|Year : 2018 | Volume
| Issue : 1 | Page : 2-6
A prospective study on the common infectious causes of thrombocytopenia (dengue fever, leptospirosis, scrub typhus and malaria) in a tertiary care teaching hospital
G Nibandhana1, Usha Kalawat1, KK Sharma1, Rashmi Patnayak2, DT Katyarmal3, Abhijit Chaudhury1
1 Department of Microbiology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Pathology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
3 Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
|Date of Web Publication||8-Jan-2019|
Professor, Department of Microbiology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: The present study was undertaken to know the contribution of four infectious causes of fever namely dengue, chikungunya, scrub typhus and malaria in patients presenting with fever of more than one week duration with thrombocytopenia in a tertiary care teaching hospital, Tirupati, Andhra Pradesh.
Methods: In this prospective study, 1014 samples from different patients who presented with fever and of more than one week duration and thrombocytopenia were collected over a period of six months and were processed for the detection of non-structural 1 (NS1) glycoprotein antigen for dengue, immunoglobulin M (IgM) antibodies for leptospirosis and scrub typhus by ELISA and malaria parasite by quantitative buffy coat (QBC).
Results: Among 1014 samples obtained from patients with fever with thrombocytopenia, 111 (10.94%) were due to thrombocytopenia due to infectious causes. Ninety (81.08%) were due to single infection and twenty one (18.92%) due to co-infections. Males were more affected. Peak incidence was in 40-49 years of age with scrub typhus as the predominant infection. Grade-3 thrombocytopenia was more common in all the four infections.
Conclusions: Our observations suggest that scrub typhus was the predominant cause of fever with thrombocytopenia, along with dengue, leptospira and malaria. Diagnostic evaluation should include search for these causes in patients presenting with fever with thrombocytopenia. This can be helpful as both are easily treatable infections with commonly available oral antibiotics.
Keywords: Dengue fever, leptospirosis, malaria, infection, scrub typhus, thrombocytopenia
|How to cite this article:|
Nibandhana G, Kalawat U, Sharma K K, Patnayak R, Katyarmal D T, Chaudhury A. A prospective study on the common infectious causes of thrombocytopenia (dengue fever, leptospirosis, scrub typhus and malaria) in a tertiary care teaching hospital. J Clin Sci Res 2018;7:2-6
|How to cite this URL:|
Nibandhana G, Kalawat U, Sharma K K, Patnayak R, Katyarmal D T, Chaudhury A. A prospective study on the common infectious causes of thrombocytopenia (dengue fever, leptospirosis, scrub typhus and malaria) in a tertiary care teaching hospital. J Clin Sci Res [serial online] 2018 [cited 2019 Oct 14];7:2-6. Available from: http://www.jcsr.co.in/text.asp?2018/7/1/2/249629
| Introduction|| |
Thrombocytopenia refers to a disorder in which there is a relative decrease of thrombocytes, commonly known as platelets in the blood. Results of The Third US National Health and Nutrition Examination Survey III support the traditional value of 150 × 109/L as the lower limit of normal. However, platelet counts between 100 and 150 × 109/L do not necessarily indicate disease if they have been stable for more than 6 months, and the adoption of a cut-off value of 100 × 109/L may be more appropriate to identify a pathologic condition., Furthermore, it is now appreciated that in many non-Western countries, the lower threshold of the normal platelet count is lower than 150 × 109/L.
Thrombocytopenia is associated with various conditions ranging from life-threatening to no risk at all conditions. Thrombocytopenia due to infectious causes is one of the important problems all over the world, especially in developing countries. Infections caused by many bacteria and viruses are the most common non-iatrogenic causes for thrombocytopenia.
Infections can affect both platelet production and survival. Many of the common causes for fever with thrombocytopenia in tropics have been viral, bacterial and protozoal infections. Established infective causes such as dengue and leptospirosis are well known for presenting with fever with thrombocytopenia. There are not many studies elucidating other infections for thrombocytopenia. Only few studies are available for malaria and scrub typhus.
This study has been undertaken to know the possible causes of fever with thrombocytopenia wherein causes of infection could be established such as dengue, malaria, leptospira and scrub typhus.
| Material and Methods|| |
This study was undertaken in the Departments of Microbiology and Pathology in SVIMS, Tirupati, Andhra Pradesh, over a period of 6 months from December 2014 to June 2015. Single sample was taken from each patient. Platelet count was done with automated counter and finally confirmed by Leishman stain. Quantitative buffy coat (QBC) analysis using QBC malaria test kit manufactured by Phillipsburg, USA, was done for the detection of malarial parasite. ELISA test was done for the detection of dengue, leptospirosis and scrub typhus, which are the common infectious causes of thrombocytopenia considered in our study.
Treatment-naive patients having fever ≥38.3°C of more than 1 week duration with thrombocytopenia were included in the study. Patients having thrombocytopenia with other pyogenic causes, drug-induced thrombocytopenia and malignant causes of thrombocytopenia were excluded.
Nonstructural protein (NS1) antigen dengue ELISA was done using Panbio dengue early ELISA kit (Standard Diagnostics, Inc., Republic of Korea). The test was performed and interpreted as per the instructions provided by the manufacturer. Antileptospiral immunoglobulin M (IgM) antibody assay was done using a commercially available kit (Scimedx Corporation, Denville, NJ, USA). The test was performed and interpreted as per the instructions provided by manufacturer.
Antiscrub typhus (IgM antibodies) was done using Scrub typhus™ ELISA (InBios International, Inc., Seattle, WA, USA). The test was performed and interpreted as per the instructions provided by the manufacturer. Malarial parasite testing by QBC method was done using QBC malaria test kit manufactured by Phillipsburg, USA. Grading of thrombocytopenia was carried out according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.
Continuous data are summarised as mean ± standard deviation. Categorical data are summarised as percentages.
| Results|| |
During the study period, a total of 1014 samples of thrombocytopenia from different patients were tested against dengue, leptospirosis, scrub typhus and malaria. Among them, 111 were seropositive for single infection whereas 21 cases were due to co-infections [Table 1] and [Table 2]. In our study, among 111 infectious causes of fever with thrombocytopenia, scrub typhus was more predominant followed by dengue fever, leptospirosis and malaria. Among 21 co-infections, 19 patients were positive for dual infections and two patients for triple infections. Leptospirosis and scrub typhus co-infections were more predominant [Table 1] and [Table 2].
In our study, among 111 infectious causes of thrombocytopenia, males (54.1%) were more affected than females (46%). Males and females tested equally positive for dengue and scrub typhus. In leptospirosis and malaria, males were more compared to females [Figure 1].
|Figure 1: Gender-wise distribution of infectious causes of thrombocytopenia|
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Among 111 cases, majority (86, 77.5%) were from the age group of 20–59 years, with peak incidence of positivity in the age group of 40–49 years. Highest positivity for dengue was in 20–29 years of age (P = 0.03), leptospirosis in the age group of 40–49, scrub typhus in the age group of 60–69 years of age and malaria cases in the age group of 20–69 years of age [Figure 2]. Grade 3 thrombocytopenia was more predominant in all the four infections as depicted in [Figure 3] and [Figure 4].
|Figure 2: Age-wise distribution of infectious causes of thrombocytopenia|
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|Figure 3: Distribution of cases according to grading of thrombocytopenia|
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|Figure 4: Distribution of infectious causes based on grading of thrombocytopenia|
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The sensitivity and specificity of dengue NS1 ELISA, leptospira IgM ELISA, scrub typhus IgM ELISA and malaria QBC were 86% and 100%, >98% and 96%, 84.2% and 98.3% and 96.22% and 93.61%, respectively.
| Discussion|| |
Establishing the true cause of thrombocytopenia among several infectious and non-infectious etiologies can be useful in proper management of patients with fever with thrombocytopenia. More hilly and forest area, woody debris, dead leaf, animal remains and overcrowded pilgrim centre with continuous flow of people contribute to increase in rodent and mosquito population. Scrub typhus generally occurs after exposure to areas with secondary (scrub) vegetation. Scrub typhus has increasingly been reported from various regions of India especially the hilly regions of the Himalayas, Assam, West Bengal and Tamil Nadu. Recent reports from several parts of India, including South India, indicate that there is a resurgence of scrub typhus. Malaria caused by Plasmodium vivax and Plasmodium falciparum is endemic in many parts of India. Thrombocytopenia and anaemia are the most frequently malaria-associated hematological complications. In case of co-infection, the progression to disseminated intravascular coagulation and multi-organ failure is very rapid due to the compounding effect of the pathogenesis of these infections. The subjects of our study were patients with more than 1 week duration with thrombocytopenia. The other clinical features noted were chills and rigor, headache, myalgia, loss of appetite, dehydration, generalised weakness, confusion and irritability. Laboratory findings other than thrombocytopenia included anemia, elevated erythrocyte sedimentation rate, C-reactive protein and procalcitonin levels.
In the present study, most patients were in the age group of 20–29 years and this is in accordance with other studies.,, As per se veral studies,,,, dengue was predominant among young males. However, in our study, males and females were equally affected in the ratio of 1:1.
In the present study, out of 23 cases of leptospirosis, 12 (52.1%) were males and 11 (47.8%) were females. This study is in accordance with another study. The most common age group affected in our study is 40–49 years of age which is in accordance with another report. In the present study, the co-infection rate of dengue and leptospirosis is 2.7%. In one study, 2.5% of the 314 dengue-seropositive samples were also positive for leptospira IgM, while in another study, 3.6% of cases were co-infected.
In the present study, 34/111 (30.06%) accounted for only scrub typhus. According to a study, 31% of cases are scrub positive with thrombocytopenia. In two studies, 63.4% and 50% cases were seropositive, respectively. For scrub typhus-positive cases, most common age group affected was 40–49 years of age (32.3%). According to a study, most common age group for scrub typhus was 51–60 years of age (21.6%) followed by age group 41–50 years of age (18.9%); our observation were similar. The prevalence of scrub typhus varies from 0% to 8% to 60% in different countries. Males and females were equally affected in our study in 1:1 ratio. However, in other studies,,, adult males are commonly affected than females.
Other co-infections of scrub typhus are associated with leptospirosis (11/21) (52.3%), dengue (4/21) (19.04%), malaria (P. vivax) (1/21) (4.76%), leptospirosis and malaria (P. vivax) (1/21) (4.76%) and dengue and leptospirosis (1/21) (4.76%). Leptospirosis and scrub typhus are major causes of acute febrile illness in the Asia-Pacific region., Both infections affect agricultural workers and have similar clinical features, including fever, myalgia, headache and lymphadenopathy, they are difficult to distinguish on clinical grounds alone. The eschar at the site of the mite bite provides access for leptospires invading the human body, allowing them to cause serious infection.
Co-infection with leptospirosis and scrub typhus was first reported in rice farmers who were hospitalised with leptospirosis in Northeastern Thailand, with 9 (40%) of 22 patients also seropositive for scrub typhus. Dual infection has also been reported in Taiwan and India.,, A rare case of pancreatitis caused by co-infection of scrub typhus and dengue in a 40-year-old farm laborer was reported. In our study, four cases were reported for scrub typhus and dengue co-infection. Co-infection of scrub typhus with malaria (P. vivax) was reported in one case in our study. However, in Sub-Himalayan region, the prevalence of malaria is low and usually not suspected and usually not sought after. However, a case was recorded in Shimla with scrub typhus and malaria (P. vivax) co-infection.
A rare case of a patient having triple infection with P. falciparum, scrub typhus and dengue virus was reported from Uttarakhand. In our study, two cases were observed to have triple infection; one case with scrub typhus, leptospirosis and malaria (P. vivax) and the other case with dengue infection, scrub typhus and leptospirosis. Cross-reactivity, infection with the as yet unrecognised viruses and other microorganisms and evolution of newer species and serotypes of the already recognised organisms due to ecological changes, may be responsible for the atypical presentations being frequently reported.
In a study, thrombocytopenia was seen in 78% cases with P. vivax as the common species. Similar results were found in another study. In one study, thrombocytopenia was reported in 72% of patients with malaria. In a study on pediatric patients, low platelet count was reported in 72% of the patients with malaria. However, few studies, reported slightly lower incidence of thrombocytopenia ranging from 40% to 59%. In our study, among other infectious causes of thrombocytopenia, malaria contributed to only 4.5%. Four cases were positive for P. vivax and one case was P. falciparum-positive. P. vivax also contributed to co-infections in our study.
Most of the malaria-positive patients with thrombocytopenia were between 20 and 70 years of age in our study which can be compared to observation reported in another study. when it was ranging from to 60 years with majority of cases between 15 and 40 years of age.
As all the four infections taken into consideration in our study have non-specific clinical manifestations, the diagnostic test has variable sensitivity and specificity diagnosis of cases with such infections being difficult. As leptospirosis and scrub typhus are endemic in our region and can be treated easily, it is better to investigate for these diseases also along with dengue fever and malaria. Our study also suggests that in few cases, tests may be positive for more than one pathogen. This may not always be due to cross-reactivity between different serological assays but may be the result of superimposed infection by one pathogen on pre-existing infection by other.
Thrombocytopenia is a manifestation of varied infectious and noninfectious aetiologies. Some of the infectious causes of fever with thrombocytopenia can result in high mortality. Establishing the cause of thrombocytopenia in patients with fever can be very helpful in prompt and timely management of patients. Therefore, confirmation of infection is necessary as the treatment protocols for all these infections vary widely and co-infection should be considered before discarding a result as cross-reactivity of serological assays as co-infections by these organisms have been well documented.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Deutschman CS, Neligan PJ, editors. Evidence-based practice of critical care. 1st
ed. Philadelphia: Saunders Elsevier; 2010. p. 645.
Cheng CK, Chan J, Cembrowski GS, van Assendelft OW. Complete blood count reference interval diagrams derived from NHANES III: Stratification by age, sex, and race. Lab Hematol 2004;10:42-53.
Stasi R, Amadori S, Osborn J, Newland AC, Provan D. Long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia. PLoS Med 2006;3:e24.
Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al.
Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report from an international working group. Blood 2009;113:2386-93.
Gauer RL, Braun MM. Thrombocytopenia. Am Fam Physician 2012;85:612-22.
Sun J, Chai C, Lv H, Lin J, Wang C, Chen E, et al.
Epidemiological characteristics of severe fever with thrombocytopenia syndrome in Zhejiang province, China. Int J Infect Dis 2014;25:180-5.
Raikar SR, Kamdar PK, Dabhi AS. Clinical and laboratory evaluation of patients with fever with thrombocytopenia. Indian J Clin Pract 2013;24:4.
U.S Department of Health and Human Services. National Cancer Institute Criteria for Adverse Events Version 3. Bethesda: U.S Department of Health and Human Services; 2006. p. 4.
Mahajan SK. Scrub typhus. J Assoc Physicians India 2005;53:954-8.
Khan DM, Kuppusamy K, Sumathi S, Mrinalini VR. Evaluation of thrombocytopenia in dengue infection along with seasonal variation in rural Melmaruvathur. J Clin Diagn Res 2014;8:39-42.
Pruthvi D, Shashikala P, Shenoy V. Evaluation of platelet count in dengue fever along with seasonal variation of dengue infection. J Blood Disorders Transf 2012;3:128.
Khan E, Kisat M, Khan N, Nasir A, Ayub S, Hasan R, et al.
Demographic and clinical features of dengue fever in Pakistan from 2003-2007: A retrospective cross-sectional study. PLoS One 2010;5:e12505.
Jayashree K, Manasa GC, Pallavi P, Manjunath GV. Evaluation of platelets as predictive parameters in dengue fever. Indian J Hematol Blood Transfus 2011;27:127-30.
Sahira H, Jyothi R, Ramani Bai JT. Seroprevalence of leptospirosis among febrile patients – A hospital based study. J Acad Ind Res 2015;3:481.
Brown MG, Vickers IE, Salas RA, Smikle MF. Leptospirosis in suspected cases of dengue in Jamaica, 2002-2007. Trop Doct 2010;40:92-4.
Sharma KK, Latha PM, Kalawat U. Coinfection of leptospirosis and dengue fever at a tertiary care center in South India. Sch Res J 2012;2:12-6.
Kumar M, Krishnamurthy S, Delhikumar CG, Narayanan P, Biswal N, Srinivasan S, et al.
Scrub typhus in children at a tertiary hospital in Southern India: Clinical profile and complications. J Infect Public Health 2012;5:82-8.
Somashekar HR, Moses PD, Pavithran S, Mathew LG, Agarwal I, Rolain JM, et al.
Magnitude and features of scrub typhus and spotted fever in children in India. J Trop Pediatr 2006;52:228-9.
Huang CT, Chi H, Lee HC, Chiu NC, Huang FY. Scrub typhus in children in a teaching hospital in Eastern Taiwan, 2000-2005. Southeast Asian J Trop Med Public Health 2009;40:789-94.
Jyothi R, Sahira H, Sathyabhama MC, Ramani Bai JT. Seroprevalence of scrub typhus among febrile patients in a tertiary care hospital in Thiruvananthapuram, Kerala. J Acad Ind Res 2015;3:542.
Ramyasree A, Kalawat U, Rani ND, Chaudhury A. Seroprevalence of scrub typhus at a tertiary care hospital in Andhra Pradesh. Indian J Med Microbiol 2015;33:68-72.
] [Full text]
Gurung S, Pradhan J, Bhutia PY. Outbreak of scrub typhus in the North East Himalayan region-Sikkim: An emerging threat. Indian J Med Microbiol 2013;31:72-4.
] [Full text]
Leelarasamee A, Chupaprawan C, Chenchittikul M, Udompanthurat S. Etiologies of acute undifferentiated febrile illness in Thailand. J Med Assoc Thai 2004;87:464-72.
Suttinont C, Losuwanaluk K, Niwatayakul K, Hoontrakul S, Intaranongpai W, Silpasakorn S, et al.
Causes of acute, undifferentiated, febrile illness in rural Thailand: Results of a prospective observational study. Ann Trop Med Parasitol 2006;100:363-70.
Ho YH, Chen LK, Tsai PJ, Wang LS. Coinfection with leptospirosis and scrub typhus – A report of four cases. Tzu Chi Med J 2006;18:237-40.
Watt G, Jongsakul K, Suttinont C. Possible scrub typhus coinfections in Thai agricultural workers hospitalized with leptospirosis. Am J Trop Med Hyg 2003;68:89-91.
Lee CH, Liu JW. Coinfection with leptospirosis and scrub typhus in Taiwanese patients. Am J Trop Med Hyg 2007;77:525-7.
Chen YS, Cheng SL, Wang HC, Yang PC. Successful treatment of pulmonary hemorrhage associated with leptospirosis and scrub typhus coinfection by early plasma exchange. J Formos Med Assoc 2007;106:S1-6.
Mahajan SK, Babu S, Singh D, Kanga A, Kaushal SS. Scrub typhus and leptospirosis co-infection in Himalayan region. Trop Doct 2012;42:176-7.
Iqbal N, Viswanathan S, Remalayam B, Muthu V, George T. Pancreatitis and MODS due to scrub typhus and dengue co-infection. Trop Med Health 2012;40:19-21.
Ahmad S, Dhar M, Bhat NK, Shirazi N, Mittal G. Rare co-infection of malaria, scrub Typhus and dengue virus in an immunocompetent patient. Int J Curr Microbiol Appl Sci 2015;4:295-7.
Gupta NK, Bansal SB, Jain UC, Sahare K. Study of thrombocytopenia in patients of malaria. Trop Parasitol 2013;3:58-61.
] [Full text]
Faseela TS, Roche RA, Anita KB, Malli CS, Rai Y. Diagnostic value of platelet count in malaria. J Clin Diagn Res 2011;5:464-6.
Colonel KM, Bhika RD, Khalid S, Khalique-ur-Rehman S, Syes ZA. Severe thrombocytopenia and prolonged bleeding time in patients with malaria (a clinical study of 162 malaria cases). World Appl Sci J 2010;9:484-8.
Jamal A, Memon IA, Latif F. The association of Plasmodium vivax malaria with thrombocytopenia in febrile children. Pak Paediatr J 2007;31:85-9.
Maina RN, Walsh D, Gaddy C, Hongo G, Waitumbi J, Otieno L, et al.
Impact of Plasmodium falciparum infection on haematological parameters in children living in Western Kenya. Malar J 2010;9 Suppl 3:S4.
Rodríguez-Morales AJ, Sánchez E, Vargas M, Piccolo C, Colina R, Arria M, et al.
Anemia and thrombocytopenia in children with Plasmodium vivax malaria. J Trop Pediatr 2006;52:49-51.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]