Transfusion-related acute lung injury in the Canadian paediatric population

Abstract

BACKGROUND:

The incidence of transfusion-related acute lung injury (TRALI) in adults is approximately one per 5000 transfusions. The Canadian Paediatric Surveillance Program undertook the present study to determine the incidence of TRALI in the paediatric population and to describe the characteristics and outcomes of children with TRALI.

METHODS:

The present surveillance study was conducted over a three-year period.

RESULTS:

Four TRALI cases were reported, yielding an incidence rate of 1.8 per 100,000 transfusions. The degree of severity varied: in two patients, only supplemental oxygen was necessary, while the other two required mechanical ventilation.

CONCLUSION:

TRALI was reported much less often in the present study compared with adult studies; therefore, it needs to be determined whether TRALI occurs less frequently in children, or alternatively, whether TRALI is recognized less often in children. The possibility that neonates who undergo cardiac surgery are at greater risk of TRALI than other patients should be addressed in future studies.

Transfusion-related acute lung injury (TRALI) is an infrequent but serious complication that occurs within hours following the transfusion of blood products (eg, red blood cells, platelets, plasma, cryoprecipitate) and is characterized by respiratory distress, hypoxemia, pulmonary edema, hypotension and fever. Most cases require oxygen support and mechanical ventilation (1). TRALI was first described as a specific transfusion reaction in 1983 by Popovsky et al (2). According to a United States Food and Drug Administration report on transfusion-related deaths (3), TRALI was the top-ranked cause of reported fatalities (n=127; 48%) from 2005 through 2009.

Two pathophysiological mechanisms have been proposed for TRALI. In the first, named the antibody hypothesis, the pathogenesis of TRALI is related to the infusion of donor antibodies that recognize leukocyte antigens in the transfused host (1,4–10). According to the second hypothesis, called the two-hit or two-event model, neutrophils of recipient origin must be primed by a pre-existing clinical condition. These primed neutrophils trigger an inflammatory response in the lung alveoli when exposed to bioactive substances in the transfused product, resulting in pulmonary edema (11–14). Recent studies suggest that the two theories may be linked (15). This has led to the development of a unifying model (the threshold model) by Bux and Sachs (16). According to this model, the level of priming of neutrophils, either directly or through activation of the pulmonary endothelium, by a patient’s clinical condition and by substances (including antibodies) present in the transfused component, is responsible for triggering TRALI in a recipient.

The incidence of TRALI is not well known. Estimates in the literature range from one in 432 to one in 725,000 units, depending on the type of product considered, the case definition of TRALI used, and the nature and size of the denominator (17–20). According to data collected by the Quebec Hemovigilance System (QHS), the incidence of TRALI was one per 23,506 units transfused during the period from 2000 to 2005 (21). The incidence of TRALI is unknown in the paediatric population.

A major obstacle in estimating the incidence of TRALI has been the absence of a standard case definition. Such a definition was developed at a consensus conference held in Toronto (Ontario) in April 2004 (11,17), which has allowed for better comparisons of incidence data in different settings. To minimize false-positives, the 2004 consensus definition was restricted to acute lung injury (ALI) occurring within 6 h of transfusion and not attributable to other causes of ALI.

The Canadian Paediatric Surveillance Program (CPSP) undertook the present study to determine the incidence of TRALI in the paediatric population and to describe patient characteristics, clinical signs and symptoms, and outcomes of TRALI in children.

METHODS

The present study was performed through the CPSP from September 2005 through August 2008. The CPSP is a national, active, surveillance program for rare paediatric diseases that involves more than 2350 Canadian paediatricians (22), including 90% of actively practising paediatricians and paediatric subspecialists across Canada.

A check-off form was mailed monthly to all participants who then answered “Yes” or “No” as to whether they saw new cases of TRALI in the previous month. When a case was reported by a paediatrician, he/she was asked to complete a detailed clinical questionnaire. Overall, the CPSP monthly reporting rate averages 80%, and the response rate for completion of the detailed questionnaire is 94%.

Confidentiality was mandatory and the study received ethics approval from the Sainte-Justine Hospital institutional review board.

Definition of TRALI

The definition of TRALI used for inclusion of patients in the present study was the definition proposed at the Toronto Consensus Conference in April 2004 (17). TRALI was defined as “a new episode of acute lung injury (ALI) that occurs during or within 6 hours of a completed transfusion, which is not temporally related to a competing etiology for ALI” (17). Specific criteria for the definition of TRALI are shown in Table 1. ALI can occur independently of transfusion in many clinical conditions. For this reason, it was considered necessary to also have a definition for “possible TRALI”, defined as “an ALI temporally related to both transfusion and at least one other risk factor” (17). Criteria for possible TRALI are shown in Table 1 and risk factors are listed in Table 2. Both definitions specifically exclude cases of circulatory overload and “cases with pre-existing ALI who subsequently receive a transfusion and whose ALI then worsens” (17). Because there was no recommended specific definition for the paediatric population from this consensus conference, this definition was used for the present study.

TABLE 1.

Recommended criteria for transfusion-related acute lung injury (TRALI) and possible TRALI

TRALI criteria ALI Acute onset Hypoxemia PaO2/FiO2 ≤300 or SpO2 <90% on room air Bilateral infiltrates on frontal chest radiograph No evidence of left atrial hypertension (ie, circulatory overload) No pre-existing acute lung injury before transfusion During or within 6 h of transfusion No temporal relationship to an alternative risk factor for ALI Possible TRALI ALI No pre-existing acute lung injury before transfusion During or within 6 h of transfusion A clear temporal relationship to an alternative risk factor for ALI

Adapted from reference 17. ALI Acute lung injury; FiO₂ Fraction of inspired oxygen; PaO₂ Partial pressure of arterial oxygen; SpO₂ Saturation of peripheral oxygen

TABLE 2.

Risk factors for acute lung injury

Direct lung injury	Indirect lung injury
Aspiration	Severe sepsis
Pneumonia	Shock
Toxic inhalation	Multiple trauma
Lung contusion	Burn injury
Near drowning	Acute pancreatitis
	Cardiopulmonary bypass
	Drug overdose

Adapted from reference 17

Incidence of TRALI

The incidence of TRALI was calculated as the number of TRALI cases reported in the Canadian paediatric population (numerator) divided by the number of transfusions in this population (denominator). A transfusion was defined as a unit of a blood component (red blood cells, platelets, plasma or cryoprecipitate) or, for smaller children, any volume of a blood component administered in a transfusion episode. The denominator (number of transfusions) for the province of Quebec was calculated using data from the Société de Gestion Informatique, which collects data from Traceline, the system used in all of Quebec’s blood banks. Using the denominator from Quebec, the number of transfusions given to Canadian children each year (using population numbers from Statistics Canada 2009) was estimated to be approximatively 74,600.

The duration of the present study was chosen according to the number of expected cases of TRALI. Based on TRALI incidence in adults (17,23), combined with estimates from paediatric population statistics and Quebec data on paediatric transfusion frequency (24), 20 paediatric cases of TRALI were expected annually. To obtain reasonably narrow CIs and to accurately characterize patients and describe treatment and outcome, it was determined that 40 cases of paediatric TRALI should be identified. Although the study was originally to be conducted over two years, because the number of cases reported per year was lower than expected, the study was extended for a third year.

Patient data

Patient characteristics included age, weight, sex, underlying condition, primary diagnosis at admission and history of previous transfusions. Transfusion data included date and time of transfusion, type of blood donation (ie, autologous, directed or regular allogenic), type of blood component and volume of blood component received.

Clinical data included signs and symptoms (eg, dyspnea, tachypnea, hypotension, fever, tachycardia) and, if available, paraclinical data (eg, central venous pressure, presence of cardiac dysfunction on cardiac ultrasound, partial pressure of arterial oxygen/worst fraction of inspired oxygen [PaO₂/FiO₂] ratio or saturation level [SpO₂]). Date and time of onset and duration of symptoms after transfusion were also collected.

Data on management of TRALI included administration of supplemental FiO₂, invasive and/or noninvasive mechanical ventilation, admission to an intensive care unit (ICU), fluid resuscitation, use of inotropes/vasopressors and use of diuretics. Finally, data on death or complications associated with TRALI were collected.

Statistics

CIs for the incidence of TRALI were calculated using the Wilson score-based binomial test.

RESULTS

Four TRALI cases were reported during the three years of surveillance, yielding an incidence rate of 1.8 per 100,000 transfusions (95% CI 1.6 to 10.3).

The first case occurred in a term neonate with transposition of the great arteries who underwent an arterial switch operation with extracorporeal circulation, who was still in the ICU at the time of the reaction. The patient had received multiple transfusions during the surgery. TRALI occurred on postoperative day 3, after the administration of an allogenic red blood cell transfusion (13 mL/kg) over 4 h. Within 1 h after the end of the transfusion, the patient presented with dyspnea (60 breaths/min) with desaturation (SpO₂ 80%). The PaO₂/FiO₂ ratio dropped from 528 mmHg to 241 mmHg. The chest x-ray, which was normal before the transfusion, revealed bilateral infiltrates. Echocardiography and central venous pressure monitoring excluded cardiac dysfunction and circulatory overload. The patient was placed on oxygen and gradually improved over the following 96 h without further complications. The medical team concluded that the TRALI constituted an acute life-threatening event with no long-term morbidity.

The second case involved an infant with anemia of unknown origin and possible metabolic disease who developed TRALI after receiving a red blood cell transfusion (15 mL/kg) over 4 h. Symptoms, which appeared 3 h after the end of the transfusion, consisted of dyspnea, desaturation (SpO₂ 88%), fever and tachycardia, and were associated with a chest x-ray showing new pulmonary edema. The ICU team was consulted but the patient was not transferred to the ICU. The patient received supplemental oxygen (1 L/min) and improved gradually over 24 h to 48 h without further complications. The medical team concluded that the TRALI caused an immediate life-threatening event with no long-term morbidity.

The third case occurred in a neonate born prematurely at 35 weeks’ gestation with severe intrauterine growth retardation and vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, esophageal atresia and renal anomalies (VACTER) malformations. He was undergoing cardiac surgery with extracorporeal circulation for tetralogy of Fallot. During the 2 h surgical procedure, he received multiple transfusions including plasma (33 mL/kg) and apheresis platelets (18 mL/kg). Signs and symptoms of TRALI developed during the procedure while the patient was intubated, mechanically ventilated and still on extracorporal circulation. The onset of the reaction occurred a few minutes after the end of administration of an allogenic red blood cell transfusion (10 mL/kg) that had lasted over 30 min. The patient presented with desaturation episodes requiring increased oxygen administration (FiO₂ 100%) as well as increased ventilatory pressures (inspiratory pressure increased from 24 cmH₂O to 40 cmH₂O). The PaO₂/FiO₂ ratio dropped from 532 mmHg to 52 mmHg. There were no signs of cardiac dysfunction. Central venous pressure and wedge pressures varied from 13 mmHg to 16 mmHg, with a maximum of 21 mmHg on one occasion. In the following hours, the patient required high-frequency ventilation, nitric oxide administration (20 ppm), sedation with paralyzing agents, a fluid bolus of more than 10 mL/kg and inotropes. He also developed a pneumothorax in the following days. After the episode of TRALI, he was ventilated for a total of 10 days, remained in the paediatric ICU for 13 days and was discharged home seven days later. The medical team concluded that the TRALI caused an immediate life-threatening event with no long-term morbidity. Because there was a temporal relationship with another risk factor for ALI, namely, extracorporal circulation, this case is categorized as a possible TRALI.

The fourth case occurred in an adolescent with acute lymphoblastic leukemia who was hospitalized for chemotherapy. The hospitalization was complicated by an infection of the central line and acute renal failure due to chemotherapy toxicity. The patient did not have any cardiac dysfunction and had been frequently transfused previously. The patient received an allogenic red blood cell transfusion (6 mL/kg) to treat chemotherapy-associated anemia. Within 2 h of the transfusion, the patient developed severe dyspnea and fever. The oxygen saturation dropped below 90% while receiving 100% oxygen, necessitating intubation and mechanical ventilation. No inotropes were required, but ventilatory support was needed for a total of 10 days. According to the medical team, the TRALI was considered to be an immediate life-threatening event with no long-term morbidity.

The secondary objective of the present study was to describe patient characteristics, clinical signs and symptoms, and outcomes of TRALI in children. Three of the four patients were younger than one year of age and three of the four patients were already in the paediatric ICU when TRALI developed. Clinical symptoms present, apart from dyspnea, were fever in two cases, tachycardia in one case and hypotension in one case. All cases of TRALI were associated with red blood cell transfusions and all patients had received multiple transfusions before the TRALI event. In all cases, the blood volume given was in the usual range (6 mL/kg to 15 mL/kg).

DISCUSSION

The wide range of reported TRALI incidence rates (5,17,18,23) can be attributed to different definitions used in studies or surveillance systems, different diagnostic criteria, different quality of denominator data used (eg, components issued versus products transfused) and, most importantly, whether the rates were derived from prospective studies or from surveillance systems; in the latter case, the rates vary according to the characteristics of the surveillance system. Between 1996 and 2005, the Serious Hazards of Transfusion (SHOT) hemovigilance system has analysed 3239 reports of adverse reactions and events associated with transfusion in the United Kingdom (25). Of those, 10% (321 reports) related to transfusion of children younger than 18 years of age. Twenty cases of TRALI occurred in children, accounting for 5% of all adverse events or reactions. This proportion was almost identical to the proportion of TRALI in adults (6% of all adverse events). In the QHS, the incidence of TRALI was one per 26,056 in the paediatric population versus one per 55,852 in the adult population during the period from 2000 to 2005 (26).

Aside from the results from a few hemovigilance systems, there has been no systematic determination of the incidence of TRALI in the paediatric population. Evidence of TRALI in children, and in neonates, is only supported by published case reports (8,27–38) or by local case series (24).

Although TRALI is becoming recognized more frequently and has been discussed extensively in recent, transfusion-related medical literature, very few cases of TRALI were reported during the present CPSP active surveillance study. Reasons for this could include:

• that TRALI is truly more rare in children, although pathophysiological reasons for this are not yet known;

• that TRALI is more difficult to differentiate from other pulmonary pathologies (eg, acute respiratory distress syndrome, pulmonary edema, allergic reaction, transfusion-associated circulatory overload, sepsis) in children than in adults;

• that the TRALI definition is not suitable in paediatrics, particularly neonates;

• that the exclusion criteria discounting patients with previous ALI are restrictive and may exclude ICU patients that are more at risk, as mentioned in the adult literature (25);

• that TRALI may be less severe in children and, therefore, less frequently recognized;

• that the methodology of the present surveillance study may result in under-reporting and may not capture all recognized cases of paediatric TRALI.

Because under-reporting could be an important factor, efforts were made to try to validate our data with other databases or surveillance programs in Canada. Our data were cross-validated with those of the QHS and Héma-Québec for the same period. According to those data, all cases of TRALI reported in Quebec were included. However, we were not able to obtain paediatric TRALI data from the Canadian Transfusion Transmitted Injuries Surveillance System. Thus, under-reporting cannot be excluded as a contributing factor for the low incidence of TRALI found in the present surveillance study.

A better way to determine the incidence of and risk factors for TRALI would be to perform a prospective study, closely monitoring all transfusions given and then confirming the diagnosis with the appropriate investigations. However, because of the very low incidence of TRALI, regional epidemiological research on this subject is not feasible. Only a hospital-based, multicentre, prospective epidemiological study could completely and accurately determine the incidence of and risk factors for TRALI.

Treatment of TRALI consists of ventilatory and hemodynamic support (39). In cases reported in the literature, oxygen administration and mechanical ventilation were necessary in 100% and 72% of cases, respectively (4). Hypotension may be unresponsive to fluid administration and may require the use of inotropes or vasopressors (1). TRALI patients usually have a good prognosis; however, the mortality rate is approximately 6% (4). There are several reports in the literature of children who have died following TRALI (30,33–35). In patients who survive, resolution is usually rapid (within 96 h) and there are no long-term sequelae (39). In some patients (20%), hypoxemia and pulmonary infiltrates persist for more than seven days (1). These data are consistent with the results of our paediatric study. Furthermore, the different degrees of severity of these four paediatric TRALI cases is important to note. In two cases, TRALI was easily managed with oxygen alone. In the remaining two cases, TRALI was immediately life-threatening and required aggressive treatment including mechanical ventilation, high-frequency ventilation, nitric oxide and inotropes.

Two of the four cases occurred in neonates with congenital cardiopathy who underwent cardiac surgery with cardiopulmonary bypass. Another case of a toddler undergoing elective surgery with cardiopulmonary bypass has been reported in the literature (28). The possibility that this population is at higher risk of TRALI should be addressed in future studies. Gajic et al (9) have demonstrated that adult ICU patients have a higher risk of TRALI (8%) than do other adults.

The present surveillance study is a useful tool to promote education among health care professionals about this uncommon transfusion reaction. Information on TRALI helps paediatricians to better recognize this rare, but serious, life-threatening complication and to acknowledge the need to immediately alert the blood bank to prevent further distribution of blood components from the same donor to other patients, thereby avoiding further TRALI episodes (36). In the present study, all TRALI events were reported to the hospital’s blood bank/transfusion service.

It is unlikely that TRALI can ever be entirely prevented, but its frequency may be reduced by measures taken by blood suppliers. Published surveys concerning blood transfusion practices and policies for Canadian paediatric patients indicate that, for neonates, a minority of centres use washed or volume-reduced red blood cell units and approximately one-half use volume-reduced platelets (40–43). Adoption of these practices could possibly contribute to a lower incidence of TRALI in neonates. In 2007, both Canadian blood suppliers (Canadian Blood Services and Héma-Québec) began introducing TRALI prevention measures (ie, use of predominantly male donors for plasma, interdiction of the use of plasma for directed donation from mother to child), which could have decreased the incidence of TRALI, particularly for TRALI associated with plasma transfusions.

In conclusion, it remains to be determined whether TRALI occurs less frequently in children, or alternatively, whether TRALI is recognized less often in children. A specific definition for paediatric patients may need to be considered, especially for patients with previous ALI or superimposed ALI.