The yin and the yang of immunosuppression with inhaled corticosteroids.

A patient who is immunosuppressed is susceptible to mycobacterial infection: are you surprised? Before you jump to conclusions, you might wish to clarify the nature and extent of immunosuppression, and whether it is through disease, therapy, or both, reserving judgement until you know more. Patients are often concerned about immunosuppressive effects of inhaled and oral corticosteroids. Asthmatics are used to infections putting them in hospital, and not unreasonably view with suspicion any treatment option that might make this more likely to happen. However, healthcare providers know that for asthmatics, appropriate local immunomodulation in the lung with inhaled corticosteroids (ICS) is associated with decreased exacerbations arising from viral infections, fewer symptoms, improved lung function and better outcomes. In subsets of patients with COPD, high-dose fluticasone with salmeterol reduces exacerbations and improves quality of life. Thus, if the only exposure of patients to anything remotely immunosuppressive is ICS, you might conclude the extent of immunosuppression is insufficient to regard the patient as immunocompromised. But will use of ICS increase susceptibility to some infections? The innate immune networks active in the lung, with their multifaceted humoral and cellular components, show intrinsic competence in keeping the human organism mostly free of serious pulmonary infection. At their heart lie strong surface barriers, an effective mechanism of sensing pathogens through a range of pattern recognition receptors, the efficient killing of microorganisms by resident and recruited phagocytes, and efficient resolution of inflammation. Alveolar macrophages are the resident phagocytes, which along with epithelial cells and T cells coordinate an immune response that may require recruitment of other inflammatory cells such as neutrophils to clear invading pathogens. Clearance of bacteria such as pneumococci relies heavily on phagocyte competence which is optimised by T cell responses. When phagocyte capacity is stressed by intracellular pathogens, such as Mycobacterium species, there is a critical dependence on T cell function mediated via the IFNγ/IL-12/IL-23 axis. 5 Steroids, including ICS, have the potential to modify all such pathways. Thus, we can happily trot out our favourite analogies describing the consequences of targeting the immune system (‘doubleedged sword’ is a particularly egregious example which every immunologist is required by some unwritten code to use intermittently). For now, we will stick with ‘yin and yang’, because any immunosuppression will modify the risks of infections while achieving therapeutic benefit. When considering the immunosuppression of ICS, a few messages have become clearer, but some have yet to be fully explored.