Fever is also called as pyrexia derived from Greek word “pyretus” which means fire. Febrile is derived from Latin word Febris, meaning fever. By definition, Fever means rectal temperature of >38°C (100.4° F)1 or axillary temperature of > 37.5°C2. It is frequent medical sign that implies increase in temperature of the body to above normal level. Fever is a natural immune mechanism to combat a threat inside the body.

Fever is a symptom due to various illnesses. Usually Fever occurs as a response to infection or inflammation. However many other causes are possible, including drugs, poisons , cancer , heat exposure, injuries or abnormalities in the brain, or disease of the endocrine (hormonal or glandular) system.

Fever rarely occurs without other symptoms or signs. It is mostly accompanied by specific complaints. Most of the times it is related with thrombocytopenia in children. The normal platelet count is 1, 50,000 - 4, 50,000 cells/cumm3. Platelet count less than 1,50,000 cells/cumm3 is called as Thrombocytopenia. It results from either decreased production, increased sequestration or destruction of platelets. The causes for thrombocytopenia are varied from idiopathic, infections to malignancies. Patients with acute febrile illnesses in India are usually due to infections with or without associated thrombocytopenia. Infectious etiologies like malaria, dengue, typhoid, and leptospirosis are some common causes to be associated with fever and thrombocytopenia. If we can analyze the low platelet count as a sort of diagnostic marker of some common infections, we can narrow down the differential diagnosis. In recent years fever and thrombocytopenia is common clinical presentation in pediatric wards. Fever with associated thrombocytopenia causes significant morbidity in the form of bleeding manifestations, hemodynamic instability and sometimes leads to mortality. This causes increased anxiety among parents. Literature shows studies about fever with associated thrombocytopenia among adults but not much data exists among children. But some studies do exist on profile of individual disease like dengue, typhoid, and malaria with thrombocytopenia in children.

Hence this study was conducted to analyze the Etiological profile, Investigative Profile in preference to infective etiology and outcome among children admitted at our hospital.

AIMS AND OBJECTIVES

• To study the Etiological profile of Fever with Thrombocytopenia in hospitalized children in the

age group of 2 months to 12 years.

• To evaluate the investigative profile of Fever with
• To study the outcome of Fever with Thrombocytopenia and associated
• To study the prevalence of Fever with Thrombocytopenia in our hospital set-up.

This was a prospective-observational study conducted at the Department of Pediatrics, Government Medical College, Anantapur over a period of 18 months from January 2021 to June 2022, among children in the age group 2 months to 12 years. In this study all children admitted with history of fever with thrombocytopenia were included. Children with known ITP, diagnosed hematological malignancies or bone marrow disorders, children on anti- platelets drugs, chemotherapy, diagnosed- case of platelet disorder / dysfunction, Pseudo-thrombocytopenia, cirrhosis or chronic liver disease were excluded. Pseudo-thrombocytopenia 21 is an uncommon-phenomena due to Platelet agglutination. Due to clumping of platelets, automated counters report lower platelet-counts than actual as these devices cannot differentiate between- platelet clumps and individual cells. Children were recruited for the study,after informed written consent from parents or care givers was obtained .Age, gender and geographical location of these children were noted in the pretested proforma. Detailed history including the duration of fever, headache, myalgia, gastro intestinal symptoms, cutaneous or gastro intestinal or other bleeds like hematuria and epistaxis, breathing difficulty, seizures, edema, puffy face, oliguria and antibiotic exposure prior to hospitalization were taken. Following this, children were subjected for a detailed clinical examination. Clinical features at admission were recorded. The parameters included fever, heart rate, respiratory rate, blood pressure, capillary refill time, hepatomegaly, eschar, splenomegaly, lymphadenopathy, petechiae and altered sensorium. Tourniquet test 22 was done by inflating blood pressure cuff to the point midway between systolic, and diastolic BP for 5 minutes. The test is said to be positive if 10 or more than 10 petechiae were observed per square inch.

Following clinical examination, all children were subjected to the investigations as per the department protocol. The investigations included Complete blood count, peripheral smear study, urine albumin, blood urea, serum creatinine, liver enzymes and serum bilirubin, x-ray chest depending upon detailed examination. On suspicion of tropical infections MP smear, dengue IgM ELISA, scrub typhus IgM ELISA, Widal test, leptospirosis IgM were performed along with blood culture and urine culture. Children with suspected hematological malignancy underwent bone marrow examination. CSF study was not undertaken in cases with Platelet count <50,000. If viral encephalitis was a suspicion, CSF analysis was done after increase in Platelet count to >50,000 as per our department policy. Children in the study group were followed up till outcome and complications like shock, bleeding manifestations, hepatic failure, renal failure, respiratory distress, cardiac failure, pulmonary edema and multi organ failure were recorded. Platelet count and hematocrit were monitored frequently, once or twice in a day in the presence of complications like shock and bleeds in PICU. Platelet count were repeated on alternate days in hemodynamically stable children until it reached 1,00,000 cells/cumm. Need for any blood product transfusion was documented. Platelet transfusion was indicated if Platelet count is <25,000 cells/cumm with bleeding manifestations or <10,000 cells/cumm irrespective of bleeding manifestations.

Final diagnosis was arrived in these children based on clinical and / or laboratory features for the common pediatric infections and other conditions as shown in table no -1. Children with acute febrile illness but could not be placed in any of the common diagnosis either clinically or by investigations were labeled as undifferentiated fever for this study category. Outcome was defined as with or without complications, discharge or referral or death.

Table 1: Diagnostic and Clinical Criteria Used in This Study

This study included 150 children with fever and thrombocytopenia. Demographics like age, gender and location of the patient were analyzed using simple statistics like proportions

Sex distribution

Among the 150 children, gender distribution revealed 52 % male and 48 % female with male female ratio of 1.1: 1 (figure.1)

Figure 1: Sex distribution

Age wise distribution:

Study group comprised of children one month - twelve years of age who were classified as infants, toddlers, preschool children and school children.

Table No. 2 Age wise Distribution

In 150 children, 68% were above 5 years, 15 % were 3 to 5 years, 11 % were 1 to 3 years, 6 % were infants. Two thirds of study group was constituted by children beyond 5 years.

Age and Sex wise distribution

Males and females in different age groups (table no.3)

Table No.3 Age and Sex wise Distribution.

In Infants, Toddlers and school children, male were affected more than female which is contrast to Preschool children, in which female were affected more.

Geographic area distribution:

Government Medical College, Anantapur is Tertiary care centre which caters to the needs of a number of nearby villages. This study had children from different localities. (table no 4.)

Table No.4. Geographic Area Distribution

Most of the children came from Anantapur 21%,17% children from Hindupur, 13% from Kalyandurg, 11% from Tadipatri, 8% from Dharmavaram, 8% from Guntakal, 6% from Rayagurgam, 6% from Puttaparthi, 5%from Gooty, 4.6% from Kadiri. 62% of the children were residing in rural areas compared to 38% residing in urban areas.

 Month wise distribution

Month wise distributions showed 85% occurring in between months of August and November.

Table No.5. Month Wise Distribution

Symptom categorization:

Clinical features of children with thrombocytopenia showed predominantly G.I symptoms followed by myalgia. Rash as a presentation was encountered in 7% of the children.

Table No.6 Symptom categorization

In this study 49% children had GI symptoms, 40% children had headache and myalgia, and 12% children had GI bleed and altered sensorium.

Table.7. Symptom distribution in age wise groups

44.4 % of infants presented with altered sensorium where as only 6.8% of school going children presented with altered sensorium.

Examination findings:

Examination findings at admission has been tabulated in table no.8

Table No 8. Examination findings at admission

Out of 150 children studied, 132 children were febrile at admission with temperature of >100.4 F. Half of the children had Facial puffiness, one third of them had Pallor ,one fourth had Lymphadenopathy, Splenomegaly and two third had Hepatomegaly. Petechiae, Eschar and Jaundice were less common.

Table No. 9. Examination findings in different age groups

Two third of infants presented with hepatomegaly, two third of toddlers presented with splenomegaly and about one third of preschool children had eschar than other groups

Among the study group 2 child had respiratory distress and subsequently required ventilator support for respiratory failure and septic shock.

Hemodynamic status:

Hemodynamic status at admission revealed the following findings.

Table no .10. Hemodynamic status at admission

In this study pulse pressure 40 mmHg was defined as wide pulse pressure. Among 100 children, 26 % developed shock of which 21% children had compensated shock and 5% children had hypotensive shock. Abnormal pulse pressure was noted in 32% children of which 20% children had narrow pulse pressure, 12% children had wide pulse pressure. The same has been shown in the following figure 8.

Table 11: Hemodynamic status at admission in different age groups

Narrow pulse pressure and compensated shock were more common in infants

Grading of Thrombocytopenia:

Severity of thrombocytopenia was graded based on the platelet count. Platelet count was graded as mild, moderate, severe and analysis was done as shown below

Platelet count between 1,00,000 cells/cumm and 1,50,000 cells/cumm is mild thrombocytopenia, platelet count between 50,000 cells/cumm and 1,00,000 cells/cumm is moderate thrombocytopenia and platelet count below 50,000 cells/cumm is severe thrombocytopenia 23.

Table 12. Grading of Thrombocytopenia

Most of the children had severe thrombocytopenia (46%).

Table 13. Comparison of physiological status with severity of thrombocytopenia

In this study, compensated shock, hypotensive shock and narrow pulse pressure were common with severe thrombocytopenia.

Etiological Profile:

Final diagnosis was arrived based on the criteria as mentioned in the methodology section. Infective etiology was the commonly identified cause and nearly 45 % of them could not be classified into any of the common illness. Majority of them may be viral or other causes of fever with thrombocytopenia. A repeat evaluation for common infections might have helped to identify more common causes however the invasive blood sampling tests were not repeated for this reason in children who had recovered. The inclusion of bone marrow analysis would have thrown more light into the etiology of thrombocytopenia especially in the undiagnosed fever group.

However this being an invasive procedure was not undertaken for ethical reasons unless clinical examination and diagnosis warranted the same.

Table no.14.Etiological profile

Analysis was undertaken to identify the severity of thrombocytopenia in different illness among the study group.

Table no .15 Grades of thrombocytopenia in specific etiology

Among the children diagnosed by Undifferentiated fever 70.5% had severe Thrombocytopenia, 26.5% had moderate thrombocytopenia, 10.1% had mild thrombocytopenia.

In Dengue fever, severe thrombocytopenia was more common and in Malaria, Scrub typhus, Enteric fever mild thrombocytopenia was more common.

Torniquet Test

Torniquet test at admission was positive in 31 children (21%)

Table no 16 Age wise distribution of Positive Torniquet Test

Positive Torniquet test at admission was more commonly associated with severe thrombocytopenia

Table no 17 Positive Torniquet Test  association with degree of  thrombocytopenia

Bleeding manifestations:

Bleeding manifestations among children with thrombocytopenia is summarized in table 18. Among the bleeding manifestations, GI bleeds were the commonest bleeding manifestation.

Table No. 18 Bleeding Manifestations

Among children with bleeding manifestation 31% had petechiae, 42.8% had GI bleeds and remaining 26.2 % children had other bleeds like epistaxis, hematuria, gum bleeds, sub conjunctival hemorrhage.

Table no.19.Bleeding manifestation in different age groups:

Bleeding manifestations were most common in Infants followed by preschool children, school going children and Toddlers.

Table no.20. Type of bleeding manifestation in different age group:

Among different bleeding manifestations GI bleeds, Petechiae, Epistaxis, Gum bleeds were more common in Infants. The same has been illustrated in the figure no.18.

Table no.21 Bleeding manifestations in different etiologies

In reference to etiology, bleeding manifestations were more common in ALL (100%)

followed by Dengue (38.4%) followed by Septicemia (33.3%). Bleeding  manifestations were not seen in children with Enteric fever (10%).

Univariate analysis of risk factors for bleeding in children with acute febrile illness and thrombocytopenia were evaluated. The study parameters are compared between two groups with bleeding manifestations and without bleeding manifestations.

Table.no.22 Uni variate analysis of risk factors for bleeding in children

The above statistics revealed association is significant between bleeding manifestation and positive tourniquet test, lowest platelet count with p value of 0.001 for both parameters.

The above analysis revealed the children without bleeds had an earlier rise in platelet count (< 3 days of hospitalization) in comparison to those with bleeds, this was statistically significant with p value0.022

The above analysis also shows statistically significant risk for bleeding with platelet count of < 50,000 cells/cumm with p value of 0.020.

Table 23. Investigative profile

Outcome:

Outcome was defined in terms of complications noted, duration of hospital stay in relation to etiology and severity of thrombocytopenia and number of children discharged, referred or succumbed to death

Table no 24. Complications noted in the study

Table no 25 Duration of Hospital stay in relation to etiology

Table no 26 Duration of Hospital stay in relation to Severity of Thrombocytopenia

Severe type of thrombocytopenia was associated with increased duration of hospital stay

Table no 27 Outcome Parameters

Among 150 children, 143 children were improved with appropriate treatment, 2 children referred for hematological malignancy evaluation and management, 5 children died of multiorgan dysfunction

As discussed in literature, fever with thrombocytopenia has varied clinical presentation and diverse etiology. In the present study, clinical profile, etiological profile of febrile thrombocytopenia and its outcome were studied.

Sex

In the present study, male: female ratio was almost equal, with male: female equal to 1.1:1 which is comparable with Rekha .M.C et al 5, Praveen Kumar et al 6 and Saba Ahmed et al7 studies that also had male: female of 1.2:1. This is an observation in the present study and also other studies

Age

In the present study, the mean age of children affected was 8.5 ± 2.95 years. Saba Ahmed et al7 and Shah G.S et al 8 studies also had a mean age of 8.3 ± 3.5 years. Infants and toddlers were less when compared to the preschool children and school going children.

Geographic area

Most of the children were from Anantapur, Hindupur and Kalyandurg. Most of the children were from rural areas.

Seasonal variation

70% of the children presented between the months of August and November.

Praveenkumar et al 6 study revealed a major distribution of cases between July to September and Muhammad Ayub et al9 study documented increased prevalence of cases between June to August.

These results were comparable to our study.

This is due to universal phenomenon where certain infective conditions like dengue and scrub are known to have seasonal presentation.

Clinical presentation

Majority of children presented with gastro intestinal symptoms followed by headache, myalgia, GI bleeds and altered sensorium.

Praveen Kumar et al6 and Saba Ahmed et al8 studies also revealed GI symptoms were the commonest followed by headache and bleeds.

Ahmed Yaramis et al 10, Aisha Sajid et al11, Chitu CH et al12 studies also showed GI symptoms were the commonest in more than two third cases. Results were comparable with the present study.

In contrast Shah GS et al8 and Nikalje anand et al 13 studies showed headache was the commonest than GI symptoms.

Clinical signs

In the present study 88% children were febrile at admission. Two third children had hepatomegaly, one third children had pallor, one fourth had splenomegaly and one sixth had petechiae at admission.

Shah G.S8 et al study revealed hepatomegaly in three fourth children, splenomegaly in one fourth of children and petechiae in half the study group.

Ahmed Yaramis et al 10 study shows hepatomegaly in two fifth of children, splenomegaly in one fifth children. These study results were comparable with present study. In contrast Saba Ahmed et al 7study showed pallor was the commonest presentation with 67 % followed by hepatomegaly in 37 % and splenomegaly in 6 % children and Aisha Sajid et al11 study showed that splenomegaly was seen in 94% of children, pallor was in 65 % of children, hepatomegaly in 64%.

Vital signs

21% children had compensated shock and 5% children had hypotensive shock. Shock was commonly associated with severe thrombocytopenia. A study by Pankaj Palange revealed shock in 35% children and out of which 17 % were having compensated type of shock and 18% were having hypotensive type of shock which is like our study.

Presenting with hypotensive type of shock means child has presented late.

This is attributed to various factors like parental ignorance, no access to nearby health care centre and inappropriate treatment.

Thrombocytopenia

Among 150 children 46% were having severe- thrombocytopenia, 43% were having moderate- thrombocytopenia, 11%were having mild- thrombocytopenia. Muhammad Ayub et al19 study conducted was having severe type of thrombocytopenia - 60% of children, moderate type of thrombocytopenia - 20%, mild type of thrombocytopenia - 20%. A study byShruthi Bhalara et al 14 was having severe type of thrombocytopenia- 50%, moderate type of thrombocytopenia - 29 %, mild type of thrombocytopenia - 21% children. A study by Pankaj Palange 9 had- severe type of thrombocytopenia- 60%, moderate type of thrombocytopenia - 27 %, mild type of thrombocytopenia - 13%. In contrast study by Kriti Mohanl15 study showed that mild type of thrombocytopenia- 48% , moderate type of thrombocytopenia -35% , severe type of thrombocytopenia -17% of children. A study by Shah G S was having mild type of thrombocytopenia - 54 %, moderate type of thrombocytopenia - 40%, severe type of thrombocytopenia - 16% of children. Study by Aisha Sajid 11 with resulting moderate type of thrombocytopenia - 68%, mild type of thrombocytopenia- 21%, severe type of thrombocytopenia - 11%. Puttasuresh et al3 study showed that thrombocytopenia in Malaria due to sequestration and immune related - destruction with elevated platelet activated immunoglobulins and thrombocytopenia in Dengue fever due to immune mediated mechanism.

Muhammed Ayub et al 9 study revealed marrow depression in acute stage of Dengue infection causes thrombocytopenia.

Bleeding manifestations

GI bleeds was seen in- 12 %, Petechiae in- 9%, other type of bleeds - epistaxis, SCH , gum bleeds- in 7%. Among bleeding manifestations, GI bleeds and Petechiae were common in Infants . A study on Saba Ahmed7 was having petechiae- in 40 % of children . Prithviraj et al16 and AmithaGGandhi -et al 17 were having petechiae as the most common bleeding manifestation later gum bleeds , epistaxis, hematuria and GI bleeds. In study by Shah GS 8 and KritiMohan15 study results revealed GI bleeds as common manifestations than petechiae. In Study on ShruthiBhalara 7 gum bleeds was the common bleeding manifestation.

In our study, bleeding manifestations- were common in children with severe thrombocytopenia with platelet count of less than 50, 000 cells / cumm. Shruthi K Bhalara et al14 and Prithvi Raj et al16 studies also shows that bleeding manifestations were more common with platelet count less than 50,000 cells/cumm. In contrast pankaj K Palange et al18, Kriti Mohan et al 15, Shah G.S et al8 , Nikalje Anandh et al8 , Shankar Raikar et al 4 study results revealed that there was no relation of PLT count with bleeding manifestations.

Etiology

In our study Dengue fever was the commonest etiology for fever with thrombocytopenia followed by Undifferentiated fever, Malaria, Scrub typhus, Enteric fever, Viral Encephalitis, Septicemia and ALL. Prithvi Raj et al ,16 Rekha M.C et al5 and Nikhalje Anand et al8 study results shows undiagnosed fever was the commonest etiology followed by dengue fever and enteric fever. These studies were comparable with present studies. Studies by Shankar Raikar et al4 and ShrutiBhalara et al14 were having Dengue fever as common etiology than malaria and sepsis, similar to our study. In Studies by Putta Suresh3, PraveenKumar6 and AmitaGandhi 7 Malaria was the common etiology than Dengue and Undiagnosed fever.

Outcome

In our study 95.3% improved and discharged, 1.3% children referred for Hemato-oncological consultation and 3.3% child expired due to MODS.

Fever associated with thrombocytopenia is a benign condition in children. GI symptoms are the commonest presenting feature. 62 % presented with hepatomegaly and 48% with facial puffiness. Shock is common in <1 year with thrombocytopenia. Severe thrombocytopenia is associated with external and internal bleeding manifestations. GI bleeds is common type of bleeding manifestation in this study. Treatment of primary pathology improves Platelet count and improvement is much earlier in children without bleeding.

Conflict of Interest: None

Funding Support: Nil

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