Acute Neurological Illness in a Kidney Transplant Recipient Following Infection With Enterovirus-D68: An Emerging Infection?

We report the first case of enterovirus-D68 infection in an adult living-donor kidney transplant recipient who developed rapidly progressive bulbar weakness and acute flaccid limb paralysis following an upper respiratory infection. We present a 45-year-old gentleman who underwent pre-emptive living-donor kidney transplantation for IgA nephropathy. Eight weeks following transplantation, he developed an acute respiratory illness from enterovirus/rhinovirus that was detectable in nasopharyngeal (NP) swabs. Within 24 h of onset of respiratory symptoms, the patient developed binocular diplopia which rapidly progressed to multiple cranial nerve dysfunctions (acute bulbar syndrome) over the next 24 h. Within the next 48 h, asymmetric flaccid paralysis of the left arm and urinary retention developed. While his neurological symptoms were evolving, the Centers for Disease Control reported that the enterovirus strain from the NP swabs was, in fact, Enterovirus-D68 (EV-D68). Magnetic resonance imaging of the brain demonstrated unique gray matter and anterior horn cell changes in the midbrain and spinal cord, respectively. Constellation of these neurological symptoms and signs was suggestive for postinfectious encephalomyelitis (acute disseminated encephalomyelitis [ADEM]) from EV-D68. Treatment based on the principles of ADEM included intensive physical therapy and other supportive measures, which resulted in a steady albeit slow improvement in his left arm and bulbar weakness, while maintaining stable allograft function.

Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy.

The current study examined whether alterations in glucocorticoid receptor (GR) binding contribute to poor response to glucocorticoid therapy in asthma. 29 asthma patients with forced expiratory volume in 1 s (FEV1) < 70% predicted were studied. Patients were classified as steroid sensitive (SS) if their morning FEV1 increased > 30% after a 1-wk course of oral prednisone 20 mg twice daily and steroid resistant (SR) if they failed to increase > 15%. PBMC obtained from these two groups, 17 SR and 12 SS, as well as 12 normal controls were analyzed. SR patients had two distinguishable GR binding abnormalities: 15 of the 17 SR patients demonstrated a significantly reduced GR binding affinity, as compared with SS patients (P = 0.0001) and normal controls (P = 0.0001). This defect was localized to T cells and reverted to normal after 48 h in culture media. However, incubation with a combination of IL-2 and IL-4 sustained this abnormality. The other two SR patients had an abnormally low GR number with normal binding affinity that was not limited to T cells. Furthermore, GR number failed to normalize after incubation in media alone or IL-2 and IL-4. Therefore, SR asthma may be due to more than one abnormality, the majority related to a reversible cytokine-induced reduction in GR binding affinity and the second related to an irreversible reduction in GR number. These findings may have important implications for the design of alternative treatment approaches for recalcitrant asthma.

Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids.

The mechanisms contributing to persistent T cell activation and poor response to glucocorticoids in chronic inflammatory illnesses such as steroid resistant (SR) asthma are poorly defined. We examined the possibility that certain cytokines, specifically IL-2 and IL-4, could affect T cell response to glucocorticoids. A [3H]dexamethasone radioligand-binding assay was used to measure the number of glucocorticoid receptors (GR) and dissociation constant (Kd) in PBMC from normal donors and patients with SR asthma, cultured in the absence and presence of these cytokines. PBMC from normal donors incubated for 48 h in the presence of combination IL-2 + IL-4 had nuclear GR with significantly reduced binding affinity (GR Kd = 36.1 +/- 1.63 nM, mean +/- SEM; p = 0.0001) as compared with PBMC incubated with medium alone (GR Kd = 6.74 +/- 0.46 nM). The cytosolic GR Kd remained unchanged. However, when PBMC were incubated with IL-2 alone or IL-4 alone, no change in GR-binding affinity was observed. Furthermore, when T cells and non-T cells were individually stimulated with combination IL-2 + IL-4, a significant reduction in GR-binding affinity was observed only in the T cell population (p = 0.0001). The IL-2 + IL-4-induced alteration in PBMC GR Kd was associated with an increase in GR number (8348 +/- 964 vs 1710 +/- 228 sites/cell; p = 0.0003). More importantly, the alteration in PBMC GR-binding affinity with IL-2 + IL-4 was associated with a functional change in T cell response to methylprednisolone MPN, i.e., a reduced inhibitory effect of MPN on PMA/ionomycin-induced T cell proliferation. These effects of IL-2 + IL-4 on PBMC GR affinity and response to MPN were blocked by co-incubation with IFN-gamma. Freshly isolated PBMC from four patients with SR asthma had a significantly reduced GR-binding affinity (Kd = 40.0 +/- 2.68 nM; p = 0.0001) when compared with seven normal subjects (7.15 +/- 0.41 nM). The altered PBMC GR binding from patients with SR asthma reversed to normal when incubated with medium alone, but was sustained with IL-2 + IL-4. These observations suggest that with persistent inflammation certain cytokines may contribute to an impaired response to glucocorticoids. Furthermore, the effects of IL-2 and IL-4 were blocked by IFN-gamma.