Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles

Abstract

Despite adequate infection prophylaxis, variation in self-reported quality of life (QOL) throughout the intravenous immunoglobulin (IVIG) infusion cycle is a widely reported but infrequently studied phenomenon. To better understand this phenomenon, subjects with humoral immunodeficiency receiving replacement doses of IVIG were studied over 3 infusion cycles. Questionnaire data from 6 time points spread over 3 IVIG infusions cycles (infusion day and 7 days after each infusion) were collected in conjunction with monitoring the blood for number of regulatory T-cells (Treg) and levels of 40 secreted analytes: primarily cytokines, chemokines, and growth factors. At day 7, self-reported well-being increased, and self-reported fatigue decreased, reflecting an overall improvement in QOL 7 days after infusion. Over the same period, percentage of Treg cells in the blood increased (p<0.01). Multiple inflammatory chemokine and cytokine levels increased in the blood by 1 hour after infusion (CCL4 (MIP-1b), CCL3 (MIP-1a), CCL2 (MCP-1), TNF-α, granzyme B, IL-10, IL-1RA, IL-8, IL-6, GM-CSF, and IFN- γ). The largest changes in analytes occurred in subjects initiated on IVIG during the study. A significant decrease in IL-25 (IL-17E) following infusion was seen in most intervals among subjects already receiving regular infusions prior to study entry. These findings reveal several short-term effects of IVIG given in replacement doses to patients with humoral immunodeficiency: QOL consistently improves in the first week of infusion, levels of a collection of monocyte-associated cytokines increase immediately after infusion whereas IL-25 levels decrease, and Treg levels increase. Moreover, patients that are new to IVIG experience more significant fluctuations in cytokine levels than those receiving it regularly.

Fig 1. Outline of study visits.

Subjects participated in three identical cycles. Each cycle consisted of an infusion-day visit and a day-7 visit (2 visits per cycle). Questionnaires were completed once per study visit day for a total of 6 time points. Blood was drawn for Treg levels and blood analytes 3 times per cycle, twice on the infusion day (before infusion and 1 hour after completion) and once at the day-7 visit.

Fig 2. Generalizable improvement of QOL measures on day 7 vs. infusion day.

. A. Paired boxplot representing the change in normalized VAS score from infusion day to the day-7 visit. The box borders represent the first and third quartiles with the whiskers extending to 1.5*(interquartile range). Median is represented by a horizonal line. VAS scores were normalized to Z-scores by subtracting the mean for each subject and dividing by the standard deviation. B. Boxplot of response to question 2 from the modified SF-12: “Compared to the week before, how would you rate your health in general now?” vs. change in normalized VAS score between infusion day and day 7. Box features as in 2A with mean scores are marked by a short horizontal bar. Intervals during which patients reported no improvement (#3) or worsening (#4) of general health had lower normalized VAS scores at day 7 and patients who reported improvement (#1 or #2) had higher normalized VAS scores. Responses: "1" = 3, "2" = 14. "3" = 30, "4" = 3. C. Paired boxplot representing change in weekly-health score (question 2) between infusion day and day 7. Scores were normalized to the mean for each subject. D. Paired boxplot representing change in fatigue scores (question 5) between infusion day and day 7. Fatigue scores were normalized to the mean for each subject. Infusion day scores are enriched for positive values (more fatigue) and day 7 scores are enriched for negative scores (less fatigue).

Fig 3. Proportion of T cells with Treg Phenotype increases from pre-infusion to day 7.

Paired boxplot representing the change in Tregs as a percentage of CD4+ T cells from the pre-infusion blood draw to day 7. Treg% was averaged for each subject before infusion and on day 7. P-value is derived from the random effects model of the relationship between day 7 and the pre-infusion draw.

Fig 4. Statistically-significant cytokine changes between the pre-infusion and post-infusion blood draws plot of the mean (dot) and confidence interval (whiskers) for the coefficients of the pre-infusion to post-infusion interval.

Subjects were separated by whether IVIG treatment was initiated during the study (naïve) or if the subject was already receiving IVIG regularly (non-naïve). P-values for coefficients were adjusted by the Benjamini-Hochberg method. Adjusted p-values < 0.05 are highlighted in red.

Fig 5. Proportions of intervals where cytokines change varies between cytokines.

Stacked bar graph for each cytokine found to change between the pre- and post-infusion measurements; A. non-naïve subjects, B. naïve subjects. Direction of change is signified by depth of color as shown in the figure legend. "Up" signifies a greater than 10% increase and "down" signifies a greater than 10% decrease.

Fig 6. Correlations of cytokines that significantly change between the pre-infusion and post-infusion blood draws pearson’s correlation between cytokine pairs is indicated by color and size of dots.

The larger and deeper colored dots indicate a higher r value. The analytes were hierarchically clustered, and the black boxes correspond to clusters generated at a level of 6 clusters.