Macrophagic myofasciitis and aluminium-containing vaccines
The emergence of a new type of histopathological lesion of unknown origin called macrophagic myofasciitis (MMF), characterized by a unique myopathological pattern, has been reported by the Groupe d’études et recherche sur les maladies musculaires acquises et dysimmunitaires (GERMMAD) of the Association française contre les myopathies.
MMF is characterized by centripetal infiltration of the epimysium, perimysium and perifascicular endomysium by non-periodic-acid-shiff (PAS) positive cells of macrophage lineage with osmiophilic crystal inclusions. MMF has been mainly detected by deltoid muscle biopsy in adult patients, although it has also been detected by quadriceps muscle biopsy in 3 young children. The histopathological lesion is localized at these sites. There is absence of necrosis (of both epithelioid and giant cells) and of mitotic figures, and inconspicuous muscle fibre damage. Determination of the chemical nature of the macrophage inclusions by nuclear microprobe, X-ray microanalysis and atomic absorption spectrometry showed that they were composed of aluminium salts. Since aluminium salts are used as an adjuvant in a number of vaccines administered intramuscularly into deltoid and quadriceps muscles, it has been hypothesized that MMF may represent an unusual reaction to intramuscular injections of aluminium- containing vaccines. Since muscle biopsies are only carried out in patients with myopathic symptoms, there is at present no information on whether the characteristic local histological pattern can occur in the normal healthy population after vaccination.
To determine whether a causal relationship can be established between MMF and aluminium-containing vaccines, the Vaccine Safety Advisory Committee was convened together with GERMADD scientists, acknowledged experts in the field of neuromuscular diseases and aluminium adjuvants, representatives from industry, the French Ministry of Health and the Agence française de sécurité sanitaire des produits de santé.
Review of the scientific evidence
The evidence presented demonstrated the existence of a distinctive histopathological entity called macrophagic myofasciitis, characterized by persistent focal accumulation in the deltoid muscle of densely packed PAS – positive macrophages with osmiophilic crystal inclusions composed of aluminium, and evidence of a focal chronic inflammatory reaction.
There are supporting data showing a comparable transient lesion after intramuscular (IM) injection of aluminium- containing vaccines in experimental animal models. Evidence suggests that the local lesion which characterizes MMF may be caused by IM injection of aluminiumcontaining vaccines. Important remaining questions are whether:
- MMF can only be associated with vaccines containing aluminium hydroxide or also with those containing aluminium phosphate;
- a vaccine antigen can be detected in the affected muscle;
- deltoid biopsies were performed at the site of the injection (it is likely however that this was done in the majority of cases since the recommended practice is to give vaccinations and take biopsies from the nondominant arm).
From an epidemiological perspective, MMF has (with few exceptions) only been observed in France. The disorder was first seen in 1993 and has been recognized with increased frequency since then.
The underlying mechanisms triggering the local MMF lesion and its persistence have not been clarified. A plausible possibility is the existence of a predisposed subset of individuals with impaired ability to clear aluminium from the deltoid muscle. Whether this reflects a macrophagic dysfunction of either genetic or acquired origin, or the tailend of a normal distribution describing the kinetics of aluminium clearance and the local tissue response to it in the general population, has not yet been defined. Different biopsy practices were given as a plausible reason to explain why MMF has almost exclusively been observed in France and not elsewhere. It was argued that, in this country, biopsies are performed in the deltoid muscle whereas in many other countries biopsies tend to be performed in other muscles. Manufacturing practices of aluminium-containing vaccines make a local pharmaceutical cause unlikely.
The increase in the number of cases diagnosed in France in the last few years may also be explained by a change of vaccine administration from the subcutaneous to the intramuscular route, or the introduction of the hepatitis B vaccine to a naïve adult population likely to respond with a stronger local inflammatory response than to booster immunizations. However, hepatitis B vaccine has also been given to adults in other countries where MMF has not been detected. Furthermore, MMF has also been observed in French adults following tetanus and DT boosters but not in other countries where these vaccines have also been widely used. Finally, the acute rise in the number of cases observed since 1998 is suggested to reflect increased detection rates.
Regarding the potential linkage of the local MMF lesion with systemic disease, the following points were made. MMF lesions have been detected in patients undergoing deltoid muscle biopsies for investigations of diffuse myalgias, arthralgias or muscle weakness, and in whom there is a history of administration of an aluminium-containing vaccine at some time in the past, the interval varying from months to several years. In a proportion of patients there was also evidence of a concurrent autoimmune disorder. Research on the potential association with autoimmune diseases was strongly encouraged.
At present, within the constraints of current knowledge, MMF does not fall within the disease entities of inflammatory myopathy, dermatomyositis, polymyositis, inclusion-body myositis or eosinophilic fasciitis. The current evidence neither establishes nor excludes a generalized disorder affecting other organs.
The small sample size on which these observations are based, together with the absence of data regarding the prevalence of local MMF lesions in the general population after vaccination, makes it difficult to assess potential links between local MMF and systemic disease. A more specific set of criteria and definitions needs to be determined in further epidemiological studies to establish whether there is an association between local MMF lesions and any systemic symptom or condition. The immunological mechanisms which might be involved in transforming a local immune reaction into a systemic disorder are numerous and need further investigation.
Recommendations of the Committee
- From the data, opinions and discussion presented, the Committee found that there is no basis at present for recommending a change in vaccination practices (vaccine selection, schedule, delivery practices or information) with aluminium-containing vaccines.
- To further understand MMF, the Committee strongly recommends that research studies be undertaken to evaluate the clinical, epidemiological, immunological and basic science aspects of MMF.
The findings of the Committee will be promptly published in the Weekly epidemiological record.