|Year : 2021 | Volume
| Issue : 4 | Page : 62-69
Efficacy and safety of orally administered heat-killed Lactobacillus paracasei LCW23 in patients with allergic rhinitis: A randomized controlled clinical trial
Chung-Bin Huang1, Ying-Hsiang Wang2, Wei-Jen Chen3, Chih-Ming Tsai4, Chia-Hao Kang4, Pai-Yin Lin3, Hsin-I Lo3, Hong-Ren Yu5
1 Department of Pediatrics, Kuang Tien General Hospital, Taichung, Taiwan, ROC
2 Department of Pediatrics, Chang Gung Memorial Hospital, Chiayi, Taiwan, ROC
3 Research and Development Department, Syngen Biotech Co., Ltd, Tainan, Taiwan, ROC
4 Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC
5 Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC; Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
|Date of Submission||10-Mar-2022|
|Date of Decision||07-Aug-2022|
|Date of Acceptance||11-Aug-2022|
|Date of Web Publication||23-Sep-2022|
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, #123 Ta-Pei Road, Niao-Sung District, Kaohsiung 833 Taiwan
Source of Support: None, Conflict of Interest: None
Objective: In this study, we primarily evaluated the effects of IMMUPHYLA LCW23 on symptoms of allergic rhinitis. IMMUPHYLA LCW23 is a commercial probiotic product containing the Lactobacillus paracasei LCW23 strain. Materials and Methods: Sixty 5–18-year-old children with allergic rhinitis positive for the dust mite-specific bivalent antibody and meeting the inclusion criteria were enrolled in this double-blind, randomized, placebo-controlled trial. They were administered 2–4 g of the probiotic product containing L. paracasei LCW23 (2.5 × 109 cells/g; n = 28) or a placebo supplement (n = 32) according to their body weights for 12 weeks. After the treatment period, a self-assessment of allergic rhinitis symptoms in the nose and eyes was performed. Results: This study results revealed that 12-week supplementation with IMMUPHYLA LCW23 is safe, with no side effects. In addition, the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) assessment revealed that the probiotic significantly alleviated general discomfort (P = 0.003) and common symptoms of allergic rhinitis, such as nasal congestion (P = 0.033), runny nose (P = 0.001), and blowing nose (P = 0.008). Conclusion: Administration of IMMUPHYLA LCW23 was safe in the long-term follow-up study. The probiotic likely reduced the risk of allergy prevalence, without any major side effects.
Keywords: Allergic rhinitis, heat-killed probiotic, IMMUPHYLA LCW23, Lactobacillus paracasei LCW23, PRQLQ
|How to cite this article:|
Huang CB, Wang YH, Chen WJ, Tsai CM, Kang CH, Lin PY, Lo HI, Yu HR. Efficacy and safety of orally administered heat-killed Lactobacillus paracasei LCW23 in patients with allergic rhinitis: A randomized controlled clinical trial. Pediatr Respirol Crit Care Med 2021;5:62-9
|How to cite this URL:|
Huang CB, Wang YH, Chen WJ, Tsai CM, Kang CH, Lin PY, Lo HI, Yu HR. Efficacy and safety of orally administered heat-killed Lactobacillus paracasei LCW23 in patients with allergic rhinitis: A randomized controlled clinical trial. Pediatr Respirol Crit Care Med [serial online] 2021 [cited 2023 Feb 2];5:62-9. Available from: https://www.prccm.org/text.asp?2021/5/4/62/356803
| Introduction|| |
Allergic rhinitis is the most common childhood illness. The prevalence of this global health concern is continuously increasing. Allergic diseases are characterized by long-term nasal symptoms of obstruction, rhinorrhea, sneezing, and itching, affecting 10%–40% of the children worldwide. According to the World Allergy Organization, more than 400 million individuals experience allergic rhinitis globally. In the European Union, one in every four children is affected by an allergic disease. Increasing adoption of western lifestyles and use of antibiotics cause changes in the normal microflora, which can predispose children to allergic diseases. In the USA, 10–30% of adults and up to 40% of children are affected by the condition.
Taiwan is an island region with a subtropical climate that is hot and humid. The air quality is also poor in the region. These factors are conducive to allergen prevalence. Allergic diseases in the region include allergic rhinitis, asthma, and insect-sting allergies. Contact or inhaled allergens cause allergic rhinitis, which is associated with a series of immune reactions that cause inflammation of the nasal mucosa. Children and adolescents have a considerably higher prevalence of allergic rhinitis than adults do. The prevalence rate decreases with age. Although allergic rhinitis is considered a mild and seasonal nuisance, it leads to a considerable economic burden and affects children’s social activities, school performance, and work efficiency.
Supplementation of specific probiotic bacteria is an attractive approach to reduce the risk of allergic rhinitis., The health benefits of lactic acid bacteria were first observed by Metchnikoff in the late nineteenth century. Currently, oral bacteriotherapy is accepted in the prevention and treatment of allergies. Probiotics have been used effectively in allergen-mediated conditions to alleviate allergy symptoms by improving the gut ecosystem. The incidence of allergic diseases has been reported to be associated with the presence of probiotics in the gut, especially Lactobacillus paracasei. A randomized, double-blind clinical trial found that the ingestion of milk fermented with L. paracasei reduced the severity and frequency of allergic rhinitis symptoms. The antiallergic mechanism of probiotics is related to immune regulation in which the Th1/Th2 balance is skewed toward Th1 by inhibiting Th2 cytokines. Another study reported that L. paracasei strains may be more beneficial than other strains are in treating allergies. Clinical trials on allergies in children administered L. paracasei supplementation reported improvement in perennial allergic rhinitis symptoms in 95% of the patients. Recent evidence indicated that a combination supplement of L. paracasei and L. plantarum for 3 months is beneficial in reducing common cold infections in children. Moreover, supplementation with L. paracasei positively and significantly improved ocular symptoms, as assessed using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Studies have also demonstrated the beneficial effects of L. paracasei LP33 on allergic rhinitis symptoms., Huang et al. revealed that children with asthma receiving L. paracasei for 12 weeks demonstrated reduced asthma severity and improved allergic rhinitis symptoms. These study results reveal the therapeutic potential and safety of L. paracasei supplementation.
Clinical studies have suggested that non-viable probiotic containing dead cells and their metabolites can exert relevant biological responses. For instance, it can release bacterial components with key immunomodulating effects,, enhancing gene expression, activated macrophages, and suppressed excessive inflammation in mice and humans.,L. paracasei LCW23 (commercially available as IMMUPHYLA LCW23®) was initially isolated from the intestinal tract of normal, healthy humans in Taiwan. Due to specific heat-killed process, L. paracasei LCW23 exert relevant biological benefit. Our animal studies have demonstrated that heat-treated L. paracasei LCW23 can significantly reduce immunoglobulin E (IgE) level and allergy-related cytokines such as interleukin-4 (IL-4) and IL-5. Besides, L. paracasei LCW23 can reduce inflammatory cell infiltration and airway obstructions when observing lung tissue in mice (data not published). Specific heat-killed process allows L. paracasei LCW23 to retain its immune activity without being restricted by temperature condition. In this investigation, we hypothesize that heat-killed L. paracasei LCW23 can improve allergic symptoms in children caused by allergic rhinitis.
| Materials and Methods|| |
This double-blind, randomized, parallel, placebo-controlled study was conducted in Taiwan. The trial was approved by the Ethics Committee of the hospital (No. 97-1580D). In total, 80 children with allergic rhinitis were recruited in this study. Signed informed consent to participate in the study was obtained from their caregivers. The children were randomly allocated to either the probiotic (n = 40) or placebo (n = 40) group. Inclusion criteria were as follows: (I) 5–18 years of age; (II) personal allergy history, (III) family allergy history, and (IV) allergy to house dust mites. Exclusion criteria were as follows: (I) use of any other steroid-containing drugs and (II) smoking. During the screening period, patient characteristics and personal histories of allergic diseases were obtained. Allergic responses were confirmed concomitantly in a positive skin prick test or specific IgE (ImmunoCAP; Pharmacia and Upjohn, Kalamazoo, MI, USA) bivalent for house dust mites.
IMMUPHYLA LCW23 and a placebo powder were prepared and coded in good manufacturing practice (GMP)-certified facilities by Syngen Biotech Co., Ltd (Tainan, Taiwan, ROC) and dispensed by a study nurse. IMMUPHYLA LCW23 comprised L. paracasei LCW23 (2.5 × 109 cells/g) heat killed at 70–75°C for 30 min. The probiotic and placebo (sharing the same physical appearance) products were stored at room temperature and administered to the participants orally once daily at night for 12 weeks. Children who weighed less than 30 kg were administered 2 g of the probiotic or placebo per day, whereas those weighing more than 30 kg were given 4 g of probiotic or placebo.
Each subject had five clinical visits (visits 0–4) in the protocol. At visit 0, which was the screening visit, general data of all children were recorded. A comprehensive medical and allergy rhinitis history were obtained from all children. A physical examination of vital signs (blood pressure, heart rate, body temperature, and respiratory rate) was performed at each visit. In addition, blood samples were collected at the baseline assessment visit (visit 1) and end-of-study visit (visit 4) for evaluation of the allergy markers of total IgE, absolute eosinophil count (AEC), and related biochemical parameters. During the trial, children and caregivers received the questionnaire assessment. The children or caregivers assessed the severity of allergic rhinoconjunctivitis symptoms in the nose and eyes, quality of life, and other symptoms by using the modified Pediatric RQLQ (PRQLQ) at the baseline assessments visit (visit 1), treatment visits (visits 2 and 3), and end-of-study visit (visit 4). Adverse events (AEs) were recorded in the diary at each visit [Figure 1].
The PRQLQ, developed by Juniper et al., is a disease-specific HRQOL instrument focussing on the physical and emotional impact of a disease. The modified PRQLQ can comprehensively evaluate the physical, psychological, and social skills of children with allergic rhinoconjunctivitis. It is divided into two parts, namely, the degree and frequency of symptoms, and each part has 20 questions in 5 domains: nasal symptoms, ocular symptoms, practical problems, other symptoms, and activity limitations. Each item is scored using a 5-point scale from 0 to 4, with 0 representing no impairment and 4 maximum impairments. The participants were asked to complete the questionnaire with assistance from their parents at visits 1–4.
Dust mite-specific IgE in total serum was measured using a fluorescence enzyme immunoassay. Peripheral blood was also sampled and measured using an automated hematology analyzer. Blood samples were analyzed for white blood cell count, red blood cell count, hemoglobin, hematocrit, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase.
Efficacy was assessed on the basis of symptoms of allergic rhinitis by using the modified PRQLQ. A χ2 test was used for comparative analysis. The differences between the study groups were compared using an unpaired t-test, and differences between visits in each group were compared using a paired t-test. A P-value of less than 0.05, with a 95% confidence interval, was considered statistically significant in all tests. All values are expressed as means ± SDs.
| Results|| |
A total of 80 participants were randomly and equally allocated to the probiotic and placebo groups for screening. Of the 80 screened children, 20 were excluded for the following reasons: 6 participants did not meet the acceptance criteria in visit 0 (e.g., those aged <5 or >18 years). In the baseline assessment during visit 1, three participants did not have positive allergy test results. Of these three participants, two had negative results for the house dust mite-specific antibody bivalent and one did not have baseline biochemical data from blood samples. In visit 2, 11 participants withdrew their consent during the experiment. Among them, seven withdrew their consent and four were excluded for taking steroids during the study period [Figure 2]. Finally, 60 children participated in this study, and their demographic data are provided in [Table 1]. No statistically significant differences were observed between the groups at baseline.
No differences in the level of general discomfort were noted in the baseline PRQLQ scores between the probiotic and placebo groups (2.50 ± 1.32 and 2.50 ± 1.31, respectively). The symptom scores for general discomfort level (P = 0.003) [Table 2], frequency of nasal congestion (P = 0.033), runny nose (P = 0.001), and blowing nose (P = 0.008) [Table 3] in the probiotic group were significantly reduced at final visit when compared with those in the placebo group. After taking the probiotic product for 4 weeks, the participants exhibited a significant improvement in 18 of the 40 items (45%) on the questionnaire regarding symptoms of allergic rhinitis. Furthermore, 32 items (80%) were significantly improved and 38 items (95%) were improved in the symptoms of allergic rhinitis at week 12.
|Table 2: Mean severity score for individual symptom items of the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire between the probiotic and placebo groups (n = 60)|
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|Table 3: Mean frequency score for individual of symptoms items of the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire between the probiotic and placebo groups (n = 60)|
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The percentage changes in IgE and AEC levels between baseline and visit 4 in the probiotic and placebo groups are presented in [Figure 3]. No significant difference in the IgE or AEC levels was noted between the groups. This was possibly due to a large variation in the level of allergen-specific IgE in serum.
|Figure 3: Change in IgE and AEC levels between baseline and visit 4 in the placebo and the IMMUPHYLA LCW23 groups|
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Adverse reactions were not noted in vital signs or physical examination of all systems in both groups. AEs were noted in seven children. Overall, 28 AEs of mild or moderate severity were reported. The most common AE was vomiting (21.4%), followed by headache (14.2%). The incidence of any other AE was <11%. The treating physician identified that one case of nausea and one case of vomiting were related to the probiotic, but their severities were mild. The probiotic group had a lower proportion of AEs (9.3%) than the placebo group did (12.5%).
| Discussion|| |
Inhaled allergens and specific IgE antibodies in the body may trigger an immune response, leading to allergic rhinitis. Mast cells, the body’s immune cells, release inflammatory substances, such as histamine, which cause inflammation of the nasal mucosa. The three most typical symptoms of allergic rhinitis are sneezing, nasal congestion, and runny nose. If the symptoms of allergic rhinitis are not well controlled, they may affect breathing and sleep quality, even resulting in poor learning ability and weakened concentration.,
The effects of probiotics on allergic rhinitis have been widely investigated in randomized clinical trials and summarized in multiple reviews and meta-analyses.,, Probiotics for the primary prevention of allergy have been investigated. L. paracasei is a member of normal human and animal gut microbiota. Previous studies have indicated that L. paracasei has antiallergic benefits possibly by modulating the immune response through rebalancing the Th1/Th2 pathway. Our study indicated that L. paracasei LCW23 exerts antiallergic benefits after 3 months of supplementation. Intake of L. paracasei LCW23 for 8 weeks can help patients achieve up to 80% of improvement in symptoms. After 12 weeks of treatment, it can help achieve 95% improvement in allergic rhinitis symptoms, with a low incidence of AEs. After the 3-month experimental period, children in the probiotic group had significantly less frequent uncomfortable symptoms such as nasal congestion, runny nose, and blowing nose than did those in the placebo group. Our findings are consistent with results of previous studies, which demonstrated that certain probiotic strains are effective in alleviating allergic rhinitis,,, with no serious AEs.,
L. paracasei LCW23 is a heat-killed probiotic. Heat treatment may affect the composition of the bacterial cell wall and modify the immunological properties of the bacterium, providing protection against enteropathogens and helping maintain intestinal barrier integrity. Previous studies have revealed that dead bacterial cells release components with key immunomodulating effects and antagonizing properties against pathogens. In a clinical study, heat-killed L. paracasei effectively improved the overall QoL of patients with allergic rhinitis. Other investigations have shown that heat-killed L. paracasei produces a high-tumor necrosis factor-α secretion of stimulated monocytes. Heat-killed bacteria are different from live bacteria in terms of their lipoteichoic acid (LTA), peptidoglycan (PGN), and exopolysaccharide contents.[16 Evidence has demonstrated that bacterial cell-wall components],[ such as PGNs and LTAs],[ stimulate IL-12 (p70) production and activate the innate immune system through pattern recognition receptors called toll-like receptors., PGNs are a major component of the probiotic cell wall, which interacts with TLR2 for Th1-cell activation and differentiation. In addition, Li et al. reported that PGNs in probiotics have preventive activity against allergic inflammatory response by regulating Treg/Th17 imbalance. In contrast, LTAs from the cell wall of heat-killed L. paracasei D3-5 can be used as a biotherapy to ameliorate leaky gut and inflammation. Non-viable probiotics can provide health benefits in terms of modulating immunity. They may further act to reduce allergic rhinitis symptoms.
Allergens taken up by antigen-presenting cells lead to the activation of Th2 cells, which help regulate cellular immunity, promote isotype transformation, and produce specific IgE antibodies from B cells. Theoretically, patients with allergic rhinitis are more likely to have an elevated total IgE level than healthy individuals, and L. paracasei may reduce IgE levels. However, previous researches showed inconsistent results. A previous study reported that L. paracasei CNCMI-1518 affects immune responses by inhibiting IgE-dependent human basophil and mouse mast-cell activation. In a 12-month study, the L. paracasei group had decreased IgE levels compared with the placebo group. However, other studies reported no significant difference in IgE levels between the probiotic and placebo groups, which were consistent with our study.,,,, These inconsistent results may be explained by the difference of study groups age, probiotic strains, and the duration of treatment.
L. paracasei LCW23 did not change the biochemical parameters in the study population at the baseline or final visit. The findings indicated that the probiotic used in our study did not have any obvious side effects in children. In addition, uncomfortable symptoms in a single child were related to the test sample, but the severity of these AEs was mild. Moreover, the probiotic group had a lower proportion of AEs (9.3%) than the placebo group did. Therefore, L. paracasei LCW23 is considered safe for use in children.
| Conclusion|| |
Supplementation with the probiotic product for 12 weeks significantly improved individual symptoms, such as frequency of uncomfortable symptoms and nasal concerns, compared with placebo supplementation. The benefits of heat-killed bacteria can be exploited in a commercial product. There are several advantages for such a product including the absence of risks for immunocompromised children, increased stability compared to products containing live bacteria, and therefore easier to ship and store. L. paracasei LCW23 appears to be safe, with potential therapeutic value in allergy alleviation.
We are grateful to Dr. Shiuan-Huei Wu and Dr. Pei-Yu Chu for discussion and comments of this article. We also thank all the participants for their contribution in this study.
Financial support and sponsorship
This study was financially supported by the Syngen Biotech Co., Ltd in Taiwan, ROC.
Conflicts of interest
The authors have no conflicts of interest. This manuscript was edited by Wallace Academic Editing.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]