The Effect of Tonsillectomy on the Salivary Immune Factors: A Systematic Review and Meta-Analysis

In their critical position at the entrance of the aerodigestive tract, the palatine tonsils play an important role in sampling antigens directly from the epithelial surfaces. The number of bacteria shed into the saliva reaches 100 billion per day in healthy individuals [1]. A healthy environment is maintained in the oral cavity by adequate salivary flow to clear the microbes and by the various local immune factors, in which the tonsils are believed to play an important role [2]. The architecture of the tonsils resembles that of a lymph node in having antigen-presenting cells, T cells, B cells [3]. The palatine tonsils produce antibodies locally and distally through their migrating B cells. They are quite active in the pediatric age group when their size is most prominent knowing that the size is directly proportional to the number of tonsillar B and T cells [4].


Introduction
In their critical position at the entrance of the aerodigestive tract, the palatine tonsils play an important role in sampling antigens directly from the epithelial surfaces. The number of bacteria shed into the saliva reaches 100 billion per day in healthy individuals [1]. A healthy environment is maintained in the oral cavity by adequate salivary flow to clear the microbes and by the various local immune factors, in which the tonsils are believed to play an important role [2]. The architecture of the tonsils resembles that of a lymph node in having antigen-presenting cells, T cells, B cells [3]. The palatine tonsils produce antibodies locally and distally through their migrating B cells. They are quite active in the pediatric age group when their size is most prominent knowing that the size is directly proportional to the number of tonsillar B and T cells [4].
Though the tonsils' role in local immunity cannot be underestimated, they are not the only source of salivary immune factors. These factors are synthesized in the salivary glands (e.g. secretory IgA, salivary peroxidase) or originate from both the glands and the blood stream (lysozyme, lactoferrin, and IgM). In addition oral polymorphonuclear leukocytes can release significant amounts of myeloperoxidase, lysozyme, and lactoferrin [2]. On the other hand, there is limited data on the role of tonsils in the immune and non-immune protection of the oropharyngeal area [3].
To better understand the role of tonsils in local oropharyngeal immunity, we underwent a systematic review of the English literature regarding the effect of tonsillectomy on the salivary immune factors.

Methods
A systematic review of the English literature was performed using Medline, Embase and Cochrane. We used the terms tonsillectomy, adenotonsillectomy, humoral immunity, immune system, immunity, saliva to look for pertinent studies. We reviewed the abstract of all articles that studied the effect of tonsillectomy on the immune system. We included in the review only the studies that included salivary immune factors among the studied parameters. We only analyzed the salivary components of the immune system in the reviewed articles. We excluded duplicate publications, reviews and studies that did not include actual measurements of the salivary immune factors (e.g. descriptive studies or those using only questionnaires). We looked at the age of the studied patient, the presence of a control group and or preoperative testing, and the timing of postoperative testing. We attempted to perform a meta-analysis where feasible.

Results
Our search identified 34 manuscripts that studied the effect of Abstract Background & objectives: The effect of tonsillectomy on the immune system is a controversial issue. The debate is largely based on contradictory findings in the literature. However, it is unlikely for tonsils to produce a negative systemic effect and it is more logical to think about a local effect that can be transient or long lasting. The aim of this systematic review is to analyze the observed changes in salivary immune factors following tonsillectomy and understand their clinical significance.

Materials & methods:
Systematic review of the English literature was performed using Medline, Embase and Cochrane. We used the terms tonsillectomy, adenotonsillectomy, humoral immunity, immune system, saliva in various combination to look for pertinent studies. We excluded duplicate publications, reviews and studies that did not analyze salivary immune factors.
Results: Thirty four manuscripts studied the effect of tonsillectomy on the immune system. Only 9 of them (including 585 patients) looked at the effect on salivary immune factors. All studies analyzed the effect on salivary Immunoglobulin (Ig) A, four of them studied additional factors such as other salivary Ig's, anti-microbial proteins (lactoferrin, peroxidases, lysozyme), anti-viral and anti-bacterial Ig's. One study showed a significant decrease in salivary IgA, another showed a decrease in salivary IgG and a third showed a decrease in salivary IgM, lactoferrin and antimicrobial salivary IgG. Two studies had non-conclusive concerns regarding the observed changes in salivary immune factors, the third study recommended measuring salivary IgA pre and postoperatively. Only 11.1% of the studied patients had on the short term, a significant decrease in SecIgA level that can be attributed to tonsillectomy.

Conclusion:
Tonsillectomy does not seem in general to negatively affect the host's salivary immune defenses. The concerns raised are based on a partial apparent down-regulation of the some of the salivary immune components. More longitudinal studies are needed to really understand the clinical effect of any observed change in the salivary immune system.

Volume 5 • Issue 2 • 1000187
Otolaryngology ISSN: 2161-119X Otolaryngology, an open access journal tonsillectomy on the immune system ( Figure 1). Of these only 9 (including 585 patients) looked at the effect of tonsillectomy on the salivary immune factors [5][6][7][8][9][10][11][12][13]. All studies analyzed the effect on salivary Immunoglobulin (Ig) A, four of them studied additional factors such as other salivary Ig's, anti-microbial proteins (lactoferrin, peroxidases, lysozyme), anti-viral and anti-bacterial Ig's (Table 1). One study showed a significant decrease in salivary IgA, another showed a decrease in salivary IgG and a third showed a decrease in salivary IgM, lactoferrin and antimicrobial salivary IgG (Table 2). Two studies had non-conclusive concerns regarding the observed changes in salivary immune factors, the third study recommended measuring salivary IgA pre and postoperatively ( Table 1).
As SIgA was the most commonly studied salivary immune factor, it was analyzed by pooling all the results (Table 3). Because there was heterogeneity in the normal reference value for SIgA and some compared postoperative values to controls while others to preoperative values, it was decided to report the values as normal (when normal or above normal) or abnormal (when considered below normal). Only 15.7% of the studied patients had an abnormally low SIgA level. However, in one of the studies that abnormality was present preoperatively which confound the real effect of tonsillectomy. Omitting that study in the analysis will result in having only 11.1% of the patients experiencing a significant decrease in SecIgA level secondary to tonsillectomy.

Discussion
The saliva is a rich medium of microbial and a mixture of anti microbial and immune factors. These factors are supplied via the surrounding blood vessels, the salivary glands and lymphoid tissues. The role of the palatine tonsils in the immune system in general and in the local oropharyngeal immunity in particular has long raised concerns about the immunological sequalae of tonsillectomy. There is no doubt that the tonsils play an important role in the immune defense mechanism of the upper aero-digestive tract.
The tonsils' crypts, which increase the tonsillar surface area up to 300cm 2 are populated by lymphocytes (50-65% B cells, most of which are memory B-cells) forming the lymphoepithelium area. Other cells present include T cells, macrophages, and dendritic cells [4,14]. Unlike lymph nodes, tonsils do not possess afferent lymph vessels; instead antigens are captured directly by epithelial cells known as M cells. M cells capture antigens via endocytosis, translocate them to the basal membrane, then exocytose them intact in intraepithelial spaces [4,15]. This will induce a cascade to activate the primary immune response. This immune reaction is transmitted to the extrafollicular area where T-B lymphocytes interaction generate a long lasting immune response by stimulating differentiation and proliferation of B lymphocytes that move to the lymphoid follicles and act as founder cells in germinal centers [16].
Tonsillar secondary immune response is characterized by a small germinal center reaction and a large extrafollicular plasma cell reaction. Memory B cells in the crypt epithelium play an important role in generating a rapid secondary immune response. In fact, they have a strong antigen presenting ability enabling them to activate memory T helper cells in the crypt epithelium rapidly [4,14,[16][17][18].
Though the main immune role of the tonsils is local, the tonsils are connected to the body immune system through trafficking of immune cells. The naïve T and B cells are transported into the tonsils via the high endothelial venules present in the extrafollicular regions, while plasmablasts migrate from the tonsils via efferent lymphatic vessels that drain in the cervical lymph nodes [4,16]. They then can join the  circulation and disseminate to the upper airway mucosa, regional exocrine glands (e.g. lacrimal and salivary glands) and to a lesser extent to the gut mucosa [17].
The effect of tonsillectomy on the systemic immune system is controversial though recent studies showed no significant effect [19][20][21]. However, it is unclear if tonsillectomy would result in compromising the local immune defenses.
During this review, it was interesting to find that most of the studies that looked at the effect of tonsillectomy on the immune system focused primarily on the systemic humoral and cellular immunity. Only quarter of the published studies dealt with salivary immune factors, especially SIgA; meaning that we need more studies in that field. Though the results of the reviewed studies are reassuring, one should be cautious about considering that this issue has been answered. That is mainly due to the heterogeneity in the way these studies were conducted in terms of timing of postoperative testing, the presence or absence of controls and sometimes considering the preoperative values as a control reference though it was not always clear if these preoperative values were actually normal compared to control levels.
Despite that, it is reassuring to see that only 2 out of the 9 studies (Cantani et al. [9] and Kirstila et al. [12]) raised some concerns about a negative effect of tonsillectomy on some salivary immune factors with Cantani A et al advising measuring SIgA levels prior and following tonsillectomy [9]. This recommendation can not be adopted without further longitudinal studies in that field to clarify what really happens months to years after tonsillectomy. In fact, Kirstila et al. [12] actually demonstrated a rise in SIgA level 6 months after tonsillectomy following an initial drop at 1 month (similar to Cantani et al. findings). This means that the salivary immune system can compensate for the loss of the tonsillar tissues several months postoperatively.
Preop, preoperative; postop, postoperative; SIg, salivary immunoglobulin;  The most commonly studied salivary immune factor is SIgA which was shown to remain within normal levels in 84.3%. Mind you that in Ostergaard PA study [7], the level of SIgA was already abnormally low preoperatively; which make us doubt that tonsillectomy caused that.

Conclusion
Tonsillectomy does not seem in general to negatively affect the host's salivary immune defenses. The concerns raised are based on a partial apparent down-regulation of the some of the salivary immune components. More longitudinal controlled studies are needed to really understand the clinical effect of any observed change in the salivary immune system.