Aging is mediated by the immune system

Immune system and immunosuppressive therapy in old age

Infectious Disease Susceptibility

In old age, the immune system is often unable to build up efficient immune responses against new, unknown pathogens or virus strains (e.g. influenza A). In contrast, latent chronic viral infections such as those caused by the cytomegalovirus (CMV) or Epstein-Barr virus (EBV) can in turn have profound effects on the immune system. Persistent CMV infections lead to changes in the adaptive immune system, namely to a so-called memory inflation with an increase in CMV-specific CD8 memory T lymphocytes over time [5]. In older individuals, up to 50% of the total CD8, and to a lesser extent the CD4 memory repertoire of the peripheral blood, can consist of CMV-specific T cells [6].

The vulnerability of the aging immune system to viral infections is currently being impressively demonstrated in the Covid 19 pandemic. With Covid-19, there is a significant age dependency for the severity of the infection and the risk of dying from the disease. In Italy, until mid-March 2020, the median age of SARS-CoV-2 infected and deceased patients was 80 years and the mean age of patients requiring intensive care was 67 years [7]. In addition, Covid-19 morbidity and fatality are dependent on the presence of serious comorbidities such as chronic obstructive pulmonary disease (COPD) and ischemic heart disease.

Inflammaging (Inflamm-Aging)

Changes in soluble immunological mediators

The loss of the “fine-tuning” of a targeted and at the same time self-protective immune response that protects one's own organism is associated with the status of a chronically smoldering inflammatory reaction (inflammation) in old age [8]. This phenomenon is known as inflammaging, a term coined by the Italian immunologist Claudio Franceschi from the University of Bologna. As part of the physiological aging process, there is an increased release of inflammatory messenger substances such as interleukin (IL) -6, tumor necrosis factor (TNF) -α and IL-1ß as well as prostaglandin E; A permanently increased C-reactive protein can often be detected in the serum. The sources of proinflammatory cytokines are discussed as the relatively increased or changed fat tissue in old age, a translocation of bacteria via the more permeable intestinal barrier and an accumulation of non-lymphoid cells, which together represent the so-called senescence-associated secretory phenotype (SASP) - see overview at [3].

Another consequence of soluble immunological factors, which typically affects the aging organism, is organ fibrosis, mediated by TGF-ß and IL-13 [9]. Compared to age-dependent inflammatory processes, the aspect of fibrogenesis (deposition of thickened and increased collagen bundles in tissues, proliferation and activation of myofibroblasts) has so far been less well investigated.

Increased incidence of chronic autoimmune diseases

Typical age-related diseases are identified in connection with inflammaging: Alzheimer's dementia, osteoporosis, arteriosclerosis, arthritis and diabetes mellitus [10]. Phenomena of inflammation have been examined more closely in rheumatology in rheumatoid arthritis (RA) and temporal arteritis / giant cell arteritis. The proinflammatory cytokine and chemokine status in RA patients - including younger RA patients - can be measurably changed months before the first clinical symptoms and resemble the aging immune system (inflammaging) [11, 12].

The aging of the immune system and the remodeling of the blood vessel wall with age are typical risk factors for the development of giant cell arteritis [13]. The autoimmune diseases with an increased first manifestation beyond the age of 60 include giant cell arteritis as well as antineutrophil cytoplasmic antibody (ANCA) -associated vasculitides with and without kidney involvement, which in turn have a worse prognosis with increasing age.

For example, ANCA-associated granulomatosis with polyangiitis (formerly known as Wegener's disease) has an initial peak in Europe between the ages of 65 and 74. Patients with ANCA-associated vasculitis manifesting in old age and those with renal impairment die significantly more often from infections than younger patients [14, 15].

Additional immunological markers for an increased risk of infection in vasculitis patients are decreased serum IgG, decreased B-lymphocytes and CD4 T-lymphocytes as well as a weakened vaccination response - this corresponds to the typical surrogate markers of immunosenescence.

Immunosuppressive therapy in old age

Immunosuppressive therapy for systemic vasculitis

Systemic vasculitis usually requires immunosuppressive treatment in patients of all age groups, with therapies including high-dose corticosteroids, methotrexate, azathioprine, cyclophosphamide, rituximab or, in the case of giant cell arteritis, IL-6 receptor antibodies (IL-6R-AK tocilizumab) can. The prognosis and lethality of systemic vasculitis depend on the age at first onset of vasculitis and on the occurrence of infection-related complications during the first six months of immunosuppressive therapy.

The risk of serious infections in induction therapy for ANCA-associated vasculitis when using rituximab is as high as with cyclophosphamide [16], but in both cases it depends crucially on the dose and the duration of the steroid therapy that is regularly combined with it. Aza-thioprine or low-dose methotrexate is often used in maintenance therapy for vasculitis. The latter should not be given at all with a glomerular filtration rate (GFR) <30 ml / min and with a GRF between 30 and 60 ml / min, as is more common in older patients, only given in half the regular dose with close monitoring of kidney function [17 ].

A special feature of therapy with the IL-6R-AK-tocilizumab is an increased incidence of complicated diverticulitis with the risk of intestinal perforation [18]. Furthermore, tocilizumab inhibits the formation of CRP, so that the latter cannot be used as a marker of a possible infection. Procalcitonin as a sepsis marker, on the other hand, is not influenced by tocilizumab.

Unfortunately, there are no recommendations for individualized immunosuppressive therapy for vasculitides or other rheumatic systemic diseases in old age that have been proven by studies. However, the following conclusions can be drawn from register data and case collections:

  1. a) A dose reduction of rituximab can halve the incidence of serious infections.
  2. b) Cyclophosphamide should be reduced by 25% in those over 60 and by 50% in those over 70.
  3. c) Consistent prophylaxis with cotrimoxazole (e.g. taking 960 mg of cotrimoxazole on three days per week) under therapy with cyclophosphamide or rituximab, for lymphopenia and - as a relatively new finding - also with prednisolone therapy with> 30 mg daily for> four Weeks [19] can not only prevent Pneumocystis jirovecii pneumonia (PJP), but also reduce other infections such as urinary tract and bronchopulmonary infections under immunosuppressive therapy [20].
  4. d) While the Cotrim treatment can be considered safe in the presence of systemic vasculitis and therapy with cyclophosphamide, there is still great uncertainty with other constellations, as it is difficult to assess the benefit of the therapy against the expected side effects. There are no guidelines or controlled studies on this point, only expert opinions. First of all, it makes sense to include further individual risk factors such as the presence of severe lymphophenia or old age in the considerations [20].

Immunosuppressive therapy in elderly kidney transplant patients

The age at which patients receive kidney transplants has increased over the past 20 to 25 years. 60% of the transplant recipients are now ≥ 60 years old; In the years 1998–2011, the number of transplants a year tripled in patients over the age of 65 [21].

A large number of studies have shown that kidney transplantation reduces long-term mortality among patients on the transplant waiting list, including elderly patients. However, these studies also showed that especially in the first few months after kidney transplantation, older patients have a higher risk of mortality, suffer more infection-related complications, but tend to have fewer acute rejection reactions than young transplant recipients [22, 23].

A recently published north-west French study on 171 patients> 70 years of age who had received a kidney transplant between January 2000 and December 2014 showed that 17 patients (9.9%) had died one year after the transplant, namely in primarily from infections (58.5%) or cardiovascular diseases (29.4%) [24]. The authors conclude that in kidney transplant recipients> 70 years of age, a cardiological evaluation and optimization of immunosuppressive therapy are crucial in order to improve the survival of the patient and the transplant in the early phase after transplantation.

Geriatric examination methods are also increasingly being used in transplant medicine, since frailty in particular is an independent risk factor for survival after kidney transplantation [25].

The immunological conditions and the fact that older patients are often excluded from drug transplant studies make the selection of the ideal and individually adapted immunosuppressive regimen a challenge. There are recommendations for action for immunosuppressive therapy after kidney transplantation, but these may differ internationally and depending on the transplant center. They are based on an individual dosage and adaptation of induction and maintenance therapy, side effects and complications and, of course, the current study situation. This article cannot go into details, but rather general principles of therapy adaptation in older patients.

In the European guidelines (EBP, European Best Practice Guidelines) it is stated that the immunosuppression should be used "with a sense of proportion" on special problems in older transplant recipients, on the one hand to prevent rejection, but on the other hand to keep side effects to a minimum, which are common in older people are more pronounced [25, 26]. There are centers which start induction therapy with lower intensity in older patients, i.e. without rabbit antithymocyte globulin (rATG) or anti-IL2-ABs.

As with younger kidney transplant recipients, corticosteroids, an antimetabolite (azathioprine or mycophenolate mofetil) and a calcineurin inhibitor (ciclosporin A or tacrolimus) are used in immunosuppressive combination therapy.

There is no uniform recommendation regarding cortisone reduction in maintenance therapy. In practice, it is important to be particularly vigilant about potential drug interactions when using ciclosporin A in elderly patients. Ciclosporin A is a substrate of both cytochrome P450 (CYP) 3A and P-glycoprotein, both of which are pharmacokinetically involved in the elimination of frequently prescribed drugs [27].

In the event of adverse effects such as leukopenia, thrombopenia, infections or malignancies, a component of the combined immunosuppression, usually the antimetabolite, is removed more often than in young transplant recipients in maintenance therapy [28]. Guideline-based specific recommendations for induction and maintenance therapy as well as for de-escalation of immunosuppression in elderly kidney transplant recipients are not available.

Summary

With the physiological aging of the immune system, immune competence decreases, i.e. the ability to deal with pathogens and malignancies, which is reflected in typical changes in the quantitative composition of the cells of the immune system and the functional capacity (immunosenescence). These processes go hand in hand with a status of chronic inflammation with increased secretion of pro-inflammatory soluble messenger substances (inflammaging) and the occurrence of chronic inflammatory and autoimmune diseases.

With an already altered immune system, increased susceptibility to infections and reduced vaccination response, older patients with rheumatic diseases, especially systemic vasculitis, are exposed to an increased risk under immunosuppressive therapy.

The same applies to older kidney transplant recipients. Guideline-based recommendations for immunosuppressive therapy in old age do not exist for autoimmune diseases or for kidney transplant recipients. Here it is important to dose the immunosuppressive drugs, including cortisone, as low as possible and closely monitor them individually, taking into account the risk factors, in order to minimize the risk of threatening infections.