Determining the True Incidence of Transfusion Reactions in Transfusion Recepients by Active Hemovigilance by Transfusion Medicine Personnel: An Indian Study

Introduction

Hemovigilance (HV) is defined as the systematic surveillance of transfusion-related adverse events (AE) and adverse reactions (AR). HV system is an integral part of quality management in transfusion medicine (TM). HV is essential for the improvement of the quality and safety of blood and blood products, it encompasses all the activities of the blood transfusion chain, i.e., from blood donation till the blood/ component is transfused and extends in post transfusion phase [1]. HV was initiated in France in 1993 with obligatory reporting and in United Kingdom (UK) voluntary reporting system in 1996. However, HV programme (HvP) in India was incepted in December 2012 as part of pharmacovigilance programme [2, 3].

It is estimated that up to 10% of the transfusions are associated with the AE [4, 5]. One of the main goals of developing HvP is to improve Blood Transfusion practices by appropriate and timely reporting of TRs. The HvP relies on the reporting of TRs by the clinicians to the Department of TM which is ultimately updated to national HV networks [2, 5]. However, the published national and international studies state that TRs like Transfusion Associated Circulatory Overload (TACO), Transfusion Associated Lung Injury (TRALI) and Delayed Haemolytic Transfusion Reaction (DHTR) are often and missed under reported [5, 6, 7, 8]. In the light of international and national studies, we conducted a study to determine the true incidence of TRs by active bed side surveillance by transfusion medicine personnel and compare it with the retrospective data of clinician directed cases.

Material and Methods

This is a cross sectional study conducted in the department of TM at a tertiary care centre in Jodhpur, Rajasthan, India for which the ethical clearance was obtained.

The study was divided into prospective and retrospective arms. The retrospective arm included TRs reported only by clinicians, whereas in the prospective arm TRs were reported both by clinicians and by active follow up of the transfusion episodes by TM residents within 24 hrs post transfusion. The incidence of TRs in retrospective analysis arm was determined for the period of four years from mid of 2015 to 2019. The prospective analysis was carried out for six months duration from July 2019 to December 2019.

• Inclusion Criteria: All the allogenic transfusions were included.
• Exclusion Criteria: The transfusions during plasma exchange were excluded because it can introduce procedure related reactions which can confound the interpretation.
• Prospective analysis group: included proactive evaluation by TM residents followed by final adjudication of TR by TM specialists to ascertain the incidence of TRs by active surveillance over and above the routine reporting of TRs by clinicians.

Hence, the prospective study was divided into two groups namely

• TRs reported by clinicians (Passively).
• TRs reported by Active HV (by TM residents).

The prospective analysis was observational study hence patient consent was not taken, but hospital transfusion policy and nursing protocols were followed as laid down. During the study period, the transfused patients were assessed bed side with regards to post transfusion clinical parameters to rule out OR establish TR vide post transfusion questionnaire to be used by TM residents, enclosed as Appendix 1.

The active bed side evaluation of the transfused patient by TM residents included collecting data related to patient demographics, diagnosis, indications of transfusion, drug history, h/o previous and multiple transfusions, component- related data (type and number of components,), pre- transfusion and post-transfusion vitals (blood pressure, heart rate, respiratory rate, oxygen saturation) laboratory parameters (blood grouping, direct Coomb’s test, indirect Coomb’s test, pre and post complete blood count, pre and post renal function test, pre and post liver function test), radiology reports (pre and post Chest X-ray) and clinical records were recorded. The immediate care givers were interviewed and clinicians too if required.

Namely, the following evaluation tools were used (Figure 1)

• Post transfusion questionnaire enclosed in the Appendix no. 1 of the study to be used by TM residents.
• Transfusion monitoring forms filled by clinical residents and paramedical staff available in-patient records.
• Compatibility cum reaction forms returned back to blood bank within 24 hours by clinicians.

Click to enlarge

The final adjudication of TR was performed by TM specialist as per institutional protocols and International Society of Blood Transfusion (ISBT) definitions. The review period was 24 hours but in cases suspicious of DHTR like inadequate increase in post transfusion haemoglobin, increase in LDH etc. These patients were followed up for seven days post transfusion.

TRs were defined and classified for Imputability & severity (association of TR with BT) according to the guidelines provided by the International Society of Blood Transfusion working party on HV (ISBT) as detailed below [9]:

Statistics

The prospective analysis data was entered into Microsoft Excel spread sheet. The data was analysed and expressed as either descriptive statistical parameters like mean with standard deviation, median and range or as absolute numbers and percentages for categorical variables. The incidence was calculated as the percentage of total number of TRs divided by the total number of blood components transfused and also incidence was calculated for each category of components. Transfusion Episodes were not taken to calculate the incidence as done in few studies as it over estimates the incidence. Statistical comparison was made with the incidence reported in the past four years using Chi-square test as the retrospective data of TRs was available in the institution. This study was also compared with the past studies published in the indexed medical journals form India to avoid population bias.

Discussion

On comparative analysis of TRs reported in studies from India, the study undertaken by Kumar P et al & Bhattacharya P et al found incidence of TRs to be 0.05% (196 out of 380,658) & 0.19% (105 out of 56,503). This can be explained as underestimation of the true incidence because of under reporting by routine clinician directed HV [12, 13] (Table 6).

HV is a standard tool to advance the quality of the BTS, primarily focusing on safety [3]. Sahu, et al. observed that the incidence of actual TRs was under reported due to several reasons as follows:

• Lack of awareness and proper knowledge among clinicians and paramedical staff.
• Temporal association with transfusion is often overlooked and particularly in cases of delayed TRs.
• Similarity between clinical presentation of TRs with other common clinical conditions is a possible reason for missed diagnosis.
• It is difficult to diagnose TRs in comatose or unconscious patients [5, 10].

The knowledge gaps related to transfusion among paramedical staff has been established in independent studies by Shivgunde, et al. and Sapkota A, et al. Hence, active involvement and training of paramedical staff in reporting of TRs will go a long way in improving the reporting rates, as they are in proximity with the patients [10, 11].

Somagari DR, et al. observed that the incidence of TRs was proportional to the number of the transfusion events [3]. As studied, earlier HvPs relied on passive reporting, national and international studies have shown that active reporting systems report higher rates of TRs than passive ones [2, 5, 6, 7, 8]. Most studies that have carried out active surveillance did it either by review of patients’ records, auditing of electronic hospital medical records, review of TR reporting forms or by active feedback forms developed during study [3, 6].

In the present study and the study done by Sahu A, et al. [5] and various international studies done by Gosmann F, et al. & Bernard RS, et al. prospectively followed all allogenic transfusions by using various methods like active bed side evaluation of the transfused patient by TM resident which included clinical, laboratory, radiological correlation. Narick C et al performed a prospective study with similar design of active HV to evaluate incidence of TACO after plasma transfusion within 24 hours [8]. Raval JS et al focused-on TACO after platelet transfusions with the similar study design [7].

In our study, FNHTRs constituted the most frequently reported TR in all three groups,

• Incidence of 53.12% in Retrospective analysis group.
• Incidence of 44.44 % in overall Prospective analysis group.
• Incidence of 40 % in group: Reported by active HV subgroup of Prospective analysis.
• This is comparable to the latest HvPI data, wherein FNHTRs constituted the most frequently reported TRs with the percentage of 40.84% [2].

(Table 6) The overall incidence of TRs in Prospective arm is 0.54%, out of which 0.34% reported by active HV and only 0.20% were passively reported/ reported by clinicians. On statistical analysis of incidence of TRs in Prospective & Retrospective data, p value was.000493, p<0.05, hence it is statistically significant. It proves the hypothesis that active HV is superior in diagnosis of TRs in comparison with passive reporting.

Hence, it can be concluded that adopting Active HV methodologies for assessment of TRs can make significant differences in the reporting. Therefore, standardisation of HV practices, training of all the para medical, medical staff to ensure uniformity and quality in reporting of TRs.

As per data available, it is observed that Non-severe TRs frequently remain un reported [16]. In the active HV group of the prospective analysis, FNHTRs, TACO, DHTR, TAD, allergic reactions were diagnosed by active surveillance, out of which DHTR, TACO can be severe, can have serious consequences for the patient. During the study, no anaphylactic, anaphylactoid or AHTRs, deaths were observed and the incidence of these entities was nil in both the arms. Delayed Haemolytic Transfusion Reactions (DHTRs). DHTRs is a potentially life- threatening complication of transfusion in multi transfused patients like, Sickle cell disease (SCD) patients. SCD patients are more likely to be alloimmunized than the general population due to discrepancies between the recipient’s and donors RBCs phenotype [17]. DHTRs are the outcome of immunological responses mounted by the recipient to the epitopes/ antigens present on the transfused blood cells. This response is delayed and manifested as accelerated destruction of transfused red blood cells (RBCs) [17].

Haemolytic Transfusion Reaction (HTR) is clinically defined by one of the following symptoms that include fever, pain, passage of dark urine, decrease in post transfusion haemoglobin concentration, increase in LDH levels [18].

Conclusion

Active surveillance of TRs has provided a true picture of the incidence of TRs. Two un reported DHTR cases were reported. DHTRs are under reported TRs due to lack of knowledge and vigilance. More studies are needed to evaluate the true incidence of DHTRs. No severe or life-threatening TRs were found during the present study.

In our study, FNHTRs constituted the most frequently reported TR in both prospective & retrospective analysis which is in line with other peer group studies. This study shows statistically significant difference in incidence of TRs reported by passive reporting and Active HV by TM personnel. It can be concluded that adopting Active HV for assessment of incidence of TRs can make statistically significant differences in the reporting; this area needs more comprehensive studies.