Estimation of weight and height of patients with primary immunodeficiency disorders and group of children with recurrent respiratory tract infections.

Primary immunodeficiences (PIDs) are a group of chronic, serious disorders in which the immune response is insufficient. In consequence, it leads to an increased susceptibility to infections. Up to date, there are about 300 different disorders classified in that group. There are also patients suffering from recurrent respiratory tract infections (RRTI), however that group doesn't present any abnormalities in terms of conducted immunological tests. Many factors, including medical, can have an impact on physical development of a child. Data such as birth weight and length, also weight, height, BMI during admission to the hospital were collected from 207 patients' medical histories from their hospitalization at Clinical Immunology and Paediatrics ward of J.Gromkowski Hospital in Wrocław. Investigated groups included patients with PIDs, RRTI and a control group of healthy children. Our purpose was to evaluate the physical growth of children with primary immunodeficiency (PID) and children with recurrent respiratory tract infections (RRTI) by assessment of their height and weight. All of parameters were evaluated using centile charts suitable best for the Polish population. between the

growth of children with PID and children with RRTI. Collaterally, we attempted to discover if there were abnormalities in birth weight and length in group of patients with PID.

Methods
The study was conducted utilizing retrospective analysis. Primary research material were medical histories of patients hospitalized in Clinical Immunology and Pediatrics Ward, J.Gromkowski Provincial Clinical Hospital in Wrocław from October 2014 up to March 2015.
The study group numbered 207 people (n=102 female, n=105 male), whose age ranged from 4 weeks old up to 21 years old. The group was divided into 3, which is shown at table 1 : PID (n=61); largest group were patients with predominantly antibody deficiencies (n=43). Most of the patients were diagnosed with IgG deficiency (n=15; 24,5%) and IgG subclass deficiency (n=12; 19,7%).
Among recurrent respiratory tract infections group (RRTI; n=76), no abnormalities in terms of immunological tests were found, but had a history of mild recurrent upper respiratory tract infections at least 8 times in 12 months and required immunological diagnostics. These patients were admitted to our clinic at the same time as PID group to conduct immunological tests.
Patients with PID treated with immunoglobulin (PID Ig+therapy) were admitted to the clinic every month or every three months. For adequate groups comparison, data were collected at the same time as PID patients were hospitalized.

Assessed parameters
Birth length and weight Height and weight during admission to the hospital Body mass index (BMI) Due to insufficient amount of patients' data about gestational age at birth, we have not assessed birth length and weight with use of centiles. We have acknowledged a cut-off point at 2500g. Analyzing height and weight during the admission, each parameter was assigned to corresponding centile intervals : <3, 3-10, 10-25, 25-50, 50-75, 75-90, 90-97, >97 centile. These values were assessed using development standards analyzed and published for the Polish children population [8] as well as WHO standards [9]. Polish development standards allowed to evaluate the development of the whole study group, based on the centile charts. The BMI was defined as : underweight, normal weight, overweight and obese, based on the latest development standards of BMI published in Poland for age 3-18 years old. Z-score was assessed for such values as : height and BMI relevant to age on the basis of WHO standards [9] for all the patients. BMI's z-score, according to WHO recommendations, was treated as incorrect when situated <-2SD (underweight), >1SD (overweight), >2SD (obesity). Both weight centiles and z-score according to WHO standards were available only for ages 0-10 years old, therefore evaluation of these parameters was excluded with WHO standards.
Statistical analysis of data was conducted using the spreadsheet of the Microsoft Office Excel 2010 (Microsoft Corp. Washington, WA, USA) and Statistica 12 -non-parametric Chi^2 Pearson test.
The study had a consent of a bioethical commission.

Birth weight
Birth weight values of 195 patients were available for analysis. The highest standard deviation (SD=721) and the lowest mean birth weight (mean 2857,3g) referred to patients with PID (Fig.1). In addition, patients treated with immunoglobulin (PID Ig+therapy) were born with a little less mean birth weight (mean 2822,88g) and higher SD (SD=785,57) than PID patients without therapy (PID Ig -therapy; mean 2897,86; SD=648,56). 29,5% (n=18) of children with PID were born with weight under 2500g, while in the RRTI group only 6,25% (n=4, among 64 available data) and in the control group 2,86% (n=2, among 6 Birth length Birth length values were collected from 170 patients. Children with PID had the lowest mean birth length (mean=50,8cm) and the highest standard deviation among all groups (SD=6,36); when dividing into groups with or without substitution of immunoglobulin, the highest SD (6,84) and the lowest mean birth length (h=50,61cm) related to PID Ig+therapy (Fig.2).

Weight during hospitalization
Weight during hospitalization data (patients were hospitalized at different ages) were available for all the patients. They were assigned to certain centiles, based on the Polish growth standards (Fig.3). Almost 20% of patients with PID (n=12) had weight under 3rd percentile, 7% (n=5) of the RRTI group. There were no statistically significant differences in weight centiles between these 2 groups (Pearson Chi^2 test, p=0,085). Relevantly more often weight under 3rd percentile affected children with PID Ig+therapy (n=11) than those without substitution (PID Ig-therapy, n=1), although there were no statistically significant differences between those groups (Pearson Chi^2 test p=0,138). A significant statistical difference was found between weight centiles of children with PID and control group (p=0,002).

Height during hospitalization
Height during hospitalization data were available as well for all the patients. They were classified to certain centiles according to both Polish (Fig.4) and WHO standards.
According to Polish standards every fifth PID patient (n=12, 20%) and 10 RRTI patients (13%) were classified in the <3 centile compartment. In the 3-10 percentile interval there were 6 patients in the PID group (10%) and 4 in the RRTI group (5%). There were no statistical differences between height assigned to certain centiles of PID and RRTI group (p=0,09) with the Polish standards. According to WHO's, 11 patients (18%) from the PID group were situated below 3rd percentile of height, same with the z-score <-2SD (Fig. 5).
There was a statistically relevant difference between female and male height Z-score from the PID group (p=0,021). There were 6 girls with height between -2SD and -3SD z-score and 0 girls with height under -3SD z-score, while 3 boys with PID had height between -2SD and -3SD z-score and 2 had height under -3SD z-score. 8 patients (10,53%) from the RRTI group had their height below Z-score <-2SD. There were no statistically significant differences between PID and RRTI group in terms of height Z-score (p=0,7) or between PID and the control group both in the height centiles of Polish standards (p=0,06) and Z-score (p=0,1).
Based on data collected from all of the patients the BMIs were calculated and classified to certain nutritional status of Polish centile charts standards (Fig.6). Nutritional status was possible to define using centile charts for age 3-18 years old (PID n=43, RRTI n=52, control group n=35). It was within normal for most of the patients (PID-67,44%, n=29, RRTI-67,3%, n=35, control group-82,86%, n=29). 10 patients over 3 years old from the PID group were underweight (23,26%, 16,39% of all participants). In the RRTI group 6 patients over 3 years old were underweight (11,54%, 7,89% of all participants). 5 PID patients and 10 RRTI were diagnosed with overweight. Obesity was observed in one person in the RRTI group, whereas in the PID group no sign of obesity was found. Nevertheless, differences between these 2 groups weren't statistically significant (test Chi^2 Pearsona, p=0,4). The statistically significant difference was between the nutritional status of PID patients and the control group (p=0,018) (Fig.6).
There was no statistically relevant difference in nutritional status using Polish standards between PID patients with or without immunoglobulin substitution (p=0,087), although it's worth noting that underweight more frequently referred to Ig+therapy patients (n=9; 33,33%), than to Ig-therapy (n=1; 5,88%) (Fig. 8). No statistically relevant difference was found either in case of BMI Z-score (p=0,129).
Among 10 underweight patients from PID group (ages 3-20), 5 people had been diagnosed with ataxia-telangiectasia, 2 with Nijmegen breakage syndrome, 1 with Edwards syndrome, 1 with main classes immunoglobulin deficiency and 1 with C-1 esterase inhibitor and partial C4 component deficiency. Among patients under 3 years old, three with main classes immunoglobulin deficiency had BMI Z-score below -2SD.

Discussion
Nutritional status is a valuable factor, which has an impact on immunological response [10]. The relationship between nutritional status and the immune system has been a topic of study for much of the 20th century [11]. With no doubt malnutrition is considered as one of the most common causes of impaired immunity worldwide [12]. As nutritional status has its influence on susceptibility to infections, so may immune system disorders have an influence on nutritional status [13]. Many original papers have proven higher frequency of malnutrition and anthropometric values abnormalities in some of diseases from the PID spectrum [14][15][16]. Because of heterogeneity of this group, results of each study should be analyzed with inclusion of certain disease characteristics.
Improper nutritional status has been seen in the patients with common variable immunodeficiency (CVID) [14,15]. Additionally, analyzed anthropometric parameters have indicated higher frequency of malnutrition in these patients' population, comparing to general population. It has been noticed that patients with CVID' had higher susceptibility to infections, persistent, prolongating diarrhea and absorption disorders, which may result in malnutrition of this group, hence causing higher risk of disease complications [14]. A study conducted on Iranian children suffering from humoral immunity disorders, including CVID (52,5% of participants) and X-linked agammaglobulinemia (27,5% of participants) underweight was detected (BMI <5 percentile) among 21,1% children, with no relevant differences between sexes [15]. Authors noticed that frequency of malnutrition of children with humoral immunity disorders is almost 4 times higher than in the healthy children population, based on data from Center for Disease Control (CDC) of year 2000. Moreover, in this study height and weight relative to age were also improper: 57,5% of patients had too small weight for their age (based on Z-score <-1) and 63,2% were too short for their age. In a study conducted by Muscaritoli et al., anthropometric measurements allowed to find out that 23% of adults with CVID had BMI <18,5 and a higher susceptibility to proteinenergetic malnutrition [14]. Other studies point to common intestinal villae atrophy occurrence in patients with CVID, which is correlated with anaemia, malnutrition and lower CD4+ lymphocytes count among these patients [16]. Three patients with CVID took part in our study. Their weight, height and BMI during hospitalization remained normal (-2<Z-score<+2; 3<centile<97). All of them had immunoglobulin replacement therapy. Four patients with main classes immunoglobulin deficiency (other than CVID) in our study had improper nutritional status according to their BMI (Z-score <-2SD and/or underweight assessed by centile charts).
1 patient with chronic granulomatous disease took part in our study. During hospitalization his weight, height and BMI remained normal. (-2<Z-score<+2). Cole et al. study compared patients with the disease after hematopoietic stem cell transplantation and without this treatment [17]. Among the assessed parameters were anthropometric ones (height, weight, BMI), which were applied to growth standards developed by WHO.
Height and nutritional status disorders were mainly found in the patients without transplantation group. 20% of this group were too short, compared to age (z-score <-2) and 16,67% had too low BMI relative to age. Weight z-score <-2SD in children without transplantation was found at 22% of patients. Pretransplantation and posttransplantation weights and heights were available for 14 children who had undergone HSCT with at least 1 year of posttransplantation follow-up. 21% (n=3) of these children had height-forage z scores <−2, which was deemed low for age before HSCT. One child continued to have low height for his/her age after HSCT. No child had low BMI for their age before or after HSCT. There was a significant improvement in height for age but no significant difference in BMI for age when comparing pretransplantation and posttransplantation data. Too small group of people under study (n=1) didn't allow for any clear conclusions about nutritional status of them.
A special group of patients with PID are the ones of chromosomal instability group (ataxiatelangiectasia (AT) and Nijmegen breakage syndrome (NBS). Apart from genetically lowered capability to DNA reparation, these two syndromes are also connected by higher tendency to immune system disorders. Because of the rarity of ataxia-telangiectasia, there are few available sources evaluating physical growth and nutritional status of this disease. In Ehlayel et al. study on 13 patients with AT, 38% were too short, based on the height standard deviation score (HtSDS) <-2SD. However, their midparental height standard deviation score was −1.3 ± 1.1 and 31% had a HtSDS <−2. Patients' HtSDS was correlated significantly with their mid-parental height standard deviation score (p < 0.001). Patients' BMI was low in 31% of them (BMI SD <−2) [18]. In our study 8 patients with AT took part. At 37,5% (n=3) BMI <-1 was noticed, at 25% (n=2) BMI <-2SD. Nijmegen breakage syndrome seems to occur worldwide, but with a distinctly higher prevalence among Central European and Eastern European populations [19,20]. The longterm study of over 70 patients with NBS conducted by Chrzanowska et al. showed retardation in their somatic growth practically since birth [21]. The mean birth anthropometric parameters, including weight, length, head and chest circumferences were significantly lower than in healthy population. Infants of both genders showed a growth deficit until the age of 2 or 3 when some gain of height and weight, but not occipitofrontal circumference was observed. In later stages of childhood and adolescence, differences in the growth pattern between girls and boys became apparent: the growth spurt in boys was poor and was absent in girls. The mean height in over half of the adult girls and boys with NBS was within lower normal ranges. Among 4 patients with Nijmegen breakage syndrome in our study (aged 1,5-11y.), one had BMI <-1SD, second one <-2SD. According to Polish centile charts, nutritional status of these 2 patients was determined as underweight.
These irregularities affected girls (n=2), boys were within norm. Both females were also born with birth weight under 2500g, while boys >2500g. In case of that disease, growth retardation, as well as microcephaly are in its symptoms spectrum. Differences between sexes and small numbers of current publications about growth and physical development of children with Nijmegen breakage syndrome suggest the need for further studies of this topic.
Evaluation of physical growth presented in our study on heterogenous group of diseases, which are primary immunodeficiency disorders, shows higher percentage of children with PID improperly developed, compared to the control group. Almost every 5th patient with PID had weight and height <3 centile, moreover 23% over the age of 3 were underweight.
It is worth to mention that improper nutritional status involves not only specific syndromes like Nijmegen breakage syndrome or ataxia-telangiectasia but also predominantly antibody deficiencies. We wanted to pay attention to higher risk of malnutrition in all PID patients, not only in particular conditions where patients are known to have growth retardation primary or secondary to their disease.
In Adimaz et al. study 11,2% of children with PID were retarded in their height and physical development and in the study on Egyptian children interrupted physical development and growth were detected among 28% of patients diagnosed with PID [22,23]. In our study higher percentage of malnourished children in Ig+therapy group can be explained by complexity of diseases' syndromes, often exceeding over immune system, which may also limit patients' development in a significant way (Nijmegen breakage syndrome, ataxia-telangiectasia). We believe the topic needs further studies on group of children with immunoglobulin substitution. It's worth to mention that in many children with PID or RRTI higher percentage of low birth weight and height is detected. This interesting finding requires further studies as well.
The study was performed as Students Research Circle's activity. Main limitations of the study were relatively short time-span and lack of data about gestational age of patients.

Conclusions
Knowledge about primary immunodeficiency disorders have expanded widely during the last few years because of assigning over 200 genes to a certain PID types [2]. Conducted American researches as screening programs of PID occurrence at newborns allow early diagnosis and proper immunotherapy treatment, as well as significantly improving quality of life and stable psychomotor growth of patients [24]. In many countries, including Poland, that kind of screenings aren't conducted and the subject of PID still remains problematic for many physicians. Propagating knowledge in both medical field and in the society of 10 warning signs which help to initially rule out or to diagnose primary immunodeficiency disorder is a valuable tool for diagnosing these diseases on preliminary, but essential level [25]. Among untreated/undiagnosed patients with PID recurrent infections significantly affect child's proper growth. Prolonged antibiotic therapy and hospitalizations, associated with infections, can cause nutritional deficiencies, which affect harmonic growth of patients. Therefore it is essential to educate physicians of all specializations about PID, since earlier diagnosis leads to faster proper treatment. Early

Declarations
Ethics approval and consent to participate The study had a consent of a bioethical commission of Wroclaw Medical University. For this type of study formal consent is not required. This article does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication
Not applicable

Availability of Data and Materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
None Authors' contributions KPS was responsible for research concept and design, collection of data, data interpretation and was a major contributor in writing the manuscript. KB collected and interpreted data and had contribution in writing the manuscript. MB and KS collected and analyzed data. ALU had influence on study design and did critical revision of the article and its final approval. All authors of the manuscript have read and agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria.

Copyright and license agreement
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All authors agree to the terms of the BioMed Central Copyright and License Agreement.       Nutritional status of participants aged 3-18 years old divided into groups.

Figure 7
BMIs Z-score of the PID, RRTI and control group.

Figure 8
Nutritional status of PID patients group divided into Ig+therapy and Ig-therapy groups.