CAUSES OF PULMONARY GRANULOMAS

In defining underlying causes of pulmonary granulomatous inflammation in their study population(s), Mukhopadhyay et al[1] correctly list immunodeficiency disorders as one possible association. They define a causal link between pathologist-observed granulomata and immune deficit where the latter has been already been identified clinically in individual patients. However, granulomatous disease can be a presenting feature of underlying, unsuspected immune deficiency, particularly in the context of some primary antibody deficiency disorders. The relationship of granulomatous inflammation in a biopsy and immunodeficiency needs to be considered beyond the simple circumstance of a patient with a previously defined immune deficit, in particular in the context of a) granulomatous disease with an alternative diagnostic label (e.g. sarcoidosis) and b) granulomatous disease of unknown aetiology. Awareness of the association of granulomata and immune deficiency is important, whether in the context of a geographically high incidence of sarcoidosis as a cause of pulmonary granulomata or of a high rate of no underlying aetiological factor being identified. Although relatively rare, primary immunodeficiency is an important issue for clinicians caring for patients with granulomatous disease to consider, identify, classify, risk assess and optimally manage.

Anecdotal local experience in the North of Scotland demonstrates that occasional 'sarcoid' patients (not included in the population studied by Mukhopadhyay et al) with pulmonary or extrapulmonary granulomatous inflammation are ultimately shown to have a primary immunodeficiency disorder (most frequently one of the common variable immune deficiency group of diseases, CVID[2]) but only after significant diagnostic delay. Such delay in these circumstances is relatively commonplace and is frequently associated with either overt or insidious secondary disease complications (usually pulmonary) which may be prevented or retarded by early immunoglobulin replacement and/or immunomodulatory treatment. Subtle histological differences have been described in the granulomata of sarcoid and CVID[3]. Granulomatous disease (particularly with splenic involvement), recurrent infections, cytopaenias and hypogammaglobulinaemia (rather than the hypergammaglobulinaemia of sarcoid) are, collectively, indicators of significant immune dysregulation and should prompt consideration of CVID as a potentially unifying diagnosis. Clinicians should consider routine measurement of serum immunoglobulins in granulomatous disease of unknown aetiology and as part of the diagnostic work-up in sarcoidosis. Similar recommendations, for similar reasons, have recently been made in the context of non-cystic fibrosis bronchiectasis[4]. Albeit relatively rarely, proactive detection of underlying immune deficiency as a cause of granulomatous inflammation will aid earlier diagnosis in conditions like CVID, allow more definitive and accurate aetiological classification of some cases at the clinician:pathologist interface and, not incidentally, will enhance opportunities for improvements in morbidity, mortality and quality of life for this group of complex patients.

REFERENCES

1. Mukhopadhyay S, Farver CF, Vaszar LT, et al. Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries. J Clin Pathol 2012; 65: 51-7

2. Morimoto Y, Routes JM. Granulomatous disease in common variable immunodeficiency. Curr Allergy Asthma Rep 2005; 5: 370-5

3. Bates CA, Ellison MC, Lynch DA et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004; 114: 415-21

4. Pasteur MC, Bilton D, Hill AT. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010; 65: i1-58

Conflict of Interest:

None declared