CROI 2009 Abstract #773

Background: The pathogenesis of immune reconstitution inflammatory syndrome (IRIS) is poorly understood, but is hypothesized to be related to dysregulation of effector and regulatory T cells. We compared plasma cytokine and chemokine profiles pre-ART and at events between patients with unmasking or paradoxical TB IRIS and those with non-IRIS clinical events.

Methods: A prospective cohort study was undertaken of 498 patients initiating ART at 2 clinics in Durban, South Africa. Patients were screened for TB prior to ART and reviewed for 6 months. We identified 4 subgroups: group 1, no TB at baseline but subsequent unmasking TB IRIS (n = 13); 2, no TB at baseline, with subsequent non-IRIS clinical event (n = 12); 3, TB at baseline on anti-TB treatment who developed paradoxical TB IRIS (n = 9); and 4, TB at baseline on anti-TB treatment with subsequent non-IRIS clinical event (n = 12). Groups 1 and 2, and groups 3 and 4, were matched on duration of ART at event, age, CD4, and viral load. Baseline and event plasma levels of 17 cytokines and chemokines were analyzed using a Luminex kit (interleukin [IL] -1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, interferon-gamma [IFN-γ], tumor necrosis factor-alpha [TNF-α], granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon-inducible protein-10 [IP-10], monokine induced by interferon-gamma [MIG], macrophage inhibitory protein [MIP] -1a, MIP-1b, and monocyte chemotactic protein-1 [MCP-1]). We conducted pair-wise comparisons between median analyte levels in groups 1 vs 2, 3 vs 4, and 1 and 3 vs 2.

Results: Overall, patients were 73% female, median age 35 years, CD4 count 74 (IQR 29 to 125), duration of anti-TB treatment pre-ART 12 weeks (IQR 8 to 18). Event samples were drawn at a median of 4 weeks of ART. Comparisons that yielded statistically significant results are shown in the table.

IRIS group	Control group	Analyte *	Median (IQR) cases *	Median (IQR) controls *	p
BASELINE
1: Unmasking	2: no TB	IFN-γ	9.1 (4.4–24.7)	0.9 (0–8.7)	0.032
1: Unmasking		CRP	25 (8–47)	6 (0–12)	0.046
1&3: Unmasking + paradoxical		IL-2	4.7 (1.8–11.4)	9.3 (4.6–25.7)	0.047**
EVENT
1: Unmasking	2: no TB	TNF-α	13.2 (9.1–20.0)	8.1 (6.7–10.4)	0.030
1: Unmasking		CRP	56 (35–107)	6 (1–35)	0.007
1&3: Unmasking + paradoxical		TNF-α	12.4 (9.0–25.3)	8.1 (6.7–10.4)	0.047**
1&3: Unmasking + paradoxical		CRP	48 (34–88)	6 (1–35)	0.007**
3: Paradoxical	4: TB, no IRIS	IL-10	22.1 (15.3–34.9)	82.2 (29.4–128.4)	0.047
		MCP-1	27.6 (20.0–29.7)	71.4 (40.6–77.8)	0.005
		GM-CSF	0.3 (0–0.3)	0.4 (0.3–0.8)	0.041

Conclusions: Patients who developed unmasking TB-IRIS had higher baseline levels of plasma IFN-γ and CRP, consistent with subclinical TB infection. No predictors of paradoxical TB-IRIS were identified. Systemic inflammatory responses (elevated TNF-α and CRP) were observed at event in unmasking and paradoxical IRIS.