ORIGINAL ARTICLE. Evaluation of Febrile Thrombocytopenia Cases in a South Indian Tertiary Care Hospital

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1 Journal of The Association of Physicians of India Vol. 66 May ORIGINAL ARTICLE Evaluation of Febrile Thrombocytopenia Cases in a South Indian Tertiary Care Hospital P Vishnuram 1*, Kumar Natarajan 2, N Karuppusamy 3, Srinivasan Karthikeyan 4, J Kiruthika 5, A Muruganathan 6 Abstract Objective: This study is aimed at analyzing the clinical symptomatology and hematological evaluation with an emphasis on platelet indices in relation to predicting the outcome of the febrile thrombocytopenic admitted in Coimbatore medical college hospital. Methods: This is a prospective study involving adult who presented to our hospital with fever and thrombocytopenia (platelet <1,5,). This study excluded with known causes of thrombocytopenia like ITP and on chemotherapy etc. Results: Out of 34 were dengue positive, 66 were dengue negative. Dengue specific symptoms like myalgia and retro-orbital pain were present in 58.88% of dengue positive and 1.6% of dengue negative. Laboratory evaluation revealed sharp rise in hematocrit with fall in platelet count in both the groups more significant in dengue positive group. Bleeding manifestation and rashes were 29.4% and 26.4% in dengue positive, 12.12% and 7.57% in dengue negative group respectively. MPV was significantly lower in with bleeding manifestations irrespective of platelet count in both the groups. Mortality in our study was 2%. Conclusion: MPV is an independent predictor of bleeding manifestation and poor outcome. Dengue virus may suppress the bone marrow as evidenced by alteration in MPV in addition to other mechanisms of thrombocytopenia. Introduction Purpura was recognized as a manifestation of pestilential fever years ago, 1 though purpura may be thrombocytopenic or non thrombocytopenic. are a-nucleated cells with circulating life span of 8-1 days and vital for hemostasis. 2 Often physicians are perplexed of febrile thrombocytopenia with definite or indefinite etiology which influence the treatment modality. We aimed at a study of adult with febrile thrombocytopenia with the criteria of platelet count < 1,5,. Causes of febrile thrombocytopenia Infection dengue virus, parvo virus, rubella, mumps, varicella, hepatitis, EBV, CMV, HIV, leptospirosis, malaria, rickettsial infections, gram negative sepsis. 2. Malignancies leukemia, lymphoma 3. Others like aplastic anemia / SLE/ HUS / TTP/ITP/DIC Table 2: Age-wise distribution Age Dengue positive Dengue negative > Mechanism of thrombocytopenia in febrile 1 a. Decreased platelet production b. Direct effect on progenitor cells c. Hemophagocytosis d. Antibody mediated destruction e. Circulating platelet destruction In our study we have used novel platelet indices like MPV and PDW to predict the risk of outcome. Materials and Methods This is a prospective study of continuous adult who were admitted during the period of January 16 to February 16. Already known thrombocytopenia with other diseases were excluded from the study. This study was approved by the hospital ethical committee and informed consent was obtained from each. Laboratory investigations like complete blood count (3 part different cell count, Impedance principle {SYSMEX} was used), liver function test, dengue serology (IgM ELISA) were done. Blood counts were periodically monitored till resolution and discharge of. Results In our study out of 34 were dengue positive and 66 were dengue negative (Tables 1, 2). Our study showed that about 58.88% of who were dengue positive had dengue specific general symptoms like (myalgia and retro orbital pain) as against 1.6% of dengue negative. Apart from the general constitutional symptoms Gastro intestinal symptoms (abdominal Table 1: Number of dengue positive and negative cases Male Female Dengue +ve 24 1 Dengue ve 26 1 Assistant Professor, 2 Professor and HOD, Department of General Medicine, Coimbatore Medical College Hospital, 3 Assistant Professor, 6 Emeritus Professor, The Tamil Nadu Dr. MGR Medical University, 4 Post Graduate, 5 Post Graduate, Department of General Medicine, Coimbatore Medical College Hospital, Coimbatore, Tamil Nadu; * Corresponding Author Received: ; Accepted:

2 62 Journal of The Association of Physicians of India Vol. 66 May 18 pain, vomiting, loose stools) were predominant, 82.35% in dengue positive and 62.12% in dengue negative, may be influenced by outside drug intake which the patient revealed poorly. Bleeding manifestations and rashes were more common in dengue positive around 29.4% and 26.4% respectively. Whereas in dengue negative bleeding manifestation was seen in 12.12% and Table 3: Clinical manifestations Symptoms Dengue positive Dengue Negative General Dengue specific 7 Bleeding 1 8 Rashes 9 5 CVS - - RS 7 16 CNS GIT Table 4: Duration for fever to subside Days at which patient became afebrile Dengue + ve Dengue ve 2-5d d 7 18 >1d 3 1 rashes in 7.57% (Table 3). Around 7.58% of dengue positive became afebrile after 2-5 days. However 8.82 % of dengue positive had prolonged fever of more than 1 days. Whereas in dengue negative 71.21% became afebrile after 2-5 days and 1.51 % had prolonged fever (Table 4). Regarding platelet count.58% of Table 5: Platelet count among Platelet Dengue + ve Dengue - ve < lac lac 4 1 Table 6: Hematocrit value among HCT Dengue +ve Dengue -ve >5 4 - Total Counts in Thousands dengue positive had severe thrombocytopenia (<,) whereas only 7.57 % of dengue negative had such low platelet counts.(table-5) While comparing the platelet count with the hematocrit, our data revealed that lower the platelet count with a significant increase in the hematocrit which had significant p value (<.5) (Table 6) (Figure 1). While comparing other platelet indices it showed that with dengue had low MPV compared to dengue negative and it was more important predictor of bleeding manifestation compared to platelet count. Comparison of platelet count with PDW did not show significant correlation (Figures 2, 3). When liver parameters were obtained it showed a greater rise of SGPT compared to SGOT as like other studies (Tables 7, 8). When USG abdomen and pelvis was done 35 out of had positive findings. Gall bladder wall edema was more seen in dengue patient % with dengue had gall bladder wall edema as against % of dengue Patients (Dengue negative) MPV MPV Patients (Dengue positive) Group Mean ± Std Deviation Dengue negative 34.57±8.2 Dengue positive 42.43±6.16 P value (t test) <.5 Fig. 1: Comparing patient groups with platelet count and hematocrit Group (MPV) Mean ± SD Dengue positive 9.82 ±.93 Dengue negative 1.37±1.13 P value (t test).2 Fig. 2: Comparing patient groups with mean platelet volume (MPV)

3 Journal of The Association of Physicians of India Vol. 66 May Table 9: USG findings among 1 USG finding % in dengue positive % in dengue negative Patients (Dengue positive) PDW Hepatomegaly 14.7% 12.12% Gall bladder wall edema 52.94% 24.24% Ascitis 5% 27.27% Pleural effusion 11.76% 13.63% Table 1: Platelet transfusion and criteria for transfusion Type of platelet Volume Platelet content Raise in platelet count infusion 14 RDP 5 ml 4.5 x BCPP 16 to ml 2.4 to 4.4 x ,-5, SDP - 3 ml 3 x ,-5, Goal or intervention 2 Desired platelet count Prevention of intracranial bleed >5-1, Prevention of mucosal bleed >1,-3, Patients (dengue negative) Group (PDW) Mean ± SD Dengue positive 14.7±2.32 Dengue negative 14.79±3.16 P value (t test) >.5 PDW Placement of central catheters >,-3 (compressible sites) >,-5, (noncompressible sites) Use of anticoagulants in therapeutic dose >,-5, Invasive procedures Endoscopy with biopsy Liver biopsy >6, >, Major surgery >,-1,, Table 11: Risk stratification score (VISKUR - Score) Variable Platelet >1 lakh 1 lakh 6-, -6, -, -, Hct MPV LFT >1 BP systolic 9-1 <9 Table 12: Risk stratification among Fig. 3: Comparing patient groups with platelet distribution width (PDW) Table 7: SGPT level among SGPT Dengue positive negative (Table 9). Dengue negative > 6 4 Though 29.4% and 12.12% of dengue positive and dengue negative respectively had bleeding manifestation only 3 required platelet transfusion while keeping criteria for transfusion as platelet count <1, or severe bleeding manifestation according to National guideline for clinical management of dengue fever by NVBDCP (National vector borne disease control programme). 14 None of the dengue negative required transfusion. Another important finding in our study showed that 32% were migrant labors. Out of them 46.87% were dengue positive, so among 34 Table 8: SGOT level among SGOT dengue positive, 44.11% were migrants. This reflects the poor working condition of the migrants. Our study had 2% mortality, both the were dengue positive with severe thrombocytopenia and bleeding manifestations with low MPV (<9.2 fl). Discussion Dengue positive Dengue negative > 3 Fever is a manifestation of are manifestation of endogenous pyrogens release mediated by cytokines. They are produced by activated immune cells causing increase in thermoregulatory set point in hypothalamus. Major endogenous pyrogens are Interleukin-1 and Interleukin 6. Minor pyrogens are TNF- Beta, Macrophage inflammatory Risk Score No. of in our study High risk Moderate risk Low risk proteins, Interferons and Interleukins. These cytokines activate the arachidonic acid pathway which releases PGE2. Effect of Cytokines on 15 a. PGE2 biphasic response stimulatory at lower concentration (platelet function increased) whereas inhibitory at higher concentrations (low platelet function) b. IL-1 increase platelet count c. IL-6 megakaryocyte proliferation and maturation d. TNF alpha enhance platelet activation e. INF alpha2b- induce thrombocytopenia The role of inhibition of Interferon alpha 2b as a therapeutic method for severe persistent thrombocytopenia is a point to be evaluated. In our study we collected data of MPV (mean platelet volume) and

4 64 Journal of The Association of Physicians of India Vol. 66 May 18 PDW(platelet distribution width). MPV indicates the average volume of platelets, calculated by platelecrit divided by number of platelets 6 and it is a surrogate marker of bone marrow activity with normal value of 8-12 fl whereas PDW shows how uniform the platelets are in size and it is a measure of platelet activation with normal value of 9-14fl. 4 Low MPV a more important predictor of bleeding manifestation. 9 In dengue, development of IgM antibody coincides with disappearance of viraemia 3. Detection of IgM at 3-5 days of fever is seen in 5% of whereas 95-98% of will be positive for IgM antibody during 6-1 days of fever. It can persist for about for about 3 months. At 9-1 days IgG starts appearing 3 Platelet transfusion for treatment of thrombocytopenia may be deferred till platelet count is <1,. In our study only 3 required transfusion all had platelet count of <1, and severe hemorrhagic manifestations (Table 1). Prophylactic platelet transfusion is avoided to prevent allo-immunisation and platelet refractoriness 11. If needed Platelet transfusion can be done either using Random donor platelets (RDP), Buffy coat pooled platelets (BCPP), Single donor apheresis (SDP).The standard dosage is 5-6 units of RDP or one unit of BCPP or SDP. 14 Packed cell transfusion/fresh frozen plasma can also be used along with platelet transfusion in severe bleeding with coagulopathy. However whole blood transfusion has no role. 14 Analyzing our study we found out that with dengue had more dengue specific symptoms 58.88% compared to others (1.6% in dengue negative) and also had more bleeding manifestation (29.4%). Moreover severe thrombocytopenia was more common in dengue (.58%) compared to non dengue (7.57%). While considering HCT, hemoconcentration was more in dengue (mean HCT 42.43±6.16) and low platelet count had higher HCT with p value<.5 which is significant. The mean MPV in dengue was 9.82 ±.93 whereas in dengue negative it was 1.37±1.13 with a p value of <.2 which is significant. Patients with low MPV had higher risk of bleeding. 9 Thus it can be used an important predictor for risk of bleeding. PDW results didn t show any significance in dengue positive and dengue negative with or without bleeding manifestation. USG also revealed that gall bladder wall edema and ascites was more common in dengue (52.94% and 5% respectively) compared to dengue negative (24.24 % and 27.27% respectively). There have been studies to show that dengue causes bone marrow suppression. 7 Low MPV is an indicator for bone marrow activity. 12,13 Our study showed relationship between low MPV and very low platelet, thus proving that dengue virus directly suppress bone marrow. 6 Thus with our data we formulated a risk stratification scoring system (VISKUR- named after the first two authors) (Tables 11, 12). Same journal had published clinical scoring system earlier which was a useful guideline. Applying within our clinic-laboratory scoring system along with the previous scoring system may predict the outcome of disease on admission. Apart from the study, in our clinical experience we have seen two of AML with positive dengue serology. The relationship between dengue and leukemia needs further studies. Conclusion In our study out of thrombocytopenic only 3 received platelet transfusion. Extensive etiological evaluation of febrile thrombocytopenic other than dengue serology may not be necessary unless warranted in specific situations. MPV is an independent predictor of bleeding manifestation and poor outcome. Dengue virus may suppress the bone marrow as evidenced by alteration in MPV in addition to other mechanisms of thrombocytopenia. References 1. Wintrobe MM. Clinical hematology. 13th ed. Philadelphia: Lea and Febiger 2. Rodgers GP, Young NS. Bethesda handbook of clinical hematology. Philadelphia: Lippincott Williams and Wilkins; 13; 9: Dr. Tejinder Singh, Atlas and Text of Hematology. 3 rd ed: Handbook of clinical management of dengue. WHO 12:1.3;16 5. Lewis SM, Bain BJ, Bates I, Dacie JV, Dacie JV. Dacie and Lewis practical haematology. Philadelphia: Churchill Livingstone/ Elsevier; Kottke ME, Bavis B. Laboratory Hemtological Clinical Practice 1st ed Vincent F.la russa, Innis BL. Baillieres s Clinical Hematology 1995; 8: Bashir AB, Saeed OK, Mohammed BA, Ageep AK, Role of platelet indices in with dengue infection in red sea state sudan. International J science and Research Katti TV, et al, How far are the platelet indices mirror image of mechanism of thrombocytopenia mystery still remains?. International J of Advance in Medicine 14; 1; Deshwal R, et al. Clinical and laboratory profile of dengue fever. J Association of Physicians of India 15; 63: Guidelines for the use of platelet transfusions. British J of Haematology 3; 122: Xu, Rui-Long et al. Platelet Volume Indices Have Low Diagnostic Efficiency for Predicting Bone Marrow Failure in Thrombocytopenic Patients. Experimental and Therapeutic Medicine 5.1 (13): PMC. Web. 1 June Noris P, Klersy C, Gresele P, et al. Platelet size for distinguishing between inherited thrombocytopenias and immune thrombocytopenia: a multicentric, real life study. British Journal of Haematology 13; 162: doi:1.1111/ bjh NVBDCP. National guidelines for managent of dengue fever. Guidelines-14.pdf 15. Norol F, Vitrat N, Cramer E, Guichard J, Burstein SA, Vainchenker W, Debili N. Effects of Cytokines on Platelet Production From Blood and Marrow CD34+ Cells. Blood 1998; Kshirsagar P, Chauhan S, Samel D. Towards Developing a Scoring System for Febrile Thrombocytopenia. Journal of The Association of Physicians of India 16; 64.

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