This study is the first to use LCPA to characterize a sample of oncology patients and their FCs using a cluster of symptoms associated with “sickness behavior” and to identify an association between these latent classes and one anti-inflammatory cytokine (i.e., IL4). The identification of distinct subgroups of individuals with different symptom experiences is consistent with previous reports.[14
] However, only one cytokine gene was associated with differences in the severity of this “sickness behavior” symptom cluster.
In this sample, three relatively distinct classes of participants were identified, namely those who reported low depression and low pain (83%), those who reported high depression and low pain (4.7%), and those who reported high levels of all four symptoms (12.3%). While our previous studies identified four distinct latent classes using the same symptom cluster,[18
] a consistent finding across all four studies is that the “All high” class constituted between 10% and 15% (mean 13.0%) of the sample. This finding suggests that a subset of individuals share some common biological mechanisms that influence their experience with the multiple symptoms associated with sickness behavior. Identification of these mechanisms could lead to the development of targeted interventions for this high-risk group.
Because LCPA is an exploratory analytic procedure that facilitates the emergence of distinct latent classes based on similarities in some dependent variables (in this study – differences in participants’ ratings of pain, fatigue, sleep disturbance, and depression), group membership can change based on sample characteristics as well as timing of the symptom assessments. Therefore, differences across studies[14
] in the number of latent classes, as well as in the symptom characteristics of the various latent classes, may be related to differences in demographic and clinical characteristics of the samples; differences in inclusion and exclusion criteria, as well as differences in some unidentified phenotypic and environmental characteristics. Because blood samples were not obtained from participants in our previous studies,[18
] the genetic association identified in this study awaits verification in future studies.
In this cohort, carrying the minor allele for IL4 rs2243248 was associated with membership in the “All high” class along with younger age, being White, being a patient (versus a FC), having a lower functional status, and having a higher number of comorbid conditions. Similar associations between higher symptom severity scores and various demographic and clinical characteristics were reported in previous studies. [14
] However, it is important to note that the genetic association was not confounded by any of these demographic or clinical characteristics. These findings are particularly interesting because IL4 was either not evaluated or identified as a candidate gene in previous research on symptoms. Previous studies found genetic associations between IL1β and IL6 and severity of fatigue,[40
] as well as associations between IL6 and TNF-α and severity of fatigue and sleep disturbance.[38
] The discrepancy in study findings may be related to differences in symptom phenotypes (i.e. single symptoms versus a symptom cluster). Given the fact that a number of reviews suggested that alterations in pro-inflammatory cytokines contributed to the symptoms associated with sickness behavior,[10
] additional research is warranted to evaluate associations between single symptoms and symptom clusters and pro- and anti- inflammatory cytokine genes.
The anti-inflammatory cytokine IL4 blocks the action of a number of pro-inflammatory cytokines (i.e., IL1-β, IL6, IL8, and TNF-α. [86
] The IL4 SNP identified in this study (rs2243248) is known to occur in an evolutionarily conserved region. While the functional effects of this SNP are not known, findings from this study suggest that carrying the minor allele may result in alterations in the regulation of several pro-inflammatory cytokines. This dysregulation in IL4 function places these individuals in a high-risk group for experiencing multiple symptoms related to “sickness behavior”.
In fact, the neuromodulatory effects of IL4 have been evaluated in animal models of sickness behavior. For example, in one study, cytokine-induced sickness behavior in rats was inhibited when IL4 was administered 12 hours prior to lipopolysaccharide (LPS) but was potentiated when IL4 was co-administered with LPS. This finding suggests that the regulation of sickness behavior by IL4 can be either inhibitory or stimulatory.[87
] Interestingly, LPS–induced sickness behavior was more profound in IL4 (−/−) mice, which suggests a more protective role for IL4.[88
]. Furthermore, Sherry and colleagues observed decreased sickness behavior in wild type mice fed a soluble fiber diet which induced the up regulation of IL4.[89
] The protective effect of the soluble fiber diet was reduced in IL-4 (−/−) mice. While research on the association between IL4 and sickness behavior in humans is limited, one study found that an eight-week meditation program increased production of IL4 and decreased production of interferon (IFN)-γ and IL10 in individuals with early stage prostate or breast cancer.[90
] These changes in serum cytokines were associated with reduced symptoms of stress (including depression), increased sleep quality, and increased QOL.
Previous work with this sample of patients and FCs identified associations between TNF-α (rs1800629) and sleep disturbance and morning fatigue[38
] and between IL6 (rs4719714) and sleep disturbance, evening fatigue, and morning fatigue.[39
] The lack of an association between these SNPs and the subgroups of participants found in this study may be explained by a number of factors. First, the symptom phenotype that was evaluated in this study (i.e., symptom cluster of pain, fatigue, sleep disturbance and depression) compared to previous studies (i.e., single symptoms) are distinctly different and may be associated with different cytokine genes. This hypothesis is supported by the fact that the p-values of the additive models for TNF-α rs1800629 (p=.422) and IL6 rs 4719714 (p=.419) in this study did not approach statistical significance (). An equally plausible hypothesis is that additional research, with larger samples might identify additional candidate genes. In addition, rather than polymorphisms in various cytokine genes being directly responsible for the symptoms associated with sickness behavior and elevations in serum levels of cytokines, polymorphisms in other gene pathways may be involved in activation or inhibition of cytokine genes. This hypothesis warrants investigation in future studies.
Several study limitations need to be acknowledged. The majority of participants were middle-aged, Caucasian, well educated, and married/ partnered, which limits the generalizability of these findings to individuals with similar demographic characteristics. The major reasons for enrollment refusal were being too overwhelmed with treatment or too busy which may have led to either underestimation or overestimation of symptoms in the individuals included in this study. In addition, the exact etiologies for and duration of each of the individual symptoms within the symptom cluster were not evaluated. While most studies of sickness behavior reported symptoms associated with an acute stimulus (e.g., administration of lipopolysaccharide),[22
] it is possible that a symptom cluster that occurs because of one or more chronic conditions is associated with genetic variations in pro- and anti-inflammatory cytokines. Future studies need to evaluate the relationships between cytokine genes and individual symptoms as well as symptom clusters.
Due to the small sample sizes for the “All high” and the “High depression and low pain” classes, it is plausible that some genetic associations were not identified because of low minor allele frequency. For example, findings for several SNPs in IL1R1, IL2, IL8, IL10, IL17A, and TNF-α approached statistical significance and warrant investigation in future studies with larger sample sizes. It is plausible that other genetic associations with symptom clusters will emerge if the same analyses are conducted at several points over the trajectory of the patient’s treatment as latent class membership can change over time.[14
] Finally, future studies may need to evaluate levels of pro- and anti-inflammatory cytokines in order to refine our understanding of the associations between genotype and self-reported symptom experiences.
In summary, the recognition of a distinct phenotype that may represent sickness behavior reveals new evidence for the role of IL4 in the modulation of this symptom cluster in oncology patients and their FCs. Using new statistical approaches like LCPA to identify distinct phenotypes may provide new information about the biologic mechanisms that underline this symptom experience. Indeed, this study uncovered a role for an anti-inflammatory cytokine in the modulation of symptom experience that was not described previously and warrants confirmation in future studies.
Distinct groups had high levels of pain, fatigue, sleep disturbance and depression.
Approximately 12% of patients reported high levels of all four symptoms.
New role for IL4 in the modulation of a sickness behavior symptom was identified.