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Correlation of histamine-2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) to the platelet count in patient with dengue viral infection

Thrombocytopenia is often associated with clinically worse outcomes in dengue viral infection (DVI) patients. Histamine-2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) have been reported to induce thrombocytopenia. These drugs are administered to DVI patients due to misinterpretation of abdominal pain. The study aimed to evaluate the correlation between H2RA and PPI administration with thrombocytopenia event on hospitalized DVI patients. An analytical retrospective cross-sectional study was conducted using medical records of the patient admitted by final diagnosed DVI in seven major hospital in Bandung from January 1st to December 31st, 2015. Patients were separated into two groups i.e. with and without H2RA and PPI. Pearson point biserial analysis was then applied to evaluate the correlation of each drug administration to platelet count of DVI. A total of 4005 patients with final diagnosed DVI involved in this study. About 11.0% and 25.1% of the patients received H2RA and PPI, respectively. Mostly the DVI patients receiving H2RA (55%) and PPI (50.8%) showed the platelet count <50.000/mm3. A very weak positive correlation between the administration of H2RA (p <0.001; r=0.103) and PPI (p <0.001; r=0.138) with the low platelet count of the patients was observed. In conclusion, the administration of H2RA and PPI is correlated to the low platelet count in DVI patients. Although the correlation is weak, H2RA and PPI should be administered with caution due to its thrombocytopenia side effect.


INTRODUCTION
Dengue viral infection (DVI) is a common arboviral disease in humans that remains to be a global burden in tropic and subtropics countries in the world. 1 Dengue viral infection  is  characterized  by  hematologic  abnormality presentation, namely, thrombocytopenia. Thrombocytopenia is one indicator of clinical severity which indirectly showed the activity of platelet activation. It is also counted to be a risk predictor for disease progression and prognosis in DVI. [2][3][4] Furthermore, severe thrombocytopenia (<50.000/mm 3 ) was independently and significantly associated with the risk of mortality. 4 According to the World Health Organization (WHO) guideline, DVI patients can be administered some symptomatic therapy such as an antiulcer for gastrointestinal bleeding. 1 Empirically, antiulcer administration in the form histamine-2 receptor antagonist (H 2 RA) and proton pump inhibitor (PPI) 5 become management for abdominal pain in DVI while this symptom was mostly manifested as the result of liver disturbance. 6 Moreover, these drugs was reported as one of the most drugs prescribed for DVI patients followed analgesic, multivitamin and antipyretic. However, H 2 RA and PPI were reported can induce thrombocytopenia event 7,8 which could worsen the thrombocytopenia condition of DVI patients. In this study, the relationship between the administration of H 2 RA and PPI and the lowest platelet counts in DVI patients was reported.

Patients
This study is part of the This study included both children and adults which admitted to those hospitals with a final diagnosis confirmed as DF, DHF, and DSS based on WHO-SEARO 2011 criteria. 5 Patient with incomplete platelet examination, no information of final diagnosis was excluded. This study used total sampling, then collected data were grouped based on the demographic characteristic of sex, age group, 6 and final diagnosis.

Protocol of study
The patients were divided into groups that received and did not receive reduced acid secretion drugs (RASDs) during their admission. The output of each group was assessed by the lowest platelet count obtained from platelet examination during the admission period which was classified in an interval manner. 7 The operational definitions used in this case are drugs that cause a reduction in gastric acid secretion, limited to H 2 RA and PPI and platelet counts, which were the lowest platelet counts during the treatment period. The lowest platelet value was selected in consideration that in dengue patients there was a tendency to have thrombocytopenia during the course of the disease. 8 Therefore, this thrombocytopenia-only condition may be caused by DVI. This study tried to evaluate the correlation whether the lowest platelet values in patients who received RASD compared to those who did not receive RASD during their treatment period were related to drugs or not. The study had passed the ethical clearance by the Research Ethics Committee, Faculty of Medicine, Universitas Padjadjaran, Bandung.

Statistical analysis
Statistics software SPSS version 25 was used for data analysis. Point biserial analysis was used to evaluate the relationship of each H 2 RA and PPI administration with the lowest platelet count in DVI patients. The p value <0.05 was considered to be a statistically significant between tested variables. The power of relation interpreted as very weak (r= 0.00-0.199), weak (r=0.2-0.299), moderate (r=0.4-0.599), strong (r=0.6-0.799) and very strong (r=0.8-1). 9

RESULTS
A total of 4005 patients who lived in Bandung had admitted to the hospital by final diagnosed DVI were involved in this study. The types of drugs given by the hospital to DVI patients in managing the cases were described based on its therapy class in     The relation of each of RASD group, specifically H 2 RA and PPI with patient low platelet count is showed in TABLE 4. Administration of H 2 RA significantly was correlated with low platelet count (p<0.05), although it was classified very weak (r=0.103). Furthermore, administration of PPI was also correlated with low platelet count (p<0.05) with very weak correlation (r=0.138).

DISCUSSION
Dengue viral infection is a common mosquito vector-borne disease in humans. This study presented the drug utilization in managing DVI. Group of antiulcer (RASD) ranked the third most drug prescribed of the hospital, PPI (25.1%) and H 2 RA (11%) respectively, following analgesic-antipyretic and antibiotic.
A retrospective study conducted in Yogyakarta also obtained similar results. 10 The provision of this administration based on complaints of abdominal pain of DVI patients, other than to prevent the occurrence of gastrointestinal bleeding. 1 This study found that about 11% of DVI patients were given H 2 RA during their admission. Most of the DVI patients had low platelet counts <50.000 /mm 3 . However, only 15% of all low platelet group patients <50.000/mm 3 , which considered severe thrombocytopenia, received H 2 RA. This large number of patients with severe thrombocytopenia despite not prescribed H 2 RA could occur as a result of thrombocytopenia caused by the dengue virus itself. Thrombocytopenia is a manifestation that often occurs in patients with DVI. Dengue virus could cause thrombocytopenia by increasing platelet destruction via immune reactions and releasing inflammatory mediators that could interfere with the process of platelet production. 11,12 Previous studies reported that thrombocytopenia could be induced by RASDs, although this event is still considered a relatively rare phenomenon. The evidence of H 2 RA induced thrombocytopenia events was confirmed by finding the presence of drug-dependent-antibodies (DDA) in the serum of patients who had severe acute thrombocytopenia after receiving H 2 RA. 13 These antibodies formed due to H 2 RA, which even in pharmacological concentrations, were able to recognize the receptor side of GPIX platelet so that they can destroy platelets and cause thrombocytopenia. Reese et al. 14 also analyzed the drugs that cause acute hospital-acquired thrombocytopenia in hospitalized patients using 3 different methods to reassert the truth of this incident. The results showed that the H 2 RA can cause thrombocytopenia based on clinical data extraction in various case reports, data mining and proven by the presence of antibodies on laboratory examination. Arnold et al. 15 also reinforced the occurrence of H 2 RA induced thrombocytopenia. The study identified drugs that clinically caused the incidence of drug-induced thrombocytopenia (DITP) included H 2 RA. Although those studies had proved the incidence of thrombocytopenia induced by H 2 RA. However, all those study were involved non-DVI patients. Until now, the studies reporting the thrombocytopenia induced by H 2 RA administration in DVI patients are limited. This study reported the positive significant correlation between H 2 RA and low platelet counts in DVI patients, although the correlation was considered very weak.
This study found about 25.1% of patients with DVI received PPIs during their admission and most (55%) had platelet counts <50.000/mm 3 or severe thrombocytopenia. Thrombocytopenia is known not to be a common side effect of PPI drugs. Nevertheless, this study showed a positive significant correlation with very weak strength. Surprisingly, that PPI had a stronger relationship with thrombocytopenia than H 2 RA. This could occur since H 2 RA has been more known to be able to cause thrombocytopenia so that its use was less than PPI.
Previous studies also reported the decreasing platelet following PPI administration. Aster et al. 16 showed that the PPI group can induce thrombocytopenia occurrence. Various PPI classes were also reported in some case reports and reviews of literature. 17,18 Retrospective analytic studies conducted at Duke University Hospital also found an significantly association between thrombocytopenia events in hospitalized patients who received PPIs during their treatment period. 19 However, these studies were conducted in patients with acute thrombocytopenia during their admission period not DVI patients. Although many studies support the relationship between PPI administration and thrombocytopenia, this phenomenon was still based on the analysis of various case reports and retrospective studies. Therefore, a prospective study is required to confirm this relationship, even less, in DVI patients.
This study has several limitations. First, this study also did not regard the coinfection of patients which might be another cause of thrombocytopenia. Second, in the obtained data, there was no information regarding the timing of starting the drug and the daily platelet value of each patient. Subsequently, this study also did not adjust the confounding variables thus that it can not be known which factors influence RASD administration and platelet count in DVI patients. Third, as this study used a retrospective approach with a cross-sectional method, the incidence of thrombocytopenia by the patients receiving RASD cannot be distinguished from the incidence of thrombocytopenia that occurs as a result of DVI itself. The limitation of available data regarding the time of RASDs administration, that it is inconvenient to decide the causal precede the effect. Further, prospective studies are needed to better understand the cause-effect of RASD administration on the platelet count.

CONCLUSION
In conclusion, the administration of H 2 RA and PPI is correlated to the low platelet count in DVI patients. Although the correlation is weak, H 2 RA and PPI should be administered with caution due to its thrombocytopenia side effect.