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Alteration in Salivary Function in Early HIV Infection
1 Departments of Dental Diagnostic Science and Correspondence: * corresponding author, Yeh{at}uthscsa.edu
The etiology of salivary gland hypofunction in HIV(+) patients is unclear. This study was designed to determine the effect of early-stage HIV(+) infection (CD4+ > 200 cells/µL; n = 139) on salivary gland function and the relationship of this dysfunction to the taking of xerostomic medications. Salivary flow rates and the content of electrolytes and antimicrobial proteins in stimulated parotid and submandibular/sublingual saliva were determined. Compared with healthy controls (n = 50), the HIV(+) group showed significant reductions in flow rates of unstimulated whole (35%), stimulated parotid (47%), unstimulated submandibular/sublingual (23%), and stimulated submandibular/sublingual (39%) saliva. The flow rates for the HIV(+) patients taking xerostomic medications did not differ from those of patients who did not. Concentrations of some salivary gland components were altered in the HIV(+) group. Analysis of these data suggests that salivary gland function is adversely affected early in HIV infection and that these changes do not appear to be compounded by the taking of xerostomic medications.
Key Words: HIV • xerostomia • saliva • salivary glands
Saliva plays an important role in maintaining the health of the oral cavity. Patients with HIV infection often complain of xerostomia (mouth dryness) (Navazesh et al., 2000; Younai et al., 2001). Reduced salivary flow has been reported in most HIV/AIDS cohorts (Yeh et al., 1988; Atkinson et al., 1990; Mandel et al., 1992; Coogan et al., 1994; Lin et al., 2001), although there are some exceptions (Muller et al., 1992; Pollock et al., 1992). With respect to saliva composition, sodium and chloride are elevated in glandular saliva collected from HIV patients (Yeh et al., 1988; Mandel et al., 1992; Lin et al., 2001). The concentrations of antimicrobial and antifungal proteins such as lysozyme, lactoferrin, secretory IgA, and histatin may be increased, decreased, or unaltered (reviewed by Lin et al., 2001). The discrepancies in findings may result from cohort effects, i.e., the stage of HIV disease, the relatively small number of patients evaluated, and/or the wide variety of medications, many of which are xerostomic, taken by HIV patients. Other factors include the methods of saliva collection, analysis, and the large inherent individual variation in salivary parameters. While xerostomia and salivary gland hypofunction in HIV-infected patients are usually attributed to xerostomic medications, whether salivary gland function can be compromised by HIV infection is unclear. This report describes the effects of early-stage HIV disease on salivary gland function in a well-defined HIV(+) cohort. The influence on salivary gland function of xerostomic medications taken by these patients is evaluated in an effort to discriminate between effects that may be due to xerostomic drugs and those due to disease.
Subjects Study subjects are participants in the US Air Force Human Immunodeficiency Virus (HIV) Natural History Study (Blatt et al., 1995). Only patients with CD4+ > 200 cells/µL were included (129 men, 10 women). Fifty HIV-negative healthy men of a comparable age range and not taking xerostomic medications were recruited from the local community as the Control group. Patient records were used to obtain CD4+ counts, viral loads, and the list of medications (prescribed and over-the-counter) taken by each participant. For some analyses, the HIV(+) group was subdivided into two groups based on whether or not they were taking prescription or over-the-counter drugs having a reported xerostomic side-effect. With the use of a xerostomic medication database (Sreebny and Schwartz, 2002), each drug was searched by name for the presence of xerostomic side-effects. The categories of xerostomic medications most commonly taken by the HIV(+) xerostomic medication subgroup included reverse-transcriptase inhibitors (n = 72 patients), protease inhibitors (n = 65), antidepressants (n = 20), asthma medications (n = 10), pain killers (n = 10), steroids (n = 10), and antihistamines (n = 9). The voluntary, fully-informed consent of the subjects used in this research was obtained as required by Air Force Regulation (AFR) 169-9. Approval to undertake this study was obtained from the Institutional Review Boards of both UTHSCSA and Wilford Hall.
Saliva Collection and Sialochemistry Analysis Stimulated glandular saliva was analyzed for content of electrolytes (sodium, chloride, potassium, and calcium), total protein, secretory IgA, lysozyme, lactoferrin, and albumin (Lin et al., 2001). We used assay kits to determine uric acid (Sigma, St. Louis, MO, USA) and total anti-oxidant capacity (Total Antioxidant Status Assay Kit, Calbiochem, San Diego, CA, USA). Total cystatin content was determined by inhibition of papain activity (Henskens et al., 1993) in only submandibular/sublingual saliva, since that of parotid saliva is too low to be accurately determined by this method (Veerman et al., 1996).
Statistical Analysis
Characteristics of the HIV-positive and Control Groups The mean age of the HIV(+) group was slightly greater (2.5 yrs) than that of the Control group (Table 1  ). Based on earlier studies (Yeh et al., 1998), this slight difference in age will not significantly affect any factor evaluated in this study. The median values for CD4+ count (520 cells/µL) and viral load (4547 copies/mL) indicate that these patients were in the early stage of HIV infection. Viral loads were not available for 13 of the HIV(+) patients. There was no difference in CD4+ count between the two HIV(+) medication subgroups. The lower viral load of the xerostomic medication subgroup is likely a function of the large number of individuals in this group who take highly active antiretroviral therapy (HAART) medications. Most, but not all, of these medications list xerostomia as a side-effect.
Salivary Flow Rates All flow rates for HIV(+) were significantly lower as compared with those for Control (Table 2 ). Unstimulated parotid saliva is not included, since its collection frequency (30%/group) is low. With respect to the effects of xerostomic medications, except for unstimulated submandibular/sublingual saliva, the flow rates for both HIV(+) medication subgroups were significantly lower than those of Control, but not significantly different from each other (Bonferroni/Dunn).
Sialochemistry of Stimulated Parotid Saliva While there were no differences in the concentrations of potassium, calcium, chloride, lactoferrin, lysozyme, and total anti-oxidant capacity between the HIV(+) group and Control, there were significant differences for sodium, total protein, albumin, secretory IgA, and uric acid (Table 3 ). Since the concentrations of most salivary components are dependent on flow rates, these variables were subjected to Analysis of Covariance with flow rate as a covariate. Under these conditions, only total protein differed between the two groups (p = 0.0431). With respect to the effects of xerostomic medications, the HIV(+) xerostomic medication group showed significant increases for protein (42%), albumin (50%), and uric acid (68%) as compared with Control. Secretory IgA was significantly increased for both HIV(+) medication subgroups as compared with Control. No component of the HIV(+) subgroup not taking xerostomic medications differed from Control. While the unpaired t test indicated a significant difference between the HIV(+) group and Control for sodium, when the HIV(+) group was subdivided, there was no difference (p = 0.081) between the Control and HIV(+) xerostomic and non-xerostomic medication subgroups. There was no significant difference for any component between the two HIV(+) medication subgroups.
The secretory rates (i.e., amount secreted per minute) for the HIV(+) group were significantly lower than those of the Control for all electrolytes, as well as for lysozyme, total anti-oxidant capacity, and uric acid (Table 3  ). There were no differences in secretory rates between the HIV(+) group and Control for total protein, albumin, lactoferrin, and secretory IgA. As compared with Control, both HIV(+) medication subgroups showed significantly reduced secretory rates for sodium, calcium, and anti-oxidant capacity. As compared with Control, potassium and chloride were significantly reduced for the HIV(+) xerostomic medication subgroup (30% and 34%, respectively), but the non-xerostomic medication subgroup did not differ from Control. Compared with Control, lysozyme and uric acid were reduced in the HIV(+) subgroup not taking xerostomic medications (39% and 33%, respectively), but the group taking xerostomic medications did not differ from Control. There was no difference between the two HIV(+) subgroups in the secretory rate of any component.
Sialochemistry of Stimulated Submandibular/Sublingual Saliva
For the HIV(+) group, secretory rates for sodium, potassium, calcium, chloride, total protein, cystatin, lysozyme, total anti-oxidant capacity, and uric acid were significantly lower and that for secretory IgA was significantly higher as compared with Control (Table 4 ). Both HIV(+) medication subgroups showed significant reductions in the secretory rates of sodium, potassium, calcium, chloride, total protein, cystatin, uric acid, and anti-oxidant capacity, as compared with Control. While there was a significant ANOVA for lysozyme (p = 0.039), by Bonferroni/Dunn post hoc analysis, the "p" values for Control vs. the HIV(+) xerostomic medication subgroup (p = 0.032) and the non-xerostomic medication subgroup (p = 0.019) were not significant (p < 0.0167 required). Although there was a significant difference between the Control and HIV(+) groups for secretory IgA (p = 0.028), there was no significant difference between the Control and the two HIV(+) medication subgroups (p = 0.081). There was no significant difference between the two HIV(+) medication subgroups in the secretory rate of any component.
Analysis of our data shows that flow rates for unstimulated whole, unstimulated submandibular/sublingual, stimulated parotid, and stimulated submandibular/sublingual saliva are decreased in the early stages of HIV infection. Not only is the secretory function of salivary glands reduced in this HIV(+) cohort, but the composition of saliva is altered as well. These changes in flow rates and composition are in general agreement with other published data (reviewed by Lin et al., 2001), most of which are based on more advanced or mixed stages of infection. The present study, based on a relatively large number of early-stage HIV(+) patients, suggests that salivary gland function is adversely affected in the early stage of this disease. One aspect of this study was to determine if the alterations in salivary gland function were related to the taking of xerostomic medications. The criteria for assigning a drug as xerostomic were based on a database of xerostomic drugs (Sreebny and Schwartz, 2002). It should be noted that the classification of a drug as xerostomic was based on clinical complaints reported by patients during the drug trial and not on objective measurements of salivary function. In a drug trial, subjective complaints of xerostomia are usually made by < 10% of the subjects. For example, most of the protease inhibitors have a xerostomia incidence of less than 3%. Thus, the vast majority of the subjects taking these medications do not experience xerostomia, and this may be the reason for our failure to see a difference between the two groups. There are reports that salivary function is decreased as the number of medications taken increases (Wu and Ship, 1993). In this study, the xerostomic medication group took an average of 5.0 medications vs. 2.1 for those taking medications in the non-xerostomic medication group. In summary, these results suggest that the taking of xerostomic medications, or the taking of medications in general, does not confound the effect of the disease on the gland. Another explanation may be that the effect of the disease on the gland may mask the effect of the taking of medications. HIV-associated salivary gland disease (HIV-SGD), usually defined with a sicca syndrome (dry mouth) and salivary gland enlargement, is well-documented (Schiødt, 1992). It is unclear whether salivary gland dysfunction in early HIV infection is a contingent process prior to the development of full-blown HIV-SGD or is a different entity. Many HIV-SGD patients have Sjögren’s-like syndrome with hyperglobulinemia along with diffuse and/or infiltrative lymphocytes within the salivary gland [also called diffuse infiltrative lymphocytosis syndrome (DILS)] (Smith et al., 2000; Patel and Mandel, 2001). Others have attributed the symptoms to cytomegalovirus (CMV) infection (Greenberg et al., 1997). Therefore, salivary gland dysfunction in early HIV infection could be secondary to autoimmunity or other infections. The nature of the salivary dysfunction warrants further investigation. Alteration of salivary function in HIV infection could have clinical implications. Even though the difference in concentrations of electrolytes between the two groups is related to flow rate, the fact that concentrations differ may be clinically relevant, for it is well-established that ionic strength can modify antimicrobial properties of several salivary proteins (Oppenheim et al., 1988). With respect to other components of saliva, albumin and secretory IgA are increased for both stimulated parotid and submandibular/sublingual saliva in HIV(+). Elevation of salivary albumin may be indicative of gland inflammation (Fox et al., 1985). Although the concentrations of many components may be increased with HIV(+), owing to the reduction in flow rate, the amount delivered to the oral cavity per unit time is reduced. For both stimulated parotid and stimulated submandibular/sublingual saliva, this includes lysozyme, total anti-oxidant capacity, and uric acid. In addition, for stimulated submandibular/sublingual saliva, the output of cystatin is reduced. The only component showing an increased secretory rate is that of secretory IgA in stimulated submandibular/sublingual saliva. The marked reduction in output of several salivary components, including the traditional antimicrobial/antifungal proteins and proteins having anti-oxidant potential (including uric acid), may contribute to the clinical oral manifestations of this disease. The findings reported in this paper indicate that HIV(+) patients have alterations in both salivary gland fluid and component secretion, and that these changes occur in the early stages of this disease. Since salivary dysfunction occurs early in the disease process, a more vigorous prophylactic regimen could be beneficial to these patients in the prevention of oral disease associated with reduced salivary gland function.
The authors thank Ms. Karen Carlson, Dr. Yi-min Wu, and Ms. Guie Wong for their excellent technical assistance and/or saliva collection, Chip Bradley (Air Force HIV/AIDS Research) and Dr. John Cornell (GRECC, STVHCS) for their assistance in data management, and Dr. Carol Ann Sims (currently at the University of Tennessee) for her initial organization of the dataset. We are also indebted to USAF Medical Officers Drs. Janice M. Rusnak, Gregory P. Melcher, and Glen D. Houston (currently at the University of Oklahoma), and Dr. E. Steven Duke (currently at Indiana University) for their coordination and encouragement to make this study possible. This study is supported by Public Health Service Grant DE12188 (C.-K.Y.) from the National Institute of Dental and Craniofacial Research, and by the US Army Medical Research and Development Command (K.T.S.). Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy of the US Department of Defense or other departments of the United States Government. Received for publication October 18, 2002. Revision received May 9, 2003. Accepted for publication June 25, 2003.
Journal of Dental Research, Vol. 82, No. 9,
719-724 (2003)
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