Dengue Fever and Malaria in Thrombocytopenic Patients

Dengue Fever and Malaria in Thrombocytopenic Patients Frequency of co-existence of dengue fever and malaria in thrombocytopenic patients presented with acute febrile illness Dr. Shazia Yasir*, Dr. Muhammad Owais Rashid, Dr. Faisal Moin, Dr. Komal Owais ABSTRACT Introduction: Hepatitis c virus infection affects more than 170 million people worldwide. [1] About 80% of patients with acute infection will afterward develop chronic disease. [15] Interferon (IFN) alpha in combination with ribavirin (RBV) is the current standard care of treatment of chronic hepatitis C virus infection worldwide. Unfortunately, both drugs have significant hematological toxic effects (anemia, neutropenia and thrombocytopenia) Objectives: To determine the frequency of hematological side effects (anemia, neutropenia and thrombocytopenia) during combination therapy with interferon and ribavirin in chronic hepatitis C patients. Study Design: Cross-sectional, observational study. Place and Duration of Study: Department of Emergency Medicine, Ziauddin University Hospital, Karachi from Ten months from April 2013 to January 2014. Methodology: A total of 228 patients of chronic HCV, and meeting inclusion criteria were included from OPD of Ziauddin Hospital North Campus Karachi, Sarwar Zuberi Liver Centre and Hepatogastroenterology Section, SIUT. After taking informed consent, patients were given injection IFN 3 MIU subcutaneously thrice weekly and ribavirin 800 – 1200 mg/day, as per body weight, that was, those less than 50 kg will receive 800 mg/day, 50 – 75 kg was received 1000 mg/kg and more than 75 kg was received 1200 mg/day. Result: Overall mean age was 39.6 ( ±9.2) years with Male: Female = 2.2: 1. Hematological abnormalities was seen in 79 (37.3%) cases. Anemia was the most common type of hematological abnormalities developed in 41 (19.3%) cases followed by neutropenia in 33 (15.6%) and thrombocytopenia in 21 (9.9%) cases. Conclusion: Amongst the hematological disorders. Anemia and thrombocytopenia was the most common and least common respectively during the combination therapy of chronic hepatitis C. while neutropenia followed as second common and serious hematological disorder. Key words: HCV, anemia, neutropenia, thrombocytopenia, Interferon, ribavirin. _____________________________________________________________________________________________ INTRODUCTION Hepatitis C Virus (HCV) infection is a global health problem. The virus infects approximately 3% of the world population; placing approximately 170 million people at risk of developing HCV related chronic liver disease. [1] Currently, chronic hepatitis C infection is the most frequent indication for liver transplantation and accounts for estimated 8000 – 10000 deaths each year in the United States. [2] HCV infection is endemic in Pakistan [3] and is a considerable threat to our population. [4] The prevalence of HCV in Pakistan is reported to be 3.29% [3], 3.3% [4] and 3.69% [5] in different studies. Cure of chronic hepatitis C in the natural course is rare, and the rate of progression to cirrhosis and hepatocellular carcinoma is also significantly high. The eradication of hepatitis C virus during the chronic stage is, therefore, extremely important. [6] - Department of Emergency Medicine, Ziauddin University Hospital, North Campus, Karachi * Correspondence Email: [emailprotected] Treatment with pegylated interferon plus ribavirin has become the standard of care for patients infected with chronic hepatitis C. [7] However, standard interferon and ribavirin combination is still widely in use in Pakistan for chronic hepatitis C infection, because of its low cost. Unfortunately, both drugs (interferon and ribavirin) have significant hematological toxic effects (anemia, neutropenia and thrombocytopenia). [8,9,10] Anemia during combination therapy for chronic hepatitis C begins to develop almost immediately after therapy is initiated and becomes most pronounced after 4 to 6 weeks of treatment.8 Hemoglobin levels do not usually change after week 12 to the completion of treatment. [6] The values for incidence and severity of anemia during combination therapy for chronic hepatitis C are higher in Asian studies than in the non-Asian studies. In a study conducted in Taiwan, the mean decrease of hemoglobin was 3.9  ± 1.3 g/dL and 39% of the patients developed severe anemia (hemoglobin levels below 10 g/dL). [9] Treatment with interferon and ribavirin combination therapy is also associated with neutropenia that is more frequent with peg interferon as compared to standard interferon. [11] A study from the National Institutes of Health specifically examined neutropenia associated with combination therapy. The mean neutrophil count decreased by 34% during the 24 to 48 week course of therapy and the frequency of neutropenia was noted to be 63%. [12] Thrombocytopenia is another well known complication of antiviral therapy for chronic hepatitis C but has been infrequently associated with dose reduction or discontinuation. [11] During therapy with at least one dose of standard or pegylated interferon, platelet count decreased by nearly 28%. [13] Few studies have been conducted in Pakistan to assess the side effects of combination therapy in chronic hepatitis C. The frequency of anemia is reported to be 19.6% and of thrombocytopenia to be 13.7% in one study. [14] Another study stated that hematological side effects were noted in 92% of the patients. [10] No local study is available reporting the frequency of neutropenia during treatment for chronic hepatitis C. Hematological abnormalities are the most common indications for dose reduction in chronic hepatitis C therapy. Hematological abnormalities accounts for at least one dose reduction in approximately 25% of patients during therapy. Dose reductions or premature discontinuations results in significantly lower sustained virological response. [11] Because hematological side effects have implications on virological response, therefore, knowledge regarding frequency of these side effects is of utmost importance. As stated earlier, there are very few trials conducted in Pakistan that examined the hematological side effects of combination therapy and most of the data in this regard have come from western population. Pakistani population is different from western population in many ways, for example, the HCV genotype 1 infection is more common in west while genotype 3 infection in Pakistan. Moreover, host factors like different genetic makeup, difference in immune status and lower body mass inde x (resulting in lesser dose of ribavirin required during therapy) for Pakistani population may have implications on frequency of the hematological side effects of combination therapy. In addition, there is an enormous difference in the frequencies of side effects reported in different studies conducted at national level. Therefore, there is a need to add-to and strengthen the national literature. This study was designed to determine the frequency of the hematological side effects of combination therapy (interferon and ribavirin) in patients with chronic hepatitis C. METHODOLOGY The study was planned to be conducted on patients attending the out-patient department of Civil Hospital Karachi, Sarwer Zuberi Liver Centre and Hepatogastroenterology Section, Sindh Institute of Urology and Transplantation. Sample size ( n ) = 182 + 25% of 182 = 228* Proportion of thrombocytopenia ( P ) = 13.7%14 or 0.137 Confidence level (1 – ÃŽ ± ) = 0.05 Margin of error (d ) = 5% * A meta-analysis noted that during treatment for chronic hepatitis C approximately 25% of patients required at least one dose reduction for hematological abnormalities (anemia, neutropenia and thrombocytopenia) [11], therefore the sample size is augmented by 25% to cover the drop-outs because of dose reduction and drug discontinuation. Patients who will require dose reduction and drug discontinuation will be excluded from the study. The criteria for dose reduction and drug discontinuation are stated in data collection. Inclusion Criteria: Patients of either gender with chronic hepatitis C: Between the age of 18 and 50 years, Presence of anti – HCV, HCV – RNA and persistently raised ALT levels for more than 6 months (on at least two occasions). HCV Genotype 2 and 3; and Compensated liver disease (indicated by presence of all of the following: no history of ascites, bleeding esophageal varices or hepatic encephalopathy, serum albumin > 3 g/dL, serum bilirubin ≠¤ 2 mg/dl and prothrombin time Exclusion Criteria: Patients with: Decompensated liver disease HCV Genotype 1 (Infection with HCV Genotype 1 requires combination therapy for 48 weeks. The study is planned to be completed in 6 months.) Co-infection with HBV Pregnancy, Significant systemic illnesses other than liver disease (cardiovascular or renal dysfunction, chronic obstructive pulmonary disease, uncontrolled diabetes) Other contra-indications or precautions to combination therapy (history of epilepsy, depression or other psychiatric disorders, thyroid dysfunction, autoimmune hepatitis) Interferon/ribavirin therapy in the past Pre-treatment hemoglobin level less than 13 g/dL in males and less than 12 g/dL in females, pre-treatment neutrophil count less than 1500 cells/ÃŽ ¼L and platelet count less than 150,000 cells/ÃŽ ¼L Who require dose reduction or drug discontinuation during treatment. Criteria are mentioned in data collection. The source of the sample was the patients attending the out-patient department of Civil Hospital Karachi, Sarwar Zuberi Liver Centre and Hepatogastroenterology Section, Sindh Institute of Urology and Transplantation. Informed consent was taken from the patients who were meet the inclusion and exclusion criteria and the patients were given injection IFN 3 MIU subcutaneously thrice weekly and ribavirin 800 – 1200 mg/day, as per body weight, that was, those less than 50 kg will receive 800 mg/day, 50 – 75 kg was received 1000 mg/kg and more than 75 kg was received 1200 mg/day. The patients were evaluated at week 4, 12 and 24 and blood was drawn for complete blood counts. Dose of the interferon and/or ribavarin was reduced for any patient in whom hemoglobin level falls below 10 g/dL and/or neutrophil count drops below 750 cells/ÃŽ ¼L and/or platelet count falls below 50,000 cells/ÃŽ ¼L during the course of treatment. The therapy was discontinued in the patients in whom hemo globin level drops below 8.5 g/dL and/or neutrophil count falls below 500 cells/ÃŽ ¼L and/or platelet count falls below 30,000 cells/ÃŽ ¼L. These criteria for dose reduction and drug discontinuation were in accordance with the guidelines for treatment of chronic hepatitis C. The patients who were required dose reduction or drug discontinuation during the course of treatment was excluded from the study. The final outcome was measured at week 24, when the values for hemoglobin level, neutrophil count and platelet count was recorded for each patient in the performa given in annex 1. The patient was said to have developed anemia if the hemoglobin level falls below 13 g/dL in males and less than 12 g/dL in females, neutropenia if neutrophil count drops below 1500 cells/ÃŽ ¼L and thrombocytopenia if platelet count falls below 1,50,000 cells/ÃŽ ¼L. Confounding variables like age, gender and body weight were controlled by stratification at the time of analysis. The collected data was analyzed with the help of SPSS program version 19.0. Frequencies and percentages were computed for presentation of qualitative variables like gender and side effects (anemia, neutropenia and thrombocytopenia). Mean  ± Standard Deviation was computed for variables like age and body weight. Confounding variables like age, gender and body weight were controlled by stratification. RESULT A total of 228 patients with chronic hepatitis C were included in this study. Sixteen (7.02%) of the patients were excluded due to dose modification or discontinuation during the follow-up period. Due to anemia dose was reduced in 6 and discontinued in 4 cases, due to neutropenia dose was reduced in 3 and discontinued in 1 case and in thrombocytopenia dose was reduced in 2 cases. Mean ( ±SD) age of patients was 39.6 ( ±9.2) years with range = 18 – 50 years. Majority of cases 113 (53.3%) had age between 20 – 40 years. Figure-1 Gender distribution showed male preponderance (male: female = 2.2: 1), 145 (68.4%) were males and 67 (31.6%) were females. Figure-2 Seventy Nine (37.3%) of the patients developed significant hematological abnormalities during treatment with interferon and ribavirin. Figure-3 Anemia was the most common type of hematological abnormalities developed in 41 (19.3%) cases followed by neutropenia in 33 (15.6%) cases and thrombocytopenia in 21 (9.9%) cases. Figure-4 Proportions of hematological abnormalities were similar in both genders. Fifty five (37.9%) were male and 24 (35.8%) were female. Figure-5 Types of hematological abnormalities were also similar in both males and females, 29 (52.7%), 23 (41.8%) and 15 (27.3%) of males and 12 (50%), 10 (41.7%) and 6 (25%) of females developed anemia, neutropenia, and thrombocytopenia, respectively in male cases. Table-1 Mean ( ±SD) age of those patients who developed hematological side effects was 38.4 ( ±8.6) years with range = 19 – 50 years. Majority of cases 56 (62.2%) had age between 20 – 40 years. Figure-6 FIGURE-1 AGE DISTRIBUTION n = 228 Mean  ±SD = 39.6  ±9.2 years Range = 18 – 50 years FIGURE-2 GENDER DISTRIBUTION n = 228 Male: Female = 2.2: 1 FIGURE-3 OVERALL HEMATOLOGICAL SIDE EFFECTS (SE) n = 212 Keys: hematological side effects were evaluated in this study as: Anemia = hemoglobin level 10 13 g/dL in males and 10 12 g/dL in females. Neutropenia = Neutrophil count between 750 1500 cells/ÃŽ ¼L. Thrombocytopenia = Platelet count of between 50,000 – 1, 50,000 cells/ÃŽ ¼L. SE = Side Effects FIGURE-4 TYPES OF HEMATOLOGICAL SIDE EFFECTS (SE) n = 212 Multiple response exist Keys: Anemia = hemoglobin level 10 13 g/dL in males and 10 12 g/dL in females. Neutropenia = Neutrophil count between 1500 750 cells/ÃŽ ¼L. Thrombocytopenia = Platelet count of between 1,50,000 50000 cells/ÃŽ ¼L. SE = Side Effects FIGURE-5 OVERALL HEMATOLOGICAL SIDE EFFECTS (SE) IN GENDER n = 212 Table-1 TYPES OF HEMATOLOGICAL SIDE EFFECTS (SE) IN GENDER n = 212 Keys: Anemia = hemoglobin level 10 13 g/dL in males and 10 12 g/dL in females. Neutropenia = Neutrophil count between 750 1500 cells/ÃŽ ¼L. Thrombocytopenia = Platelet count of between 50,000 150000 cells/ÃŽ ¼L. FIGURE-6 OVERALL HEMATOLOGICAL SIDE EFFECTS (SE) IN AGE GROUPS n = 212 Mean  ±SD = 38.4  ±8.6 years Range = 19 – 50 years DISCUSSION The treatment of CHC is now well established with conventional interferon or pegylated interferon in combination with ribavirin. [61] However, one of the main drawbacks of this combination therapy is the development of side effects, which can result in suboptimal dosing or discontinuation of therapy. This can limit the likelihood of SVR, since one of the determinants of SVR is adequate dose and duration of therapy, as previously discussed in this supplement. Among the side effects of combination therapy, hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia have been reported to result in dose reduction and discontinuation of therapy in up to 25% and 3% of patients, respectively. [11] The withdrawal rate increases with both the duration of treatment and use of combination therapy. [101] For example, therapy was stopped in 13–14% of patients treated with interferon mono therapy for 48 weeks [102] compared with 19–21% of patients receiving combination therapy for the same duration. The withdrawal rate for combination therapy was lower when therapy was administered for only 24 weeks (8%). [103] Mean ( ±SD) age of patients was 39.6 ( ±9.2) years with range = 18 – 50 years. In this study seventy Nine, 37.3% of the patients developed significant hematological abnormalities during treatment with interferon and ribavirin and Sixteen (7.02%) of the patients were excluded due to drug modification or discontinuation during the follow-up period. A study from USA reported 38.2% of the cases developed hematological side effects during the combination therapy, a figure is similar to what is seen in this study.104 Another study conducted in Pakistan reported 92% mild to moderate hematological side effect during the combination therapy. [10] In this study anemia was the most common type of hematological abnormality seen in 19.3% of cases followed by neutropenia in 15.6% and thrombocytopenia in 9.9% cases. Study from USA reported 20.6%, 22.1%, and 8.1% developed neutropenia, anemia, and thrombocytopenia, respectively. [104] In another study from Pakistan, mild to modest anemia was noted in 70 % of the patients. [10] Anemia is caused both by interferon due to myeloseupression and ribivirin causing hemolysis. [24, 25] In same study mild to moderate neutropenia was reported in 64% of cases and thrombocytopenia in 61% of patients. [10] neutropenia is one of the expected side effects of combination therapy but the risk of the serious infection is very low even with severe neutropenia. [12] Similarly in clinically practice thrombocytopenia does not pose significant problem. [11] In conclusion hematologic abnormalities are common during combination antiviral therapy for chronic hepatitis C. Although dose reduction or discontinuation is tool of overcome these side effects, they can adversely affect the efficacy of combination antiviral therapy. This is especially true in the cases of ribavirin induced anemia. Recent evidence has led to increasing recognition that optimal dosing of ribavirin is a crucial determinant of viral clearance. Preliminary data suggest that hematopoietic growth factors may be useful for managing the hematologic side effects of combination therapy (especially anemia). CONCLUSION The frequency of hematological abnormalities during the treatment of chronic hepatitis C (HCV) in this study was comparable to those seen in certain other studies. Anemia was the most common and thrombocytopenia was the least common hematological side effect noted. The number of patients excluded from the study because of dose modification or drug discontinuation was also greatest due to anemia and least due to thrombocytopenia ACKNOWLEDGEMENT We would like to acknowledge faculty of Ziauddin Hospital, North Campus for helping us during the study, staff for helping in data collection and all others who have given their input. SOURCE OF FUNDINGS We would like to thank HighQ pharma for financially aiding the research and authors for their contribution. CONFLICT OF INTEREST There is no conflict of interest in any term regarding the article from any authors. REFERENCE Dengue Fever and Malaria in Thrombocytopenic Patients Dengue Fever and Malaria in Thrombocytopenic Patients Frequency of co-existence of dengue fever and malaria in thrombocytopenic patients presented with acute febrile illness Dr. Shazia Yasir (PG Emergency Medicine)*, Dr. Owais , Dr. Faisal Moin ABSTRACT Introduction: Both dengue fever and malaria can present with thrombocytopenia. Thrombocytopenia is a consistent finding in dengue fever and is regarded as a strong predictor of dengue fever. Thrombocytopenia is also considered criterion of disease severity, bad prognostic factor and its presence is associated with increase probability of malaria Objectives: To determine frequency of co-existence of dengue fever and malaria in thrombocytopenic patients presented with acute febrile illness in tertiary care hospital Study Design: Cross-sectional, observational study. Place and Duration of Study: Department of Emergency Medicine, Ziauddin University Hospital, Karachi from Ten months from April 2013 to January 2014. Methodology: A total of 159 patients meeting inclusion criteria were included in this study. 5ml of blood by venupuncture in EDTA anti-coagulant for platelet count and preparing thick and thin films and 2 ml of blood in plain bottle for detection of dengue specific IgM was collected from all patients. Thick films are used to identify malarial parasites and thin films to identify specie. Dengue fever was diagnosed on positive dengue IgM. Co-existence was labeled as positive if malarial parasites and dengue IgM found to be present at the same time. This diffusion susceptibility test was use to determine susceptibility of bacterial agents to antibiotics. Data was analyzed by descriptive statistics using SPSS software version 19. Result: Overall mean ( ±SD) age was 38.3 ( ±7.9) years, with Male to female ratio was 1.1: 1. Co-infections (Dengue and Malaria) were diagnosed in 5 (5.6%) of cases. From 5 cases, 3 (60%) were male and 2 (40%) were female. Mean ( ±SD) age of 5 positive cases of co-infection was 37.8 ( ±8.3) years. Conclusion: Concurrent infections were found 5.6% in this study. Although this percentage is slightly low; special attention should be given to the possibility of co-infection with malaria and dengue. Key words: Dengue fever, Malaria, Immunoglobulin-M (IgM), febrile illness, Thrombocytopenia _____________________________________________________________________________________________ INTRODUCTION Dengue Virus is becoming an increasing health problem. Over 99% cases of viral hemorrhagic fever reported worldwide are due to dengue hemorrhagic fever (DHF). [1] Dengue fever is cause by dengue viruses (DENVs) which are members of Flaviviridae family. [2] It has been estimated that 2.5 billion people live in areas which are at risk of epidemic transmission and over 50 million of DENV infections occur globally each year [3,4]. Since we are living in region where malaria is endemic and is considered as the most common cause of fever and in general practice empirical anti-malarial therapy is common, it is important to distinguish the two conditions due to clinical similarities and unexpected progress of dengue fever (DF) to DHF and dengue shock syndrome (DSS). [5] - Department of Emergency Medicine, Ziauddin University Hospital, North Campus, Karachi * Correspondence Email: [emailprotected] Both dengue fever and malaria can present with thrombocytopenia. Thrombocytopenia is a consistent finding in dengue fever and is regarded as a strong predictor of dengue fever. [6] Thrombocytopenia is also considered criterion of disease severity, bad prognostic factor and its presence is associated with increase probability of malaria [7, 8] In a local study Ali et.al showed that Out of 11 patients diagnosed as having dengue fever on serology 9 (81.8%) also had co-existence of malaria and thrombocytopenia was present in 90% of such patients. [5] Out of 11 DENV positive patients three patients died and first DENV positive patients who died was prescribed anti-malarial by general practitioner in outdoor. [5] On autopsy plasmodium falciparum rings were found in blood and DENV IgM was detected in serum samples [5] Due to clinical similarities in two conditions and possibility of extensive mosquito exposure, high co-existence of both conditions cannot be excluded. [5] This study aims to determine frequency of co-existing dengue fever and malaria in thrombocytopenic patients presenting with acute febrile illness so that magnitude of the condition could be assessed. The findings could be used to plan that all patients with acute febrile illness with thrombocytopenia must be screened for dengue fever without delay. METHODOLOGY This study was carried out at the department of emergency medicine, Ziauddin University Hospital, Karachi, Pakistan. Patients of either gender with more than 12 years of age presenting to Ziauddin Hospital Karachi with acute febrile illness and found to have thrombocytopenia were included in the study while patients known to have disease causing thrombocytopenia e.g. systemic lupus erythematous, idiopathic thrombocytopenic purpura and patients with other causes of acute febrile illness such as pneumonia, meningitis, enteric fever etc. diagnosed on blood culture, chest X-ray sputum C/S, urine D/R were excluded from the study. A total of 159 patient’s fulfilling inclusion criteria were included in the study. 5ml of blood by venupuncture in EDTA anti-coagulant for platelet count and preparing thick and thin films and 2 ml of blood in plain bottle for detection of dengue specific IgM was collected from all patients. Thick films are used to identify malarial parasites and thin films to identify specie. Dengue fever was diagnosed on positive dengue IgM. To minimize bias all specimen was sent to single central laboratory of the hospital. A proforma especially designed for the study was used to documents findings such as paients age, gender, name, malaria parasite, dengue IgM by the researcher. Co-existence was labeled as positive if malarial parasites and dengue IgM found to be present at the same time. Data was entered in computer and analyzed by SPSS version 19.0 frequency and percentages were calculated for categorical variables such as gender, co-existing dengue fever and malaria. Mean standard deviation was calculated for numerical variables like age. Stratification was done in terms of age and gender to see the effect of that on outcome. RESULT During the study, a total of 159 cases with thrombocytopenia of age > 12 years were included. From 159 cases, 82 (51.6%) were male and 77 (48.4%) were female. (Figure-1) Mean ( ±SD) age of 159 cases was 38.3 ( ±7.9) years with range = 15 – 53 years. Majority 66 (41.5%) of cases had age between 30 – 44 years. (Figure-2) Out of 159 thrombocytopenic cases presented with acute febrile illness, malaria was diagnosed in 55 (34.6%) cases. (Figure-3) Dengue fever was diagnosed on positive dengue IgM. Out of 159 cases, 34 (21.4%) of cases were diagnosed as dengue. (Figure-4) Co-infections (Dengue and Malaria) were diagnosed in 5 (5.6%) cases. (Figure-5) Out of 5 positive cases of co-infection, 3 (60%) were male and 2 (40%) were female. Mean ( ±SD) age of 5 positive cases of co-infection was 37.8 ( ±8.3) years with range = 15 – 52 years. Majority 3 (60%) of cases had age between 30 – 44 years. (Figure-6) DISCUSSION Despite a wide overlap between malaria and dengue endemic areas, published reports of co-infections are scarce in the literature. Malaria and dengue must be suspected in febrile patients living in or returning from areas endemic for these infections. The confirmation of malaria is rapid, and after malaria is confirmed, dengue is usually ruled out without screening for it. Two methods can confirm dengue: dengue-specific IgM sero-conversion or detection of dengue virus particles during the acute phase (day 0 to day 4 after onset of fever) by RT-PCR, which is faster and more specific. In published case reports, [9 – 12] the diagnosis of dengue infection is usually made based on positive dengue IgM; however, this cannot confirm recent dengue, because IgM can persist for months and cross-react with other arboviruses. [13] If RT-PCR requires a specific laboratory and cannot be performed on site, a new test, the Platelia, is now easily included in any laboratory and is indicated particularly for early-acute phase samples. [14] To investigate the frequency of dengue and malaria co-infection, the Platelia test should be used in all cases of dengue-like or malaria-like syndrome, even when malaria diagnosis was positive, in regions w here both infections may overlap. Both dengue fever and malaria can present with thrombocytopenia. Thrombocytopenia is a consistent finding in dengue fever and is regarded as a strong predictor of dengue fever. [6] Thrombocytopenia is also considered criterion of disease severity, bad prognostic factor and its presence is associated with increase probability of malaria. [7, 8] Mixed infections with many etiologic agents are not uncommon in malaria. [15] Despite scant data, dengue and malaria coinfection should be common in areas where both diseases are co-endemic in many places of the world. [16] In a study regarding diagnostic techniques and management of dengue and malaria co-infection, all patients with dual infection presented prolonged fever for more than seven days, myalgia, bleeding manifestations, rash and anemia. [17] Moreover, according to Vasconcelos et al, the continuous fever caused by arboviral infection can mask the periodic fever associated with malarial parasites. [18] Out of 159 thrombocytopenic cases presented with acute febrile illness, malaria was diagnosed in 55 (34.6%) cases while 34 (21.4%) of cases were diagnosed as dengue. Of the 89 patients of dengue and malaria in this study, 5.6% had concurrent dengue and malaria. This percentage is relatively high as compared with other international studies. A study from France reported that 1% concurrent dengue and malaria. [19] Another study from Brazil reported 1.8% concurrent dengue and malaria. [20] Very high percentage was found in a local study Ali et.al showed that Out of 11 patients diagnosed as having dengue fever on serology 9 (81.8%) also had co-existence of malaria and thrombocytopenia was present in 90% of such patients. [5] In this study from 9 positive cases of co-infection, 3 (60%) were male and 2 (40%) were female. Mean ( ±SD) age of positive cases of co-infection was 37.8 ( ±8.3) years. Although a reduced sample number was assessed in this study, a limitation that we acknowledge, it is important to remember that dengue and malaria co-infection requires special attention because delayed diagnosis and appropriated treatment can result in fatal complications. [16, 21] Both diseases causes similar symptoms and simultaneous infections with two different infectious agents may result in overlapped symptoms, [22] diagnosis of malaria and dengue based purely on clinical grounds may become difficult for physicians [16] and it is possible that either clinical spectrum of the disease or treatment may also be affected. [23] Finally, it is important to remember that both diseases have similar clinical findings, thus the diagnosis could be made concomitantly for dengue and malaria in patients living or returning from areas where both diseases are endemic or during dengue outbreaks. CONCLUSION Concurrent infections were found 5.7% in this study. Although this percentage is slightly low; special attention should be given to the possibility of co-infection with malaria and dengue. The distinction between severe dengue and severe malaria must be made in an emergency department or hospital setting because in both situations, early diagnosis is essential for patient care. Finally, it is important to remember that both diseases have similar clinical findings, thus the diagnosis could be made concomitantly for dengue and malaria in patients living or returning from areas where both diseases are endemic or during dengue outbreaks. Acknowledgement: We would like to acknowledge faculty of Ziauddin Hospital, North Campus for helping us during the study, staff for helping in data collection and all others who have given their input. REFERENCE Rigau-Perez JG, Clark GG, Gulber DJ, Reitee P, Sanders EJ, Vorndam AV. Dengue and dengue hemorrhagic fever. Lancet 1998;352:971-7. Henchal EA, Putnak JR. The dengue viruses. 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