The wafer test: a semi-quantitative test to screen for xerostomia

J. Sánchez-Guerrero, E. Aguirre-García, M. R. Pérez-Dosal, A. Kraus, M. H. Cardiel and A. E. Soto-Rojas

Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 México, D.F. Mexico


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 
Objective. To develop a screening test for xerostomia.

Methods. A cross-sectional study was conducted among 152 healthy subjects aged <20–60 yr, 30 patients with primary Sjögren's syndrome and 60 patients with other connective tissue diseases, sampled randomly. A validated screening questionnaire for sicca syndrome and the Schirmer-1 and wafer tests were carried out in all subjects. In addition, non-stimulated whole salivary flow was measured in a random sample of 113 participants. The main outcome was the time of dissolution of the wafer.

Results. Time of dissolution of the wafer was 2.8±2.1 min in the healthy group, 3.3±1.5 min in the connective tissue diseases group, and 9.2±3.9 min in the primary Sjögren's syndrome group (P<0.001). The correlation coefficient between the wafer test and non-stimulated whole salivary flow was -0.60 [95% confidence interval (CI) -0.47, -0.71]. A cut-off value of 4 min (‘wafer 4’) showed sensitivity of 92.9%, specificity of 71.7%, a positive predictive value of 31.7%, a negative predictive value of 98.6%, accuracy of 74.3%, an ROC (receiver operating curve) value of 82.3 and a likelihood ratio of 3.3 (95% CI 2.3, 4.6) for xerostomia. The proportion of patients with wafer 4 was 8% in the healthy group, 23% in the connective tissue diseases group and 93% in the primary Sjögren's syndrome group (P<0.001). Wafer 4 was a significant predictor of xerostomia after controlling for age, gender, temperature and relative humidity.

Conclusion. The wafer test is valid and reliable for identifying subjects with xerostomia.

KEY WORDS: Xerostomia, Screening, Sicca syndrome, Sjögren's syndrome.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 
Symptomatic xerostomia is the subjective feeling of oral dryness. In the general population, 6–29% of subjects report the symptom when asked directly [13]. Among patients with chronic diseases, such as rheumatoid arthritis, this percentage rises to 50% [4]. Although symptomatic xerostomia is positively correlated with a decrease in the flow of saliva, some individuals who complain of a dry mouth do not demonstrate a reduced flow rate and vice versa [5]. When accompanied by a severe reduction in the secretion of saliva produced under basal conditions, it seriously disturbs the quality of life and may be an important indicator of systemic disorders, such as autoimmune diseases [5, 6]. In fact, it is one of the main features of Sjögren's syndrome (SS) [7, 8].

The diagnosis of xerostomia (salivary flow rate low enough to produce the objective abnormalities of dry mouth) is based upon information derived from the patient's history, oral cavity examination and sialometry [5]. Other techniques, e.g. sialography, salivary scintigraphy and lip biopsy, are employed in selected patients to identify structural and functional defects in the salivary glands.

Non-stimulated whole salivary flow (NSWSF) reflects the basal flow from all glands taking place during most of the day [7, 9, 10]. Flow rates >=0.3 ml/min are considered normal [5]. Although no agreement exists about the definition of low salivary flow [8, 10], values <=0.1 ml/min are considered low enough to produce xerostomia [9]. However, such low flow rates are rare unless massive (60–75%) salivary gland impairment is present [5]. Non-xerostomic low salivary flow rates (>0.1–<0.3 ml/min) may be present with early salivary gland dysfunction and herald the onset of xerostomia. Such flow rates may cause no symptoms to the subject and go unrecognized until further damage is present. Paradoxically, this early stage may provide useful information for understanding the pathogenesis and natural history of salivary gland dysfunction. It may also be at this stage when early treatment might be effective, because the amount of saliva produced is related to the viability of the residual salivary gland tissue. Unfortunately, at this time there is no way to recognize systematically subjects with early dysfunction of the salivary glands.

Several screening instruments have been proposed for the identification of subjects with xerostomia or sicca syndrome, including questionnaires [2, 1113], specific tests [1416], devices [17] and physical signs on physical examination [5, 8]. However, none of them is widely used, in part because they have not been validated, require special equipment or are invasive.

Here we present a semi-quantitative test, the wafer test, which may be useful for screening patients with early salivary gland dysfunction and xerostomia.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 
A total of 242 subjects were included in the study; 152 healthy subjects (30 subjects from each of the age decades <=20, 31–40, 41–50 and 51–60 yr, and 32 subjects aged 21–30 yr), were sampled randomly from the medical students' list and the payroll of the hospital. Individuals who had any systemic disease, were taking any medication regularly or had taken any medication that may reduce salivary flow (e.g. antihistaminics, sedatives) within 48 h before the study were excluded. In addition, from our register of patients 90 patients were chosen randomly: 30 patients with primary Sjögren's syndrome (PSS) [18] and 60 patients with other connective tissue diseases but without SS (CTDs) (16 with systemic lupus erythematosus, 14 with mixed connective tissue disease, 15 with scleroderma and 15 with rheumatoid arthritis), diagnosed on the basis of accepted classification criteria [1922].

All participants were asked to refrain from eating, drinking, smoking, chewing or oral hygiene procedures for at least 1 h before the study. Subjects were seen in a closed room with no air-conditioning or heating, between 9.00 and 11.00 a.m. In all subjects, a validated screening questionnaire for sicca syndrome [12], the Schirmer-1 test and the wafer test were carried out. In a random sample of 113 participants, NSWSF was measured by a second investigator (AESR), who remained blinded to the subject's health status and the results of the questionnaire, wafer and Schirmer-1 tests.

The sequence for the performance of the tests was specified to avoid the possibility of one test influencing the results of the following one, or the investigator's judgement, as follows: questionnaire, Schirmer-1 test, NSWSF, wafer test.

Geographical and weather conditions
Mexico City is located at an altitude of 2240 m. The median annual temperature is 18°C (7–28°C) and the relative humidity 53% (20.5–89%). Because the tests were performed during all seasons of the year, we obtained a daily record of the temperature and relative humidity at Mexico City from the National Meteorological Service.

Definitions
The following definitions are used in this paper: ‘symptomatic xerostomia’ refers to dry mouth symptoms; ‘xerostomia’ refers to a salivary flow rate low enough to produce the objective abnormalities of dry mouth (<=0.1 ml/min) [9]; ‘low salivary flow’ (LSF) refers to a non-xerostomic low salivary flow rate (>0.1 to <0.3 ml/min).

European questionnaire for sicca syndrome
A recently validated six-item screening questionnaire for sicca syndrome [12] was translated into Spanish by three rheumatologists (JSG, AK, MHC). All the translators were Mexican and able to speak, read and write both languages fluently. An initial translation was completed by each translator independently; all translators then came together to discuss the differences among the translations and produce a consensus version. The final Spanish version (Appendix 1) was self-administered to all study subjects.

The wafer test
A round wafer made of wheat flour was used in the study. The wafer had the following dimensions: diameter 37.21±0.02 mm; thickness 1.135±0.142 mm; weight 0.285±0.0256 g. The main outcome was the time of dissolution of the wafer.

Test procedure.
The subject was asked to sit in a relaxed and upright position and not to speak during the test. After the subject had swallowed any residual saliva, the wafer was put on the centre of the subject's tongue. The subject was asked to close the mouth and keep the wafer in the mouth without chewing or swallowing it, but swallowing saliva was allowed. Time of dissolution was measured from the moment when the wafer was put on the tongue (time 0) (Fig. 1bGo) up to the time when the wafer had dissolved (time 1) (Fig. 1iGo). Every minute, the investigator asked the subject to open the mouth to verify the presence of the wafer. The subject reported to the investigator the moment when the wafer dissolved, which was verified by direct inspection.



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FIG. 1.  The wafer test.

 
The procedure was repeated three times in each subject with a resting period of 5 min between each test. The mean of the three results was the score recorded. When the wafer did not dissolve in a 15 min period, the test was stopped and 15 min was recorded as the time of dissolution. If the time of dissolution was 15 min in the first and second tests, the third test was omitted and the mean of the first two tests was the score recorded.

Schirmer-1 test
The Schirmer-1 test was done as described previously [23], using two standardized sterile filter paper strips (Sno* strips; Chauvin Pharmaceuticals, Romford, Essex, UK). We considered the test as positive if the moistened area was <=5 mm in 5 min.

Non-stimulated whole saliva flow
NSWSF was measured by the spitting method [24] in a random sample of 113 individuals (73 healthy, 18 patients with PSS and 22 patients with other CTDs). The technique has been described previously [24]. In brief, with the subject seated comfortably with eyes open and head tilted slightly forward, he was instructed to rest for 5 min before the procedure, minimize orofacial movements, and not to speak. At time 0, but not later, the patient swallowed any residual saliva. He was asked to allow all saliva to accumulate on the floor of the mouth and to spit it into a graduated test tube every minute. Saliva was collected for a period of 5 min [1, 24]. After collection, the volume of saliva was allowed to settle and was then measured gravimetrically, assuming a specific gravity of 1.0.

Statistical analysis
Descriptive statistics were used to define the subjects' characteristics in each group. Categorical variables were compared using the {chi}2 test or Fisher's exact test. Continuous variables were analysed by one-way analysis of variance and the Bonferroni t method for multiple comparisons. The relationship between continuous variables was estimated using Pearson's correlation coefficient, and 95% confidence intervals (CI) were calculated using Fisher's z transformation.

The reproducibility of the wafer test was assessed using Pearson's correlation coefficient between the first and second, first and third, and first and mean values. In addition, the three values in each group were compared using paired t-test.

In order to define the wafer test value that best identified individuals with LSF and xerostomia, 2x2 tables and receiver operating curves (ROC) were used at different cut-off points. We calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) [25] and accuracy, which was defined as the proportion of subjects correctly classified as having decreased or normal salivary flow, given that the screening test was positive or negative. PPV and NPV were calculated according to the prevalence seen in the study population (26% for LSF and 12% for xerostomia).

The validity of the wafer test and the translated version of the European questionnaire for identifying subjects with LSF and xerostomia was also analysed using 2x2 tables. The likelihood ratio and the 95% CI were calculated for the screening questionnaire and the wafer test as sensitivity/(1-specificity). The ability of the wafer test to predict LSF and xerostomia, after adjusting for variables such as age, sex, temperature, relative humidity and smoking, was assessed using logistic regression.

The P value was set at <0.05, two-tailed. Analysis was performed using the Stata 5.0 computer program (Stata Corporation, College Station, TX, USA). The study was approved by the Institutional Committee of Biomedical Research.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 
Population characteristics
Females constituted 76% of the total population; both groups of patients had a higher proportion of women than the healthy subject group (P=0.02). Patients with PSS were older (P<0.001) and gave up smoking more frequently than the other two groups (P=0.05) (Table 1Go).


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TABLE 1.  Characteristics of study population

 

European questionnaire
At least one affirmative answer to the screening questionnaire (hereafter referred to as ‘EQ 1’) (the cut-off value) was seen in 53 (35%) individuals of the healthy group, 21 (35%) in the CTD group and 30 (100%) in the PSS group (P<0.001). When we considered ocular and oral sections separately, patients in the PSS group also had a higher percentage of affirmative answers (P<0.001). The questionnaire was well understood by all the participants; a ‘do not know’ answer to any of the six questions was obtained from 11 (5%) individuals, this proportion being similar in all the groups.

Schirmer-1 test
The results of the test were not different between the two eyes in any of the groups, and we considered the value obtained in the right eye in the analysis. The mean value (±SD) was 24.2±16.4 mm in the healthy group, 16.7±11.5 mm in the CTD group and 6.9±11.5 mm in the PSS group (P<0.001). The proportion of subjects with a positive test result differed between the PSS group and the healthy and CTD groups (P<0.001), and a difference was also seen between the CTD and healthy groups (P=0.05).

NSWSF
The mean value was 0.52±0.26 ml/min in the healthy group, 0.49±0.18 ml/min in the CTD group and 0.15±0.19 ml/min in the PSS group (P<0.001). The proportion of individuals with LSF and xerostomia was higher in the PSS group than in the other two groups (P<0.001).

Wafer test
Time to dissolution of the wafer was 2.8±2.1 min in the healthy group, 3.3±1.5 min in the CTD group and 9.2±3.9 min in the PSS group (P<0.001). A significant difference was seen between the PSS group and the healthy and CTD groups (P<0.001), but not between the healthy and the CTD groups (P=0.39).

As the test would be performed only once in a busy clinical practice or during population screening, we also analysed the time of dissolution of the first wafer test. In the healthy group it was 2.9±2.2 min, in the CTD group it was 3.4±1.8 min and in the PSS group it was 8.0±3.8 min (P<0.001).

The reproducibility of the test between the first and second, first and third, and first and mean values was r=0.85 (95% CI 0.79, 0.89), 0.82 (95% CI 0.75, 0.87) and 0.92 (95% CI 0.89, 0.94) respectively. No difference was seen when the three values in each group were compared (P>0.15).

The correlation coefficient between the mean value of the wafer test and the NSWSF was -0.60 (95% CI -0.47, -0.71) (Fig. 2Go) and that between the first wafer test and NSWSF was -0.54 (95% CI -0.39, -0.66).



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FIG. 2.  Correlation between the wafer test and NSWSF.

 
The test was easy to perform in terms of time involved and patient comfort, it was well accepted by all the participants, had no complications or secondary effects, and the cost of each wafer was less than US$0.01.

Wafer test cut-off value for screening low salivary flow and xerostomia
The best balance between sensitivity and specificity was seen with a cut-off value of 4 min (‘wafer 4’) (Table 2Go). As the time of dissolution of the wafer became longer, the specificity for reduced salivary flow increased. Therefore, we considered wafer 4 useful in screening for LSF and xerostomia.


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TABLE 2.  Performance of the wafer test at different cut-off values (min) as a predictor of LSF and xerostomia

 
Among the three study groups, the numbers of subjects with wafer 4 were 12 (8%) for the healthy group, 14 (23%) for the CTD group and 28 (93%) for the PSS group (P<0.001) (Table 3Go).


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TABLE 3.  Results of the European questionnaire, Schirmer-1 test, NSWSF and wafer test in the study population

 

Validation of the wafer test as a screen for LSF and xerostomia
In order to validate the wafer test as a screening instrument for LSF and xerostomia, we compared wafer 4 with the European questionnaire (EQ 1) [12] and with the oral section (Oral 1) of the same questionnaire. For LSF, EQ 1 and wafer 4 showed identical sensitivity, although wafer 4 showed higher specificity, PPV, NPV and accuracy. Comparing wafer 4 with Oral 1, the specificity, PPV and accuracy of the questionnaire improved but the sensitivity and NPV decreased importantly. For xerostomia, the performance of wafer 4 was better than that of EQ 1 and Oral 1, and wafer 4 showed high sensitivity (92.9%) and NPV (98.6%). All three tests showed appropriate likelihood ratios for distinguishing between normal and decreased salivary flow (Table 4Go).


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TABLE 4.  Comparison among the European Questionnaire (EQ 1), the Oral section of European questionnaire (oral 1) and the Wafer test (wafer 4) for screening LSF and xerostomia

 
Wafer 4 was a significant predictor of LSF and xerostomia after controlling for age, gender, temperature, relative humidity and EQ 1 (Table 5Go).


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TABLE 5.  Predictive value of wafer 4 for LSF and xerostomia

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 
The wafer test showed high accuracy in the classification of patients with normal and decreased salivary flow and had a good correlation with sialometry. The distribution of wafer 4 among the study groups, defined by the clinical diagnosis, correlated with the distribution seen for the screening questionnaire, the Schirmer-1 test and the NSWSF rate.

Salivary flow was defined as normal, low or xerostomic according to the NSWSF result. Saliva was collected by the spitting method for 5 min (which has been shown to be an adequate collection period [1, 24]) and to be reproducible and reliable [24]. Because salivary flow rates vary significantly among individuals and in the same individual under different conditions, we standardized saliva collection for body position, time of the day, time since the last major oral stimulation, exposure to light and olfactory stimuli. In the analysis, we adjusted for environmental temperature and relative humidity. An important factor that may potentially affect NSWSF and that we could not control for was the degree of hydration; however, as it is a randomly distributed variable it should not have affected our results.

Wafer 4 showed the best balance between sensitivity and specificity and was a strong predictor of LSF and xerostomia. Therefore, it could be used to identify subjects for the further evaluation of salivary gland dysfunction. In addition, as the time of dissolution of the wafer becomes longer, the specificity for reduced salivary flow increases.

The wafer that is used in the test (a non-consecrated host) is made of wheat flour according to a universal recipe and has a standard weight and size. We obtained the wafers from a convent that supplies Catholic churches in Mexico City.

Although xerostomia is a common problem in the general population, it receives little attention [9]. The lack of a screening test has contributed to the underestimation of its relevance as a public health problem. Even in Sjögren's syndrome (SS), of which xerostomia is one of the main features, its assessment is complicated. During the development of the European criteria for the syndrome [12], patients with PSS, secondary SS, CTDs without SS and controls were studied. Assessment of the ocular and oral components was uneven. Schirmer-1 test was the test used most commonly to evaluate the ocular component; 91% of all subjects underwent the test, and this proportion was similar among the four study groups (89–93%, P=0.57). However, the evaluation of the oral component was heterogeneous. Lip biopsy was the test employed most commonly in the study population (72%), but the proportion of subjects who had the test was different among the four groups (85, 77, 56 and 52%, P<0.001). Among the patients with CTDs without SS and normal controls, the most commonly performed test was non-stimulated salivary flow (58 and 53%). Difficulty in evaluating the oral component of SS objectively, even under research conditions, has also been experienced in other studies [2628].

Epidemiological data about SS is scarce. The US National Arthritis Data Workgroup, the single source of national data on the prevalence and socioeconomic impact of the rheumatic disorders, did not include SS, either in the 1989 report [29] or in its updated version in 1998 [30]. A book about the epidemiology of rheumatic diseases does not include SS [31]. Paradoxically, SS has been considered to be probably the most common CTD. Perhaps 1–2 million individuals in the USA are affected, but most cases are undiagnosed [32]. In a population study conducted in a Greek rural community, a diagnosis of definite/probable PSS was made in 3.6% (95% CI 2.4, 5.1) of 837 women aged 18 yr or older [3]. This estimate is similar to the 4.8% reported in another Greek study conducted in an elderly population [33].

PSS, like most CTDs, may have an insidious onset, variable course and a wide spectrum of clinical manifestations [3, 26, 27, 3335]. Due to the variability of the condition at disease presentation, patients may be missed or misclassified [27, 36]. In a population-based study, patients identified as having primary SS had had mild complaints of dry eyes and mouth for several years. They were not aware of the disease and none of them had asked for medical care for their condition [3]. In clinical practice, only subjects with definite symptoms or keratoconjunctivitis sicca (KCS) are investigated for SS [27, 36]; patients with symptomatic xerostomia alone are investigated only if they are very symptomatic. Paradoxically, in subjects with sicca symptoms who later develop Sjögren's syndrome, oral symptoms are found more frequently than ocular symptoms at baseline [27]. As a result, the diagnosis of PSS is made later than that of the secondary form [37] or is conditional on the presence of KCS [36]. This may explain why patients with secondary SS show abnormal results in the oral and ocular tests less frequently and less markedly compared with patients with primary SS [35]. The scarcity of information about SS at earlier stages and in patients with predominantly oral involvement [13] produces biased and incomplete knowledge. Early recognition of decreased salivary flow will be helpful in the understanding of salivary gland dysfunction.

Several sets of classification criteria for Sjögren's syndrome have been proposed for patients with a complete spectrum of manifestations [12, 18, 3840], but mild, early and atypical forms of SS may be excluded. As definite cases represent only a subset of the entire population of patients with a specific disease, classification criteria are not useful for epidemiological surveys.

Questionnaires have been the screening instruments used most commonly. However, although symptomatic xerostomia is positively correlated with a decrease in salivary flow, the subjective complaint of dry mouth is highly individual [9] and some subjects do not demonstrate a reduced flow rate [4, 5]. In addition, subjective complaints of dry mouth may not be reliable indicators of early salivary gland dysfunction either, because salivary flow must be reduced by approximately 50% before an individual becomes symptomatic [5].

The European questionnaire has been proposed for use in the selection of potential patients with sicca syndrome in epidemiological surveys [12]. In a population-based study, a weak association between the questionnaire and objective tests results was seen. The questionnaire did not identify the subgroup of subjects who were more likely to have abnormalities on objective testing of lachrymal and salivary flow. The authors recommend that the clinical significance of these symptoms in the community needs reappraisal [1]. For 636 patients in the Oslo Rheumatoid Arthritis Register, the European questionnaire showed a very weak correlation with the Schirmer's test result (r=0.14) and NSWSF (r=0.24), even in patients with the most severe symptoms [4].

In a separate study, symptoms of dry mouth (as defined by two questions reported previously [11, 41]) were correlated with stimulated saliva production among 2520 subjects of both sexes aged 65–84 yr. The questionnaire had a sensitivity of 27%, a specificity of 84%, a PPV of 21%, an NPV of 88% and an accuracy of 77% in the detection of low salivary production at or below the 10th percentile of the population [2].

Other tests, e.g. sialography, salivary scintigraphy, parotid ultrasound and lip biopsy, are useful in the evaluation of salivary gland function in subjects in whom suspicion of dysfunction has already been raised, but they are not useful in screening.

Some potential limitations of the study need to be considered. The study was conducted among patients attending a tertiary care centre and healthy controls whose health status was well defined. Whether the results obtained will be reproduced in a group of subjects with undefined health status or in a population-based study needs to be explored.

The test was developed in a population aged between <20 and 60 yr, and its performance in people aged over 60 yr therefore needs to be assessed.

An abnormal wafer test result may be indicative of saliva hyposecretion due to any cause but does not provide information about the structural and functional defects in the salivary glands, nor is it specific for any disease. The clinician should decide whether additional diagnostic evaluation is justified.

It is possible that repeated wafer tests caused some learned behaviour in the subjects studied or stimulation of the salivary glands, introducing variation into the values obtained. However, when we compared the mean score with the results of the first wafer test, no difference was seen. In addition, the correlation coefficient among the three measurements was high and no difference was found when the three values in each group were compared.

The results of this study should not be interpreted as showing that the wafer test performs better than the European questionnaire in screening for xerostomia, as the study was designed as a means of developing the test, not to compare it with other methods of evaluation.

The characteristics of the wafer (diameter, thickness and weight) may vary among places, and it is therefore possible that the cut-off value of the test may need to be modified. Nevertheless, the performance of the test should be unaffected by these adjustments.

In conclusion, this study validated a semiquantitative test to discriminate between subjects with normal and reduced salivary flow. The wafer test is suitable, easy to administer, inexpensive and imposes minimal discomfort on the subject. The results are valid, reliable and reproducible. If the usefulness of the wafer test as a screening tool is confirmed, it will be of use in the establishment of the prevalence, spectrum, course and response to treatment of xerostomia.


    Appendix 1
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 
European questionnaire

1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
Ha tenido sensación de ojos secos, que le produzca molestias todos los días, en forma persistente por más de 3 meses?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
Tiene usted sensación recurrente de tierra o arenillas en los ojos?
3. Do you use tear substitutes more than 3 times a day?
Utiliza lágrimas artificiales más de 3 veces al día?
4. Have you had a daily feeling of dry mouth for more than 3 months?
Ha tenido sensación de boca seca todos los días por más de 3 meses?
5. Have you had recurrent or persistently swollen salivary glands as an adult?
Ha tenido hinchazón de las glándulas salivales (similar a paperas) en forma recurrente o persistente siendo adulto?
6. Do you frequently drink liquids to aid in swallowing dry foods?
Ingiere líquidos con frecuencia para ayudarse a pasar comidas secas?


    Acknowledgments
 
The authors would like to thank Laboratorios Sophia, Guadalajara, Jalisco, México, for donating the tear-flow test strips, and the personnel and medical students of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán for their participation. This work was supported in part by grants from the Consejo Nacional de Ciencia y Tecnologia de México (CONACYT) 3367P-M and 25556-M.


    Notes
 
Correspondence to: J. Sánchez-Guerrero, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, 14000 México, D.F. Mexico. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix 1
 References
 

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Submitted 20 March 2001; Accepted 12 October 2001