Discussion
To the best of our knowledge, the present study demonstrated for the
first time using a large cohort of patients with KD in multicenter that
pretreatment PNI was negatively associated with biomarkers of
immunity/inflammation (NLR and PLR) and positively associated with age,
platelet, serum sodium. Low PNI was significantly associated with higher
levels of CRP and higher the incidence of IVIG resistance. As with NLR
and PLR, PNI was an independent predictor of IVIG resistance.
Pretreatment PNI was not inferior to NLR and PLR for predicting IVIG
resistance.
In the present study, the percentage of IVIG-resistance was 14.9%,
which was far higher the 6.25% determined by Xu-Hai Tan et al[7] and was consistent with the 10-20% reported by Fukunishiet al [21] and Sleeper et al [22]. The discrepancy
could be attributed to the different study populations, the sample size
and the definition of IVIG-resistance. IVIG-resistant KD has been
observed to be associated with a higher incidence of CALs, which is
detrimental to the outcome of KD. Early additional treatment before the
initial use of IVIG could decrease the occurrence of CALs in IVIG
resistant KD. Therefore, it is essential to investigate simple and
feasible indictors for IVIG resistance.
Consistent with previous data [4-6], the markers of inflammatory and
immunological activation, NLR and PLR, were associated with IVIG
resistance in the present study. Systematic immunonutritional status has
been refined by introduction of PNI, a continuous variable based on
serum albumin concentration and total lymphocyte count in peripheral
blood, which was associated with the mortality and morbidity in patients
with cardiac diseases [23], acute kidney injury [24] and cancer
[10]. The present study revealed that low PNI was significantly
associated with high levels of CRP and low counts of platelet.
Furthermore, an inverse correlation between PNI and the biomarkers of
immunity/inflammation (NLR and PLR) was observed in the present study,
which was in accordance with patients with osteosarcoma [10]. PNI
was also demonstrated to be correlated with disease activity in patients
with systemic lupus erythematosus [25, 26]. Besides, several
previous studies reported that hyponatremia was observed in children
with KD, particularly children with IVIG resistant KD [27-29] and
was associated with the extent of inflammation [30, 31]. In line
with these studies, low PNI was demonstrated to be closely associated
with low serum sodium in the present study. These results clearly convey
the notion that PNI may be associated with IVIG resistance.
PNI brings two important measurements together. On the one hand, serum
albumin is known as an indicator of host inflammatory and nutritional
status [8], and its levels are associated with higher mortality in
several different types of tumor. Hypoalbuminemia was observed in IVIG
resistant KD [32] and has been confirmed to be also closely
associated with inflammatory markers, such as NLR and PLR. Additionally,
research has shown that malnutrition was associated with the
immune-suppressed condition [33, 34], impaired respiratory function,
and poor wound healing [24], as well as increased risks of
postoperative morbidity and mortality and prolonged hospital
stays[24]. On the other hand, lymphocytopenia is regarded as the
marker of a depressed cell-mediated immunity [35], which can lead to
the development of systemic inflammatory response syndrome and is
closely associated with immunity and inflammation. It has been reported
that critically ill patients with shock and sepsis had marked
lymphocytopenia, and that the severity of the clinical course was
correlated with the divergence of the lymphocyte (lower) counts
[35]. Lymphocytopenia was also associated with decreased survival in
advanced carcinoma, sarcoma and lymphoma [36], similar to
hypoalbuminemia. Numerous studies from large samples of multiple
research centers in Asia have indicated that lymphocyte counts were
significantly decreased in IVIG resistant KD when compared with IVIG
responsive KD [7, 37, 38]. In the present study, low PNI was
associated with decreased albumin and/or lymphocytes. The patients with
lower PNI had significantly higher the incidence of IVIG resistance in
the present study, which was consistent with previous findings [18].
According to these results, PNI, combined with albumin and lymphocyte
levels, could be a superior index that reflects inflammation, immune
system and nutritional status in IVIG resistant KD.
Valid prediction of the IVIG-treatment response is crucial to the
patients with KD. A number of clinical and inflammatory indexes (age
<12 months, platelet <300 ×109/L,
higher total bilirubin levels and CRP levels, serum sodium levels, NLR
and PLR) for predicting IVIG resistance have been reported [3, 7, 37,
39]. The results of the present study further confirmed those
indictors (age <12 months, serum sodium, CRP, NLR and PLR),
implying that the results of the present study are convincing.
Regretfully, the aforementioned parameters had relatively low predictive
power for IVIG resistance according to previous investigations. The
prognostic value of PNI has been investigated in certain types of human
cancer [9, 10], postoperative septic complications, ST segment
elevation myocardial infarction [14]. PNI can also predict the
clinical outcome of the pediatric population in the intensive care unit
after cardiac operation [40].Accordingly, both univariate and
multivariate analyses suggested that pretreatment low PNI was an
independent predictor for IVIG resistance in the present study. Although
the discriminatory ability of NLR and PLR to predict IVIG resistant KD
has been demonstrated in previous reports [5, 6, 37], as well as in
the present study, pretreatment PNI having the highest AUC was not
inferior to NLR and PLR as an indicator for predicting IVIG resistance
determined by ROC analysis. The investigation performed by Miriliet al [41] in malignant melanoma was in accordance with the
results of the present study. In addition, pretreatment NLR, PLR and PNI
are emerging as predictors of the treatment response to neoadjuvant
chemoradiotherapy in rectal cancer [42]. Taken together, PNI is a
potential as a candidate for predicting IVIG resistance. As PNI is
routinely available and can be measured accurately, it may become a
useful and inexpensive approach to the IVIG-treatment response
prediction in KD. Accordingly, it has been suggested that the patients
with KD having lower PNI levels may be a potential candidate for an
aggressive treatment strategy. Nevertheless, further studies should be
warranted to verify the findings.
However, it is necessary to recognize limitations in the present study.
First, the results have the potential to be biased in terms of the
population choice. Second, although a multivariable analysis was used,
the possibility of residual unmeasured covariables that may influence
the outcomes cannot be excluded. For example, genetic, ethnic and
regional factors, and IVIG metabolic factors have not been taken into
account. Finally, the data sample used in the present study remains
relatively small and only located in western China. Thus, these
limitations can potentially limit the accuracy of the results in the
present study. Therefore, the ability and accuracy of the PNI in
predicting IVIG resistance should be further validated by performing
additional prospective, multicenter studies.