Disseminated invasive aspergillosis is a serious fungal infection particularly affecting the immune compromised individuals. Risk factors are immune deficiency either primary, or secondary to cytotoxic drugs, steroids, prolonged antibiotic use and haematological or solid organ malignancies. Structural lung disease and valve disease predispose to pulmonary aspergillosis and endocarditis respectively. This patient was on steroids, had myelodysplasia and severe B cell deficiency with IgM deficiency and T cell dysfunction with transient neutropaenia (that rapidly recovered with treatment of CMV). Immune response against Aspergillus is predominantly innate system dependent and neutrophil mediated [3]. Nevertheless, disseminated aspergillosis in a patient with selective IgM deficiency has been described before [4].
Multiple embolic events are known to occur in patients with Aspergillus endocarditis [1] and aortitis [2, 5, 6]. However, repeated trans-esophageal echocardiograms and magnetic resonance aortogram did not show valve defects, vegetations, aortitis or aneurysms. Therefore, we postulate that pulmonary aspergillosis was the primary focus from where fungal particles embolized through pulmonary veins and left heart into systemic circulation.
Splenic abscess was an incidental finding in our patient who did not have symptoms attributable to it. We think this was due to blood borne dissemination of M. tuberculosis bacilli, which was subsequently invaded by Aspergillus during a fungaemic phase. Caseating granuloma characteristic of tuberculosis was observed in splenic tissue (Fig. 3). Mycobacteria were not visualized microscopically or cultured from the abscess fluid, probably because 4 months of anti-tuberculosis therapy was completed by the time of splenectomy. Furthermore, Aspergillus has never been reported to cause caseating granulomas. Larger fungal embolization in to spleen with secondary tuberculous infection seems less likely due to the tortuous course of splenic artery and acute angle at the coeliac trunk origin. Furthermore, the patient never developed acute left hypochondrial pain suggestive of embolic splenic infarct. Fungal filaments were observed within the caseating granulomas in splenic tissue, which suggests co-infection of an existing caseating abscess. Although Aspergillus was never isolated from peripheral blood cultures, it does not rule out a fungaemia. Negative peripheral blood fungal cultures are not uncommon with disseminated fungal infection [7].
Disseminated tuberculosis would have formed splenic granulomas which were co-infected with Aspergillus during fungaemic phase. Complex alterations in immune system caused by glucocorticoids would have facilitated this unusual co-infection. Infections themselves can alter the immune response (e.g.: neutropaenia and T cell dysfunction due to CMV). This would also have contributed to the unusual co-infection.
Management of splenic abscess was challenging. Initial treatment with anti-fungals and percutaneous aspiration failed to clear the abscess necessitating splenectomy, despite the risks of surgical complications and further compromise of immunity. Voriconazole-rifampicin interaction and its poor penetration into abscess may have contributed to antifungal failure. Therapeutic drug monitoring (target trough level > 1 mg/L) is recommended when treating patients with voriconazole, especially when interacting drugs are co-prescribed [8]. Unfortunately, this facility was not available for us.
Assessment of the patient’s immune system revealed severe IgM deficiency, mild IgA deficiency, severe B cell deficiency and impaired T cell functions but normal T cell counts, neutrophil counts and functions on nitro-blue tetrazolium assay. Although glucocorticoids may give rise to some of the above abnormalities, IgM deficiency is not a recognized effect of glucocorticoid therapy [9, 10]. Nephrotic syndrome causes immunoglobulin deficiency. However this patient’s glomerular disease with subnephrotic proteinuria cannot explain B cell deficiency and predominant IgM rather than IgG deficiency.
Multiple severe unusual infections in this patient developed after commencement of glucocorticoids. Immune deficiencies completely reversed after its discontinuation. The patient had no features of immune defects prior to this illness. Therefore glucocorticoids are the most likely cause for the immune dysfunction. Impact of glucocorticoids on immune system are predominantly on T cells [11]. T cell dysfunction is a risk factor for CMV infection and was the likely culprit in our patient. Although steroids slightly reduce B cell numbers, immunoglobulin production is not affected in short term [9, 12]. B cells require assistance of T cells for normal immunoglobulin production. After years of glucocorticoid therapy, suppression of T cells can therefore reduce immunoglobulin synthesis. However, this occurs only with long term glucocorticoids therapy and IgA and IgG are the predominantly affected subtypes [13]. Therefore, observations in our patient are unusual, as the B cell depletion was marked, and it developed within few months of steroid therapy and, IgM was predominantly affected subtype. Glucocorticoids induced severe B cell depletion in our patient would have lead to IgM deficiency. No other factor could explain the transient immune dysfunction in the patient.
CMV infection itself is known to suppress T cell mediated immunity by TNF-alfa mediated expression of arachidonic acid and prostaglandin-E2 from infected monocytes [14]. This extreme state of T cell dysfunction with glucocorticoids and CMV infection would have predisposed him to develop disseminated tuberculosis. However, CMV infection activates plasmacytoid dendritic cells which increase proliferation and activation of B cells [15]. Therefore, CMV infection does not explain our patient’s severe B cell deficiency.
