Adverse reactions and events related to musculoskeletal allografts: reviewed by the World Health Organisation Project NOTIFY.

PURPOSE: The use of bone and connective tissue allografts has grown rapidly and surpassed the use of autografts in many countries. Being of human origin, bone and tendon allografts carry the risk of disease transmission and complications have been reported. As part of the Project NOTIFY led by the World Health Organisation, an effort to improve recognition, reporting, tracking and investigation of adverse outcomes of allografts was initiated, achieving a comprehensive review of associated disease transmission and failures. Those involving the use of musculoskeletal allografts are reported here. A major objective is to involve orthopaedic surgeons in the improvement of the safe use of the musculoskeletal allografts. METHODS: We reviewed the medical literature, requested reports from surgeons in selected professional organisations and informally surveyed tissue bank organisations and selected tissue bank professionals to discover reported and unreported cases of adverse outcomes. We analysed each case to decide the likelihood that the complication was truly allograft related. RESULTS: The efficiency of the procedures involved in bone banking and bone and tendon allograft has improved significantly during the last three decades. The evolution of the incidence of reported adverse reactions and events reflects positively on the safety of transplanted tissues. Cases of bacterial and viral transmission by bone and tendon allografts occurred mainly with those that contained viable cells, were not processed to remove cells, or were not disinfected or sterilised. We documented cases of transmission of human immunodeficiency virus (HIV), hepatitis C virus (HCV), human T-lymphotropic virus (HTLV), unspecified hepatitis, tuberculosis and other bacteria. Reporting of these adverse outcomes has led to corrective actions and has significantly improved the safety of allograft use. However, it is probable that not all cases have been reported and investigated. CONCLUSIONS: Considering the high quality standards achieved in many countries, the best approach for further improvement in the safety of allografts is through a systematic reporting of all serious adverse reactions and events in the context of a global biovigilance programme.

The role of cytokines in blood transfusion reactions.

Recent advance in the understanding of the mechanism of hemolytic transfusion reactions results from the investigation of cytokine generation in in vitro models of incompatible red blood cell transfusion. Cytokines with pyrogenic and pro-inflammatory activities as well as cytokines with activating properties for granulocytes, monocytes and endothelial cells are produced in both 'intravascular' and 'extravascular' types of hemolytic reactions. It has also been demonstrated that cytokines are generated and accumulated in blood components such as platelet concentrates, during storage. A large part of febrile transfusion reactions results from transfusion of stored platelet concentrates containing high cytokine levels and not from antigen-antibody reactions. Prestorage removal of white blood cells, which generate cytokines during storage, from platelet concentrates reduces strongly the reaction incidence and should be standard practice.

Assessment of anti-HLA antibodies in sera being tested for platelet reactivity by a platelet lymphocyte immunofluorescence test (PLIFT).

An indirect immunofluorescence test using a platelet mononuclear cell suspension is described. The test is a simple and sensitive method to assess the contamination by anti-HLA antibodies of sera being tested for platelet reactivity and eliminates the need to support two independent test systems such as lymphocytotoxicity and immunofluorescence testing. The test could be of value in routine platelet serology testing and platelet crossmatching.

A seroepidemiological survey of HTLV-I/HTLV-II in selected Belgian populations.

A preliminary survey of the prevalence of HTLV-I antibody during 1987 and 1988 in Belgium revealed no positive results among selected blood donors who sided for some length of time in areas where HTLV-I/HTLV-II is endemic (n = 270), in development-aid workers (n = 145), or in missionaries (n = 35) serving in developing countries. Among foreign groups, African students (n = 212), and political refugees (n = 311), HTLV-I/HTLV-II antibodies were detected and confirmed in 3 cases. Limited data from 1987 and 1988 suggest that HTLV-I/HTLV-II poses no major public health problem in Belgium.

Absence of linkage with the Duffy blood group in a family with Charcot-Marie-Tooth neuropathy.

We report a large Belgian family with Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy type I (HMSN-I). The pedigree consists of 5 generations with 350 family members comprising 42 patients. The disease is transmitted according to an autosomal dominant inheritance pattern. Several HMSN-I families have been reported to be closely linked to the Duffy blood group marker on chromosome 1. These families were designated HMSN-Ib families, opposed to the HMSN-Ia families which do not show evidence for such a linkage. Therefore we examined our family for the Duffy linkage relationship. We found no evidence for a strong linkage of the disease to the Duffy blood group locus, indicating that this family is of genetic subtype Ia.

Linkage analysis of distal hereditary motor neuropathy type II (distal HMN II) in a single pedigree.

We describe a six generation family affected with the autosomal dominant form of distal hereditary motor neuropathy type II (distal HMN II). The distal HMN shows similarities with the hereditary motor and sensory neuropathies type I and II (HMSN I and HMSN II) or Charcot-Marie-Tooth disease type 1 and 2 (CMT 1 and CMT 2) and with some proximal HMN or spinal muscular atrophies (SMA). Gene loci have been assigned to chromosomes 1q, 17p, and 19q for CMT 1 and to chromosome 5q for recessive SMA. In this study we excluded all four regions for the presence of distal HMN II, indicating that this neuropathy is genetically different from CMT 1 and recessive SMA.

Exopeptidases in human platelets: an indication for proteolytic modulation of biologically active peptides.

The determination in human platelets of four exopeptidases--aminopeptidase P, dipeptidyl peptidase IV, carboxypeptidase N, and angiotensin converting enzyme--by means of fluorometric or liquid chromatography techniques was carried out. The results obtained show that the specific activities of dipeptidyl peptidase IV, carboxypeptidase N, and angiotensin converting enzyme in intact and disrupted platelets are small compared to their specific activities in serum. However, for aminopeptidase P the specific activity of this enzyme is much higher in platelets than in serum. This suggests that circulating platelets may have a significant role as scavengers for circulating peptides containing bonds susceptible for aminopeptidase P.

Binding of serum ferritin to concanavalin A in patients with malignancy.

The percentage non-glycosylated, tissue type ferritin was measured in the serum of 30 cancer patients and 11 normal subjects, as well as in 10 tumour cytosols. As expected, in normal subjects the larger part of serum ferritin corresponded to glycosylated ferritin, and in tumour cytosols the larger part corresponded to non-glycosylated ferritin (tissue ferritin). In all but one cancer patients a significant part of the protein did not bind to Con A, thus behaving as tissue ferritin. The findings obtained suggest release of tissue type, non-glycosylated, ferritin by damaged cells or through abnormal secretion. This relative increase of the non-glycosylated ferritin fraction appears to be very frequently present in cancer, although not specific for it. Assaying for Con A binding may prove to be valuable in the study of malignant disease, and therefore deserves further investigation.

In Belgium, viral hepatitis A is predominantly childhood disease.

Data from medical histories and seroepidemiological surveys of blood donors offer good grounds for regarding viral hepatitis A in Belgium primarily as a childhood disease. The epidemiology of anti-HA has thoroughly altered over the last few decades, which correlates with radical socioeconomic changes and improved hygienic living conditions. The rate of HLA-antigens shows in general no different patterns in groups with or without a recognized history of HAV infections.

Recommendations in the event of a suspected transfusion-related acute lung injury (TRALI).

The following recommendations, which aim at improving the clinical diagnosis ofTRALI and the laboratory investigations that can support it, were drawn up by a working group of the Superior Health Council. TRALI is a complication of blood transfusion that is both serious and underreported. Systematic reporting may help to develop preventive actions. Therefore, the Superior Health Council recommends that there should be a more stringent surveillance of patients who receive a blood component transfusion. The clinician should pay very close attention to any change in the patient's respiratory status (cf. dyspnoea and arterial desaturation), which should be notified systematically to the haemovigilance contact person in the hospital.

Recommended indications for the administration of polyclonal immunoglobulin preparations.

The following recommendations, which aim at standardising and rationalising the clinical indications for administering polyclonal immunoglobulins in Belgium, were drawn up by a working group of the Superior Health Council. To this end, the Superior Health Council organised an expert meeting devoted to"Guidelines for the use of immunoglobulins". The experts discussed the indications for immunoglobulin use, the'ideal'immunoglobulin preparation, its mechanisms of action, the practical issues involved in administering immunoglobulins and their potential side effects. The recommendations formulated by the experts were validated by the Superior Health Council working group with the purpose of harmonising immunoglobulin use in Belgium

Guidelines for the use of fresh frozen plasma.

Recommendations, which aim at standardising and rationalising clinical indications for the transfusion of fresh frozen plasma (FFP) in Belgium, were drawn up by a working group of the Superior Health Council. For this purpose the Superior Health Council organised an expert meeting devoted to "Transfusion Guidelines: Pathogen reduction, products and indications for the transfusion of plasma" in collaboration with the Belgian Haematological Society.The experts discussed the indications for the transfusion of FFP, pathogen reduction for FFP and the practical issues of administering FFP and plasma-derived concentrates. The recommendations formulated by the experts were validated by the working group with the purpose of harmonising FFP transfusion in Belgian hospitals.

Guidelines for the transfusion of red cells.

The following recommendations, which aim at standardising and rationalising clinical indications for the transfusion of red cells in Belgium, were drawn up by a working group of the Superior Health Council. To this end, the Superior Health Council organised an expert meeting devoted to "Guidelines for the transfusion of red cells" in collaboration with the Belgian Hematological Society. The experts discussed the indications for red cell transfusions, the ideal red cell concentrate, the practical issues of administering red cells, and red cell transfusions in patients in a critical condition. The recommendations formulated by the experts were validated by the working group with the purpose of harmonising red cell transfusion in Belgian hospitals.

Guidelines for the transfusion of platelets.

Recommendations aiming at standardising and rationalising clinical indications for the transfusion of platelets in Belgium were drawn up by a working group of the Superior Health Council. To this end the Superior Health Council organised an expert meeting devoted to "Guidelines for the transfusion of platelets" in collaboration with the Belgian Hematological Society. The experts discussed the indications for platelet transfusions, the ideal platelet concentrate and the optimal platelet transfusion therapy. The recommendations prepared by the experts were validated by the working group with the purpose of harmonising platelet transfusion in Belgian hospitals.

Prevalence of antibodies to hepatitis viruses in blood donors with a clinical history of hepatitis.

A comparison between the 1979, 1982 and 1989 findings indicates that the number of adults susceptible to HAV infections has increased. This fact should be given attention in view of the strongly altered travelling pattern of fairly large sections of the population. It should also be kept in mind that the group of adults born between 1951 and 1960 comprises those adults who have the most frequent contacts with younger children being at the greatest risk of acquiring HAV infection.

Hepatitis A virus antibodies in Belgium: relationship between prevalence and age.

Epidemiological data from various countries show that the frequency of Hepatitis A virus antibodies (anti-HAV) in different population groups is largely dependent on the geographical and age distribution of the population surveyed. As regards Europe anti-HAV antibodies are generally frequent in all groups in Southern Europe while in Northern Europe these antibodies are common in older people only. The prevalence data collected in 1979 and in 1989 show that the anti-HAV antibodies rate is a function of age, but the rates for all age groups were lower in 1989 compared to 1979. In 1979, at an age between 25 and 30, some 50% of the population was anti-HAV antibody positive. The same results were obtained in another Belgian study conducted in 1979. In 1989 50% positivity was only reached at an age between 35 and 40 years. The present study confirms that anti-HAV antibody prevalence decreases with higher socioeconomic status. The higher rate relative to age is associated with socioeconomic and hygienic living conditions at the time when most infections occur, i.e. before the age of 20. It can be concluded by comparing the 1979 and 1989 results that the number of adults susceptible to HAV infections has increased. This fact drew attention in view of the strongly altered travelling pattern of fairly large sections of the population.

Effect of prestorage leukocyte removal on the cytokine levels in stored platelet concentrates.

The effect of the prestorage removal of leukocytes from platelet concentrates (PC) on the cytokine levels during its storage was studied. Two methods for leukocyte removal were examined: filtration and preparation of the PC by the buffy coat method. Cytokine levels were measured at various storage times. Highly increased levels of tumor necrosis factor-alpha (TNF-alpha; 120 +/- 131 ng/l) and interleukin 6 (IL-6; 988 +/- 494 ng/l) were found after a 5-day storage in the control group, whereas no increased levels were found in filtered PC (TNF-alpha 14 +/- 4 ng/l, IL-6 < 4 ng/l) or in buffy coat PC (TNF-alpha 8 +/- 2 ng/l, IL-6 < 4 ng/l). Furthermore an effect of the pooling of buffy coats or PC on the cytokine levels was not found. Transfusion of PC containing high levels of IL-6 and TNF-alpha has been associated with febrile transfusion reactions in the recipient and therefore the prestorage leukocyte removal might prevent these febrile transfusion reactions. The preparation of buffy coat PC, through its simplicity, seems to be the method of choice.

Possible implication of sterile connecting device in contamination of pooled platelet concentrates.

Considering the possibility that a pooled random donor platelet concentrate could become contaminated by welding with a sterile connecting device, we undertook a study to determine the influence of pooling on the contamination rate. As a control group, apheresis platelets were examined. Bacteriological testing was done with a sensitive CO2 detecting culture system, the BacT/ Alert. Out of 1105 pooled platelet concentrates prepared by the buffy coat method, 15 (1.4%) were confirmed as contaminated, all with Staphylococcus epidermidis and two with a second bacterial species, i.e. Staphylococcus capitis and Propionibacterium acnes, respectively. Median detection time by the BacT/Alert was 23 h. Twelve pools of five units were contaminated, which is significantly more than the three contaminated pools of four units. On the other hand, the reuse of the welding wafers proved not be a risk factor for contamination. One welded tubing segment of a contaminated platelet concentrate failed the air leakage test, an incident which was 73 times more frequent than with the sterile platelet concentrates. We found five pooled platelet concentrates containing Staphylococci from which no bacteria could be grown from the individual buffy coats that had been pooled. We suggest the contamination here to have occurred after separation of the buffy coat from the whole blood, possibly during the welding process. Finally, none out of 378 apheresis platelet concentrates was contaminated. All our observations highlight the potential risk for contamination when making pooled platelet concentrates with a sterile connecting device. For this type of transfusion product, we advocate bacteriological screening of all units before release. The incubation time for the sterility test should, however, be limited to 36 h, if logistical problems with the availability of platelets are to be avoided.