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Treatment of oral thrush in HIV/AIDS patients with lemon juice and lemon grass (Cymbopogon citratus) and gentian violet.

Abstract

Purpose: The purpose of the study was to investigate the safety and efficacy of lemon juice and lemon grass (Cymbopogon citratus) in the treatment of oral thrush in HIV/AIDS patients when compared with the control group using gentian violet aqueous solution 0.5%. Oral thrush is a frequent complication of HIV infection.

In the Moretele Hospice, due to financial constraints, the treatment routinely given to patients with oral thrush is either lemon juice directly into the mouth or a lemon grass infusion made from lemon grass (Cymbopogon citratus) grown and dried at the hospice. These two remedies have been found to be very efficacious therefore are used extensively. Gentian violet, the first line medication for oral thrush in South Africa, is not preferred by the primary health clinic patients due to the visible purple stain which leads them to being stigmatized as HIV-positive. Cymbopogon citratus and Citrus limon have known antifungal properties.

Methods: The study design was a randomised controlled trial. Ninety patients were randomly assigned to one of three groups: gentian violet, lemon juice or lemon grass. Inclusion criteria included being HIV-positive with a diagnosis of oral thrush. The study period was 11 days and patients were followed up every second day. International ethical principles were adhered to during the study.

Results: Of the 90 patients, 83 completed the study. In the intention-to-treat analysis, none of the p-values were significant therefore the null hypothesis could not be rejected. In the analysis of the participants who actually completed the trial, the lemon juice showed better results than the gentian violet aqueous solution 0.5% in the treatment of oral thrush in an HIV-positive population (p<0.02). The null hypothesis in terms of the lemon grass and gentian violet could also be rejected on the basis of the Chi-square test and the likelihood ratio test (p<0.05).

Conclusions: Though the patient population was small, the use of lemon juice and lemon grass for the treatment of oral candidiasis in an HIV population was validated by the randomised controlled trial. [c] 2008 Elsevier GmbH. All rights reserved.

Keywords: Oral candidiasis; HIV-positive; Lemon juice; Lemon grass; Cymbopogon citratus; Gentian violet

Introduction

Oral thrush is a common, and if severe, debilitating complication of immuno-suppressed individuals. In South Africa, the first line of treatment in primary care clinics is gentian violet 0.5% solution that is applied to the inside of the mouth three times a day to be continued for 2 days after cure (Department of Health, 2003). In practice, however, several barriers exist that makes the use of gentian violet problematic. The first problem is that the person has to be able to afford transport to the nearest clinic and feel healthy enough to attempt the trip. A second problem is the visible nature of the medication. The purple stain is a visible evidence of thrush therefore it exposes the person to be stigmatised due to HIV/AIDS.

Oral thrush is caused by Candida albicans, the predominant causative agent of all forms of mucocutaneous candidiasis. According to Fichtenbaum et al. (2000), Candida is part of the normal flora of the human gastro-intestinal tract and may be recovered from up to one third of the mouths of normal individuals and two thirds of those with advanced HIV disease. Erkose and Erturan (2007) found oral Candida colonisation in 82.8% of asymptomatic HIV-positive individuals. The importance of oral thrush, especially in more severe cases, is that the person finds it difficult to swallow. This further compromises the individual's nutritional status and ability to swallow medication. The symptoms of oral thrush include a burning pain, altered taste sensation, and difficulty swallowing liquids and solids. Less commonly, persons may present with acute atrophic candidiasis or chronic hyperplastic candidiasis involving the tongue, or angular cheilitis (Arendorf et al., 1998; Ranganathan et al., 2000; Shobhana et al., 2004, p. 152).

As is well known, Sub-Saharan Africa has the highest number of people living with AIDS and in South Africa alone, 1500 individuals are infected daily with the HIV virus. In the Moretele Hospice, due to financial constraints, the treatment routinely given to patients with oral thrush is either lemon juice directly into the mouth or a lemon grass infusion made from lemon grass (Cymbopogon citratus) grown and dried at the hospice. These two remedies have been found to be very efficacious; therefore they have been used extensively since the hospice opened in 1997. Literature is available on the antifungal properties of lemon grass (Pedroso et al., 2006; Fiori et al., 2000; Lorenzetti et al., 1991). In addition Caccioni et al. (1998) and Wang et al. (2007) have reported on the antifungal characteristics of lemon juice. However, no literature could be found on the use of lemon juice or lemon grass for the treatment of oral thrush.

The Moretele Hospice has a daily support group for people living with AIDS. A pre-condition for joining the support group is the willingness to disclose their HIV status. It was therefore feasible to conduct the study at the hospice. A randomised control trial was designed to obtain objective proof of the safety and efficacy of the two remedies when compared with the first line treatment prescribed by the Essential Drug List of South Africa (Department of Health, 2003). Proving safety and efficacy is important because either establishing a lemon tree or growing lemon grass is easy for every household, as well as being cost-effective.

The study was undertaken to investigate the safety and efficacy of lemon juice and lemon grass (Cymbopogon citratus) in the treatment of oral thrush in HIV/AIDS patients when compared with the use of gentian violet aqueous solution 0.5%.

Two hypotheses were designed for the study:

H01. Gentian violet aqueous solution 0.5% is equal to lemon juice and lemon grass in the treatment of oral thrush in HIV/AIDS patients in the intention-to-treat analysis.

H02. Gentian violet aqueous solution 0.5% is equal to lemon juice and lemon grass in the treatment of oral thrush in HIV/AIDS patients.

Materials and methods

The study design was a randomised control trial. Ninety patients were randomly assigned to one of three groups: gentian violet, lemon juice or lemon grass. Randomisation was done prior to the start of the study and stored in sealed, opaque, identical envelopes, which were numbered sequentially. Patients were recruited from the HIV/AIDS support group at the Moretele Hospice. A flow chart of the participants in the study is provided in Fig. 1.

[FIGURE 1 OMITTED]

The ineligible patients did not have thrush at the time of the study. The target population for the study fulfilled the criteria for inclusion: a positive diagnosis of oral thrush, currently not on any medication for oral thrush, HIV-positive and willingness to participate. The oral thrush was diagnosed and graded according to the oral thrush scale provided in Table 1.
Table 1. Oral thrush scale.

Grade Definition

0 No thrush

1 Painless white, curdy-like plaques in the throat area

2 White, curdy-like plaques in throat and spread over tongue

3 Severe thrush in throat, tongue with difficulty to swallow

4 Severe thrush in throat, over tongue, with ulcerations and
 bleeding and or angular cheilitis, difficulty to swallow


Informed consent was signed before participation in the study. Patients who were not expected to remain alive for the study period of 10 days were excluded. The study period continued for 11 days with a final evaluation on the 11th day. The study was an open label study as, once the patient was assigned to a group, the treatment was known to the patient and the registered nurses.

Study treatments

The study participants received one of three treatment schedules:

Control treatment: Gentian violet aqueous solution 0.5% Gentian violet aqueous solution 0.5% is prescribed as a first line treatment for oral thrush in the Standard Treatment Guidelines for Primary Health Care 1998 (Department of Health, 2003, p. 12). The gentian violet aqueous solution 0.5% served as the control treatment for comparison of the two other experimental groups. Method of use:

1. Apply gentian violet aqueous solution topically.

2. Paint the inside of the mouth three times daily.

3. Continue for two days after clinical cure.

4. Maximum allowed treatment period is 10 days.

Experimental treatment 1: Lemon juice Method of application:

1. Squeeze lemon juice is squeezed from a fresh lemon.

2. Dilute 20 ml lemon juice with 10 ml water.

3. Place half the mixture in the mouth and rinse inside of mouth with the diluted lemon juice and spit out.

4. Wait approximately 5 min and place the other half of the mixture in the mouth keeping the lemon juice in contact with the affected areas as long as possible. Then swallow the lemon juice.

5. Use 2-3 drops of pure lemon juice 3 times per day for the next 10 days or until clinical cure.

6. Maximum allowed treatment period is 10 days.

Experimental treatment 2: Lemon grass Method of application:

1. Take half a packet (12.5 ml) of dried lemon grass (Cymbopogon citratus) supplied by the Moretele Hospice and make an infusion with 500 ml boiling water.

2. Boil the infusion for 10 min and cool.

3. First treatment: drink 125 ml of lemon grass infusion; thereafter drink at least 250 ml twice a day.

4. Treatment period: 10 days.

5. A fresh infusion must be made every 24 h.

Escape clause in case of treatment failure

The escape clauses for all three treatments groups were as follows:

* No improvement for 2 consecutive days (48 h).

* Increased difficulty in swallowing or painful swelling as compared with day 1 of study.

* Uncertain diagnosis.

* Unacceptable adverse events as evaluated by the patient.

In case of treatment failure, the patient was treated with Nystatin suspension oral 100 000 IU/ml. Patients took 1 ml four times daily and continued for 48 h after clinical cure (Department of Health, 2003).

Adverse events

Adverse events were reported at every visit. Patients were not prompted for adverse events but if they reported any adverse event spontaneously, it was recorded on the case report form. If the adverse events were unacceptable to the patient himself or herself, the treatment was terminated and the patient placed on Nystatin[R] suspension oral l00 000 IU/ml (Department of Health, 2003). In case of an adverse event, physical signs and symptoms were re-evaluated and the results were recorded on the case report form.

The staff at the Moretele Hospice was trained to implement the study procedures. The registered nurses and caregivers were knowledgeable about oral thrush and the three treatments before the study began. The measurement variables are provided in Table 2.
Table 2. Variables measured and study procedures completed at every
visit.

 Visit 1 Visit 2 Visit 3

Day 1 3 5

Range [+ or -] 1 day [+ or -]1 day

Informed consent X

Randomisation X

Patient demographics X

Medical history X

Inclusion/exclusion criteria X

Concomitant medication X X X

Oral thrush scale X X X

Heart rate and blood pressure X X X

Adverse events X X X

Study medication X X X

 Visit 4 Visit 5 Visit 6

Day 7 9 11

Range [+ or -] 1 day [+ or -] 1 day [+ or -] 1 day

Informed consent

Randomisation

Patient

demographics

Medical history

Inclusion/exclusion
criteria

Concomitant medication X X X

Oral thrush scale X X X

Heart rate and X X X

blood pressure

Adverse events X X X

Study medication X X


A case report form was developed to record the data.

Statistical analysis was used to analyse the data. Most of the clinical characteristic data were gathered as ordinal data with the exception of the weight and height which were interval data. The BMI categories calculated from the weight and height were, however, converted to ordinal data. The heart rate and blood pressure data were also categorised in the final analysis. Several tests, Fisher's exact test, Chi-square test, Chi-square test with the continuity correction and the likelihood ratio were used to test the hypothesis for the study.

Validity and reliability were ensured as follows:

* The research proposal was approved by Faculty Research and Innovation Committee as well as the Ethics Committee of Tshwane University of Technology.

* The registered nurses had used the oral thrush scale before the study therefore they were capable of rating the severity of the oral thrush according to the scale.

* The registered nurses at the hospice were trained in the study procedures before commencement of the trial.

* The research team of Tshwane University of Technology visited visit the hospice regularly to do audit checks thereby ensuring the quality of the data.

* The randomisation procedure was carried out before commencement of the study. The Department of the Statistical Support at Tshwane University of Technology did the statistical analysis.

Ethical considerations were complied with as follows:

* Informed consent was obtained from the patients. The registered nurses at the hospice informed the patients about the study in their own language and each patient was given an information leaflet. Contact information was provided on the information leaflet.

* Anonymity and confidentiality was ensured, as the patient's name did not appear on the case report form where the trial data were recorded.

* Adverse events were recorded to address safety issues and the patient's subjective evaluation of unacceptable adverse events terminated his or her participation.

* The patient had the right to withdraw from the study at any time.

* An escape clause was provided to ensure that patients were not disadvantaged by remaining on the treatment. The treatment that followed termination of the trial was prescribed by the Department of Health (2003). There was no placebo group. The two experimental treatment groups were compared with the control group as prescribed by the Department of Health (2003).

Results

Ninety patients were enrolled in the study, but only 82 had complete and acceptable data (Fig. 1). The clinical characteristics of the three groups are provided in Table 3.
Table 3. Clinical characteristics.

Characteristics Gentian violet Lemon juice Lemon grass
 (n = 29) (n = 30) (n = 23)

Age (proportion 92.7% 73.4% 60.9%
< 34 years)

Male 9 (31.0%) 8 (26.7%) 5 (21.7%)

Female 20 (69.0%) 22 (73.3%) 18 (78.3%)

HIV-positive 29 (100%) 30 (100%) 23 (100%)
status

BMI category
Underweight 8 (27.6%) 8 (26.6%) 8 (34.8%)

Normal 15 (51.7%) 13 (43.3%) 11 (47.8%)

Overweight/ 6 (20.7%) 9 (30.1%) 4 (17.4%)
obese

Number of days
with symptoms

1-5 20 (71%) 22 (73%) 16 (70%)

6-10 4 (14%) 3 (10%) 4 (17%)

> 10 4 (14%) 5 (17%) 3 (13%)
Oral thrush scale
on admission

1 9 (31.0%) 6 (20.7%) 7 (24.1%)

2 12 (41.4%) 13 (44.8%) 6 (20.7%)

3 6 (20.7%) 9 (31.0%) 9 (31.0%)

4 2 (6.9%) 2 (6.9%) 1 (3.4%)

Blood pressure 7 (24%) 5 (17%) 2 (9%)
(hypotension)

Heart rate 9 (31%) 10 (33%) 7 (30%)
(tachycardia)


On inspection, the three groups were similar in their baseline statistics (Table 3). Due to the debilitating effect of HIV/AIDS (Kulstad and Schoeller, 2007), the patients' weight and height were measured to calculate the body mass index (kg/[m.sup.2]) (van der Merwe, 2004) to be able to determine if the underweight patients were equally distributed in the trial.

Adverse events

The patients who did not report for follow-up are listed in Fig. 1. The adverse events reported for the gentian violet group were purple discolouration, cracked lips and dry mouth. Those reported for the lemon juice group were changed taste in the mouth and abdominal cramps. The lemon grass group had only one adverse event reported namely increased appetite. It was reported by the registered nurses that the high rate of absconding in the gentian violet group was due mainly to the discolouration of mouth. The visibility of the gentian violet affected compliance with the medication.

The outcome of the study is provided in Table 4.
Table 4. Outcome of the treatment.

Outcome Gentian violet Lemon juice Lemon grass
Clinical success 9 16 15
Clinical failure 8 2 2
Total 17 18 17

Withdrawn 12 12 6
Total complete data 29 30 23

Incomplete data 1 0 6
Total included in study 30 30 30


The intention-to-treat analysis will be reported first. Thereafter the results of the participants who completed the study will be given.

Intention-to-treat analysis

Lemon juice versus (n = 30) gentian violet 0.5% solution (n = 30)

None of the p-values was less than 0.05, the specified level of significance, hence the difference between the two treatments (lemon juice and gentian violet) is not statistically significant. Inspection of the difference between the two proportions shows that proportionally more respondents were treated successfully with lemon juice than with gentian violet. A larger sample is necessary to establish if the true difference is statistically significant.

Lemon grass (n = 30) versus gentian violet 0.5% solution n = 30)

None of the p-values was less than 0.05, the specified level of significance, hence the difference between the two treatments (lemon grass and gentian violet) is not statistically significant.

Participants who completed the trial

Lemon juice versus (n = 18) gentian violet 0.5% solution (n = 17)

Based on the sample sizes of those respondents who completed the treatment, all the p-values are less than 0.05, the specified level of significance, indicating that the difference between the two treatments (lemon juice and gentian violet) is statistically significant. The p-values for the various tests were Fisher's exact test (p = 0.02), Chi-square test (p = 0.01), Chi-square test with the continuity correction (p = 0.04) and likelihood ratio (p = 0.01). The null hypothesis can thus be rejected. Lemon juice is better than the gentian violet aqueous solution 0.5% in treating oral thrush in an HIV-positive population.

Lemon grass (n = 17) versus gentian violet 0.5% solution (n = 17)

Based on the sample sizes of those participants who completed the treatment, the Chi-square test and the likelihood ratio test have p-values that are less than 0.05, the specified level of significance, indicating that the difference between the two treatments (lemon grass and gentian violet) is statistically significant. Fisher's exact test and the Chi-square test with the continuity correction have p-values marginally larger than 0.05 (p = 0.057 and 0.059, respectively). The null hypothesis can thus be rejected. Lemon grass is better than the gentian violet aqueous solution 0.5% in treating oral thrush in an HIV-positive population.

Discussion

The data support the hypotheses that both lemon juice and lemon grass are better than gentian violet aqueous solution 0.5% in the treatment of oral thrush in HIV/AIDS patients. In addition, due to its visibility and the stigma attached to HIV/AIDS, compliance with gentian violet regimen is low. Lemon juice on the other hand, stings but cures oral thrush within a number of days. The lemon grass infusion had the lowest number of adverse events and compliance was high.

However, a limitation of the study is the small number of participants. This preliminary study should be followed by a large-scale study. Another point is the natural setting in which the study was conducted. Though participants were informed and gave consent, they were free to continue to participate or not. There was no financial incentive for the participants to complete the study. Though the registered nurses at the hospice conducted the study and though trained and audited, 8 patients had incomplete data.

In South Africa, hospices and people living with AIDS are frequently financially constrained therefore effective therapies, in terms of both efficacy and cost, are imperative. Lemon trees and lemon grass can be grown in any garden. These are cheap, perennial plants that will present people living with AIDS with a viable resource to treat oral thrush.

References

Arendorf, A.M., Bredekamp, K., Cloete, C.A., Sauer, G., 1998. Oral manifestations of HIV infection in 600 South African patients. J. Oral Pathol. Med. 27, 176-179.

Caccioni, D.R.L., Guizzardi, M., Biondi, D.M., Renda, A., Ruberto, G., 1998. Relationship between volatile components of citrus fruit essential oils and antimicrobial action on Penicillium digitatum and Penicillium italicum. Inter. J. Food Microbiol. 43 (1-2), 73-79.

Erkose, G., Erturan, Z., 2007. Oral Candida colonization of human immunodeficiency virus infected subjects in Turkey and its relation with viral load and CD4+ T-lymphocyte count. Mycoses 50, 485-490.

Fichtenbaum, C.J., Koletar, S., Yiannoutsos, C, Holland, F., Pottage, J., Cohn, S.E., Walawander, A., Frame, P., Feinberg, J., Saag, M., van der Horst, C, Powderly, W.G., 2000. Refractory mucosal candidiasis in advanced human immunodeficiency virus infection. Clin. Infect. Dis. 30, 749-756.

Fiori, A.C.G., et al., 2000. Antifungal activity of leaf extracts and essential oils of some medicinal plants Didymella bryoniae. J. Phyto. 148, 483-187.

Kulstad, R., Schoeller, D.A., 2007. The energetics of wasting diseases. Curr. Opin. Clin. Nutr. Metab. Care 10, 488-93.

Lorenzetti, B.B., Souza, G.E., Sarti, S.J., Santos Filho, D., Ferreira-Filho, D., Ferreira, S.H., 1991. Myrcene mimics the peripheral analgesic activity of lemongrass tea. J. Ethnopharm. 34, 43-48.

Pedroso, R.B., et al., 2006. Biological activities of essential oil obtained from Cymbopogon citrates on Crithidia deanei. Acta Protozoa 45, 231-240.

Ranganathan, K., Reddy, B.V., Kumarasamy, N., Solomon, S., Viswanathan, R., Johnson, N.W., 2000. Oral lesions and conditions associated with human immunodeficiency virus infection in 300 south Indian patients. Oral Dis. 6, 152-157.

Shobhana, A., Guha, S.K., NeogI, D.K., 2004. Mucocutaneous manifestations of HIV infection. Indian J. Dermatol. Venereol. Leprol. 70, 82-86.

van der Merwe, M.T., 2004. The importance and predictive value of BMI and waist circumference in the development of type 2 diabetes. S. Afr. Fam. Prac. 46, 10-14.

Wang, Y., Chuang, Y., Ku, Y., 2007. Quantitation of bioactive compounds in citrus fruits cultivated in Taiwan. Food Chem. 102, 1163-1171.

South Africa Department of Health, 2003. Essential Drug List: South Africa. CTP Book Printers, Cape Town.

S.C. Wright (a,*), J.E. Maree (a), M. Sibanyoni (b)

(a) Adelaide Tambo School of Nursing Science, Tshwane University of Technology, Staatsartillerie Road, Pretoria-West, Pretoria 0001, Gauteng, South Africa

(b)Moretele Hospice, South Africa

Statement of Phytomedicine editors: Although the present (printed) pilot study does not fullfill the requirement of Good Clinical Practice (GCP), the editors have decided to publish the results of this observation study (pilot study) to encourage other doctors to test this preparation and to motivate pharmaceutical firms to develop a chemically standardized phytopreparation based on the proved herbcombination. It should be not too difficult to improve the efficiency because all constituents of both herbal drugs are known and more pharmacological investigations than listed in the paper do exist describing the antifungal (anticandida) activities of lemon juice and lemon grass infusion.

*Corresponding author. Tel.: +27 0123825470; fax: +27012 382 5033. E-mail address: wrightscd@tut.ac.za (S.C. Wright).
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Author:Wright, S.C.; Maree, J.E.; Sibanyoni, M.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Mar 1, 2009
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