Clinical Profile of Co-Infections and Bacterimia in Adults with Malaria An Experience from a Tertiary Care Hospital in Northeastern India

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1 174 Original Study Clinical Profile of Co-Infections and Bacterimia in Adults with Malaria An Experience from a Tertiary Care Hospital in Northeastern India Debaprasad Chakrabarti, Associate Professor, Soma Saha, Assistant Professor, Anindya Sundar Trivedi, Postgraduate Trainee, A. K. Bhattacharyya, Professor and Head Department of Medicine, Tripura Medical College & Dr. BRAM Teaching Hospital, Hapania, Agartala. Abstract Bacterial co-infection associated with malaria is potentially important but poorly documented. Published reports are mainly from African children while data from adult Indian population are limited. To determine the spectrum of concurrent bacterial infection in malaria the present study was conducted in department of Medicine at Tripura Medical College. Out of eighty patients, 58 had falciparum, 15 had dual infection and 7 had vivax malaria. Blood culture failed to confirm bacteraemia in any sample with the exception of one case of complicated malaria showing the growth of Escherichia Coli. Urine culture also grew Escherichia Coli in 2.5% of enrolled patients. Anti salmonella IgM antibody was detected in 7.5% of the study population. Sputum culture was positive of streptococcus pneumoniae in single patient with radiological evidence of consolidation. CSF culture was sterile in cases with cerebral malaria. Thus the present study shows that bacteraemia is uncommon in adults with malaria compared to children of endemic areas. Presence of other co-existent infections should be sought in clinically suspected cases only. We propose a restrictive antibiotic policy in the setting of malaria. Keywords malaria, bacterial co-infection Introduction Malaria is a major disease of public health importance with high morbidity and mortality in tropical countries. The national vector born disease control program (NVBDCP) has reported 1.06 million cases of malaria and 519 malaria related deaths in India in the year The pathogenesis of severe disease is related to host and parasite interaction and recently malaria has also shown to strongly predispose individuals to bacteraemia 2. There is lab evidence of impaired immune function in malaria. Opsonisation and phagocyte killing by macrophages becomes impaired after ingestion of parasite derived hemozoin 3. Deficient cell mediated cytotoxicity has been demonstrated even in patients of low level parasitemia. Patients with malaria have reduced circulating T- Lymphocyte, impaired proliferative T-Cell response and have plasma anti lymphocyte antibodies. Humoral immunity has also been shown to be impaired in malaria 4. Therefore malaria and subsequent transient immune suppression can lead to opportunistic infections in previously immunocompetent individuals. Streptococcus pneumonae, Address for correspondence: Dr. Debaprasad Chakrabarti, Associate Professor of Medicine, Tripura Medical College & Dr. BRAM Teaching Hospital, Hapania, Agartala, Tripura (West), Pin drdebaprasad2007@ rediffmail.com

2 175 gram negative bacteria, staphylococcus aureus and non typhoid salmonella (NTS) were most commonly isolated organisms among severe malaria cases, with NTS being the commonest. To what extent there is a causal relationship between plasmodium infection and bacteraemia is unknown, and there is no enough data regarding bacterial co-infection in mild malaria or in adult population. It has been observed that patients with Plasmodium falciparum infection who have concurrent bacteraemia have increased risk of severe malarial anaemia, cerebral malaria, ARDS and mortality. This has forwarded the use of antibiotics in-combination to antimalarial drugs in severe malaria without any convincing evidence that this can reduce the mortality. Hence the present study is designed with the following objectives 1. To study the clinical profile of secondary infections in patients of malaria. 2. To investigate the concurrent bacteremia and its impact on different categories of malaria. Material and Methods Eighty consecutive patients of 18 years and above with freshly diagnosed cases of malaria admitted in the department of medicine, Tripura Medical College, over a period of one year (February January 2013) were included in the study. The subjects were enrolled after obtaining informed consent. The study was approved by institutional ethical committee. The diagnosis of malaria was based on findings of malaria parasites in peripheral smear by Giemsa stained thick and thin blood smears or malarial antigen assay (RDT) in smear negative patients. We excluded the patients who had history of prior antibiotic administration, patients known to be suffering from immunosuppressive disease or undergoing treatment with immunosuppressants. Similarly remote infections if persisting during the episode of malarial illness was also excluded. All patients were assessed clinically by relevant history, physical examinations. Routine haematological and biochemical tests were done to assess severity. Clinical categorization was done based on WHO 2000 guidelines 5. All subjects also underwent chest x-ray, urine culture, blood culture and salmonella typhi IgM antibody test. CSF analysis was carried out whenever required. Blood Culture The site selected for venipuncture was disinfected using 70% isopropyl alcohol followed by iodine to prevent contamination by bacterial flora of skin. The top of the collection bottle was cleaned using 70% isopropyl alcohol immediately before collection. Two samples were collected over a min interval. 10 ml of blood was drawn into a syringe and was aseptically introduced into commercially available glucose broth w/0.05% SPS. Majority of the blood cultures were drawn on the day of admission. Any growth was identified according to standard laboratory methods. Bacteraemia was considered as the isolation one non-contaminant bacteria from the admission blood culture. Coagulase negative staphylococci, anaerobic diptheroid positive findings were regarded as contaminants if detected in one bottle only. Urine was cultured on macconkey agar plates according to standard laboratory procedures. Statistical Analysis Data were entered into Microsoft excel 2010 and analysed by using the SPSS version 23.Analysis include the computation of descriptive statistics. Data were expressed as mean ± SEM. Differences between means were analysed by unpaired Student s t test. A p-value of<0.05 was considered to reveal a significant difference. Results A total of 80 patients were studied comprising of 59 males and 21 females. Baseline characteristics of the study population including malarial species are shown in Table 1. Plasmodium falciparum was most common species (72.5%), followed by mixed plasmodium infection (18.7%) and P. Vivax (8.7%). Out of them 22.5% had complicated malaria and 77.5% had uncomplicated malaria. Noncerebral severe malaria was the commonest manifestation in the cohort of complicated malaria. There was no significant difference in the duration of illness between patients of uncomplicated malaria when compared to the patients with other subtypes of severe malaria. There was also no significant difference in the levels of Total count (TLC), Differential leucocyte count (DLC), platelet and FBS between uncomplicated and complicated malaria. However, the difference in levels of haemoglobin, serum creatinine, serum bilirubin and SGPT, SGOT were statistically significant in patients with severe malaria (Table 2).

3 176 Subject Table 1 Demographic and Clinical Categories of study population Complicated Malaria (n=18) CM NCSM Un-complicated Malaria Total no. of patient Male/ Female 16/2 Mean Age ± ±8.93 P. Falciparum ( n=58) P. Vivax (n=7) Mixed (PF+PV) (n=15) Duration of illness (Day) 3.9± ±1.5 Mortality Note: CM-Cerebral malaria, NCSM-non cerebral severe malaria Table 2 Bio-chemical and hematological parameters of study population and statistical comparison in complicated and un-complicated malaria Parameters Un-complicated Malaria (n=62) Severe Malaria (n=18) p-valve Hb (gm/dl) ± ± 3.02 <0.01 TLC (cmm) ± ± NS Platelet count (10 3 /µ L) ± ± NS FBS (mg/dl) ± ± Creatinine (mg/dl) 1.05 ± ± 0.87 <0.01 Biliribin (mg/dl) 1.24 ± ± 1.0 <0.01 SGOT (IU/L) ± ± <0.01 SGPT (IU/L) ± ± <0.01 ALP (IU/L) ± ± NS CRP (mg/dl) 6.85 ± ± 6.6 NS Salmonella IgM Blood culture positivity 0 1 NA Data were expended as mean ± SD : * Statistically significant at p<0.05 N number of individual. * NS :- Non-significant. Blood culture revealed growth of Escherichia coli in single patient with severe malaria, representing 1.25% of all patients. Anti salmonella IgM antibody was found to be positive in 7.5% of patients. Urine culture was performed in all patients and out of them 2.5% had positive cultures for Escherichia coli. Chest radiography was normal in all with exception of one case having lung consolidation where sputum culture revealed growth of Streptococcus Pneumonae. CSF culture was sterile for any growth (Table 3). There was no mortality in the uncomplicated

4 177 Specimen Type Table 3 Bacterial cultures in Malaria Drawn No. (%) of culture Positive Bacterial Finding Blood 76 (95%) 1 (1.3%) E. Coli Urine 80 (100%) 2 (2.5%) E. Coli Sputum 15 (18%) 1 (6.6%) S. Pneumoniae CSF 4 (5%) 0 Sterile group. Single patient died from complicated malaria, however there was no evidence of secondary infection in that subject. Antibiotics were administered in all complicated malarial cases irrespective of positivity of blood cultures. Discussion This study of eighty adult patients with malaria has been categorized into various degrees of severity in order to analyse bacteraemia in individual groups. Establishing the importance of bacterial co-infection is essential for clinical management and can also contribute to an increased understanding of the pathogenesis of co infection. Out of 80 patients, bacteraemia were detected only in one case with gram negative bacteria which is in contrast to the high prevalence of bacteraemia reported in children with malaria in African settings 6,7. Published reports also reveal non typhoid salmonella being the commonest isolate in patients of severe malaria and associated with highest mortality 8,9. However none of our patients tested positive for non-typhoid salmonella. It is hypothesised that the beneficial cytoprotective effects of heme oxygenase-1 (HO-1) in malaria infection are counterpoised by higher susceptibility to nontyphoidal Salmonella (NTS) bacteraemia due to impaired oxidative burst and production of ROS in granulocytes leading to increased susceptibility to NTS bacteria and bacteria proliferation 10. In a recent study of 67 adults with different severities of malaria in India only one patient with uncomplicated malaria had bacterial growth of streptococcal pyogenes 11. It is possible that adult population may be more resistant to bacterial invasion unlike African children whose immune status is not comparable. Young Children are more vulnerable due to factors such as decreased gastric acidity or immaturity of gut lymphoid tissue 12. In our study Escherichia coli was isolated in two patients on urine culture without evidence of bacteraemia in them. We also observed anti-salmonella IgM antibody (Typhidot) in 7.5% of patients, however none of them grew S typhi on blood culture. Typhidot is a rapid dotenzyme immune assay (EIA), which detects IgG and IgM antibodies to a specific 50 kd outer membrane protein (OMP) antigen of Salmonella enterica serotype Typhi. Important to mention here that in comparison to the gold standard test ie blood culture, Typhidot has very high sensitivity and specificity of 92% and 98% respectively 13. Hence it can be surmised that 6 number of patient who tested positive for IgM anti Salmonella antibody could have true coexistence of enteric fever along with malaria. Ammah et al 14 reported that in 200 patients with fever, 17% had concurrent malaria and typhoid fever based on bacteriologically proven diagnosis. The poor yield by blood culture in our study could be explained by the fact that whilst highly specific, blood culture is an investigation of low sensitivity. All such cases received antibiotics active against salmonella in addition to antimalarial treatment. CSF analysis performed in all patients of cerebral malaria did not reveal any bacterial pathogen. Though all our patients of complicated malaria received antibiotics on admission, only one had blood culture suggestive of concurrent bacteraemia while two patients had Escherichia coli grown on urine cultures and one had sputum positive for S. pneumonae. However, it is important to mention here that according to WHO national guidelines the threshold for broad-spectrum antibiotics should be low in the management of patients of severe malaria and/or secondary bacterial infections 15.

5 178 In conclusion the frequency of bacterial co infection was low in our study as compared to higher prevalence previously described in children of endemic areas. Thus bacteraemia being uncommon in adult patients of severe malaria antibiotic therapy should be individualised based on the clinical profile. The study population being small in number, a larger study including more number of adult cases of malaria from different areas are needed to provide information whether the issue of bacterial co-infection are area specific and thus can guide the rational use of antibiotics in malaria. References 1. NVBDCP Government of India Report. Ministry of Health and Family Welfare, Scott J.A., Berkley J.A., Mwangi I., Ochola L., Uyoga S., Macharia A., Ndila C., Lowe B.S., Mwarumba S., Bauni E., Marsh K., Williams T.N. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case control study and a longitudinal study. Lancet. 378, , Scorza T., Magez S., Brys L., De bbbaetselier P. Hemozopin is a key factor in induction of malariaassociated immunosuppression. Parasite Immunol. 21: , Okwara F.N., Obimbo E.M., Wafula E.M., Murila F.V. Bacteraemia, urinary tract infection and malaria in hospitalised febrile children in Nairobi: Is there an association? East African Medical Journal. 81(1):47-50, WHO. Severe and complicated malaria. Trans of the R soc. Of Trop med and hyg. 94(suppl 1):1-90, Bassat Q., Guinovart C., Sigauque B., Mandomando I., Aide P., Sacarlal J., Nham-possa T., Bardaji A., Morais L., Machevo S., Letang E., Macete E., Aponte J.J., Roca A., Menendez C., Alonso P.L.. Severe malaria and concomitant bac-teraemia in children admitted to a rural Mozambican hospital. Trop. Med. Int. Health. 14, , Berkley J., Mwarumba S., Bramham K., Lowe B., Marsh K.,. Bacteraemia complicating severe malaria in children. Trans. R. Soc. Trop. Med. Hyg. 93, , Were T., Davenport G.C., Hittner J.B., Ouma C., Vulule J.M., Ong echa J.M., Perkins D.J. Bacteremia in Kenyan children presenting with malaria. J. Clin. Microbiol. 49: , Bronzman R.N. et al. Bacteraemia in Malawian children with severe malaria: prevelance, etiology, HIV coinfection, and outcome. J. Infect. Dis. 195: , Cunnington A.J., de Souza J.B., Walther M., Riley E.M. Malaria impairs resistance to Salmonella through heme- and hemeoxygenase dependent dysfunctional granulocyte mobilization. Nature Medicine. 18, , Pattanaik S.S., Tripathy R., Panda A.K., Sahu A.N., Das B.K. Bactaremia in adult patients presenting with malaria in India. Acta Trop. 12: , Evans J.A., Adusei A., Timmann C., May J., Mack D., Agbenyega T., Horstmann R.D., Frimpong E. High mortality of infant bacteremiaclinically indistinguishable from severe malaria. QJM. 97: , Jesudason M.V., Sivakumar S. Prospective evaluation of a rapid diagnostic test Typhidot for typhoid fever. Indian J Med Res. 123: , Ammah A., Nkuo-Akenji T., Ndip R., Deas J.E. An update on concurrent malaria and typhoid fever in Cameroon. Trans R Soc Trop Med Hyg. 93: , World Health Organization. Guidelines for the treatment of ma-laria. World Health Organization, Geneva, Switzerland, 2010.

BACTERAEMIA, URINARY TRACT INFECTION AND MALARIA IN HOSPITALISED FEBRILE CHILDREN IN NAIROBI: IS THERE AN ASSOCIATION?

January 2004 EAST AFRICAN MEDICAL JOURNAL 47 East African Medical Journal Vol. 81 No. 1 January 2004 BACTERAEMIA, URINARY TRACT INFECTION AND MALARIA IN HOSPITALISED FEBRILE CHILDREN IN NAIROBI: IS THERE