Table 1.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome – knowledge summary

Knowledge summary		Key references
Incidence	Adults overall: 18% (95% CI 16–21%), with a range of 4–54%; higher rates in patients with lower CD4 counts (up to 57% in patients with CD4 count <200 cells/μl).	Reviewed in [2] Recent cohort described in [3▪]
	South African children: 6.7% reported in a recent prospective study	[4]
Risk factors	Low CD4 count at ART initiation; High HIV viral load at ART initiation	Reviewed in [2]
	Shorter time between TB treatment initiation and ART initiation	Meta-analyses reported in [5,6]
	Disseminated TB/high mycobacterial load.	[3▪,7▪]
Clinical presentation	Systemic, pulmonary and lymph node presentations most common	Reviewed in [2]
	In a recent study, median days to symptom onset reported as 6 (range 1–23)	[3▪]
Mortality	All-cause mortality rate of 7% (95% CI 4–11%) and IRIS-attributable deaths of 2% (95% CI 1–3%)	Reviewed in [2]
	Higher mortality in CNS TB-IRIS	Reviewed in [8]
Pathogenesis	Innate immune cell activation, including neutrophils, monocytes and NK cells; Antigen-specific upregulation of cytotoxic mediators Inflammasome activation; Hypercytokinaemia (including IL-1β, IL-6 and TNF-α) and MMP upregulation/secretion	Reviewed in [9]; see also, [3▪,7▪,10▪]
Treatment	Prednisone (1.5 mg/kg for 2 weeks followed by 0.75 mg/kg for 2 weeks) for treatment of paradoxical TB-IRIS reduced length of hospital admission and number of therapeutic procedures required, and improved symptoms in paradoxical TB-IRIS	Randomized-controlled trial reported in [11]
	Consensus is not to stop ART, but to investigate fully for alternative causes, and provide symptomatic treatment	Reviewed in [9]
Prevention	Prednisone (40 mg daily for 2 weeks, followed by 20 mg daily for 2 weeks) from ART initiation reduces the risk of future paradoxical TB-IRIS by 30%	[12▪▪]
	Do not delay ART initiation beyond 2 weeks after TB treatment initiation in patients with CD4 count <50 cells/mm3, unless CNS TB diagnosed (then delay 4–8 weeks). Early ART improves survival in patients with CD4 < 50 cells/mm3 even though it increases TB-IRIS risk > two-fold	Meta-analyses reported in [5,6]