A and B, Viral infections, Cytomegalo virus, congenital syphilis,

toxoplasmosis, , Ebstein bar virus) Autoimmune diseases

Nonimmune Destruction

Viral, Rickettsial, fungal infection Hemolytic uremic syndrome

Disseminated intravascular coagulation

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Septicemia

Organ transplant rejection

Cyanotic congenital heart disease Bacterial toxin mediated syndromes Malaria

Pseudothrombocytopenia

When electronic cell analysers not count the platelets PATHOPHYSIOLOGY:

Thrombocytopenia usually results from 4 processes.

1. Artifactual thrombocytopenia 2. Abnormal distribution of platelets 3. Deficient platelet production 4. Accelerated destruction

A single platelet count that is lower than normal should always be

confirmed by a second count. Thrombocytopenia should also be confirmed by the examination of blood film. The electronic particle counters that has been now widely employed gives accurate results.

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PATHOPHYSIOLOGIC CLASSIFICATION OF

THROMBOCYTOPENIA

A. Artifactual Thrombocytopenia B. Increased platelet destruction

i) Immunologic process ii) Nonimmunologic process C. Decreased platelet production

D. Abnormal platelet pooling.a ETIOLOGY:

The infections which cause Fever with thrombocytopenia which is common in india are

1. Denguea 2. Malaria a 3. Enteric fever a 4. Sepsis a

5. Leptospirosis a 6. Scrub typhus a

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DENGUE

Dengue is most important arthropod borne disease. It is said that 3 billion people live in the areas which are at risk of contracting dengue. It is estimated that 300 million infections and 20,000 deaths occur every year. Dengue viruses are of 4 types, DENV-1,DENV-2, DENV-3, and DENV-4; Aedes mosquitoes are mainly responsible for human to human transmission, the main species responsible are Ae. aegypti and Ae.

albopictus. One serotype of the virus provide immunity to that species only. Dengue is prevalent in tropical areas of all continents. From 1980 Latin America and Caribbean responsible for major outbreaks. In US dengue out breaks has occurred in Florida, Texas and Hawali.

The incubation period of dengue usually lasts for 4 to 10 days.

Many infections are usually asymptomatic or it can cause mild illness.

The old classification of dengue are: dengue shock syndrome, dengue haemorrhagic fever, and classical dengue fever. Recently WHO classifies dengue into three major categories : Severe dengue, Dengue with warning signs and Dengue without warning signs. The warning signs in dengue consists of active mucosal bleeding, change in mental status, Fluid accumulation, intense abdominal pain, Persistent vomiting, Hepatomegaly and progressive increase in haematocrit. If the patients

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present with any one of the following symptoms then the patient is considered to be in severe dengue. The symptoms are Shock/Respiratory distress due to plasma leakage, Clinically important bleeding, severe organ impairment. Shock is mainly due to uncontrolled release of cytokines otherwise called cytokine tsunami. If the case is not managed properly, the chance of case fatality is very high. Severe dengue can also occur following a primary dengue virus infection, but more commonly it occurs following a secondary infection. Dengue virus rarely infects liver, Myocardium and CNS resulting in hepatitis, Myocarditis and encephalitis. According to WHO, there are three clinical phases of dengue, acute phase, critical phase and recovery phase.

In the beginning of acute phase there is fever, headache and retro orbital pain that usually which is usually accompanied by maculopapular rash, joint pain, and a body pain. The other manifestation of acute phase are thrombocytopenia, leukopenia, conjunctival injection, vomiting, and anorexia. Positive tourniquet test (when BP cuff is inflated appearance of petechiae in a 2.5 cm square patch of skin) is a main feature of dengue fever, and the common haemorrhagic manifestations are epistaxis and gum bleeding. It is very important to distinguish dengue fever from other febrile illness. In a report from one endemic area, the retro orbital pain

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correlates with laboratory confirmation of dengue fever, appearance of rash correlates with dengue in children older than 9 years.

Table 1. Medical complications seen in the febrile, critical and recovery phases of dengue

1

Febile phase

dehydration, Neurololgical disturbances and febrile seizures due to high fever in children

2

critical phase

ogan impariment shock from plasma leakage, severe hemorrhage

3

Recovery phase

Excessive iv fluid therap leads to hypervolaemia and acte pulmonary oedema

Course of illness: The febrile phase lasts for 2-7 days. During this period patient has high level of virus in their blood. The critical phase lasts for 3-5 days. During this period patient went for shock due to plasma leakage, Organ impairment, Fall in platelets, Rise in haematocrits. The recovery phase consists of reabsorption of already leaked fluid which sometimes leads to fluid overload, rise in platelets, Fall in haematocrit, rise in IgM titres. The rule of 20 in dengue consists of Rise in haematocrit >20%, Increase in pulse rate by 20bmp, Fall in blood pressure characterised by narrow pulse pressure <20mmHg,

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Presence of petechiae >20 in square patch of skin followed by inflation of BP cuff.

When thrombocytopenia occurs in children less than 10 years, it may be predictive of dengue. When leukopenia occurs in children older than 20 years, it may be predictive of dengue When defervesence occurs the critical phase usually begins. It lasts from 2-7 days from the beginning of the illness . Many patients with dengue fever got improved after this phase, sometimes there may be a biphasic fever. Few patients exhibit manifestation of severe dengue such as rising haematocrit, progressive leukopenia and thrombocytopenia. The most common warning signs of severe dengue include increasing haematocrit, severe mucosal bleeding , extravascular fluid accumulation, persistent vomiting, lethargy, restlessness, hepatomegaly, and serial decreasing platelet count. Ascites is shown by x-ray or ultrasound abdomen. The consequences of plasma leakage are shock, disseminated intravascular coagulation and narrow pulse pressure. Some cases have severe haemorrhage/critical organ dysfunction occurs without plasma leakage . When the case is detected early and appropriate fluid management is initiated the case fatality rate can be reduced to 1%. When the critical phase is managed properly, the phase resolves within 2 days which is followed by recovery phase. The recovery phase is marked by

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reabsorption of extravascular fluid in the following 2 days . The manifestations of recovery phase are bradycardia, pruritus and erythematous rash.

The Criteria to transfer to intensive care unit are

1. When the patient needs respiratory support or patient needs inotropes

2. When respiratory distress occurs due to plasma leakage 3. When shock does not responds to conventional mode of

treatment

4. When life threatening bleeding occurs

5. When there is presence of organ failure(Liver failure, myocarditis, Encephalitis)

When the pulse pressure is < 20mm Hg, or if the pulse is rapid and weak and at least two signs of poor capillary perfusion are present (cold limbs/

delayed capillary refill >2 seconds/mottled skin); it is the same for children and adults. A pulse pressure of ≤20 mmHg may indicate a more severe shock. Hypotension is usually seen in prolonged shock, it is usually a late sign of shock , it is mainly associated with major bleeding.

In presence of hypotension MAP should be monitored frequently. A MAP below 70 mmHg is considered hypotension. In children,

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tachycardia is the early sign of hypotension. Lower value of MAP below the minimum expected for a child’s age and sex may be associated with shock or lead to it.

When the fluid is administered excess pulmonary edema or congestive cardiac failure occurs. Patients without warning signs or those do not have indication to admit in the hospital can be managed as OPD. Aspirin and ibuprofen should not be given. Congenital DENV infection rarely occurs but the exact incidence is not available.

There are several factors associated with bleeding mainly due to imbalance between thrombosis and fibrinolysis. The major bleeding is associated with shock, When it combines with hypoxia and acidosis , it leads to multiorgan dysfunction. Massive bleeding may occasionally occur without prolonged shock. This kind of manifestation can occur due to the consequences of administration of acetylsalicylic acid (aspirin), nonsteroidal anti-inflammatory medications , or anticoagulants .

The manifestations of severe bleeding are

1. Fall in haematocrit after administration of fluid bolus 2. The shock which not responds to 40-60 ml of fluid

correction

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3. The presence of hypotension with low haematocrit

4. Worsening metabolic acidosis with normal systolic blood pressure

Vertical transmission in dengue: Maternal dengue infections during pregnancy is associated with increased risk of preterm and lowbirth weight. Neonates born to dengue positive mother may present as congenital dengue can have had clinical manifestations ranging from fever with thrombocytopenia to shock, severe hemorrhage, and pleural effusion. The main complications are severe bleeding during the delivery, especially when surgery is performed during critical phase. The fluid management is same for all pregnant and non pregnant individuals.

MALARIA

Four species of malarial parasites infect humans: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum is the most lethal and the most drug-resistant of them all. Of the human species, P. vivax was the most widely distributed and best adapted to survive in temperate climates. However, successful mosquito eradication programs in the U.S. and Europe essentially eliminated P. vivax from these regions. P. falciparumis he most prevalent species in sub-Saharan Africa. P. ovale occurs mainly in the western areas of sub-Saharan

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Africa.Recently, P. knowlesi, a species that usually infects macaques in Southeast Asia, has been found to be the cause of significant numbers of malaria cases in humans. Different stages of P. knowlesiclosely resemble P. malariae, thus making it difficult to diagnose by microscopy. In contrast to the usually benign infections with P.malariae, infection with P. knowlesi can be rapidly fatal, so it is important to consider this possibility when treating patients from this region, or who have traveled to this region, to reduce morbidity and mortality. The immunity against the infecting species of plasmodium mainly determines the clinical features of malaria. The persons who are not immune to malaria, who are not living in the endemic area, have symptomatic infection. The infections caused by P. faciparum is more severe when compared to infections caused by other species.

The hallmark feature of malaria is febrile paroxysm which usually lasts for 10 to 12 hours and consists of a period of severe rigors or chills, followed by high fever which is followed by profuse sweating.

Other s nonspecific complaints include arthralgia, malaise, myalgia, and headache. GI tract symptoms, including diarrhoea, vomiting, and abdominal pain, can also occur. People are asymptomatic between the episode but some patients experience prostration. A high index of suspicion for malaria should be considered in people who returns from

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endemic area. Despite low level of parasitemia non immune individuals presents with clinical symptoms. To exclude malaria some people recommends 3thick and thin smears. Plasmodium falciparum infections mainly leads to significant morbidity and mortality because of its cerebral effects. In high fever delirium and confusion occurs but the most dangerous thing is declining metal status. Symptoms cans rapidly progress to coma.

The CNS manifestation of malaria are symmetrical upper motor neuron dysfunction, meningismus and generalised seizures. The recovery of CNS function is rapid and there is lack of sequlae, all of them indicates it is a metabolic dysfunction. When there is clinical features of ICT, hypoglycaemia, prolonged coma, multiple seizures, the risk of neurological sequlae is high. When there is renal failiure and respiratory compromise in P.falciparam infection, the mortality rate is very high. Respiratory distress syndrome can occur and can be exacerbated by vigorous fluid resuscitation. Because of hypotension, there is hypoperfusion to kidneys, leading to acute tubular necrosis and thereby renal dysfunction. Non immune adults are more prone for this condition when compared to children. P.malaria infections are associated with Nephrotic syndrome and glomerulonephritis. The P.falciparum infection associated with hyperparasitemia in non immune individuals

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are associated with severe hypoglycaemia, metabolic acidosis and hypotension. They are due to parasitemia and cytokine disturbances.

When the patient has GI tract symptoms, gram negative septicaemia should be suspected.

Whenever there is hypoglycaemia it should be managed aggressively especially when patient is on quinine therapy. Whenever there is hyperparasitemia, anemia should be expected. The anemia is due to erythrocytic parasitosis, hyperspleenism leading to RBC destruction.

The thick and thin smear used to identify malarial parasite are used to diagnose malaria, they are mostly stained by Giemsa stain. The more sensitive technique is thick flim preparation, but the inexperienced examiners found it very difficult. Species differentiation usually is performed with a thin smear. For initial management, it is most important to identify the presence or absence of malaria parasites. If present, determining the presence of parasitemia is essential for managing the patient as patients with ≥5% infected RBCs have greater incidence of complications and require immediate intravenous therapy . P.falciparum is strongly suggested by RBC parasitemia >2%, RBCs containing multiple parasites, the exclusive presence of ring forms, and by lack of schizonts. P. falciparum is identified pathognomonically by the banana-shaped gametocyte form. Late trophozoite stages of P.

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falciparum rarely are seen except in the setting of high parasitemia. A quantitative assessment of the initial parasitemia also is useful in assessing response to therapy.

Generally, patients have a normocytic, hemolytic anemia with a variable white blood cell count and differential count.

Thrombocytopenia is present often. In patients with cerebral malaria, lumbar puncture shows increased opening pressure, CSF analysis shows lymphocytic pleocytosis and increased protein levels. In severe malaria electrolyte disturbances are more common, the manifestation are tissue hypoxia, renal failiure, vomiting and dehydration. Hypoglycemia is more commonly seen. During fever urine analysis shows proteinuria.. In urine analysis, there is hemoglobinuria in case of brisk haemolysis, proteinuria is seen in case of nephrotic syndrome. Some patients shows mild elevation in serum hepatic transaminases, indirect hyperbilirubinemia is seen, hepatic failure is uncommon. Patients with severe malaria should be given an intravenous loading dose of quinidine unless they have received >40 mg/kg of quinine in the preceding 48 hours or if they have received mefloquine within the preceding 12 hours.

Consultation with a cardiologist and a physician with experience treating malaria is advised when treating patients with malaria using quinidine.

Electrocardiogram should be performed prior to initiation of quinidine

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therapy to determine baseline QTc interval. During administration of quinidine, monitoring of blood pressure (for hypotension) and continuous cardiac monitoring (for widening of the QRS complex and/or lengthening of the QTc interval) are required, and blood glucose should be evaluated (for hypoglycaemia) periodically.

Cardiac complications, if severe, may warrant temporary discontinuation of the drug or slowing of the intravenous infusion.

Exchange transfusion should be considered strongly if the initial parasitemia is >10% or if altered mental status, acute respiratory distress syndrome (ARDS), or renal complications are present. The percentage of infected RBCs should be monitored to assess response to therapy.

Exchange transfusion should be continued until the parasitemia is <1%

(usually requires replacement of 1 to 2 blood volumes). Intravenous quinidine administration should not be delayed for an exchange transfusion and can be given concurrently throughout the exchange transfusion. Oral chloroquine can be used in individuals with uncomplicated malaria due to P. falciparum if the patient is able to take oral medication. Individuals with P. falciparum malaria acquired in all other geographic areas should be treated with artemether-lumefantrine, atovaquone-proguanil, or with oral quinine sulfate plus either tetracycline, doxycycline, or clindamycin, depending on the age of the

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patient, because of the high risk of chloroquine resistance. Artemether- lumefantrine is a newer antimalarial agent that is highly malariacidal and results in rapid parasite clearance. For patients with malaria acquired in SoutheastAsia, treatment with quinine should be continued for 7 days (instead of 3 to 7 days) because of evidence of declining efficacy.

Doxycycline, tetracycline, or clindamycin should not be used lone for malaria therapy because of the delayed onset (48 hours) of action of these drugs.

SCRUB TYPHUS:

Scrub typhus is caused by Orientia tsutsugamushi,, transmitted by larval mites. It also infects macrophages and cardiac myocytes.

PATHOGENESIS

The Vascular endothelial cells are initially affected, which leads to disseminated vasculitic and perivascular inflammation. Immune mediated inflammation follows the infection, both of them contributes to significant vascular leakage. End organ injury is the net result of vascular compromise, The end organ injury is mostly seen in brain and lungs. Most vasculotropic rickettsioses show these kind of manifestations.

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CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS

The signs and symptoms are from mild to severe. In most cases fever presents for 9-11 days. The common signs are spleenomegally, hepatomegaly, and local/generalised lymphadenopathy. Most common GI manifestations are diarrhoea, vomiting, and abdominal pain, also can occur. The most common findings are painless eschar at the site of chigger bite in 5-70% cases and the next common manifestation is maculopapular rash. Some cases show Hemophagocytic lymphohistiocytosis . In CBC total count and platelet count are mostly within normal ranges but thrombocytopenia seen in 25-35%. Some patients show increase in total counts.

DIAGNOSIS

Serological tests confirms the diagnosis of scrub typhus. The commonly used serological tests are indirect fluorescent antibody or immunoperoxidase assays. Polymerase chain reaction tests are not producing promising results now a days, and these diagnostic methods are not widely available also.

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TREATMENT AND SUPPORTIVE CARE

The drug used in the treatment of scrub typhus is doxycycline(4 mg/kg/day PO or IV BD maximum dose is 200 mg/day). The next drug most commonly used are tetracycline (25-50 mg/kg/day qid ) or chloramphenicol (50-100 mg/kg/day IV qid; maximum: 4 g/24 hr). The response to doxycycline or chloramphenicol is dramatic usually within 1-2 days. The next drug commonly used are Azithromycin and Rifampicin.

SEPSIS

Suspected or proven infections otherwise called SIRS. E.coli and Group b streptococcus are most common cause of sepsis in neonatal period.

Other organisms causing sepsis are Streptococcus pneumoniae, Haemophilus influenza, Staphylococcus aureus ,Listeria monocytogenes, and Enterococci. Sepsis caused by S. aureus and Streptococcus pyogenes, leads to toxic shock syndrome. The infections caused by salmonella and rickettsiae can lead to sepsis (e.g., Rocky Mountain spotted fever). Sepsis can also caused by malaria and dengue fever.

Candida species, S. aureus, gram-negative bacilli,and Coaglase negative staphylococci cause sepsis in children with central venous catheter.

These kind of organisms commonly cause sepsis related to central lines.

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The multidrug organisms causing sepsis is gradually increasing (extended spectrum β-lactamase [ESBL] the strains, Carbapenamase resistant organisms) and Vancomycin resistant Enterococci. S.

pneumoniae and Neisseriameningitidis cause sepsis in infants beyond neonatal period. Haemophilus influenzaetype b (Hib) cause sepsis in the incompletely vaccinated children.

Pathophysiology

Host defense mechanism get activated once the microbe enters the intravascular compartment. In healthy children transient bacteraemia do not produce any symptoms. Depending on the therapeutic intervention, the virulence of the pathogen and number of pathogens in the blood, and the age and immunocompetence of the patient, the host's systemic inflammatory response gets stimulated and ultimately lead to successful eradication of the microbe. Although SIRS is mainly caused by infection , a number of other entities, including pancreatitis, burns, neoplasm, ARDS, and trauma, also are recognized causes. In combination with bacterial toxins the imbalance exists between pro inflammatory and anti inflammatory cytokines responsible for pathogenesis of sepsis. The activation of innate immune response is responsible for the development of severe sepsis. This severe sepsis is caused by multiple pathogens.

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When triggered, the response leads to activation of coagulation, increased apoptosis, secretion of pro inflammatory and anti inflammatory cytokines and inhibition of fibrinolysis and activation and mobilization of leukocytes.

Due to activation of coagulation of system, generation of the production of thrombin causes its deposition in micro vessels and also increases the on-going inflammation by several mechanisms. The innate immune response can limit the local microbe dissemination, but large amount of those response leads to detrimental effects, they are macrovascular thrombosis, vasodilation, capillary injury and cardiac dysfunction. Inspite of early initiation of antibiotics and intensive care, this process leads to long term neurological morbidity, organ dysfunction, thrombotic complication and death. The clinical features of systemic inflammation are hepatic dysfunction, thrombocytosis, leucocytosis, tachycardia, tachypnea, widened pulse pressure, metabolic acidosis, flushed warm skin, abnormal temperature regulation . As the syndrome progresses, hepatic failure, Oliguric/renal failure, anemia, myocardial failure, decreased neurologic function, acute respiratory failure, multi organ failure, leukopenia, hypotension, and thrombocytopenia, can ultlimately lead to death.

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Clinical and Laboratory Findings

The most common findings are Fever, tachycardia and tachypnoea, even though they are insensitive and nonspecific. Other signs of sepsis are prolonged capillary refill time, poor feeding, pale or grey skin color, decreased tone, and decreased activity. Biochemical markers are more useful when compared to physiological findings, but there is no definite biochemical marker used for the identification of sepsis and to assess the response to therapy. In septic shock, because there is no biochemical test available , clinical findings are used in the dignosis. The use of clinical or biochemical marker are none, because very early treatment with antimicrobials and fluid resuscitation are useful in reducing both morbidity and mortality.

Laboratory Findings

Biomarkers that are commonly used include glucose , platelet count, erythrocyte sedimentation rate, Lactate, procalcitonin, base deficit, interleukin-6, C- Reactive protein, total peripheral white cell count , and organ-specific markers (e.g., coagulation, alanine aminotransferases, creatinine, Blood urea nitrogen).We can not say which test is sensitive or specific. The gold standard test is culture and sensitvity.

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Management

Antimicrobial Therapy

The causative organisms are targeted in empirical therapy. The penetration in to tissues and compartments, host immune status, community vs hospital acquisition, and child`s age should be considered while selecting a regimen. When the clinical signs and symptoms suggestive of staphylococcal infection. The treatment schedule should consists of vancomycin and MRSA is more frequently isolated in the specific geographical area. If the infections are caused by E.Coli/Klebsiella species, the organisms should be tested for ESBL production, for ESBL producing organisms carbapenum are drug of choice . Organisms resistant to carbapenum are increasing worldwide and have been reported mainly in paediatric populations. Multidrug- resistant pathogens should be identified at the nationa, regional, and local level.

Enteric Fever

Enteric fever (i.e., typhoid fever) classically is caused by Salmonella typhi and Salmonella paratyphi. Some other salmonella species can also mimic enteric fever. It is difficult to differentiate the enteric fever due to S.typhi and S.paratyphi. During the first week of illness, there is

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stepladder pattern of fever, which finally becomes unremitting and that stage is associated with systemic symptoms like abdominal pain, myalgia, malaise, lethargy, and headache.

In the second week of illness Hepatospleenomegally and rose spots are seen; headache is followed by drowsiness. Relative bradycardia is not routinely seen in children. In the fourth to fifth week intestinal haemorrhage and perforation occurs: fever begins to decrease in morning and generally the recurrence of fever decreases. Myocarditis, shock, meningitis, and pneumonia can complicate the course of illness.

The child have bloody diarrhoea and faecal leucocytes in the first few weeks, in some patients diarrhoea itself not begin till third week.

Sometimes the resolution does not occur till sixth week of illness.

Recurrences are common in the pre antibiotic era after a initial period of resolution. Death related to perforation, intestinal haemorrhage, or central nervous system involvement usually may not occur after the first week of illness. The manifestation of enteric fever in small children is less severe cause minimal fever and toxicity, it may be misdiagnosed as viral infection.

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DIAGNOSIS:

The investigation of choice for the diagnosis of enteric fever is blood culture and BSIs that can complicate other Salmonella infections. The volume of blood sampled in children and adults is an important determining factor in the sensitivity of blood culture. The most sensitive investigation is Bone marrow culture, because most children in endemic areas are treated as OPD , bone marrow culture is not possible. Bone marrow culture is very much useful treating a difficult fever case. Focal infections by salmonella species are common and are best diagnosed by taking cultures from the CSF, biopsy specimens, or aspirates of pus.

TREATMENT:

The duration of treatment in enteric fever is 10-14 days. The initial i.v.

drug of choice is Ceftrioxone, because the other agents are showing resistance. For susceptible strains, fluroquinolones, chloramphenicol, and trimethoprim-sulfamethoxazole have been used successfully, and ampicillin have been used successfully, even in children living in endemic areas. For the fever to settle in enteric fever, 36 hours of treatment is required, and fever can last upto 5 to 7 days, even when effective treatment is given. When the organisms are showing resistant to first line agents Azithromycin can be effective. Corticosteroids can be

(37)

added to the treatment regime when the patient presents wilth shock, coma, stupor, obtundation, or delirium in children with typhoid fever. In patients with intestinal perforation, surgery coupled with broad-spectrum antibiotics against anaerobic and gram negative enteric bacteria should be given. The intestinal perforation have 10-30% mortality.

LEPTOSPIROSIS

L. interrogans has a predisposition to infect the liver and kidney, although any tissue can be infected. The organism leads to hepatocellular dysfunction, which can lead to jaundice, mostly without producing necrosis. L. interrogans can cause renal tubular dysfunction leading to renal failure, and hemorrhagic vasculitis

Clinical manifestation

The incubation period ranges fom, 7 to14 days. There are 2 phases of the disease, Septicaemic phase and immune phase. The severity of the disease is classified into anicteric leptospirosis, icteric Weil syndrome and classic leptospirosis

(38)

Anicteric Leptospirosis

The clinical manifestations begins with viral-like illness marked by myalgia, headache and fever. It is followed by conjunctival effusion, anorexia, diarrhoea, vomiting, and abdominal pain. Rarely, circulatory collapse can also occur. During the prodromal phase, organisms are present in the CSF and blood stream. Patients exhibits variable range of severity, symptoms usually present for 4 to 7 days and resolve byitself.

The second phase is called immunologic phase of the illness, it usually starts after 1 to 3 days with low-grade fever. During which hepatomegaly, conjunctival suffusion, rash, myalgia, and headache are seen. Abdominal pain, vomiting, and vomiting are present. The headache is usually severe and it is associated with nuchal rigidity.

These kind of symptoms are mostly seen in aseptic meningitis. The presence of encephelits suggests the immune mediated nervous system disease.

Mononeuropathy or polyneuropathy of the cranial or peripheral nerves, radiculomyelitis, Gulliain-Barre syndrome. Interstitial nephritis is also commonly seen in this disease, the manifestations ranges from proteinuria, hematuria, pyuria and renal failure. Patients with right

(39)

upper quadrant abdominal pain can have a mass from acalculous cholecystitis and the gall bladder may have hydrops.

The disease can cause pulmonary symptoms. The rash seen in leptospirosis is usually mediated by immune system and nonspecific and it can be purpuric, maculopapular, petechial, urticarial, or macular. The immune and infectious phases of leptospirosis usually relived by 2 weeks .

Icteric Leptospirosis (Weil Syndrome)

This is the severe form of leptospirosis, also called Weil syndrome, it is caused by any serovar of L. interrogans, is indistinguishable in the early phase from the anicteric form of leptospirosis. The hallmarks of Weil syndrome are hemorrhage, azotemia, and jaundice– the symptoms starts at 4 to 6 days of illness, it can lasts upto second week of illness.

Fever can continuously last upto 2-3 weeks and the biphasic nature of the illness obscure the symptoms.

Although jaundice, hepatocellular injury, and hepatomegaly are commonly seen in Weil syndrome, necrosis and hepatic failure are rarely seen, and there is no residual hepatic damage in survivors. The renal impairment is very severe in weil syndrome , which occurs to a varying degree in both forms of leptospirosis. The toxicity mediated by bacteria

(40)

to the renal tubules is aggravated by shock and, in some instances by hemoglobinemia from haemolysis and leads to renal failure and acute tubular necrosis. Due to advances in supportive care, the number of patients survived from this disease increased dramatically. Renal dysfunction is mostly reversible in most but not all cases. Significant cardiac dysfunction is rarely seen, although many patients have nonspecific electrocardiographic abnormalities (such as first degree heart block) during the first week of the illness. In patients of weil syndrome cardiovascular collapse and CCF occurs.

LABORATORY FINDINGS AND DIAGNOSIS

The patients with leptospirosis have many laboratory abnormalities, which is based on the organ system involved, phase of illness and severity. Nothing is specific. During the early phase the patient shows neutrophilia and leukocytosis. Anemia is not present in anicteric leptospirosis but it is commonly seen in Weil syndrome. Serum concentrations of blood urea nitrogen, creatinine, and hepatic enzymes usually are elevated modestly (if present at all) in patients with anicteric leptospirosis and can be extremely elevated in Weil syndrome. During immune phase of illness half of the patients have clinical signs of meningitis with three-quarters have cerebrospinal fluid (CSF)

(41)

pleocytosis; in early disease neutrophils predominate but later mononuclear cells are more in number; protein concentration is normal or elevated; glucose concentration is usually normal. In the early phase of the disease, the urine usually contains protein, red and white blood cells, and cellular casts. The differential diagnosis of leptospirosis are very large. Most often, leptospirosis should be differentiated from viral illness and other causes of aseptic meningitis or meningoencephalitis.

The differential diagnosis of leptospirosis are Kawasaki disease and other causes of hepatitis, acute tubular necrosis, interstitial nephritis, and hepatorenal syndrome. Leptospirosis is diagnosed when L.interrogens are isolated from tissue or body fluids or when leptospiral antibodies are raised more than 4 fold in microscopic agglutination test and convalescent sera in a patient with a compatible clinical illness. A diagnosis of leptospirosis can be made when patient showing clinical features of leptospirosis and when antileptospiral antibodies of ≥1 : 100 by the microscopic agglutination test or a positive macroscopic agglutination test. Routine microscopy do not show L.interrogans ; organisms are visualised by modified silver stains on tissue or fluorescent antibody techniques on urine or tissue specimens. Rarely, Dark field microscopy shows L.interrogans when the organisms are more in number.

(42)

Culture

L. interrogans can be isolated from blood or CSF during the septicemic phase, and from urine during the immune phase of leptospirosis. Special media are required and include Tween 80-albumin, Fletcher, and Ellinghausen–McCullough–Johnson– Harris semisolid media; Tween 80-albumin is available commercially and may be superior. Solid media are less reliable for primary isolation of organisms but are useful for secondary isolation of L. interrogans from semisolid media contaminated with other organisms. Because of difficulty isolating L.

interrogans and inexperience in clinical microbiology laboratories, specimens for culture from suspected cases should be sent to the National Leptospirosis Laboratory at the Centres for Disease Control and Prevention. Polymerase chain reaction assays for L. interrogans are under development.

Serology

The macroscopic slide agglutination test is the most useful test for rapid screening. Twelve serotypes of killed L. interrogans (representing strains responsible for most infections in the U.S.) are included in this test. The microscopic agglutination test uses live organisms and is the

“gold standard” for detecting antibodies to L. interrogans. Generally,

(43)

agglutination tests are not positive until after the first week of infection;

antibody levels peak 3 to 4 weeks after the onset of symptoms and can persist for years, although concentrations may decline over time.

Demonstration of a 4-fold or greater rise in antibodies between acute and convalescent serum samples tested together is most definitive. Newer serologic tests may become useful in making the diagnosis of leptospirosis and include indirect hemagglutination tests, a passive microcapsule agglutination test, and enzyme immunoassays.

TREATMENT

Because leptospirosis occurs only sporadically, is generally selflimited, and cannot be confirmed early in the course of infection, clinical trials of efficacy of treatment are difficult to perform. Even when the treatment is started late, it is benefitial to the patiens. This positive effect of treatment is based on limited data from clinical trials, in vitro susceptibility of L.

interrogans,the efficacy of antimicrobial treatment of experimental leptospirosis in animal models (when treatment is begun early), and numerous case reports. An open-label randomized clinical trial conducted in Thailand found that for treatment of patients

with severe leptospirosis, penicillin G, cefotaxime, and doxycycline all were highly efficacious. Frequent occurrence of a Jarisch– Herxheimer

(44)

reaction also supports an effect of treatment. Treatment should begin as early in the course of the illness as possible. Aqueous penicillin G (200,000 to 250,000 U/kg/day in divided doses administered every 4 to 6 hours; maximal dose, 12 million U/day) is recommended for serious infection. Less seriously ill patients can be treated with doxycycline orally (2 mg/kg/day divided into 2 doses with maximum of 100 mg twice a day, only for children 8 years or older) or amoxicillin (50 mg/kg/day in divided doses three times a day; maximum of 500 mg per dose). Therapy is continued for 7 to 14 days.

(45)

STUDY JUSTIFICATION

Fever with thrombocytopenia is considered to be a leading cause of morbidity and mortality in children <12yrs. The causes of fever with thrombocytopenia ranges from deadly dengue fever to bacterial sepsis.

In tertiary care centre number of fever with thrombocytopenia cases getting admitted keeps on increasing for the past 5 years. The mortality and morbidity of those cases also remains high.

From 1970 it has been shown that, Liver is the most common organ involved in the cases of fever with thrombocytopenia. By studying liver function tests in these patients, we can establish the relation between severity and elevated transaminases. This study consists of all the children below 12 years admitted with fever with thrombocytopenia.

It aims to establish relation between hepatic dysfunction and outcome in cases admitted with fever with thrombocytopenia in a tertiary care hospital.

(46)

AIM OF THE STUDY

The study of Liver function test in predicting the outcome of children with fever with thrombocytopenia in children below 12 years admitted in Tirunelveli Medical College during the time period 2017 and 2018.

(47)

MATERIALS AND METHODS

STUDY CENTRE:

Our study was conducted at Department of Paediatrics, Tirunelveli medical college hospital.

STUDY GROUP:

All cases of fever with thrombocytopenia age less than 12 years and more than 1 month admitted during the a period of 2017 and 2018 in Department of paediatrics, Tirunelveli medical college.

STUDY DESIGN:

Prospective observational study STUDY DURATION:

December 2017 to December 2018 INCLUSION CRITERIA:

All the patients between 1 month to 12 years presenting with the complaints of fever(99.9 deg F) with thrombocytopenia(less than 1.5 L/dl)

(48)

EXCLUSION CRITERIA:

Patients positive for HbsAg, HAV, HCV

Patients with known case of liver disease/Cirrhosis a Patients with seizure disorder on drugs

Age<1month

Patient presents with thrombocytopenia without fever.

Diagnosed case of ITP

Patients with thrombocytopenia already diagnosed to have haematological malignancy/ on treatment with chemotherapy and immunosuppressive agent

Diagnosed case of platelet disorder/dysfunction

Patient on treatment with antiplatelet drugs /other drugs causing thrombocytopenia.

The children of those parents who did not give consent to undergo study was excluded.

(49)

METHODOLOGY:

Pre structured proforma was used to obtain information from the parents.

Following parameters at admission are studied to predict the outcome among the study group.

 Age

 Sex

 Locality

 Day of fever

 Warning signs

 Total Bilirubin

 Aspartate aminotransferase(AST)

 Alanine aminotransferase(ALT)

 Alkaline Phosphatse(ALP)

 Packed cell volme(PCV)

 Platelet count

 Coagulation profile

 Serum protein

 Albumin

(50)

After getting consent, detailed history, clinical details and investigations were collected and entered in the proforma. It includes age, sex and locality.

We got history regarding day of fever, warning symptoms including abdominal pain, vomiting , hematemesis, reduced urine output, passing black colour stools .

Clinical features consists of respiratory distress(tachypnea, retractions), abdominal distension, tender hepatomegaly, Jaundice are recorded at the time of admission.

Blood investigations including Platelet count, PCV, Live enzymes(

normal AST<40, ALT<32, ALP<420), serum albumin (normal 3), coagulation profile(normal PT 16, aPTT 36,INR<1.5) are noted at the time of admission .

Outcome was assessed as Dengue with warning signs, Dengue without warning signs, Fever with thrombocytopenia with warning signs, Fever with thrombocytopenia without warning signs.

(51)

RESULTS

Age

Table 1: Age Distribution of the sample

Mean 5.58

Std. Error of Mean .374

Median 4.50

Mode 2

Std. Deviation 3.742

Variance 14.004

Range 13

Minimum 1

Maximum 14

(52)

Figure 1: Age distribution of the sample

The mean age of the study sample was 5.58±3.742

(53)

Table 2 : Gender wise distribution of study participants

Gender Frequency Percent

Female 46 46.0

Male 54 54.0

Total 100 100.0

(54)

Figure 2: Distribution of Gender

In this study, male participants (54%) were higher than the female participants (46%).

(55)

Table 3: Distribution of the study sample based on the place of residence

Place of residence Frequency Percent

Rural 39 39.0

Urban 61 61.0

Total 100 100.0

(56)

Figure 3: Distribution of locality in the study population

In this study, it is found that 61% of the sample from urban area while others from rural area.

(57)

Table 4: Distribution of the sample population based on the level of

Total Bilirubin

Level of Total Bilirubin Frequency Percent

<1.3 95 95.0

>1.3 5 5.0

Total 100 100.0

(58)

Figure 4: Distribution of Total bilirubin in the study population

It is found that 95 % of the participants’ blood sample shows total bilirubin level less than 1.3 and only 5% shows total bilirubin level more than 1.3

(59)

Table 5: Distribution of the sample population based on the level of AST

AST level Frequency Percent

<40 62 62.0

>150 20 20.0

41-80 6 6.0

81-150 12 12.0

Total 100 100.0

(60)

Figure 5: Distribution of AST in study sample

It is found that 62 % of the participants’ blood sample shows the level of AST less than 40 and 20% of the participants’ blood sample shows the level of AST more than 150

0 10 20 30 40 50 60 70

<40 41-80 81-150 >150 62

6

12 Percentage 20

AST AST

(61)

Table 5: Distribution of the sample population based on the level of ALT

level of ALT Frequency Percent

<32 62 62.0

>132 18 18.0

33-66 11 11.0

67-132 9 9.0

Total 100 100.0

(62)

Figure 6: Distribution of ALT in study population

It is found that 62 % of the participants’ blood sample shows the level of ALT less than 32 and 18% of the participants’ blood sample shows the level of ALT more than 132

0 10 20 30 40 50 60 70

<32 33-66 67-132 >132

62

11 9

Percentage 18

ALT

ALT

(63)

Table 7: Distribution of the sample population based on the level of

ALP

level of ALP Frequency Percent

<420 97 97.0

>420 3 3.0

Total 100 100.0

(64)

Figure 7: Distribution of ALP in study population

It is found that 97 % of the participants’ blood sample shows the level of ALP less than 420 and only 3% shows ALP level more than 420

(65)

Table 8: Distribution of the sample population based on the level of PT APTT

level of PT

APTT

Frequency Percent

Increased 18 18.0

Normal 82 82.0

Total 100 100.0

(66)

Figure 8: Distribution of PT aPTT in study sample

It is found that only 18 % of the participants’ blood sample shows the increased level of PT APTT

18

82

PT APTT

Increased Normal

(67)

Table 9: Distribution of the sample population based on the level of PCV

Level of PCV Frequency Percent

<30 27 27.0

>40 23 23.0

30-35 24 24.0

35-40 26 26.0

Total 100 100.0

(68)

Figure 9: Distribution of PCV in study sample

Nearly one-fourth (26 %) of the participants’ blood sample shows the increased level of PCV (35 – 40)

21 22 23 24 25 26 27

<30 30-35 35-40 >40

27

24

26

Percentage 23

PCV

PCV

(69)

Table 10: Distribution of the sample population based on Platelet count

Level of Platelet Frequency Percent

<10K 6 6.0

10K-30K 9 9.0

30K-50K 14 14.0

50K - 1.5L 71 71.0

Total 100 100.0

(70)

Figure 10: Distribution of Platelet count in study sample

Nearly three-fourth 71% of the participants’ blood sample shows platelet count 50K - 1.5L

(71)

Table 11: Distribution of study participants based on the outcome

Outcome Frequency Percent

DWOWS 29 29.0

DWWS 25 25.0

FWTWOWS 30 30.0

FWTWWS 16 16.0

Total 100 100.0

(72)

Figure 11: Distribution of outcome in the study sample

This study observed that 29% of the study sample had Dengue without warning signs, 25% had dengue with warning signs, 30% had Fever with Thrombocytopenia without warning signs and 16% had Fever with Thrombocytopenia with warning signs

(73)

Table 12: Distribution of study sample based on the level of AST and Outcome

Level of AST Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

AST <40 28 0 30 4 62

45.2% 0.0% 48.4% 6.5% 100.0%

>150 0 16 0 4 20

0.0% 80.0% 0.0% 20.0% 100.0%

41-80 1 2 0 3 6

16.7% 33.3% 0.0% 50.0% 100.0%

81-150 0 7 0 5 12

0.0% 58.3% 0.0% 41.7% 100.0%

Fisher's Exact Test value = 97.566 P value = 0.000

Fisher's Exact test of significance was used to test the association between the level of AST and Outcome which is found to be statistically significant (P value = 0.000)

(74)

Table 13: Distribution of study sample based on the level of ALT and Outcome

Level of ALT Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

ALT <32 28 0 30 4 62

45.2% 0.0% 48.4% 6.5% 100.0%

>132 0 14 0 4 18

0.0% 77.8% 0.0% 22.2% 100.0%

33-66 1 3 0 7 11

9.1% 27.3% 0.0% 63.6% 100.0%

67-132 0 8 0 1 9

0.0% 88.9% 0.0% 11.1% 100.0%

Fisher's Exact Test value = 100.618 P value = 0.000

Fisher's Exact test of significance was used to test the association between the level of ALT and Outcome which is found to be statistically significant (P value = 0.000)

(75)

Table 14: Distribution of study sample based on the level of PCV and Outcome

Level of PCV

Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

PCV <30 0 0 26 1 27

0.0% 0.0% 96.3% 3.7% 100.0%

>40 0 19 0 4 23

0.0% 82.6% 0.0% 17.4% 100.0%

30-35 15 0 4 5 24

62.5% 0.0% 16.7% 20.8% 100.0%

35-40 14 6 0 6 26

53.8% 23.1% 0.0% 23.1% 100.0%

Fisher's Exact test value: 125.519 P Value: 0.000

Fisher's Exact test of significance was used to test the association between the level of PCV and Outcome which is found to be statistically significant (P value = 0.000)

(76)

Table 15: Distribution of study sample based on the gender and Outcome

Gender Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

Female 11 10 16 9 46

23.9% 21.7% 34.8% 19.6% 100.0%

Male 18 15 14 7 54

33.3% 27.8% 25.9% 13.0% 100.0%

Pearson Chi-Square value = 2.445 P value = 0.498

Pearson Chi-Square test of significance was used to test the association between Gender and Outcome which is found to be not statistically significant (P value = 0.498)

(77)

Table 16: Distribution of study sample based on the place of residence and Outcome

Place of residence

Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

Rural 11 8 12 8 39

28.2% 20.5% 30.8% 20.5% 100.0%

Urban 18 17 18 8 61

29.5% 27.9% 29.5% 13.1% 100.0%

Pearson Chi-Square value = 1.355 P value = 0.724

Pearson Chi-Square test of significance was used to test the association between the place of residence and Outcome which is found to be not statistically significant (P value= 0.724)

(78)

Table 17: Distribution of study sample based on the number of days of fever and Outcome

Number of days of fever

Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

Day of fever

<4 days

14 15 15 6 50

28.0% 30.0% 30.0% 12.0% 100.0%

>4 days

15 10 15 10 50

30.0% 20.0% 30.0% 20.0% 100.0%

Fisher's Exact Test value = 2.034 P value = 0.578

Fisher's Exact test of significance was used to test the association between the number of days of fever and Outcome which is found to be not statistically significant (P value = 0.578)

(79)

Table 18: Distribution of study sample based on the level of total Bilirubin and Outcome

level of total Bilirubin

Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

T.Bil <1.3 29 20 30 16 95

30.5% 21.1% 31.6% 16.8% 100.0%

>1.3 0 5 0 0 5

0.0% 100.0% 0.0% 0.0% 100.0%

Fisher's Exact Test value = 9.985 P value = 0.002

Fisher's Exact test of significance was used to test the association between the level of total bilirubin and the Outcome which is found to be statistically significant (P value = 0.002)

(80)

Table 19: Distribution of study sample based on the level of ALP and Outcome

level of ALP Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

ALP <420 29 22 30 16 97

29.9% 22.7% 30.9% 16.5% 100.0%

>420 0 3 0 0 3

0.0% 100.0% 0.0% 0.0% 100.0%

Fisher's Exact Test value = 5.448 P value= 0.018

Fisher's Exact test of significance was used to test the association between the level of ALP and the Outcome which is found to be statistically significant (P value = 0.018)

(81)

Table 20: Distribution of study sample based on the level of PT APTT and Outcome

level of PT APTT

Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

PT APTT Increased 0 15 0 3 18

0.0% 83.3% 0.0% 16.7% 100.0%

Normal 29 10 30 13 82

35.4% 12.2% 36.6% 15.9% 100.0%

Fisher's Exact Test value = 39.155 P value = 0.000

Fisher's Exact test of significance was used to test the association between the level of PT APTT and the Outcome which is found to be statistically significant (P value = 0.000)

(82)

Table 20: Distribution of study sample based on Platelet count and Outcome

Level of Platelet count

Outcome Total

DWOWS DWWS FWTWOWS FWTWWS

Platelet <10K 0 6 0 0 6

0.0% 100.0% 0.0% 0.0% 100.0%

10K- 30K

0 6 0 3 9

0.0% 66.7% 0.0% 33.3% 100.0%

30K- 50K

0 7 1 6 14

0.0% 50.0% 7.1% 42.9% 100.0%

50K - 1.5L

29 6 29 7 71

40.8% 8.5% 40.8% 9.9% 100.0%

Fisher's Exact test value: 56.680 P value: 0.000

Fisher's Exact test of significance was used to test the association between Platelet count and the Outcome which is found to be statistically significant (P value = 0.000)

(83)

DISCUSSION

Fever with thrombocytopenia is one of the most common cause for hospital admissions in recent years. It can lead deadly bleeding and can lead to death. The most common cause of these deaths are Dengue and bacterial sepsis. In most cases , liver is affected in variable severity , it ranges from asymptomatic rise of liver enzymes to acute fulminant hepatitis. There were only few studies which documents the hepatic involvement and degree of hepatic injury in fever with thrombocytopenia. The aim of my study is to identify the correlation between hepatic dysfunction and outcome in children admitted with fever with thrombocytopenia. It was conducted during the period between December 2017 to December 2018. All the children between 1 month to 12 years admitted with fever with thrombocytopenia in these period are studied prospectively.

In our study sex, locality of the patient didn’t show much significance with p values of about 0.498, 0.724 respectively.

(84)

Among 100 children in our study 41(41%) belongs to 1-5 years age group, 59(59%) belongs to 6-12 age group, it showed that most of the study population was in the age group of 6-12 years. 54(54%) of the study population were males and 46(46%) were females, indicating a slight female predominance.

Totally 100 cases were studied. Among them, 29% had Dengue without warning signs, 25% had Dengue with warning signs, 30% had fever with thrombocytopenia without warning signs, 16% had fever with thrombocytopenia with warning signs. Most of the children (30%) presented with thrombocytopenia without warning signs. The most common warning signs are abdominal pain and abdominal tenderness.

This is comparable to the study of Jayaratne SD, Atukorale V, Gomes L, et al(7).

The influence of platelets at initial presentation in outcome is significant with p value 0.00. 6 children had platelet count <10000 all of them develops dengue with warning signs. This is comparable to the study of Pires Neto Rda J, de Sá SL, Pinho SC, et al(15)

(85)

SGOT levels were measured at the time of admission. 62(62%) of patients had SGOT <40. 6(6%) had SGOT between 41-80. 12(12%) had SGOT between 81-150. 20(20%) had SGOT >150. This shows that most of the children with suspected dengue fever showed an elevation in SGOT levels. This is comparable to the study of Roy A, Sarkar D, Chakraborty S, et al(14).

SGPT levels are also measured at the time of admission. 62(62%) of patients had SGPT <32. 11(11%) of patients had SGPT 33-66.

9(9%) of patients had SGPT 67-132. 18(18%) of patients had SGPT

>132. This shows that SGPT levels are also raised along with SGOT.

This study is comparable to Fernando S, Wijewickrama A, Gomes L, et al(13).

Out of 100 study subjects final IgM Dengue ELISA test showed 54%(54) to be IgM positive and 46%(46) found to be IgM negative.

3%(3) of study subjects died.

Association between severity of thrombocytopenia and IgM dengue positivity was studied. A positive correlation was found between severity of thrombocytopenia and IgM dengue positivity with a p value 0.00. This is comparable to the study of

References

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