Frequently Ill Children

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Tatiana Markova and Denis Chuvirov

Federal Educational Establishment Advanced Study Institute, FMBA, Moscow, Russia, [email protected]

Abstract. Frequently ill children (FIC) show persistence of infection in the nasopharynx, disbiosis of intestinal flora, and concomitant and allergic diseases. As per our results, FIC with acute respiratory diseases (ARD) frequency of 6-15 times a year plus chronic infection foci at the age of 2-15 y/o at the remission period have heterogeneous nature of immune system disorders. It depends on the age, frequency of ARD, and chronic infection foci. About 20-50% of children have low number of T cells and 70% of children have high number of activated T cells. About 5-23% of children have low level of serum IgG or IgA, while low level of saliva IgA has been determined in 94% of children and low synthesis of IFN-a in 80% and of IFN-y in 30% of children. About 50% of kids have high level of common IgE (160-220 ME/ml) and diagnostic sensitization to various allergens. In contrast, only 25% of children with ARD frequency of 4-6 times a year without chronic infection foci had low synthesis of IFN-a, 30% had low IgA level in saliva, and 8.3% had low IgA level in serum. After vaccination against hepatitis B, antibody level to HBs-Ag and time of their circulation at FIC had been lower than in children with ARD frequency of 4-6 times a year. Examination of FIC at the remission period showed polymorphism of natural and adaptive immunity disorders associated with the immune system developmental delay and subsequent forming of chronic infection foci being an aggravating factor for these disorders.

1. Introduction

Frequently ill children (FIC) are kids liable to frequent respiratory infections, mainly due to transient deviations and age peculiarities of the child immune system, who go for regular medical check-up. FIC are characterized by a number of acute respiratory diseases (ARDs) per year (Albickiy and Baranov 1986). ARD prevalence in FIC is higher (once a month) than in occasionally ill children, thus being one cause for the frequent visits to pediatricians and hospitalization in the case of complications. Factors affecting the frequency of infections are developmental lag of the immune system, anatomic-physiological peculiarities of children's respiratory tract, and social living conditions. Localization of infection foci and nosologic forms of diseases in

FIC vary: (1) upper airways (nasopharyngitis, acute otitis, sinusitis, and tonsillitis), (2) "false" croup and laryngotracheobronchitis, and (3) inferior airway infections (bronchiolitis and pneumonia). Consecutive infections may be caused by (i) bacteri-ums, (ii) viruses, or (iii) pathogenic organisms: Chlamydia pneumonia and Mycoplasma pneumonia.

Up to 83% of all diseases in FIC refer to the orinasal and respiratory tract pathology. Viral infections are seen in 65-90% of cases, monoinfection in 52% of cases, and association of two and more infections in 36% of cases. A combination of carrier and sowing of Streptococcus pneumonia and Haemophilus influenzae is observed twice more often in FIC than in rarely sick kids (Markova et al. 2003; Makarova 2005).

Here, in order to further characterize children with ARD frequency from 6 to 15 times a year, we analyzed their immune status and evaluated the presence of immune-mediated diseases.

2. Experimental Procedures

Two hundred seventy FIC (160 girls and 110 boys, 2-15 y/o) have been selected during 1-3 years and examined. Most of them were diagnosed with a combined pathology at the orinasal side of the upper airways (Table 1). At the beginning of surveillance, 37 patients (13.7%) were diagnosed with concomitant recurrent herpetic infection (relapse number 5-9 times a year); 30 patients (11.1%) had manifestation of atopic dermatitis with localized foci. As a control, 60 children (35 girls and 25 boys, 2-15 y/o) with ARD frequency within 4-6 times a year and without chronic infections were also investigated. Furthermore, 60 FIC (35 girls and 25 boys, 6-15 y/o) without antibodies (Ab) to HBs-Ag have been vaccinated at the remission period against hepatitis B (Ingerix B vaccine). The control was represented by 30 children (17 girls and 13 boys, 6-15 y/o) with ARD frequency within 4-6 times a year and no foci of chronic infection who also received the same vaccine.

Table 1. Concomitant pathology in frequently ill children (FIC)

Concomitant pathology

Number of children

ARD more than 6 times

a year

270

Chronic adenoiditis

67

Chronic tonsillitis

42

Chronic otitis

62

Chronic pharyngitis

67

Lingering laryngotrcheitis

50

Recurrent herpetic infection

37

Atopic dermatitis

30

Bowels dysbacteriosis

200

Immunodeficiency development has been estimated as described earlier (Markova et al. 1997). Immunoassay procedures included detection of CD3+, CD4+, CD8+, CD16+, CD 19+, HLA-DR+, CD3+HLA-DR+, and CD4+CD45+RO+ cells, phagocytosis, chemiluminescence indices, serum IgG, A, M and E, IgA in saliva, serum IFNs, and cellular IFN-a and IFN-y (Khaitov et al. 1995; Ershov 1996). Cells were analyzed by FACScan (Calibur) or LKB-Wallac 1251 Luminometer. Mycoplasma pneumonia and Chlamydia pneumonia infections were determined by PTsR-diagnostic procedures (DNA-Technology, Russia). All immunoglobulins were assessed by ELISA (CHEMA or Vector, Russia).

3. Results

Bacterial infection persistence at the respiratory tract has been confirmed by a smear flora analysis taken from mucosa (Table 2). A single microbial agent was detected in 40% of children, two and more agents in 47.2% of patients, and combined bacterial and fungi flora in 10% of children. The persistence of infection was less in control group. Antibodies to M. pneumonia (IgM titer 1:8-1:32 and IgG titer 1:16-1:64) were seen in 50% of children. Antibodies to C. pneumonia (IgM titer 1:8-1:64 and IgG titer 1:16-1:128) were determined in 40% of kids. About 30% of children had combined infections. Verification of Streptococcus haemolyticus-P, Chlamydia, and M. pneumonia infections has been used as an indication for antibacterial therapy. Next, 74% of FIC had bowels dysbacteriosis, low index of Bifido- and lactobacteri-ums, and hemolyzed and/or lactose-negative Escherichia coli sowing. Our results thus show that FIC at the age of 2-15 y/o during the remission period have heterogeneous nature at immune disorders, which might depend on the age, ARD frequency, and type of chronic infections (Table 3).

Furthermore, 20% of kids at the age of 2-7 y/o had low number of T cells (CD3+ CD4+), while at the age of 7-15 y/o, 50% of children had these values out of normal

Table 2. Sowing microflora taken from fauces of examined children

Agent

% of children with sowing agent

ARD 6-12 times a year

ARD 4-6 times a year

Staphylococcus spp.

80

60

Staphylococcus aureus

66

50

Staphylococcus haemolyticus

40

20

Streptococcus spp.

60

40

Sreptococcus haemolyticus-ß

30

6

Neisseria perflava

30

30

Corynebacterium pseudo-

diphtheriae

14

6

Candida albicans

14

10

Flora has not been determined

10

20

Table 3 Immunological indices of immune system with chronic infection foci in frequently ill children (FIC)

Immunological parameters

% of children with immune disorder

IFN-a synthesis

Low level in 80% of children

IFN-y synthesis

Low level in 30% of children

T cells

20-50% of kids have low number of CD3+ or

CD4+ cells. 70% of kids have high number of

activated T cells (CD3+HLA-DR+ cells)

Macrophages

Low index of spontaneous chemiluminescence in

20% of children

Immunoglobulins

IgG or IgA low blood level in 20% of children;

IgA low level in saliva in 94% of children; IgE

high level in 50% of children

EK cells

Low number of CD16+ cells in 15% of children

B cells

Low number of CD19+cells in 15% of children

range. In addition, 70% of children had high number of activated T cells (CD3+HLA-DR+), 15 kids (25%) with ARD frequency 4-6 times/year had down-regulated synthesis of IFN-a, 20 children (30%) had low IgA level in saliva, and 5 kids (8.3%) demonstrated decreased concentrations of IgA in the blood.

During a 2-year observation period, we detected an increase in total and specific IgE levels in dynamics, sensitization to allergens, and development of allergic diseases: 60% of children had rhinosinusopathy, 30% allergic rhinitis, 11.1% atopic dermatitis, 30% recurrent bronchitis, and 10% of children developed bronchial asthma; 14.8% of children had pharyngomycosis.

Next, FIC and age- and gender-matched control children were vaccinated during the remission period and levels of specific antibodies against HBs-Ag were measured 1, 6, and 12 months after vaccine administration (Table 4). A local reaction at the vaccination site was reported in five patients from control group and in three kids from FIC group; a system reaction — rise of temperature up to 37-37.2°C—was observed in two patients from control group and one child from FIC group. Antibody titers assessed 1, 6, and 12 months after vaccination were significantly lower in FIC when compared with control children.

Table 4. Antibody levels in frequently ill children after (FIC) vaccination against hepatitis B

Antibodies level to HBs-Ag

; mME/ml

Group

Before

In 1 month

In 6

In 1 year

vaccination

months

FIC, mean ±

0

107 ± 1.9

113 ± 2.1

84 ± 2.5

SD

Control, mean

0

672 ± 11.3

496 ± 10.1

440 ± 12.6

± SD

/>-value

<0.001

<0.001

<0.001

Table 5. CD45RO+ T cells (vaccination against hepatitis B)

Group

Indices

Before vaccination

In 1 month

In 6 months

FIC, mean

CD4+CD45+RO+

%

38 ± 1.9

39.6 i 2.2

39 i 2.8

i SD

cells

x109/l

0.84 ± 0.12

0.86 i 0.1

0.81 i 0.08

Control,

CD4+CD45+RO+

%

36.5 ± 1.9

42.7 i 2.3

41 i 1.9

mean i

cells

SD

x109/l

0.86 ± 0.07

0.99 i 0.05

0.96 i 0.05

p-value

<0.05

<0.05

Evaluation of T cells in vaccinated patients (Table 5) revealed increase of absolute number of CD4+CD45RO+ cells in control children 1 and 6 months after vaccination (p < 0.05).

4. Discussion

For the first time, we reported significant abnormalities in the immune status and immune responses in FIC in comparison with healthy controls. This confirms our earlier observations of decreased functional activity of T and B cells in these children (Markova and Kharianova 2001). High levels of IgA in the saliva and low levels of serum IgG and IgG1 have been reported in children with recurrent infections (Mancini et al. 1996; Hewson-Bower and Drummond 1996). Results of multicenter examination of 180 FIC from various megapoleis (Moscow, Baku, and Krasnoyarsk) during acute period of ARD showed low levels of IFN-y, IL-2, IL-4, IL-8, IgG, and IgM, as well as increase in CD25+ T cells (Namazova et al. 2005). Interestingly, IFN-y synthesis in rarely sick children has been shown to be much higher in fall and winter seasons, while it is lower in FIC. Systemic "early" synthesis of IFN seen in FIC indicates the functional immaturity of the system and may be due to genetic predisposition. Indeed, decreased synthesis of IFN has been determined in FIC's mothers and sibs. Low levels of secretory IgA were reported in 85% of FIC (Albickiy and Baranov 1986; Markova et al. 2003; Makarova 2005). It has been recently speculated that most chronic diseases seen in adults are the result of maturation abnormalities of the immune system in childhood (Holt and Sly 2002). Our own analysis of FIC suffering from frequent ARD and chronic infection foci during remissions showed a polymorphism of natural and adaptive immune abnormalities and suggests that delay of the immune system development and subsequent formation of chronic infection foci may be aggravating factors for these disorders.

References

Albickiy, V.Y. and Baranov, A.A. (1986) Frequently Ill Children: Clinical and Social Aspects. Saratov, Russia.

Ershov, F.I. (2005) Interferons and their Inductors. Goatar-Media Publishing, Moscow, Russia.

Hewson-Bower, B. and Drummond, P.D. (1996) Secretory immunoglobulin A increases during relaxation in children with and without recurrent upper respiratory infections. J. Dev. Behav. Pediatr. 17, 311-316.

Holt, P.G. and Sly, P.D. (2002) Interactions between RSV infection, asthma, and atopy: unraveling the complexities. J. Exp. Med. 196, 1271-1275.

Khaitov, R.M., Pinegin, B.V. and Istamov, H.I. (1995) Ecological Immunology. VNIRO Publishing, Moscow, Russia.

Makarova, Z.S. (2005) Frequently ill children and their rehabilitation at pediatric polyclinic. Polyclinic (Russ.) 14, 19.

Mancini, C., Iacovani, R. and Fiermonte, V. (1996) Evaluation of serum IgG subclasses at children with recurrent respiratory infections. Minerva Pediatr. 48, 79-83.

Markova, T.P., Chuvirov, D.G. and Chuvirov, G.N. (2003) Children getting ill frequently and for a long time. In: Clinical Immunolology and Allergy Medicine. Ed. Gianni Marone. JGC Publishing, Naples, Italy. 62, 425-429.

Markova, T.P., Khaitov, R.M. and Tchouvirov, G.N. (1997) Methodological approaches to immunological diagnosis. Immunol. Lett. 56, 332.

Markova, T.P. and Kharianova, M.E. (2001) Postvaccinal immunity forcing at frequently and lasting ill children. Allergy Asthma Clin. Immunol. 1, 75-77.

Namazova, A.S., Botvinjeva, V.V. and Torchoeva, R.M. (2005) Frequently ill children of megapolysis. Pediatr. Pharmacol. 2, 3-7.

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