Highlights
- •Helminthiasis in children is positively associated with asthma.
- •The extent of helminth infestation is not associated with asthma.
- •Trichiuris trichura but no other helminths are associated with asthma.
Abstract
Objectives
The association between helminthiasis and asthma remains inconclusive but can only be investigated in counties where helminthiasis is transitioning from a high to low burden. We investigated this association using data from a childhood respiratory cohort in Sri Lanka.
Methods
A case-control study was nested within a population-based cohort of children aged 6-14 years in Sri Lanka. The stool samples of 190 children with asthma and 190 children without asthma were analyzed to assess the burden of helminth infestation. Logistic regression models were fitted to investigate the association of gastrointestinal helminth species with asthma.
Results
Helminthiasis in children with and without asthma was 23.3% (n = 44) and 15.3% (n = 23), respectively. Those with asthma were more likely to have helminthiasis (odds ratio 3.7; 95% confidence interval 1.7, 7.7; P = 0.001), particularly with Trichiuris trichura (odds ratio 4.5; 95% confidence interval 1.6, 12.3; P = 0.004). Helminth eggs per gram of feces were not associated with asthma (P >0.05).
Conclusion
Our findings demonstrate a positive association between T. trichura infestation and asthma and point to the need to fully characterize this association to understand the likely immunological mechanism that drives it. This association highlights an important public health intervention in countries where these infestations are still prevalent, affecting 24% of the population worldwide.
Keywords
Background
Asthma has a high global prevalence and disease burden [
[1]
]. Its prevalence has increased in high-income countries while remaining relatively low in low-income countries [[2]
]. However, some increase in asthma prevalence has also been reported in low-income countries with improving socioeconomic conditions [[2]
]. Attempts to explain this inverse relationship between better socioeconomic conditions and asthma and allergic diseases include the hygiene hypothesis [[3]
], which helped broaden the understanding of the environmental origin of asthma and suggested that low early-life exposure to infective agents predisposed children to subsequent allergic diseases/immune-mediated disorders, including asthma [[4]
]. However, it could not explain the high prevalence of asthma in the poor urban communities in high-income countries. The microbiome hypothesis [[5]
] and the theory of developmental origins of health and disease [[6]
] attempted to provide other explanations. These hypothesized how humans, together with all cohabiting and parasitic organisms, collectively evolve under evolutionary pressures and how epigenetic mechanisms govern health and disease, including asthma.Asthma results from airway hyper-responsiveness due to various triggers [
[7]
]. The mechanism by which these triggers induce asthma is helpful to understand asthma endotypes and better manage asthma [[8]
]. Asthma mostly results from initial sensitization of airways to common aeroallergens that induces immune-mediated bronchial reaction when re-exposed [[9]
]. The pathophysiology of respiratory reactions in asthma is complex and mediated by several interlinked inflammatory pathways and inflammatory chemical mediators [[7]
]. Some of the triggers for asthma are infections that induce immune responses, but there are other mechanisms that modulate host immunity to minimize sensitization to allergens and thereby reduce asthma [[10]
]. Some of this immune regulation was suggested to occur in the presence of helminth infestations because the regulation of immune reaction might have been of evolutionary benefit to both the helminths and the host [- Fiuza BSD
- Fonseca HF
- Meirelles PM
- Marques CR
- da Silva TM
- Figueiredo CA.
Understanding asthma and allergies by the lens of biodiversity and epigenetic changes.
Front Immunol. 2021; 12623737https://doi.org/10.3389/fimmu.2021.623737
[3]
]. This immune modulation by gastrointestinal helminth infestations is believed to reduce allergic conditions [[11]
], likely due to the immune regulatory potential of helminths, which is used to suppress the host immune system to establish chronic infestation and have an indirect suppressive effect on host responses against allergens [[12]
]. This was supported by the increase in host reactivity to allergens subsequent to antihelminth treatment for chronic helminthiasis [[13]
] and by the increase in asthma seen in high-income countries as they transitioned from having high to low prevalence of helminthiasis [[1]
]. This inverse association has recently been seen in some low-income countries as well, where the prevalence of allergic diseases was increasing, with a reduction in gastrointestinal helminthiasis [[2]
,[14]
]. However, there are some studies that showed no protective effect of helminth infestation on asthma or showed that such infestations increased the risk of asthma [[15]
]. A recent systematic review also found the current evidence on this association to be inconclusive [[16]
].Resolving this uncertainty in the association between helminthiasis and asthma has significant implications for asthma-related health policies and targeted population-based interventions in low- and middle-income countries where helminthiasis is still prevalent. A demonstrated consistent positive association would inform improvements to existing policy and interventions for mitigation of asthma that these countries already have in place and/or introduction of new policy/interventions. Implications of such resolution is enormous, given that 1.5 billion individuals, that is 24% of the global population, are currently affected by helminthiasis [
[17]
]. However, the nature of this association between helminthiasis and asthma can no longer be sufficiently characterized in high-income countries because helminthiasis is already low in those countries. On the other hand, countries that are currently transitioning from high to low burden of helminthiasis are likely to provide an ideal platform to investigate this association further. The evidence for this association from such countries is limited [World Health Organization. Soil-transmitted helminth infections, https://www.who.int/news-room/fact-sheets/detail/soil-transmitted-helminth-infections#:∼:text=More%20than%201.5%20billion%20people,soil%2Dtransmitted%20helminth%20infections%20worldwide; 2022 (accessed 01 September 2022).
[14]
] but likely to help resolve the ambivalent nature of current evidence [[18]
]. Investigating this association in Sri Lanka, which is currently undergoing this transition from high to low burden of helminthiasis [- Calvert J
- Burney P.
Ascaris, atopy, and exercise-induced bronchoconstriction in rural and urban South African children.
J Allergy Clin Immunol. 2010; 125 (100–5.e1–5)https://doi.org/10.1016/j.jaci.2009.09.010
[14]
] and has reported increasing prevalence of childhood asthma [19
, 20
, 21
], is likely to provide additional evidence for the link between gastrointestinal helminthiasis and asthma. Given this backdrop, we conducted a population-based study to determine the association between gastrointestinal helminthiasis and asthma in a subsample of a large cohort of children in Sri Lanka.Materials and methods
Study design and the sample
This study was nested in a subsample of a larger study aimed at establishing a cohort to study risk factors and consequences of chronic sleep and respiratory diseases in children in Sri Lanka. A community-based stratified cluster sampling method was used to recruit 1500 children aged 2-14 years from the Eastern Province of Sri Lanka. Clusters were randomly selected from a list of field health areas that catered to about 500 families. A total of 20 families with eligible children were randomly selected from a list maintained by the field health workers of these areas for provision of child and adolescent health care. When there was more than one eligible child in a family, only one child was selected randomly.
From the children aged 6-14 years in this sample, a subsample of 190 children with current asthma and 190 children without current asthma were randomly selected to study any gastrointestinal helminthiasis that they may have. Asthma status was determined using parents’ responses to validated questions [
[22]
] (see subsequent section for details). The children in the subsample represented all field health areas included in the larger study. The children with severe mental disability, severe physical disability, and on immunocompromising systemic treatment were excluded. Ethical approval for this study was granted by the ethics review committee of the District General Hospital/Trincomalee of the Provincial Department of Health/Eastern Province (approval number ERC/2018/06).Study instruments and data collection
Parents of all children aged 6-14 years provided responses to cross-culturally adapted questions on asthma that have been validated to be used in the local context. These were based on the International Study of Asthma and Allergies in Childhood questionnaire [
[22]
]. Current asthma was defined as (i) ever having asthma/wheezing or whistling in the chest and having wheezing or whistling in the chest at least four times during the past 12 months or (ii) being on an inhaler for diagnosed asthma. Information on sociodemographics and other likely risk factors were additionally collected using pretested questions validated using modified Delphi technique.Stool sample collection and microscopic analysis
Each child provided a fresh stool sample for parasitological analyses. Stool samples were transported maintaining the cold chain from the homes of children to the laboratory and stored at 4°C until processed. The presence of helminth eggs in each sample was assessed using a modified sucrose flotation method [
[23]
,- Jenkins TP
- Rathnayaka Y
- Perera PK
- Peachey LE
- Nolan MJ
- Krause L
- et al.
Infections by human gastrointestinal helminths are associated with changes in faecal microbiota diversity and composition.
PLoS One. 2017; 12e0184719https://doi.org/10.1371/journal.pone.0184719
[24]
]. From each stool sample, approximately 2 g were measured and mixed with distilled water in a capped centrifuge tube to a final volume of 15 ml. The mixtures were stirred thoroughly and centrifuged at 2045 g for 20 minutes at room temperature (∼27°C). Subsequently, the supernatants were discarded and the pellets at the bottom of the tubes were resuspended in distilled water and centrifuged (twice) until clear supernatants were obtained. The pellets were then emulsified using saturated sucrose solution, mixed thoroughly, and centrifuged for 20 minutes at 2045 g. Approximately 5 ml of the top meniscus of the resulting suspensions were collected in a centrifuge tube and mixed with distilled water up to a final volume of 15 ml and centrifuged for 10 minutes at 1370 g. This procedure was repeated and 1 ml of each suspension with the pellet was transferred to 1.5-ml Eppendorf® tubes using a Pasteur pipette. Distilled water was added to a final volume of 1.5 ml and the tubes were centrifuged at 1150 g for 10 minutes. The clear supernatants were discarded, and microscope slides were prepared using the remaining 0.5 ml pellets and examined under a light microscope. Helminth eggs were identified using both morphology and morphometry []. The egg count in 0.50 ml was assessed as eggs per gram (EPG) of feces, assuming that the Modified Sheather sucrose flotation method has concentrated all the eggs/cysts in the whole 2 g of feces to the 0.5 ml that was used for direct counting [[23]
,- Jenkins TP
- Rathnayaka Y
- Perera PK
- Peachey LE
- Nolan MJ
- Krause L
- et al.
Infections by human gastrointestinal helminths are associated with changes in faecal microbiota diversity and composition.
PLoS One. 2017; 12e0184719https://doi.org/10.1371/journal.pone.0184719
[24]
].Statistical analysis
The distributions of variables were described using numbers and proportions or means and standard deviations. Student's t-test and chi-square test were used appropriately to check differential distribution of these variables among those with and without asthma. Logistic regression models were used to determine the association of gastrointestinal helminthiasis with asthma. Adjustments were made for the effects of relevant confounding variables. The associations were presented as unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
Role of the funding source
The funders had no role in study design, in the collection, analysis, or interpretation of data, in the writing of the manuscript, and/or in the decision to submit the paper for publication.
Results
The final sample that was used for analysis consisted of 189 children with asthma and 190 children without asthma. The stool sample of one child with asthma could not be used. Those with asthma in this sample were more likely to be male and have better educated mothers (Table 1).
Table 1Sociodemographic information of the sample.
| No asthma (n = 190) | Asthma (n = 189) | P-value | ||
|---|---|---|---|---|
| N (%) or mean (SD) | N (%) or mean (SD) | |||
| Age | 8.2 (3.0) | 8.1 (3.2) | 0.869 | |
| Sex | Male | 88 (46.3) | 109 (57.7) | 0.027 |
| Female | 102 (53.7) | 80 (42.3) | ||
| Ethnicity | Tamil | 115 (60.5) | 120 (63.5) | 0.271 |
| Moor | 68 (35.8) | 66 (34.9) | ||
| Sinhala | 0 (0.0) | 1 (0.5) | ||
| Burgher | 7 (3.7) | 2 (1.1) | ||
| Religion | Hindu | 107 (56.3) | 109 (58.0) | 0.850 |
| Islam | 67 (35.3) | 66 (35.1) | ||
| Christianity | 16 (8.4) | 13 (6.9) | ||
| Maternal educational level | Grades 1-5 | 15 (9.9) | 17 (10.7) | 0.001 |
| Grades 6-11 | 97 (63.8) | 79 (49.7) | ||
| Passed GCE/OL | 32 (21.0) | 40 (25.2) | ||
| Grades 12-13 | 2 (1.3) | 18 (11.3) | ||
| Graduate | 6 (4.0) | 2 (1.3) | ||
| Postgraduate | 0 (0.0) | 3 (1.9) | ||
| Paternal educational level | Grades 1-5 | 34 (22.3) | 24 (15.5) | 0.047 |
| Grades 6-11 | 81 (54.3) | 82 (52.9) | ||
| Passed GCE/OL | 22 (14.9) | 38 (24.5) | ||
| Grades 12-13 | 6 (4.0) | 5 (3.2) | ||
| Graduate | 5 (3.4) | 2 (1.3) | ||
| Postgraduate | 0 (0.0) | 4 (2.6) | ||
| Maternal occupation | No occupation or homemaker | 159 (89.8) | 171 (94.5) | 0.339 |
| Elementary occupations/ Agriculture/ Fisheries | 6 (3.4) | 4 (2.2) | ||
| Clerical / Sales/ Technical | 10 (5.6) | 4 (2.2) | ||
| Professional or similar | 2 (1.1) | 2 (1.1) | ||
| Paternal occupation | No occupation or homemaker | 65 (39.4) | 76 (44.4) | 0.332 |
| Elementary occupations/ Agriculture/ Fisheries | 67 (39.4) | 61 (35.1) | ||
| Clerical / Sales/ Technical | 27 (15.8) | 32 (18.1) | ||
| Professional or similar | 9 (5.4) | 4 (2.3) | ||
| Monthly household income (Sri Lanka Rupees) | 24000 (3000, 85000) | 24000 (4500, 90000) | 0.177 |
a Out of the valid responses.
b Median (range).
c For Wilcoxon rank-sum test.GCE/OL, General Certificate of Education/Ordinary Level.
Gastrointestinal helminthiasis was present in 23.3% of children with asthma and 15.3% of children without asthma (Table 2). Only three children (0.8%) had co-infestations by more than one gastrointestinal helminth: two children with Ascaris lumbricoides and Trichiuris trichura and one child with T. trichura and hookworm spp. The intensity of the infestations was low [
[26]
], ranging from 0.03 (± 0.02) EPG for hookworm spp. to 0.34 (± 0.13) EPG for any helminth species.Table 2Association of asthma with the type of gastrointestinal helminths and the burden of helminths (eggs per gram of feces).
| No asthma (n = 190) N (%)/ mean (SD) | Asthma (n = 189) N (%)/ mean (SD) | Unadjusted OR (95% CI); P-value | Adjusted OR (95% CI); P-value | ||
|---|---|---|---|---|---|
| Gastrointestinal helminths | 29 (15.3) | 44 (23.3) | 1.7 (1.01, 2.8); 0.049 | 3.7 (1.7, 7.7); 0.001 | |
| Gastrointestinal helminth species | |||||
| Ascaris lumbricoides | 11 (5.8) | 16 (8.5) | 1.5 (0.7, 3.3); 0.314 | 2.9 (0.9, 9.6); 0.079 | |
| Trichiuris trichura | 17 (9.0) | 28 (14.8) | 1.8 (0.9, 3.4); 0.080 | 4.5 (1.6, 12.3); 0.004 | |
| Hookworm spp. | 3 (1.6) | 1 (0.5) | 0.3 (0.03, 3.2); 0.341 | 0.4 (0.03, 4.6); 0.454 | |
| Number of helminth eggs in 1 g of feces | |||||
| A. lumbricoides | 0.17 (0.11) | 0.10 (0.03) | 0.9 (0.8, 1.2); 0.552 | 4.4 (0.9, 22.0); 0.069 | |
| T. trichura | 0.14 (0.04) | 0.13 (0.06) | 1.0 (0.7, 1.4); 0.861 | 1.4 (0.8, 2.6); 0.198 | |
| Hookworm spp. | 0.03 (0.02) | 0.00 (0.00) | 0.2 (0.01, 5.4); 0.364 | 0.2 (0.01, 4.8); 0.307 | |
| Any helminth species | 0.34 (0.13) | 0.25 (0.05) | 0.9 (0.8, 1.1); 0.458 | 1.7 (1.0, 2.9); 0.070 |
a Column percentages.
b Adjusted for age, gender, maternal educational level, paternal educational level, maternal occupation, and paternal occupation.CI, confidence interval; OR, odds ratio.
The odds of having gastrointestinal helminths were significantly higher among children with asthma than those without asthma (OR 3.7; 95% CI 1.7, 7.7; Table 2). The children with asthma had a higher odds of harboring T. trichura (OR 4.5; 95% CI 1.6, 12.3), but asthma was not associated with harboring other helminths or the total or species-specific intensity of infestation as measured by EPG (P <0.05; Table 2).
Discussion
We investigated the association between gastrointestinal helminthiasis and asthma in children and found that those with gastrointestinal helminths, particularly T. trichura, were at higher odds of having asthma. The socioeconomic environment of our study area likely represents that of low- and lower-middle-income countries that are transitioning from high to low prevalence of gastrointestinal helminthiasis. Investigating the helminth-asthma association in this setting enabled us to provide evidence that adds to the current limited knowledge on how this association evolves together with the socioeconomic environment.
The high prevalence of asthma in regions in the world where there are better hygienic practices has long been tied to reduced exposure to infections in early life that would increase the later propensity for allergy sensitization. However, other evidence shows no definite relationship between asthma and hygiene, which challenges this hypothesis [
[27]
]. The presence of gastrointestinal helminths in children often suggests poor hygiene and is a proxy for early exposure to infections in general but also are known to induce immunoglobulin (Ig)E producing Th2 immune responses and change the host microbiome [[28]
]. In our study, we found that the proportion of gastrointestinal helminth infestations to be 23% in those with asthma and 15% in those without. This compares with the prevalence of helminthiasis reported in recent studies in Sri Lanka that ranges from 0% to 29% [29
, 30
, 31
]. The significantly higher proportion of children with asthma harboring gastrointestinal helminths does not support the hygiene hypothesis proposed for asthma and adds to the growing body of evidence against it [- Ubhayawardana N
- Gammana Liyanage I
- Herath HMJCB
- Amarasekera U
- Dissanayake T
- de Silva S
- et al.
Direct microscopy of stool samples for determining the prevalence of soil-transmitted helminthic infections among primary school children in Kaduwela MOH area of Sri Lanka following floods in 2016.
J Environ Public Health. 2018; 20184929805https://doi.org/10.1155/2018/4929805
[15]
,[32]
,[33]
]. On the other hand, the induction of IgE producing Th2 immune responses [[28]
] by helminths may have strong potential to cause asthma [[34]
] and may explain our findings, at least in part. Although the potential of helminthiasis leading to asthma through changes in the host microbiome could not be characterized within our study, there is evidence that gastrointestinal helminths influence the composition of intestinal microbiota [[35]
,[36]
], which has a profound effect on human health, including development of immune-mediated diseases [[37]
].The significant association that we saw between asthma and current infestation with T. trichura is also unusual. A. lumbricoides and hookworms, such as Ancylostoma duodenale and Necator americanus, migrate through the respiratory tract during their lifecycle and potentially give rise to respiratory symptoms that may be misconstrued as symptoms of asthma [
[32]
], but T. trichura has no pulmonary migration in its life cycle. In contrast to our findings, there are reports of children with a heavy burden of T. trichura in early childhood having a significantly reduced sensitization to many different types of aeroallergens as evidenced by subsequent skin prick tests, even in the absence of current infestations [[38]
,[39]
]. However, there is another evidence that T. trichura infestation is strongly associated with sensitization to house dust mite (Dermatophagoides pteronyssinus) allergens in rural areas similar to those in our study [[40]
], which may explain our finding but could not be tested with the data that we have. Another proposed explanatory model is that of mutual immunomodulation between T. trichura infestation and asthma with positive modulation of both pro- and anti-inflammatory cytokine levels [[41]
] that could lead to chronic sustenance of both conditions in children. However, this hypothesis needs more direct evidence to support it.- Gonçales JP
- Nobrega CGO
- Nascimento WRC
- Lorena VMB
- Peixoto DM
- Costa VMA
- et al.
Cytokine production in allergic and Trichuris trichiura-infected children from an urban region of the Brazilian northeast.
Parasitol Int. 2020; 74101918https://doi.org/10.1016/j.parint.2019.04.015
Interestingly, co-infestation by more than one gastrointestinal helminth species was almost non-existent in our sample, which likely suggests low community reservoirs for gastrointestinal helminths and infestations through sporadic sources. However, the most common gastrointestinal helminths that are found elsewhere were all observed in these children but with very low [
[26]
] worm load, as shown by the EPG values. We could not find a significant association between the worm load as indicated by the EPG and asthma, which might partly be due to this low worm load seen in both groups. Similarly low worm load has also been reported recently by others for Sri Lanka [[23]
], which is likely to be due to mass anthelmintic programs that particularly targeted socioeconomically challenged communities.- Jenkins TP
- Rathnayaka Y
- Perera PK
- Peachey LE
- Nolan MJ
- Krause L
- et al.
Infections by human gastrointestinal helminths are associated with changes in faecal microbiota diversity and composition.
PLoS One. 2017; 12e0184719https://doi.org/10.1371/journal.pone.0184719
Because this study was nested in another cohort study, there were both advantages and limitations. As already consented participants of a cohort study, the invitees were more likely to consent to the substudy and provide responses and stool samples, unlike in the case of a separate independent study. The cohort had near-zero nonresponse rate, which helped to minimize any selection bias due to selective nonresponse and therefore is representative of the general child population. This advantage was also seen in the nested study, which had no refusals. The data collectors and other staff were already familiar with the cohort and how it functioned, which made data collection and sample collection easy. Due to the same reason, the logistics were better managed, allowing us to maintain strict cold chain without difficulty and leading to a minimal loss of stool samples. However, because the respondents had already responded to lengthy questionnaires within the existing cohort, the questionnaire in the nested study had to be made as short as possible to minimize undue burden on the cohort members, and the data that we collected had to be limited. As a result, data collection was on a minimum number of variables, which in turn prevented us from performing more complex analyses to explain our findings. Given this, the possibility of unmeasured variables influencing our findings remains. The detection of helminths was done using a flotation technique, followed by microscopic analysis on a single stool sample due to resource and time limitations. This method has a low sensitivity and can additionally be influenced by the skills and experience of the microscopist [
[42]
]. Similarly, the sucrose concentration method that we used may not concentrate eggs of trematodes (e.g., schistosome eggs) and Strongyloides larvae. Any resulting misclassifications are likely to have affected the prevalence estimates nondifferentially and therefore underestimated the strengths of the associations that we detected. Finally, given the nature of this epidemiological study, asthma was defined using validated clinical questions. Therefore, we did not have measures of sputum or peripheral blood eosinophils nor IgE levels, which would have assisted in phenotyping asthma in the participants. Such information would also have allowed a more detailed consideration of potential mechanisms underpinning the relationship between helminth infection and asthma.Despite these limitations, our findings confirm and add to the existing evidence on a positive association between helminthiasis and asthma to help resolve the inconclusive nature of this association. Given that 1.5 billion individuals amounting to 24% of the global population are affected by helminthiasis, which can be significantly reduced by low-cost interventions [
[17]
], the resolution of this association to inform policy and population-based interventions to mitigate the burden of asthma has immense health and financial benefits.World Health Organization. Soil-transmitted helminth infections, https://www.who.int/news-room/fact-sheets/detail/soil-transmitted-helminth-infections#:∼:text=More%20than%201.5%20billion%20people,soil%2Dtransmitted%20helminth%20infections%20worldwide; 2022 (accessed 01 September 2022).
In conclusion, using a case-control study nested in a cohort study of children, we found that T. trichura infestation is strongly associated with current asthma but that other gastrointestinal helminthiasis or the helminth load are not associated with asthma. Our findings add to the limited evidence on the positive association between T. trichura and asthma that needs to be fully characterized in future research.
Declaration of competing interest
The authors have no competing interests to declare.
Funding
This study was funded by the University of Peradeniya (Research Grant No URG/2016/88/S) and the Non-Communicable Diseases Research Centre of the University of Sri Jayewardenepura.
Ethical approval
This study conforms to the amended Declaration of Helsinki. It was approved by the ethics review committee of the District General Hospital/Trincomalee of the Provincial Department of Health/Eastern Province (approval number ERC/2018/06).
Acknowledgments
The authors thank all members of the cohort, their families, and the field health staff of the study area for their contributions and cooperation.
Author contributions
CS conceptualized, designed, and conducted the study, analyzed the data, and drafted successive versions of the manuscript. PKP provided inputs to the planning of the study and managed and oversaw the full laboratory component. SA managed and oversaw the administrative and field data collection processes. NA conducted the laboratory analyses of stool samples. PP managed data entry and cleaning. GH, GN, and RR provided inputs for the planning of the study and revised successive drafts of the manuscript. SD supervised and guided all steps of the study process. All authors contributed to critical interpretation of the data and revised and approved the final manuscript.
Data availability
All manuscript related data are available in the tables. Further information can be obtained from the corresponding author.
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Article info
Publication history
Published online: January 08, 2023
Accepted:
January 3,
2023
Received in revised form:
December 21,
2022
Received:
September 24,
2022
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© 2023 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
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