Epidemiological Differences in Hajj-Acquired Airborne Infections in Pilgrims Arriving from Low and Middle-Income versus High-Income Countries: A Systematised Review

This systematised review aims to compare the epidemiological patterns of Hajj-acquired airborne infections among pilgrims from low and middle-income countries (LMIC) versus those from high-income countries (HIC). A PubMed search was carried out for all published articles before February 2023, using a combination of MeSH terms and text words. The Newcastle–Ottawa Scale (NOS) was used to assess data quality. From a total of 453 titles identified, 58 studies were included in the review (LMIC = 32, and HIC = 26). In the pooled sample, there were 27,799 pilgrims aged 2 days to 105 years (male: female = 1.3:1) from LMIC and 70,865 pilgrims aged 2 months to 95 years (male: female = 1:1) from HIC. Pilgrims from both HIC and LMIC had viral and bacterial infections, but pilgrims from HIC tended to have higher attack rates of viral infections than their LMIC counterparts. However, the attack rates of bacterial infections were variable: for instance, pilgrims from LMIC seemed to have higher rates of meningococcal infections (0.015–82% in LMIC vs. 0.002–40% in HIC) based on the study population, but not Mycobacterium tuberculosis (0.7–20.3% in LMIC vs. 38% in HIC). Targeted measures are needed to prevent the spread of airborne infections at Hajj.


Introduction
Hajj is an annual religious mass gathering (MG) held in Makkah, the Kingdom of Saudi Arabia (KSA), which, during a non-pandemic year, attracts more than two million pilgrims to attend the pilgrimage [1]. During the Hajj pilgrimage, the climatic conditions and inevitable overcrowding of pilgrims in Makkah and the surrounding holy sites significantly increase the likelihood of contracting and transmitting infectious diseases [2]. Pilgrims come from over 180 countries, including both high-income and low-income nations, with various unique cultural, nutritional and health behaviour backgrounds. Pilgrims originating from regions with variable disease profiles present one of the most significant challenges to the host country. Certain diseases or infectious agents may be prevalent in some regions but not in others [3], which makes it difficult for the host country to apply a uniform preventive guideline. Additionally, pilgrims from countries with a low burden of disease may acquire infection from pilgrims from countries with a high burden of disease, due to their close contact in confined spaces in accommodation and during rituals [2]. Also, many pilgrims, particularly those from developing countries, may have limited access to adequate healthcare services and preventative measures, e.g., vaccinations before they commence their journey [4]. Such diversity in the pilgrim population might determine the burden of health risks acquired during this MG event.
In particular, airborne infections are a major public health issue and a significant cause of morbidity at Hajj. Pneumonia is the leading cause of hospitalisation during Hajj and the second or third most common cause of admission to the intensive care unit (ICU) during Hajj [5]. Furthermore, many airborne infections have emerged in recent decades, including severe acute respiratory syndrome (SARS) in 2003, the influenza A (H1N1)pdm09, the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and, more recently, the novel coronavirus disease 2019  in 2019, presenting a major public health and infection control challenge for both the authorities in KSA and the national authorities in the pilgrims' countries of origin [6,7].
A handful of systematic reviews have provided a comprehensive overview of available evidence on the burden of respiratory infections in Hajj [5,[8][9][10][11]; however, no study was undertaken to compare the burden of infections at Hajj among participants from low and middle-income countries (LMIC) and high-income countries (HIC). This comparison is important, as it can inform future public health policy and identify potential prevention and control strategies. Therefore, this systematised review aims to compare the epidemiological patterns of Hajj-acquired airborne infections among pilgrims from LMIC versus HIC. By the term 'airborne infection', we mean any infection transmitted by respiratory route, irrespective of whether it primarily causes respiratory infection or not, so infections like 'meningococcal disease' were also included.

Search Strategy and Study Selection
This review was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12]. However, we did not attempt to register this systematised review with PROSPERO or other registry databases as the process takes much longer during the COVID-19/post-COVID-19 period, and we did not intend to delay this important systematic review.
The PubMed electronic database was comprehensively searched for all relevant articles published from inception to February 2023. Also, a manual search was conducted to identify additional potentially eligible articles by reviewing the reference lists of the included studies. The search strategy was developed using a combination of MeSH terms and keywords, including: 'Hadj' OR 'Hadz' OR 'Hajj' OR 'Mecca' OR 'Makkah' OR 'pilgrimage' OR 'pilgrims' AND 'respiratory tract infection' OR 'airborne infection' OR 'acute respiratory infection'.
Three independent reviewers (HAM, M. Alluhidan, and HR) evaluated the retrieved studies for eligibility by screening titles and abstracts, selected relevant manuscripts based on the inclusion criteria, and then reviewed the full texts of each paper potentially meeting the inclusion criteria. If any discrepancies or disagreements arose, they were resolved through discussion among the researchers. The inclusion criteria included primary studies reporting microbiological data on viral or bacterial respiratory infections involving Hajj pilgrims of any age, gender, or country of origin that employed a laboratory-based diagnostic method. Only English language articles were considered for this review. Studies conducted outside the Hajj setting or involving non-pilgrim participants rather than Hajj pilgrims or reporting only clinical or self-reported respiratory symptoms or infections without laboratory-confirmed data were excluded. The pilgrims' countries of origin were classified based on the 2021-2022 World Bank Classification for countries by income (https://datatopics.worldbank.org/world-development-indicators/the-world-byincome-and-region.html accessed on 2 March 2023).

Data Extraction and Synthesis
The data were independently extracted from each included article by two authors (HAM and M. Alluhidan) into an extraction spreadsheet. The extracted data were then cross-checked for accuracy by another reviewer (HR). The extracted data included the year of study, selection method/case ascertainment, testing methods, study sample, nationality, age and gender of participants, risk factors, influenza and pneumococcal vaccine uptake, and burden of airborne infections.
The studies were heterogeneous in terms of study sites, diagnostic tests applied, and research outcomes assessed; hence, a meta-analysis or correlation analysis has not been attempted. However, a narrative synthesis was carried out by providing the upper and lower ranges of proportions for comparative variables and attack rates of airborne infections.
The study quality was assessed by two authors (HAM and HR) using the Newcastle-Ottawa Scale (NOS), in which an observational study is scored based on a 'star system' across three broad domains: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or outcome of interest. Conventionally, a score of 6-9 is considered good quality, a score of 3-5 as average and a score of 0-2 as poor (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp accessed on 5 April 2023).

General Description of Included Studies and Quality Assessment
As shown in the PRISMA flowchart ( Figure 1) database searches and hand searching resulted in a total of 453 hits; these 79 full texts were reviewed, of which 58 studies finally met the inclusion criteria: 32 involved pilgrims from LMIC (Table 1) and 26 from HIC ( Table 2). The studies involved pilgrims who attended Hajj from 1987 to 2021, with study sample sizes varying widely from 7 to 58,428 participants. The studies were heterogeneous in terms of study sites, diagnostic tests applied to identify the causative agents of infections (such as polymerase chain reaction (PCR) or viral/bacterial culture), and outcomes assessed.

Comparative Variables and Attack Rates of Hajj-Acquired Airborne Infections
The most commonly reported chronic medical conditions among pilgrims from LMIC were chronic lung and cardiovascular diseases; noting that, the highest proportions of these conditions (71% and 43%, respectively) were observed in one study that studied a highly selective cohort of pilgrims admitted to ICU with severe sepsis and septic shock [16]. On the other hand, the most frequently observed chronic medical conditions among pilgrims arriving from HIC were variable, with diabetes ranging from 1% among pilgrims from Australia [34] to 32% among pilgrims from France [62], and hypertension ranging from 9% among pilgrims from Turkey [59] to 28% among pilgrims from France [62].  Table 3 provides a detailed comparison of the demographic data, risk factors, vaccination uptake, and burden of confirmed airborne infections between pilgrims from LMIC and HIC. In the pooled sample, there were 27,799 pilgrims from LMIC with ages ranging from 2 days to 105 years and a male-to-female ratio of 1.3:1, and 70,865 pilgrims from HIC with ages between 2 months and 95 years and an equal gender ratio of 1:1. Most pilgrims from LMIC arrived from Africa, Southeast Asia, and the Eastern Mediterranean, whereas most pilgrims from HIC mainly arrived from Europe, the Eastern Mediterranean, and the Western Pacific. The most commonly reported chronic medical conditions among pilgrims from LMIC were chronic lung and cardiovascular diseases; noting that, the highest proportions of these conditions (71% and 43%, respectively) were observed in one study that studied a highly selective cohort of pilgrims admitted to ICU with severe sepsis and septic shock [16]. On the other hand, the most frequently observed chronic medical conditions among pilgrims arriving from HIC were variable, with diabetes ranging from 1% among pilgrims from Australia [34] to 32% among pilgrims from France [62], and hypertension ranging from 9% among pilgrims from Turkey [59] to 28% among pilgrims from France [62].

Comparative Variables and Attack Rates of Hajj-Acquired Airborne Infections
Studies that reported the pilgrims' vaccination uptake revealed a wide variation in uptake both among LMIC and HIC pilgrims. Influenza vaccine uptake rates in LMIC ranged from 20% among Egyptian Hajj pilgrims in the years 2012 to 2015 [51] to 100% among Iranian pilgrims in 2009 [46]. As for HIC, a study involving French pilgrims in 2013 found that none of them had received an influenza vaccine before departing for Hajj, due to the unavailability of the vaccine at that time [60], while another study involving Chinese pilgrims indicated that all of them had received the vaccine in the years 2013 and 2015 [45]. The uptake rates of the pneumococcal vaccine in LMIC varied between 1% and 4% among Hajj pilgrims during the year 2013 [38,39]. Regarding HIC, a study conducted among French pilgrims between 2014 and 2018 revealed that 31% of them received the vaccine before embarking on their Hajj journey [62]; in contrast, a separate study conducted on French pilgrims in 2013 reported that 51% of them had received the vaccine [60].
Epidemiological patterns of proven viral airborne infections seemed to show higher attack rates of viral infections among HIC pilgrims than among LMIC pilgrims. Human rhinoviruses were the most prevalent viral agent among pilgrims in both groups, followed by influenza and human coronaviruses, including SARS-CoV-2. On the other hand, the attack rate of confirmed bacterial airborne infections varied more widely across the groups. For instance, pilgrims from LMIC tended to have higher rates of meningococcal and Staphylococcus aureus infections, whereas pilgrims from HIC seemed to have higher rates of other bacterial infections such as M. tuberculosis, Streptococcus pneumoniae, Klebsiella pneumoniae, and Haemophilus influenza infections (see Table 3 for detailed comparative results).
In terms of quality assessment of the included studies, most LMIC and HIC studies were average in quality, as defined by a NOS score of total stars of between three and five; however, four LMIC studies [37][38][39]54] and nine HIC studies [31,33,34,56,[60][61][62]65,67] received a good quality rating of between six and nine stars (Table 4).

Discussion
This systematised review presented the epidemiological patterns of airborne infections acquired during Hajj among pilgrims from LMIC and HIC. The qualitatively synthesised data showed that pilgrims from both resource-rich and resource-poor settings are at risk of acquiring airborne diseases during Hajj, but some infections are more common in LMIC or HIC than others, and vice versa. Hajj is an overcrowded event, and the proximity of participants, along with environmental conditions, amplifies the risk of transmitting respiratory pathogens, thus contributing to outbreaks of airborne infections [2]. Previously published systematic reviews also reported the occurrence of airborne/respiratory infections to be common among pilgrims. For instance, in a review of studies published prior to February 2018 reporting the prevalence of symptomatic respiratory infections among Hajj pilgrims, Benkouiten et al. found that influenza-like illness (ILI) ranged from 8% to 78% and pneumonia from 0.2% to 55% [9]. Safarpour et al. demonstrated in a meta-analysis that all serotypes of influenza viruses were identified among pilgrims, with estimated prevalence rates of 3.6%, 2.9%, and 0.9% for influenza types A, B, and C, respectively [10].
This systematised review uniquely shows wide variations in the burden of airborne infections between LMIC and HIC pilgrims. Despite the fact that Hajj pilgrims hail from resource-rich salubrious countries and therefore have better compliance with, and awareness about, the preventive measures, and access to more advanced public health services, the microbiological data paradoxically show that they may be at a higher (or at least at an equal) risk of developing viral infections compared to those from LMIC. On the other hand, the attack rates of bacterial infections demonstrated a more varied pattern. Pilgrims from LMIC seemed to have higher rates of certain bacterial infections, such as meningococcal infection, as was found among 82% of pilgrims with suspected infection at the time of an outbreak during the 1987 Hajj season [19], whereas some other bacterial infections were more prevalent among HIC pilgrims, for instance, M. tuberculosis infection, as was recorded among 38% of Singaporean Hajj pilgrims after the year 2002 pilgrimage [64].
This wide range of yielded rates may have been attributed to disparities in study settings, sample types, pilgrims' pre-existing immunity including previous infection, and diagnostic methods used. A number of other factors may have also contributed to these differences. For instance, pilgrims participating in Hajj either from developed or developing countries share equally the same rituals as instructed by Islam; there is no discrimination between pilgrims based on their gender, income, or ethnicity, so HIC pilgrims were not actually at an advantage compared to their LMIC counterparts. Furthermore, differences in hygiene practices, living conditions, and sociodemographic factors may have influenced the transmission dynamics of such infections among pilgrims. Due to disparities in healthcare expenses, infrastructure, and resources, including diagnostic capacity, there could be variations in diagnostic yields for infectious pathogens between HIC and LMIC. For instance, HIC may employ more sophisticated and expensive diagnostic protocols, leading to more accurate and comprehensive data, while LMIC may rely on less-advanced diagnostic methods, potentially resulting in variations in the reported incidence of infections.
Although vaccination against influenza is strongly encouraged as part of pre-Hajj health preparations for all pilgrims, the results showed a wide variability in vaccination uptake, likely due to differences in seasonal vaccine availability and vaccination policies across countries. This was clearly noticed among pilgrims from France during the 2013 Hajj season, where none of them managed to receive an influenza vaccine before departing for Hajj, because they needed to set out on Hajj before the seasonal vaccine was available in their jurisdictions [60]. The Scientific Committee for Influenza and Pneumococcal Vaccination guidelines as part of the Saudi Thoracic Society recommends the following for Hajj pilgrims: all persons of ≥50 years are recommended to receive a combined vaccination with a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a 13-valent pneumococcal conjugate vaccine (PCV13) before Hajj (for those planning immediately before Hajj, at least one dose of PPSV23), immunocompetent persons of <50 years with risk factors are recommended to receive a single dose of PPSV23 at least 3 weeks before Hajj, and it is not recommended that the vaccine be routinely provided to healthy persons aged <50 years [71]. However, the uptake of a pneumococcal vaccine is suboptimal among the general population of KSA and other Gulf countries. For example, only 6% of Saudi adults have received the vaccination amidst the COVID-19 pandemic [72]. It is common for HIC to implement a policy that suggests or provides pneumococcal vaccination for elderly individuals and those with pre-existing medical conditions [73]; consequently, a significant number of pilgrims from these countries would likely have received the pneumococcal vaccine [5].
These findings emphasise the need for targeted interventions, such as enhanced pre-Hajj vaccination and awareness programs for all pilgrims, regardless of their income status. Non-pharmaceutical interventions (e.g., facemasks, hand hygiene, cough etiquette, and physical distancing) have been used to prevent airborne infections at Hajj, but these interventions are underutilised, or at least the evidence of their effectiveness among Hajj pilgrims is inconclusive or unproven. For instance, a large-scale randomised controlled trial (RCT) among pilgrims found that the efficacy of using a facemask against viral respiratory infections was inconclusive [31]. Similarly, a recent pilot RCT conducted during the COVID-19 pandemic among Umrah participants (the abbreviated pilgrimage that Muslims can take year-round) failed to yield conclusive evidence regarding the protective effects of hand hygiene [74].
As the host country of this MG event, KSA has demonstrated notable success in safeguarding the well-being and safety of participants in the modern era through advance planning, comprehensive healthcare plans, preventive strategies, and risk-based infection control measures to contain the health risks associated with this pilgrimage [75]. The significant contribution of KSA in preventing and controlling the dissemination of emerging infectious diseases in recent Hajj seasons has been lauded worldwide and proven by some of the studies included in this review. The low prevalence of pandemic infections like COVID-19 and influenza A (H1N1)pdm09, and the absence of MERS-CoV at Hajj are testament to this.
A key limitation of this review is limiting the search strategy to only English language articles, but because most original Hajj-related manuscripts are generally published in English, the possibility of missing any important publication is very remote. An additional limitation was the clinical heterogeneity of the included studies, meaning that a metaanalysis was not feasible. Also, the way the results were presented in the included papers precluded us from carrying out any quantitative synthesis. We presented the results as lower and upper ranges of proportions and rates. We have called this a 'systematised review' because not all standard steps of a 'systematic review' could be followed; for instance, this review was not registered in PROSPERO, although it utilised a rigorous and comprehensive study design, including adherence to the PRISMA statement and the use of the NOS quality assessment tool. Furthermore, databases other than PubMed were not searched because from our experience most good-quality Hajj-related manuscripts are indexed in PubMed. There could be some manuscripts that are published in non-PubMed-indexed journals. Finally, we could not focus on other parallel information about the identified pathogens including their genetic characteristics, virulence, or drug resistance. Despite these limitations, this study significantly contributed by shedding light on the epidemiological patterns of airborne infections among attendees of MG events, which hold substantial implications for policymakers in host countries and offer valuable information that can inform decision-making processes. Given the recent announcement by the World Health Organization (WHO) that COVID-19 no longer constitutes a public health emergency of international concern, coupled with the anticipated increase in the number of Hajj participants in 2023 [76,77], it becomes important to direct future studies to provide a head-to-head comparison of the epidemiological patterns of Hajj-acquired airborne infections among pilgrims from LMIC and HIC using similar (if not identical) study settings.

Conclusions
This review comprehensively assessed the burden and epidemiological patterns of airborne infections among Hajj pilgrims from LMIC and HIC. The findings showed that pilgrims from both regions are at risk of acquiring airborne diseases during Hajj. More Hajj pilgrims from HIC seemed to develop viral respiratory infections compared to those from LMIC; however, such a difference did not seem to exist for bacterial respiratory infections. The findings highlight the need for improved vaccination coverage and effective infection control measures to prevent the spread of airborne infections during the Hajj pilgrimage and ensure the safety and well-being of all pilgrims, irrespective of their socioeconomic status or country of origin.