WHO > Programmes and projects > Vaccine Safety > Causality assessment of adverse events following immunization
Main content Causality assessment of adverse events following immunization
Appears in WER 23 March 2001:
- English/French [pdf 160kb]
Since the inception of vaccination, it has been recognized that adverse events following immunization (AEFIs) will occur. The frequency of AEFIs is directly related to the number of vaccine doses administered. AEFIs can be causally related to the inherent properties of the vaccine, linked to errors in the administration, quality, storage and transport of the vaccine (programmatic errors), but it must be recognized that when large populations are vaccinated, some serious events that occur rarely with or without vaccination will be observed coincidentally following vaccination. Thus, investigating causality of AEFIs, particularly those that are most serious, is challenging.
The clearest and most reliable way to determine whether an adverse event is causally related to vaccination is by comparing rates of the event in a vaccinated and non-vaccinated group in a randomized clinical trial. Such trials, however, can never be large enough to assess very rare events, and postmarketing surveillance systems are required to identify events potentially related to vaccination. Postmarketing surveillance capability is improving; more countries now have AEFI monitoring systems, and more importance is attached to the reporting of suspected links between vaccination and adverse events. These systems have been successful in bringing to light serious AEFIs after vaccines have been marketed. A recent example is intussusception after administration of reassortant rhesus rotavirus vaccine.
Assessments of whether a given vaccine causes a particular adverse reaction vary from the casual observation to the carefully controlled study. The majority of individuals are not trained in interpreting such studies and are unlikely to understand the enormous difference in significance between these two extremes. Nonetheless, the public frequently forms a decision about a vaccine safety based on the information available to them, often a report based on unscientific observations or analyses that fail to stand the scrutiny of rigorous scientific investigation. Certain reports of AEFIs published in the medical literature over the past few years have resulted in controversy. The studies on which these reports are based, while generating provocative hypotheses, have generally not fulfilled the criteria that would be needed to be able to draw conclusions about vaccine safety with any degree of certainty. Yet these reports have had a major influence on public debate and opinion-making. When this debate spills over to the political arena, to policy-making and to determining the public acceptance of a vaccine by balancing the known benefits against possible but unverified risks, it is clear that a correct assessment of causality is vital.
Submitting a study to a scientific process rather than to partially informed opinion is crucial in determining whether a vaccine actually causes a given reaction. If undertaken carelessly or without scientific rigour, the study results will be inconclusive at best, may result in the inappropriate withdrawal of a valuable vaccine from use, or at worst may result in the exposure of a population to a dangerous vaccine. In 1999, WHO launched the Immunization Safety Priority Project to establish a comprehensive system to ensure the safety of all immunizations given in national immunization programmes. The development of mechanisms to respond promptly and effectively to vaccine safety concerns is a major area of focus of this project. As part of this effort, the Global Advisory Committee on Vaccine Safety (GACVS) was constituted by WHO in September 1999. The Committee's mandate is to enable WHO to respond promptly, efficiently and with scientific rigour to vaccine safety issues of potential global importance.
Building on the seminal work on determining causality of the Surgeon Generalís Advisory Committee on Smoking and Health (1964), the generally established criteria underpinning vaccine adverse event causality assessment that the GACVS uses may be summarized as follows: Consistency. The association of a purported adverse event with the administration of a vaccine should be consistent, i.e. the findings should be replicable in different localities, by different investigators not unduly influencing one another, and by different methods of investigation, all leading to the same conclusion(s). Strength of the association. The association should be strong in the magnitude of the association (in an epidemiological sense), and in the dose-response relationship of the vaccine with the adverse effect. Specificity. The association should be distinctive, the adverse event should be linked uniquely or specifically with the vaccine concerned, rather than its occurring frequently, spontaneously or commonly in association with other external stimuli or conditions. Temporal relation. There should be a clear temporal relationship between the vaccine and the adverse event, in that receipt of the vaccine should precede the earliest manifestation of the event or a clear exacerbation of an ongoing condition. For example, an anaphylactic reaction seconds or minutes following immunization would be strongly suggestive of causality; such a reaction several weeks after vaccination would be less plausible evidence of a causal relation. Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease.
Clearly, not all these criteria need to be present, and neither does each carry equal weight for a causal relationship between an adverse event and the vaccine to be determined. In addition to the general principles mentioned above, there are a number of provisos or considerations that need to be applied for determining causality in the special field of vaccine safety. They are:The requirement for biological plausibility should not unduly influence negatively a consideration of causality. Biological plausibility is a less robust criterion than the others described. If an adverse event does not fit into known facts and the preconceived understanding of the adverse event or the vaccine under consideration, it clearly does not necessarily follow that new or hitherto unexpected events are improbable. ìBiological plausibilityî is most helpful when it is positive; it is less so when negative.
Consideration of whether the vaccine is serving as a trigger (trigger in this context is an agent that causes an event to happen which would have happened some time later anyway). When acting as a trigger, the vaccine may expose an underlying or pre-existing condition or illness. An example of the latter would be an auto-immune condition triggered non-specifically by the immune stimulus of the vaccine.
In the case of live attenuated vaccines, if the adverse event may be attributable to the pathogenicity of the attenuated vaccine microorganism and thus not be distinguishable (except, perhaps, in severity) from the disease against which the vaccine is being administered, a causal connection is more plausible. Identification of the vaccine organism in diseased tissue and/or in the body fluids of the patient in such a situation would add weight to causality. There are exceptions to both these above points. An association between vaccine administration and an adverse event is most likely to be considered strong when the evidence is based on:Well-conducted human studies that demonstrate a clear association in a study design that is determined a priori for testing the hypothesis of such association. Such studies will normally be one of the following, in descending order of probability of achieving the objective of the study: randomized controlled clinical trials, cohort studies, and case-controlled studies and controlled case-series analyses. Case reports, however numerous and complete, do not fulfil the requirements for testing hypotheses, although on occasion such reports can be compelling if there are clear biological markers of the association, as is the case for vaccine-associated paralytic poliomyelitis.
An association that is demonstrated in more than one human study and consistent among the studies. The studies would need to have been well conducted, by different investigators, in different populations, with results that are consistent, despite different study designs. Demonstrable association in the studies between dose and the purported adverse effect (either the dose or the number of doses administered, or both) will, in many cases, strengthen the causal association between the vaccine and the adverse event. This is not always the case, especially if there is an immunological relationship. A strong similarity of the adverse event to the infection the vaccine is intended to prevent, and there is a non-random temporal relationship between administration and the adverse incident.
It is important that there should be a strict definition of the adverse event in clinical, pathological and biochemical terms, as far as that is achievable. The frequency in the nonimmunized population of the adverse event should be substantially different from that in the immunized population in which the event is described, and there would not normally be obvious alternative reasons for its occurrence that are unrelated to immunization.
An adverse event may be caused by a vaccine adjuvant or excipient, rather than by the active component of the vaccine. In this case, it might spuriously influence the specificity of the association between vaccine and adverse event. As far as possible, safety issues should be clarified in premarketing controlled clinical studies, with attention being given in such studies to safety issues and their monitoring, although with extremely rare unexpected events, this may not be achievable because of the need for extremely large sample sizes to detect them.
When adverse events are attributable to a vaccine, it is important to determine whether there is a predisposed set of subjects (by age, population, genetic, immunological, environmental, ethnic, sociological or underlying disease conditions) for any particular reaction. Such predisposition is most likely to be identified in case-controlled studies.
A systematic effort should always be made to exclude confounding programmatic errors and variability and aberrations in vaccine manufacture. The latter quality issues are most likely to be revealed by careful attention to batch and lot testing.
Since observational studies are not randomized and since individuals who are ill are generally less likely to be immunized (but more likely to have an adverse outcome), epidemiological studies on vaccine safety need to pay special attention to contraindications as potentially confounding factors. The consequences of this bias may be false-negative studies.
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Building on the seminal work on determining causality of the Surgeon Generalís Advisory Committee on Smoking and Health (1964), the generally established criteria underpinning vaccine adverse event causality assessment that the GACVS uses may be summarized as follows:
* Consistency. The association of a purported adverse event with the administration of a vaccine should be consistent, i.e. the findings should be replicable in different localities, by different investigators not unduly influencing one another, and by different methods of investigation, all leading to the same conclusion(s).
* Strength of the association. The association should be strong in the magnitude of the association (in an epidemiological sense), and in the dose-response relationship of the vaccine with the adverse effect.
* Specificity. The association should be distinctive, the adverse event should be linked uniquely or specifically with the vaccine concerned, rather than its occurring frequently, spontaneously or commonly in association with other external stimuli or conditions.
* Temporal relation. There should be a clear temporal relationship between the vaccine and the adverse event, in that receipt of the vaccine should precede the earliest manifestation of the event or a clear exacerbation of an ongoing condition. For example, an anaphylactic reaction seconds or minutes following immunization would be strongly suggestive of causality; such a reaction several weeks after vaccination would be less plausible evidence of a causal relation.
* Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease.
Building on the seminal work on determining causality of the Surgeon Generalís Advisory Committee on Smoking and Health (1964), the generally established criteria underpinning vaccine adverse event causality assessment that the GACVS uses may be summarized as follows:
* Consistency. The association of a purported adverse event with the administration of a vaccine should be consistent, i.e. the findings should be replicable in different localities, by different investigators not unduly influencing one another, and by different methods of investigation, all leading to the same conclusion(s).
* Strength of the association. The association should be strong in the magnitude of the association (in an epidemiological sense), and in the dose-response relationship of the vaccine with the adverse effect.
* Specificity. The association should be distinctive, the adverse event should be linked uniquely or specifically with the vaccine concerned, rather than its occurring frequently, spontaneously or commonly in association with other external stimuli or conditions.
* Temporal relation. There should be a clear temporal relationship between the vaccine and the adverse event, in that receipt of the vaccine should precede the earliest manifestation of the event or a clear exacerbation of an ongoing condition. For example, an anaphylactic reaction seconds or minutes following immunization would be strongly suggestive of causality; such a reaction several weeks after vaccination would be less plausible evidence of a causal relation.
* Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease.
HS & DIC 皆可經由AUTOIMMUNE & VIRAL INFECTION 導致而成.因此要解釋到底是B19 還有VACCINE 引起時HS & DIC 必須要符合WHO上述條件,
相信很多醫師對於B19的引起的疾病NATURE HISTORY 已經於論壇討論過,因此在此要向你請益的是你仍然認同劉小弟的HS & DIC 是B19造成的嗎? ( Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease)
至於犀牛橫行,對於犀牛我曾引用過,有興趣請看過去我的有關犀牛PO文.
至於什麼是野豬橫行就要向你請益.
Building on the seminal work on determining causality of the Surgeon Generalís Advisory Committee on Smoking and Health (1964), the generally established criteria underpinning vaccine adverse event causality assessment that the GACVS uses may be summarized as follows:
* Consistency. The association of a purported adverse event with the administration of a vaccine should be consistent, i.e. the findings should be replicable in different localities, by different investigators not unduly influencing one another, and by different methods of investigation, all leading to the same conclusion(s).
* Strength of the association. The association should be strong in the magnitude of the association (in an epidemiological sense), and in the dose-response relationship of the vaccine with the adverse effect.
* Specificity. The association should be distinctive, the adverse event should be linked uniquely or specifically with the vaccine concerned, rather than its occurring frequently, spontaneously or commonly in association with other external stimuli or conditions.
* Temporal relation. There should be a clear temporal relationship between the vaccine and the adverse event, in that receipt of the vaccine should precede the earliest manifestation of the event or a clear exacerbation of an ongoing condition. For example, an anaphylactic reaction seconds or minutes following immunization would be strongly suggestive of causality; such a reaction several weeks after vaccination would be less plausible evidence of a causal relation.
* Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease.
HS & DIC 皆可經由AUTOIMMUNE & VIRAL INFECTION 導致而成.因此要解釋到底是B19 還有VACCINE 引起時HS & DIC 必須要符合WHO上述條件,
相信很多醫師對於B19的引起的疾病NATURE HISTORY 已經於論壇討論過,因此在此要向你請益的是你仍然認同劉小弟的HS & DIC 是B19造成的嗎? ( Biological plausibility. The association should be coherent; that is, plausible and explicable biologically according to known facts in the natural history and biology of the disease)
至於犀牛橫行,對於犀牛我曾引用過,有興趣請看過去我的有關犀牛PO文.
至於什麼是野豬橫行就要向你請益.
Abstract and Introduction
Clinical Features
Epidemiology
HLH and Infection
Pathophysiology
Prognosis and Therapy
Conclusions
Acknowledgments
References
Information from Industry
Assess clinically focused product information on Medscape.
Click Here for Product Infosites – Information from Industry. Abstract and Introduction
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, splenomegaly, jaundice, and the pathologic finding of hemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors) in bone marrow and other tissues. HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection. Hyperproduction of cytokines, including interferon-gamma and tumor necrosis factor-alpha, by EBV-infected T lymphocytes may play a role in the pathogenesis of HLH. EBV-associated HLH may mimic T-cell lymphoma and is treated with cytotoxic chemotherapy, while hemophagocytic syndromes associated with nonviral pathogens often respond to treatment of the underlying infection.
not all these criteria need to be present, and neither does each carry equal weight for a causal relationship between an adverse event and the vaccine to be determined.
H1N1 Influenza (inactivated--flu shot) vaccine side-effects
What are the risks from 2009 inactivated H1N1 influenza vaccine? NEW Oct 2009
A vaccine, like any medicine, could cause a serious problem, such as a severe allergic reaction. But the risk of any vaccine causing serious harm, or death, is extremely small.
The virus in inactivated 2009 H1N1 vaccine has been killed, so you cannot get influenza from the vaccine. The risks from inactivated 2009 H1N1 vaccine are similar to those from seasonal inactivated flu vaccine:
Mild problems:
soreness, redness, tenderness, or swelling where the shot was given
fainting (mainly adolescents)
headache, muscle aches
fever
nausea
If these problems occur, they usually begin soon after the shot and last 1-2 days.
Severe problems:
Life-threatening allergic reactions to vaccines are very rare. If they do occur, it is usually within a few minutes to a few hours after the shot.
In 1976, a certain type of swine flu vaccine was associated with cases of Guillain-Barré Syndrome (GBS). Since then, flu vaccines have not been clearly linked to GBS.
Abstract and Introduction
Clinical Features
Epidemiology
HLH and Infection
Pathophysiology
Prognosis and Therapy
Conclusions
Acknowledgments
References
Information from Industry
Assess clinically focused product information on Medscape.
Click Here for Product Infosites – Information from Industry. Abstract and Introduction
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, splenomegaly, jaundice, and the pathologic finding of hemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors) in bone marrow and other tissues. HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection. Hyperproduction of cytokines, including interferon-gamma and tumor necrosis factor-alpha, by EBV-infected T lymphocytes may play a role in the pathogenesis of HLH. EBV-associated HLH may mimic T-cell lymphoma and is treated with cytotoxic chemotherapy, while hemophagocytic syndromes associated with nonviral pathogens often respond to treatment of the underlying infection.
not all these criteria need to be present, and neither does each carry equal weight for a causal relationship between an adverse event and the vaccine to be determined.
H1N1 Influenza (inactivated--flu shot) vaccine side-effects
What are the risks from 2009 inactivated H1N1 influenza vaccine? NEW Oct 2009
A vaccine, like any medicine, could cause a serious problem, such as a severe allergic reaction. But the risk of any vaccine causing serious harm, or death, is extremely small.
The virus in inactivated 2009 H1N1 vaccine has been killed, so you cannot get influenza from the vaccine. The risks from inactivated 2009 H1N1 vaccine are similar to those from seasonal inactivated flu vaccine:
Mild problems:
soreness, redness, tenderness, or swelling where the shot was given
fainting (mainly adolescents)
headache, muscle aches
fever
nausea
If these problems occur, they usually begin soon after the shot and last 1-2 days.
Severe problems:
Life-threatening allergic reactions to vaccines are very rare. If they do occur, it is usually within a few minutes to a few hours after the shot.
In 1976, a certain type of swine flu vaccine was associated with cases of Guillain-Barré Syndrome (GBS). Since then, flu vaccines have not been clearly linked to GBS.
Abstract and Introduction
Clinical Features
Epidemiology
HLH and Infection
Pathophysiology
Prognosis and Therapy
Conclusions
Acknowledgments
References
Disseminated infection with an unusual organism in a patient with HLH may represent secondary infection in an immunocompromised host; however, the resolution of HLH following treatment of infection suggests that, in many cases, HLH is secondary to the underlying infection.
A diagnosis that takes into account all the underlying diseases associated with HLH would not be practical, and formal guidelines for evaluating patients with suspected infection-associated HLH have not been established. Nevertheless, all patients meeting the criteria for HLH should undergo initial diagnostic tests that include routine cultures of blood and urine and chest radiography to screen for such infections as miliary tuberculosis. Attempts should be made to screen for infection with EBV, CMV, and parvovirus B19, either through serologic testing or polymerase chain reaction, in-situ hybridization, or (in the case of CMV) immunofluorescent antigen testing. Serologic testing for HIV and human herpesvirus-6 infection should also be considered, and throat and rectal swabs should be taken for viral culture. Because of the association between HLH and fungal infections, lysis-centrifugation blood cultures and fungal antigen testing should be considered for all patients with HLH. Even if an infection known to be associated with HLH has been confirmed, cell marker and T-cell receptor gene rearrangement tests should be performed on bone marrow or other tissue specimens to determine whether an underlying T-cell lymphoma is present.
Extensive testing for underlying infecting organisms should be guided by epidemiologic data and the patient's medical history. For example, in a patient with underlying HIV infection, HLH has been associated with infections that commonly affect patients with AIDS (e.g., pneumococcal disease, pneumocystosis, histoplasmosis, and infection with Penicillium marneffei) and with T-cell lymphoma. Patients with a history of travel or animal exposure should be screened for such infections as leishmaniasis, brucellosis, rickettsioses, and malaria. In bone marrow transplant patients, attempts should be made to isolate adenovirus from urine, nasopharyngeal and rectal swabs, and tissue specimens.
Because so many immunologic, neoplastic, genetic, and infectious disorders may be associated with HLH, clinicians should work closely with pathologists and microbiologists to clearly define precipitating or underlying illnesses.
Disseminated infection with an unusual organism in a patient with HLH may represent secondary infection in an immunocompromised host; however, the resolution of HLH following treatment of infection suggests that, in many cases, HLH is secondary to the underlying infection.
A diagnosis that takes into account all the underlying diseases associated with HLH would not be practical, and formal guidelines for evaluating patients with suspected infection-associated HLH have not been established. Nevertheless, all patients meeting the criteria for HLH should undergo initial diagnostic tests that include routine cultures of blood and urine and chest radiography to screen for such infections as miliary tuberculosis. Attempts should be made to screen for infection with EBV, CMV, and parvovirus B19, either through serologic testing or polymerase chain reaction, in-situ hybridization, or (in the case of CMV) immunofluorescent antigen testing. Serologic testing for HIV and human herpesvirus-6 infection should also be considered, and throat and rectal swabs should be taken for viral culture. Because of the association between HLH and fungal infections, lysis-centrifugation blood cultures and fungal antigen testing should be considered for all patients with HLH. Even if an infection known to be associated with HLH has been confirmed, cell marker and T-cell receptor gene rearrangement tests should be performed on bone marrow or other tissue specimens to determine whether an underlying T-cell lymphoma is present.
Extensive testing for underlying infecting organisms should be guided by epidemiologic data and the patient's medical history. For example, in a patient with underlying HIV infection, HLH has been associated with infections that commonly affect patients with AIDS (e.g., pneumococcal disease, pneumocystosis, histoplasmosis, and infection with Penicillium marneffei) and with T-cell lymphoma. Patients with a history of travel or animal exposure should be screened for such infections as leishmaniasis, brucellosis, rickettsioses, and malaria. In bone marrow transplant patients, attempts should be made to isolate adenovirus from urine, nasopharyngeal and rectal swabs, and tissue specimens.
Because so many immunologic, neoplastic, genetic, and infectious disorders may be associated with HLH, clinicians should work closely with pathologists and microbiologists to clearly define precipitating or underlying illnesses.
Hemophagocytic syndrome (HPS) is a clinicopathological condition characterized by the activation of histiocytes with prominent hemophagocytosis in bone marrow and other reticuloendothelial systems. The occurrence of HPS is usually associated with underlying disorders such as infection and lymphoma. Recently, we described patients with autoimmune disease who developed HPS. In these cases there was no evidence of underlying infection and malignancy, and the occurrences of HPS were associated withactive autoimmune disease. Based on these observations, we described autoimmune-associated hemophagocytic syndrome (AAHS). This disease entity is becoming better known, and case reports presenting features compatible with clinical AAHS are increasing. Here, we review the clinical aspects, mechanisms, diagnosis, and treatment of AAHS according to our data and that in the literature.
Abstract
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. Uncontrolled T-lymphocyte activation is responsible for increased TH1 cytokines secretion such as IFN-γ, IL-12 and IL-18 that promotes macrophage activation. Genetic defects specific for cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have been identified in patients with primary HPS that are responsible for altered cell death and apoptosis induction or target killing. HPS may be secondary to malignancy, infection or autoimmune disease, and mechanisms involved are poorly understood. However, in adult-onset Still's disease, juvenile chronic arthritis and probably systemic lupus erythematosus, IL-18 might play a role in initiating macrophage activation.
Hemophagocytosis is not equal to Hemophagocytosis syndrome ....
hemophagocytosis只是免疫失調,Macrophage被過度激化的結果:
4月3日台灣醫學界發現病人的白血球減少,尤其是淋巴球,他們的骨髓細胞出現問題.他們發現病人有血球吞噬現象(hemophagocytosis)〔組織球吞噬紅血球(hemophagocytosis)則是一種嚴重的免疫失調現象統稱,人體內負責防衛工作的組織球失去常態,攻擊血球、釋放各式免疫調節物質造成免疫系統陷入混亂。〕。而IVIG有調節患者免疫反應的作用.在病患血清及肺臟檢體檢查,也證實SARS是一種病毒感染引起宿主之細胞激素風暴(cytokine storm),並首度發現SARS可以發生血球吞噬現象(hemophagocytosis)
Hemophagocytic syndrome (HPS) is a clinicopathological condition characterized by the activation of histiocytes with prominent hemophagocytosis in bone marrow and other reticuloendothelial systems.
Abstract
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. HPS may be secondary to malignancy, infection or autoimmune disease, and mechanisms involved are poorly understood. However, in adult-onset Still's disease, juvenile chronic arthritis and probably systemic lupus erythematosus, IL-18 might play a role in initiating macrophage activation.