Samir Benkouiten

Jaffar A Al-Tawfiq

Ziad A Memish

Ali Albarrak

MD Philippe Gautret
email: philippe.gautret@club-internet.fr

Clinical respiratory infections and pneumonia during the Hajj pilgrimage: A systematic review

Keywords: Hajj, Pneumonia, Pneumococcal, Respiratory Tract Infections, Syndromic Surveillance

BACKGROUND:

The Islamic Hajj pilgrimage to Mecca is one of the world's largest annual mass gatherings. Inevitable overcrowding during the pilgrims' stay greatly increases the risk of acquiring and spreading infectious diseases, especially respiratory diseases.

METHOD:

The MEDLINE/PubMed and Scopus databases were searched for all relevant papers published prior to February 2018 that evaluated the prevalence of clinical symptoms of respiratory infections, including pneumonia, among Hajj pilgrims, as well as their influenza and pneumococcal vaccination status.

RESULTS: A total of 61 papers were included in the review. Both cohort-and hospital-based studies provide complementary data, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during the Hajj. Respiratory symptoms have been common among Hajj pilgrims over the last 15 years. In cohorts of pilgrims, cough ranged from 1.9% to 91.5%. However, the prevalence rates of the most common symptoms (cough, sore throat, and subjective fever) of influenza-like illness (ILI) varied widely across the included studies. These studies have shown variable results, with overall rates of ILI ranging from 8% to 78.2%. These differences might result from differences in study design, study period, and rates of vaccination against seasonal influenza that ranged from 1.1% to 100% among study participants. Moreover, the definition of ILI was inconsistent across studies. In hospitalized Hajj pilgrims, the prevalence of pneumonia, that remains a major concern in critically ill patients, ranged from 0.2% to 54.8%.

CONCLUSIONS: Large multinational follow-up studies are recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. Matched cohorts ensure better comparability across studies. However, study design and data collection procedures should be standardized to facilitate reporting and to achieve comparability between studies. Furthermore, the definition of ILI, and of most common symptoms used to define respiratory infections (e.g., upper respiratory tract infection), need to be precisely defined and consistently used. Future studies need to address potential effect of influenza and pneumococcal vaccine in the context of the Hajj pilgrimage.

Introduction

The yearly "Hajj" (also known as the pilgrimage to Mecca) in the Kingdom of Saudi Arabia (KSA) is the "Fifth Pillar of Islam" and is mandatory once in a lifetime for all adult Muslim who are physically and financially able. The Hajj is one of the world's largest annual mass gatherings. In 2016, around 1.3 million foreign visitors, from more than 180 countries, gathered in the KSA to complete the Hajj, in addition to over 500,000 domestic Hajj pilgrims [START_REF]The General Authority for Statistics in the Kingdom of Saudi Arabia[END_REF]. Also, about 5-6 million pilgrims perform the "Umrah" (also known as the lesser pilgrimage) each year.

The Hajj and its rituals are physically demanding for Hajj pilgrims, the majority of whom are elderly [2], with chronic conditions. Although the Hajj rituals only take one week, pilgrims usually stay in the KSA for several weeks throughout the month-long Hajj season, presenting a major public health and infection control concern, and a challenge both for the Saudi authorities, as well as for the national authorities of the countries of origin of the pilgrims. In addition to physical exhaustion, sleep deprivation [START_REF] Gatrad | Hajj: journey of a lifetime[END_REF], and heat stress [4], inevitable overcrowding, both in housing and ritual sites, especially in Mina encampment (this is approximately a 3-kilometer square area where pilgrims are accommodated in air-conditioned semi-permanent tents, some with up to 50-100 people) and inside the Sacred Mosque in Mecca (with up to six pilgrims per square meter) [START_REF] Alnabulsi | Social identification moderates the effect of crowd density on safety at the Hajj[END_REF], greatly increases the risk of acquiring and spreading infectious diseases [START_REF] Memish | Hajj: infectious disease surveillance and control[END_REF][START_REF] Abubakar | Global perspectives for prevention of infectious diseases associated with mass gatherings[END_REF][START_REF] Ahmed | Health risks at the Hajj[END_REF], especially respiratory diseases [START_REF] Al-Tawfiq | Respiratory tract infections during the annual Hajj: potential risks and mitigation strategies[END_REF][START_REF] Alzeer | Respiratory tract infection during Hajj[END_REF]. To minimize the spread of infections during the pilgrimage or in the pilgrims' home countries upon their return, vaccination and non-pharmaceutical interventions are thus recommended by national and international public health agencies [START_REF] Algarni | Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj) -2015[END_REF][START_REF]Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj), 2016[END_REF].

We carried out a systematic review of cohort and hospital studies that reported the prevalence of clinical symptoms of respiratory infections and pneumonia among pilgrims during the Hajj, and both their influenza and pneumococcal vaccination status, with the aim to provide data allowing the investigation of the impact of this large mass-gathering event on public health policies and services and to identify potential targets for preventive measures.

Search Strategy and Selection Criteria

This review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (http://www.prismastatement.org).

The MEDLINE/PubMed and Scopus databases were searched for all relevant papers published prior to February 2018, using the terms: In addition, the Saudi epidemiology bulletin (http://seb.drupalgardens.com/) was hand searched for additional papers for inclusion. Finally, the reference lists of reviewed articles were searched for additional relevant papers.

For inclusion, the article had to meet the following criteria: (1) Original study involving Hajj pilgrims; (2) detailed description of the study population, including influenza and pneumococcal vaccination status when available; (3) clinical or self-reported respiratory symptoms and diseases. Only articles published in English were included for review. We excluded cohort studies with less than 50 participants and case reports. We also excluded studies conducted among selected groups of individuals suffering from respiratory tract infections, due to lacking denominator data.

The two authors independently performed the searches, screened titles/abstracts for eligibility, selected papers that appeared to be relevant according to the review's inclusion criteria, and reviewed each of the selected manuscripts in full. The data were extracted from the included papers by one reviewer (SB) and collected in the summary table that was included in the review. The extracted data were checked by the two authors (SB and PG) for accuracy. Minor discrepancies were resolved by the authors′ discussion.

Results

Included studies

The search strategy initially yielded 391 records, of which 143 were duplicates. Twenty-nine additional papers were identified through manual searches. Of the 277 papers identified 183 records were excluded after screening the title and abstract. Of the 94 full text articles reviewed, 61 were deemed suitable for inclusion in this review according to the inclusion/exclusion criteria. The results of the search strategy are shown in Figure 1.

Cohort studies addressing the prevalence of respiratory tract infections among Hajj pilgrims

A total of 45 publications were identified. These studies were conducted among cohorts of pilgrims from the 1999 through the 2015 Hajj seasons. The results of these studies are presented in Table 1. Various study designs were used, including cross-sectional studies, casecontrol studies, and prospective cohort studies with follow-up of pilgrims, before, during and after the Hajj. Participants were from different countries and continents (Africa, North America, Asia, Europe, as well as from Australia), with the majority from Iran, and they were recruited from different settings, including travel medicine clinics, vaccination centers, Hajj travel agencies, international airports and transit zones, Mecca's city and Mina encampments.

Their numbers varied widely in these studies, ranging from 106 to 107,074.

Respiratory symptoms were common during the Hajj. Overall, the prevalence of cough ranged from 1.9% in domestic and international pilgrims in 1999 [START_REF] Fatani | Health Status of Non-organized Hajjees (Muftaresheen) during 1420H, Hajj Season[END_REF] to 91.5% in Malaysian pilgrims in 2007 [START_REF] Deris | The prevalence of acute respiratory symptoms and role of protective measures among Malaysian hajj pilgrims[END_REF][START_REF] Deris | The association between pre-morbid conditions and respiratory tract manifestations amongst Malaysian Hajj pilgrims[END_REF] (Table 3). More recent studies, conducted in different populations of pilgrims during the 2011-2014 Hajj seasons, reported prevalence of cough ranging from 46.3% to 86.8% [START_REF] Gautret | The inevitable Hajj cough: Surveillance data in French pilgrims, 2012-2014[END_REF][START_REF] Annan | High prevalence of common respiratory viruses and no evidence of Middle East respiratory syndrome coronavirus in Hajj pilgrims returning to Ghana, 2013[END_REF][START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Benkouiten | Acquisition of Streptococcus pneumoniae carriage in pilgrims during the 2012 Hajj[END_REF][START_REF] Barasheed | Pilot Randomised Controlled Trial to Test Effectiveness of Facemasks in Preventing Influenza-like Illness Transmission among Australian Hajj Pilgrims in 2011[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF][START_REF] Rahimian | Serological study of Bordetella Pertussis, Mycoplasma Pneumonia and Chlamydia Pneumonia in Iranian hajj pilgrims with prolonged cough illnesses: A follow-up study[END_REF]. These studies also reported a comparable prevalence of sore throat ranging from 34.7% to 91% among pilgrims [START_REF] Gautret | The inevitable Hajj cough: Surveillance data in French pilgrims, 2012-2014[END_REF][START_REF] Annan | High prevalence of common respiratory viruses and no evidence of Middle East respiratory syndrome coronavirus in Hajj pilgrims returning to Ghana, 2013[END_REF][START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Benkouiten | Acquisition of Streptococcus pneumoniae carriage in pilgrims during the 2012 Hajj[END_REF][START_REF] Barasheed | Pilot Randomised Controlled Trial to Test Effectiveness of Facemasks in Preventing Influenza-like Illness Transmission among Australian Hajj Pilgrims in 2011[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF].

In addition, many of these studies have investigated the epidemiology of respiratory tract infections among pilgrims by estimating the common prevalence of upper respiratory tract infection (URTI), acute respiratory infection (ARI) or influenza-like illness (ILI), which were inconsistently defined across studies by a combination of general symptoms (e.g. cough, sore throat and fever). Overall prevalence of ILI varied in these studies from 8% to 78.2% [START_REF] Deris | The prevalence of acute respiratory symptoms and role of protective measures among Malaysian hajj pilgrims[END_REF][START_REF] Deris | The association between pre-morbid conditions and respiratory tract manifestations amongst Malaysian Hajj pilgrims[END_REF][START_REF] Gautret | The inevitable Hajj cough: Surveillance data in French pilgrims, 2012-2014[END_REF][START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Benkouiten | Acquisition of Streptococcus pneumoniae carriage in pilgrims during the 2012 Hajj[END_REF][START_REF] Barasheed | Pilot Randomised Controlled Trial to Test Effectiveness of Facemasks in Preventing Influenza-like Illness Transmission among Australian Hajj Pilgrims in 2011[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF] (Table 3). In large studies conducted among Iranian pilgrims between 2003 and 2005, the prevalence of ILI was, respectively, 70.1% and 35.8% in 2003 and 2004 [START_REF] Razavi | The Comparison of Influenza Vaccine Efficacy on Respiratory Diseases among Iranian Pilgrims in the 2003 and 2004 Seasons[END_REF][START_REF] Razavi | The incidence of influenza like illness and determination of the efficacy of Flu vaccine in Iranian pilgrims during Hajj pilgrimage[END_REF], but 19.6% in 2005 [START_REF] Meysamie | Comparison of mortality and morbidity rates among Iranian pilgrims in Hajj 2004 and 2005[END_REF]. In another large 5-year (2004-2008) follow-up study conducted among 254823 Iranian pilgrims, only 10.7% of pilgrims complained of ILI during the Hajj [START_REF] Razavi | Treatment and prevention of acute respiratory infections among Iranian hajj pilgrims: a 5-year follow up study and review of the literature[END_REF][START_REF] Razavi | Trend of diseases among Iranian pilgrims during five consecutive years based on a Syndromic Surveillance System in Hajj[END_REF]. However, the ILI syndromic case definition used in the 2003-2004 study (ILI was defined as cough and fever of more than 38°C with or without the coryzal symptoms and myalgia) [START_REF] Razavi | The Comparison of Influenza Vaccine Efficacy on Respiratory Diseases among Iranian Pilgrims in the 2003 and 2004 Seasons[END_REF][START_REF] Razavi | The incidence of influenza like illness and determination of the efficacy of Flu vaccine in Iranian pilgrims during Hajj pilgrimage[END_REF] was different with that used in the 2004-2008 study (ILI was defined as symptoms and signs such as sudden headache, dry cough, high grade fever, myalgia, coryza, malaise and loss of appetite with an abnormal general appearance) [START_REF] Razavi | Treatment and prevention of acute respiratory infections among Iranian hajj pilgrims: a 5-year follow up study and review of the literature[END_REF][START_REF] Razavi | Trend of diseases among Iranian pilgrims during five consecutive years based on a Syndromic Surveillance System in Hajj[END_REF]. Also, it is unclear from the 2005 study [START_REF] Meysamie | Comparison of mortality and morbidity rates among Iranian pilgrims in Hajj 2004 and 2005[END_REF] if the definition used was consistent with those used in the two previous studies [START_REF] Razavi | The Comparison of Influenza Vaccine Efficacy on Respiratory Diseases among Iranian Pilgrims in the 2003 and 2004 Seasons[END_REF][START_REF] Razavi | The incidence of influenza like illness and determination of the efficacy of Flu vaccine in Iranian pilgrims during Hajj pilgrimage[END_REF][START_REF] Razavi | Treatment and prevention of acute respiratory infections among Iranian hajj pilgrims: a 5-year follow up study and review of the literature[END_REF][START_REF] Razavi | Trend of diseases among Iranian pilgrims during five consecutive years based on a Syndromic Surveillance System in Hajj[END_REF]. In a recent large study, conducted among 3364 Egyptian pilgrims between 2012 and 2015, the prevalence of ILI was 30.4% (ILI was defined according to the World Health Organization definition as the presence of measured fever of ≥ 38 C°, and cough; with onset within the last 10 days) [45]. Other studies of different sizes (from 129 to 468) and design were conducted from 2007 through 2014 among different populations of pilgrims using a common ILI definition (the association of cough, sore throat, and subjective fever). These studies have shown variable results, with overall rates of ILI ranging from 8% to 78.2% [START_REF] Deris | The prevalence of acute respiratory symptoms and role of protective measures among Malaysian hajj pilgrims[END_REF][START_REF] Deris | The association between pre-morbid conditions and respiratory tract manifestations amongst Malaysian Hajj pilgrims[END_REF][START_REF] Gautret | The inevitable Hajj cough: Surveillance data in French pilgrims, 2012-2014[END_REF][START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Benkouiten | Acquisition of Streptococcus pneumoniae carriage in pilgrims during the 2012 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF][START_REF] Hashim | The prevalence and preventive measures of the respiratory illness among Malaysian pilgrims in 2013 Hajj season[END_REF][26][START_REF] Gautret | Relative risk for influenza like illness in French Hajj pilgrims compared to non-Hajj attending controls during the 2009 influenza pandemic[END_REF][START_REF] Saeed | Occurrence of acute respiratory infection, diarrhea and jaundice among Afghan pilgrims, 2010[END_REF][START_REF] Gautret | Protective measures against acute respiratory symptoms in French pilgrims participating in the Hajj of 2009[END_REF]. Thus, during the 2013 Hajj season, while the highest prevalence of ILI was observed among Malaysian pilgrims, with a prevalence estimated at 78.2% [START_REF] Hashim | The prevalence and preventive measures of the respiratory illness among Malaysian pilgrims in 2013 Hajj season[END_REF], a lower prevalence was observed among French pilgrims (47.3%) [START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF].

Coverage of seasonal influenza vaccination among pilgrims was evaluated in many studies, which have yielded varying results, with reported rates of influenza vaccination ranged from 1.1% to 100% [START_REF] Deris | The prevalence of acute respiratory symptoms and role of protective measures among Malaysian hajj pilgrims[END_REF][START_REF] Deris | The association between pre-morbid conditions and respiratory tract manifestations amongst Malaysian Hajj pilgrims[END_REF][START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF][START_REF] Hashim | The prevalence and preventive measures of the respiratory illness among Malaysian pilgrims in 2013 Hajj season[END_REF]26,[START_REF] Memish | Mass gathering and globalization of respiratory pathogens during the 2013 Hajj[END_REF]29,[START_REF] Gautret | Relative risk for influenza like illness in French Hajj pilgrims compared to non-Hajj attending controls during the 2009 influenza pandemic[END_REF][START_REF] Kabbash | Patterns of diseases and preventive measures among domestic hajjis from Central, Saudi arabia [complete republication[END_REF][START_REF] Kabbash | Patterns of diseases and preventive measures among domestic hajjis from Central, Saudi Arabia[END_REF][START_REF] Balaban | Protective practices and respiratory illness among US travelers to the 2009 Hajj[END_REF][START_REF] Al-Jasser | Pattern of diseases and preventive measures among domestic Hajjis from Riyadh, 1431 H[END_REF][START_REF] Gautret | Protective measures against acute respiratory symptoms in French pilgrims participating in the Hajj of 2009[END_REF][START_REF] Razavi | The Comparison of Influenza Vaccine Efficacy on Respiratory Diseases among Iranian Pilgrims in the 2003 and 2004 Seasons[END_REF][START_REF] Razavi | The incidence of influenza like illness and determination of the efficacy of Flu vaccine in Iranian pilgrims during Hajj pilgrimage[END_REF][START_REF] Al-Mudameigh | Incidence of Hajj-related Acute Respiratory Infection among Hajjis from Riyadh, 1423 H[END_REF][START_REF] Qureshi | The incidence of vaccine preventable influenza-like illness and medication use among Pakistani pilgrims to the Haj in Saudi Arabia[END_REF][45][START_REF] Meysamie | Comparison of mortality and morbidity rates among Iranian pilgrims in Hajj 2004 and 2005[END_REF][START_REF] Razavi | Treatment and prevention of acute respiratory infections among Iranian hajj pilgrims: a 5-year follow up study and review of the literature[END_REF][START_REF] Razavi | Trend of diseases among Iranian pilgrims during five consecutive years based on a Syndromic Surveillance System in Hajj[END_REF][START_REF] Gautret | Incidence of Hajj-associated febrile cough episodes among French pilgrims: a prospective cohort study on the influence of statin use and risk factors[END_REF][START_REF] Ma | No MERS-CoV but positive influenza viruses in returning Hajj pilgrims, China, 2013-2015[END_REF][START_REF] Hasan | Effect of Influenza Vaccination on Acute Respiratory Symptoms in Malaysian Hajj Pilgrims[END_REF][START_REF] Ziyaeyan | Pandemic 2009 influenza A (H1N1) infection among 2009 Hajj Pilgrims from Southern Iran: a real-time RT-PCR-based study[END_REF][START_REF] Maslamani | Health related experiences among international pilgrims departing through King Abdul Aziz international airport, Jeddah, Saudi Arabia, Hajj 1431 H (2010)[END_REF][START_REF] Dabiran | Effects of flu vaccine, solely or accompanied by pneumovax-23 vaccine on clinical consequences of the respiratory diseases among Iranian pilgrims in Hajj[END_REF][START_REF] El Bashir | Influenza among U.K. pilgrims to hajj, 2003[END_REF]. A variation over time in influenza vaccination coverage was observed, as exemplified by a rate of 10.5% observed in a survey of pilgrims from Riyadh in 2003 [START_REF] Al-Mudameigh | Incidence of Hajj-related Acute Respiratory Infection among Hajjis from Riyadh, 1423 H[END_REF], but 94.4% in a similar survey in 2010 [START_REF] Kabbash | Patterns of diseases and preventive measures among domestic hajjis from Central, Saudi arabia [complete republication[END_REF][START_REF] Kabbash | Patterns of diseases and preventive measures among domestic hajjis from Central, Saudi Arabia[END_REF][START_REF] Al-Jasser | Pattern of diseases and preventive measures among domestic Hajjis from Riyadh, 1431 H[END_REF]. During the 2013 Hajj season, influenza vaccination rates also varied according to pilgrims' country of origin [29], with 20% observed among Saudi pilgrims, 80% among Qatari pilgrims, and 87% among Australian pilgrims, while a study involving French pilgrims interestingly reported that none of them had received the 2013 influenza vaccine before departing for the Hajj because the vaccine was not available at this time [START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF]. The majority of the studies reported influenza vaccination coverage among pilgrims, but only 13 [START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Benkouiten | Acquisition of Streptococcus pneumoniae carriage in pilgrims during the 2012 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF][START_REF] Hashim | The prevalence and preventive measures of the respiratory illness among Malaysian pilgrims in 2013 Hajj season[END_REF][START_REF] Memish | Impact of the Hajj on pneumococcal transmission[END_REF][START_REF] Memish | Mass gathering and globalization of respiratory pathogens during the 2013 Hajj[END_REF][START_REF] Gautret | Relative risk for influenza like illness in French Hajj pilgrims compared to non-Hajj attending controls during the 2009 influenza pandemic[END_REF][START_REF] Meysamie | Comparison of mortality and morbidity rates among Iranian pilgrims in Hajj 2004 and 2005[END_REF][START_REF] Razavi | Treatment and prevention of acute respiratory infections among Iranian hajj pilgrims: a 5-year follow up study and review of the literature[END_REF][START_REF] Razavi | Trend of diseases among Iranian pilgrims during five consecutive years based on a Syndromic Surveillance System in Hajj[END_REF][START_REF] Dabiran | Effects of flu vaccine, solely or accompanied by pneumovax-23 vaccine on clinical consequences of the respiratory diseases among Iranian pilgrims in Hajj[END_REF] reported their pneumococcal vaccination status, with rates ranging from 1.2% among a multinational cohort of 1676 pilgrims from 13 countries (from Africa, Asia, USA and Europe) in 2013 [START_REF] Memish | Mass gathering and globalization of respiratory pathogens during the 2013 Hajj[END_REF] to 51.2% among a small study of 129 French pilgrims in 2013 [START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF].

Hospital-based studies addressing the prevalence of respiratory tract infections among ill Hajj pilgrims

Of the 61 publications that were included in this review, 16 specifically addressed ill Hajj pilgrims at health care facilities from 1993 through 2014 Hajj seasons. Medical facilities included primary health care centers (PHCCs) and different specialized wards in tertiary care hospitals, including ear, nose and throat (ENT) departments, intensive care units, emergency units, infectious disease units and unspecified medical units. Pilgrim participants were included either as inpatients or outpatients. The results of these studies are summarized in Table 2.

Overall, the prevalence of upper respiratory tract infections (URTI) ranged from 1.4% to 42.1% (Table 3). This prevalence was 1.4% among 141 Pakistani pilgrims who attended the King Abdul Aziz hospital in Medina during the 1992 Hajj [START_REF] Yousuf | Medical problems of Pakistani pilgrims in Saudi Arabia[END_REF] and 42.1% among 3087 Saudi and non-Saudi patients (47.5% of them were pilgrims) who attended the ENT clinic at Al-Noor Specialist Hospital in Mecca during the 2009 Hajj [START_REF] Alherabi | Impact of pH1N1 influenza A infections on the Otolaryngology, Head and Neck Clinic during Hajj, 2009[END_REF]. Pharyngitis was also frequently reported among ill pilgrims. Thus, in this study of 3087 pilgrims during the 2009 Hajj, the overall prevalence of pharyngitis was 45.7% [START_REF] Alherabi | Impact of pH1N1 influenza A infections on the Otolaryngology, Head and Neck Clinic during Hajj, 2009[END_REF]. More recently, in 2008, the prevalence of pharyngitis in a large cohort of 4136 outpatients patients from 82 nationalities who attended 13 randomly selected Mina PHCCs (94.9% of whom were pilgrims) was found to be 23.7% [START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF][START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF], and 61% in a study of 1047 Saudi and non-Saudi patients (2.3% of them were inpatients) [START_REF] Alherabi | Road map of an Ear, Nose, and Throat clinic during the 2008 Hajj in Makkah, Saudi Arabia[END_REF]. However, in this second study of 1047 patients, only 34.5% were pilgrims.

On the contrary, lower prevalence rates of bronchitis were reported during the Hajj (1.4%-9.6%) [START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF][START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF][START_REF] Alherabi | Road map of an Ear, Nose, and Throat clinic during the 2008 Hajj in Makkah, Saudi Arabia[END_REF][START_REF] Madani | Causes of hospitalization of pilgrims in the Hajj season of the Islamic year 1423 (2003)[END_REF][START_REF] Ma | Pattern of surgical and medical diseases among pilgrims attending Al-noor hospital makkah[END_REF]. A recent retrospective cross-sectional multicenter study of 185 Turkish inpatients (87.5% were pilgrims) who returned to Turkey from the Arabian Peninsula countries between 2012 and 2014 reported a slightly higher prevalence of acute tracheobronchitis (13.6%) [START_REF] Erdem | Infections in travellers returning to Turkey from the Arabian peninsula: a retrospective cross-sectional multicenter study[END_REF]. In addition, in this study, pneumonia was among the most common clinical diagnosis among the hospitalized Hajj patients and represented about half of diagnoses [START_REF] Erdem | Infections in travellers returning to Turkey from the Arabian peninsula: a retrospective cross-sectional multicenter study[END_REF]. As pneumonia remains a major concern in critically ill patients, most of them reported the prevalence of pneumonia among pilgrims [START_REF] Yousuf | Medical problems of Pakistani pilgrims in Saudi Arabia[END_REF][START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF][START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF][START_REF] Madani | Causes of hospitalization of pilgrims in the Hajj season of the Islamic year 1423 (2003)[END_REF][START_REF] Ma | Pattern of surgical and medical diseases among pilgrims attending Al-noor hospital makkah[END_REF][START_REF] Erdem | Infections in travellers returning to Turkey from the Arabian peninsula: a retrospective cross-sectional multicenter study[END_REF][START_REF] Mandourah | Clinical and temporal patterns of severe pneumonia causing critical illness during Hajj[END_REF][START_REF] Baharoon | Severe sepsis and septic shock at the Hajj: etiologies and outcomes[END_REF][START_REF] Al-Quwaidhi | Pattern of diseases among visitors of health care facilities in Madinah during Hajj season, 1428 H (2007 G)[END_REF][START_REF] Madani | Causes of admission to intensive care units in the Hajj period of the Islamic year 1424 (2004)[END_REF][START_REF] Khan | Pattern of medical diseases and determinants of prognosis of hospitalization during 2005 Muslim pilgrimage Hajj in a tertiary care hospital. A prospective cohort study[END_REF][70][START_REF] Yousuf | Pattern of medical problems among Haj pilgrims admitted to King Abdul Aziz Hospital, Madinah Al-Munawarah[END_REF], with reported rates ranging from 0.2% in 2008 in 13 randomly selected Mina primary health care centers [START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF][START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF] to 54.8% in 2004 in two ICU in Mecca [START_REF] Madani | Causes of admission to intensive care units in the Hajj period of the Islamic year 1424 (2004)[END_REF] (Table 3). The prevalence of pneumonia was not reported in 3 papers [START_REF] Alherabi | Impact of pH1N1 influenza A infections on the Otolaryngology, Head and Neck Clinic during Hajj, 2009[END_REF][START_REF] Alherabi | Road map of an Ear, Nose, and Throat clinic during the 2008 Hajj in Makkah, Saudi Arabia[END_REF][START_REF] Khamis | Epidemiological pattern of diseases and risk behaviors of pilgrims attending mina hospitals, hajj 1427 h (2007 g)[END_REF]. Pneumonia was the second most common admitting diagnosis (22%) in a study of 140 patients admitted to the ICUs in four hospitals in Mina during the 2004 Hajj [START_REF] Madani | Causes of admission to intensive care units in the Hajj period of the Islamic year 1424 (2004)[END_REF]. This result is further confirmed by a recent study of 452 critically ill Hajj patients, of over 40 nationalities, admitted to 15 hospitals in 2009 and 2010. In this study, pneumonia was defined as the primary cause of critical illness (27.2%) of all ICUs admissions during the Hajj [START_REF] Mandourah | Clinical and temporal patterns of severe pneumonia causing critical illness during Hajj[END_REF]. Also, in another prospective study of pilgrims admitted in two major ICUs in Mecca for the 2004 Hajj season, community acquired pneumonia (CAP) was the commonest source of sepsis, 54.8% [START_REF] Baharoon | Severe sepsis and septic shock at the Hajj: etiologies and outcomes[END_REF].

Discussion

The purpose of this review was to provide syndromic surveillance data that may be useful, in conjunction with microbiological data that will be presented in further papers, for the surveillance of respiratory infections and pneumonia during the Hajj. Despite the fact that some of the included studies in our review were performed among small numbers of pilgrims and cannot be extrapolated, it is clear from this work that respiratory symptoms have been common among Hajj pilgrims over the last 15 years, as evidenced by the high prevalence of cough (over 90%) among Malaysian pilgrims during the 2007 Hajj [START_REF] Deris | Preference of treatment facilities among Malaysian Hajj pilgrims for acute respiratory symptoms[END_REF]. Cough is a common symptom among pilgrims [START_REF] Gautret | The inevitable Hajj cough: Surveillance data in French pilgrims, 2012-2014[END_REF][START_REF] Shafi | Hajj: health lessons for mass gatherings[END_REF] and likely results from crowded conditions during the Hajj. This close contact among such individuals may increase the risk of the transmission of respiratory pathogens, and therefore may contribute to respiratory disease outbreaks. Climatic conditions and air pollution in Mecca and surrounding holy sites during the Hajj [START_REF] Simpson | Air quality in Mecca and surrounding holy places in Saudi Arabia during Hajj: initial survey[END_REF] may also play a role. Recent follow-up studies thus evidenced a significant acquisition of respiratory viruses, particularly rhinovirus, influenza virus, and coronaviruses other than Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and of bacteria, including Streptococcus pneumonia, Hemophilus influenza, Staphylococcus aureus and Klesiella pneumonia by Hajj pilgrims upon their return from the Hajj [START_REF] Gautret | Hajj-associated viral respiratory infections: A systematic review[END_REF][START_REF] Gautret | Circulation of respiratory pathogens at mass gatherings, with special focus on the Hajj pilgrimage[END_REF]. Respiratory diseases are the most common diseases observed among pilgrims attending Mina primary health care centers [START_REF] Alzahrani | Pattern of diseases among visitors to Mina health centers during the Hajj season, 1429 H (2008 G)[END_REF] and a major cause of hospital admission during the Hajj [70], with pneumonia a leading cause of admission to intensive care units [START_REF] Madani | Causes of hospitalization of pilgrims in the Hajj season of the Islamic year 1423 (2003)[END_REF][START_REF] Madani | Causes of admission to intensive care units in the Hajj period of the Islamic year 1424 (2004)[END_REF], where they are responsible for about half of the cases of sepsis [START_REF] Baharoon | Severe sepsis and septic shock at the Hajj: etiologies and outcomes[END_REF]. Unfortunately, while numerous articles on Hajj pilgrims were retrieved from our literature search, relatively few recent articles specifically addressed ill pilgrims in the context of hospital settings. The use of cohort studies allows investigators to evaluate the actual incidence of clinical events in Hajj pilgrims since it provides a denominator, but may not identify and capture the prevalence of some underlying conditions and of severe forms of respiratory tract infections, which are more likely to be evidenced in hospital patient populations. Conversely, hospital studies use data that may be biased, frequently lacking denominator values, and so probably overestimating the occurrence of severe illness. Moreover, a hospital-based study will, by definition, not capture some minor illness cases that do not require hospitalization.

The prevalence rates of cough, sore throat and subjective fever varied widely across the included studies. These differences may result from differences in study design that may lead to potential biases (for example bias related to the method of data collection, using either selfreport questionnaires or telephone interview), study period (with regards to the seasonality of respiratory viral infections), and rates of vaccination against seasonal influenza among study participants which may widely vary from one study to another, as described in this review.

Thus, all data regarding the pilgrims, including demographic data, medical history, clinical data and information on vaccination status and compliance with non-pharmaceutical preventive measures, should be carefully collected by using standardized questionnaires. In addition, in the context of syndromic surveillance for respiratory pathogens, data regarding the pilgrim's symptoms should be collected prospectively during face-to-face interviews by trained medical investigators who travel with the pilgrims. One important result of this review is the finding of a lack of consistency ILI syndromic case definitions across included studies.

Thus, in a 2003 study (that did not fulfill the inclusion criteria for this review) [START_REF] Mustafa | A case-control study of influenza vaccine effectiveness among Malaysian pilgrims attending the Haj in Saudi Arabia[END_REF], of 1310 Malaysian pilgrims who had a clinic visit for upper respiratory tract symptoms at five clinics during the 2000 Hajj, with the aim of determining influenza vaccine effectiveness against clinically defined ILI, 63% had ILI (defined as sore throat in combination with either temperature ≥38°C or cough) and 14% had influenza by the CDC definition (defined as measured fever [≥100°F (37.8°C)] and a cough and/or a sore throat). Only one of the studies reported here used the CDC definition of ILI or the WHO definition (an acute respiratory infection with measured fever of ≥38 C° and cough, with onset within the last 10 days) [45].

In his paper, Rashid et al. demonstrated the low sensitivity of the CDC criteria and proposed therefore the use of the triad of 'cough, sore throat and subjective fever' to clinically define ILI at the Hajj or other mass gatherings, since this new simple clinical case definition is more specific and sensitive than the CDC definition [START_REF] Rashid | Influenza and the Hajj: defining influenza-like illness clinically[END_REF]. This definition was used over the last years by French [START_REF] Gautret | The inevitable Hajj cough: Surveillance data in French pilgrims, 2012-2014[END_REF][START_REF] Benkouiten | Respiratory viruses and bacteria among pilgrims during the 2013 Hajj[END_REF][START_REF] Benkouiten | Acquisition of Streptococcus pneumoniae carriage in pilgrims during the 2012 Hajj[END_REF][START_REF] Gautret | Lack of MERS coronavirus but prevalence of influenza virus in French pilgrims after 2013 Hajj[END_REF][22][START_REF] Gautret | Lack of nasal carriage of novel corona virus (HCoV-EMC) in French Hajj pilgrims returning from the Hajj 2012, despite a high rate of respiratory symptoms[END_REF][START_REF] Gautret | Relative risk for influenza like illness in French Hajj pilgrims compared to non-Hajj attending controls during the 2009 influenza pandemic[END_REF][START_REF] Gautret | Protective measures against acute respiratory symptoms in French pilgrims participating in the Hajj of 2009[END_REF], Malaysian [START_REF] Deris | The prevalence of acute respiratory symptoms and role of protective measures among Malaysian hajj pilgrims[END_REF][START_REF] Deris | The association between pre-morbid conditions and respiratory tract manifestations amongst Malaysian Hajj pilgrims[END_REF][START_REF] Hashim | The prevalence and preventive measures of the respiratory illness among Malaysian pilgrims in 2013 Hajj season[END_REF], Indian [26] and Afghan [START_REF] Saeed | Occurrence of acute respiratory infection, diarrhea and jaundice among Afghan pilgrims, 2010[END_REF] investigators leading cohort studies among Hajj pilgrims, thus allowing more reliable comparisons of findings between studies (Table 1).

Respiratory diseases are a major concern during the Hajj. Non-pharmaceutical interventions (e.g., hand hygiene, wearing face masks, social distancing) are known to reduce the spread of respiratory viruses from person to person and are therefore recommended to pilgrims by public health agencies. Although hand hygiene compliance is high among pilgrims, face mask use and social distancing remain difficult challenges. Data about the effectiveness of these measures for preventing acute respiratory infections at the Hajj are limited, and results are contradictory, highlighting the need for future large-scale studies [START_REF] Benkouiten | Non-pharmaceutical interventions for the prevention of respiratory tract infections during Hajj pilgrimage[END_REF].

In addition to non-pharmaceutical interventions, vaccination against influenza is

recommended for all Hajj pilgrims by the Ministry of Health of Saudi Arabia [START_REF] Algarni | Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj) -2015[END_REF][START_REF]Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj), 2016[END_REF]. Differences in study design and heterogeneity in the ILI definition across studies make it difficult to compare findings from different studies and inhibits the drawing of conclusions regarding the potential effects of this vaccination on related clinical symptoms of influenza disease. However, recent papers by Alqahtani et al. and Alfelali et al. found the influenza vaccine to be effective, respectively, against both laboratory-confirmed influenza [START_REF] Alqahtani | Vaccinations against respiratory tract infections at Hajj[END_REF] and clinical influenza [START_REF] Alfelali | Changes in the prevalence of influenza-like illness and influenza vaccine uptake among Hajj pilgrims: A 10-year retrospective analysis of data[END_REF]. As influenza vaccination is generally considered effective in reducing influenza-related infections, the Scientific Committee for Influenza and Pneumococcal Vaccination guidelines (SCIPV) thus recommends, in its recent guidelines, an influenza vaccination for all people, especially those at high risk, at least 2 weeks before the Hajj [START_REF] Zeitouni | The Saudi Thoracic Society guidelines for influenza vaccinations[END_REF].

It also recommends, for the next Hajj seasons that will take place from June to September, the administration (prior to the Hajj) of the Southern Hemisphere influenza vaccine for pilgrims from the Southern Hemisphere (where influenza positivity rates are higher during this period).

Furthermore, as the influenza vaccine is not expected to be available for pilgrims from the Northern Hemisphere before these next Hajj seasons, the SCIPV also recommends the administration of the Southern Hemisphere influenza vaccine for those pilgrims from the opposite hemisphere before the Hajj [START_REF] Zeitouni | The Saudi Thoracic Society guidelines for influenza vaccinations[END_REF]. Because of the mismatching between circulating and vaccine strains that has frequently occurred since 2003 [START_REF] Alfelali | Mismatching between circulating strains and vaccine strains of influenza: Effect on Hajj pilgrims from both hemispheres[END_REF], Alfelali et al. recommends, when the composition of influenza vaccines differs and whenever logistically feasible, taking into consideration the dual vaccination of Hajj pilgrims with both the Southern and Northern Hemispheres' vaccines. However, such strategy is impaired by the frequent unavailability of the Southern Hemisphere influenza vaccine in the Northern Hemisphere. The issue of influenza vaccine availability to match Southern and Northern hemispheres was discussed by the Saudi Ministry of Health in consultation with the WHO and it was recommended to use the available hemisphere strain as long as there is a match in circulating strains [START_REF] Al-Tawfiq | Expected immunizations and health protection for Hajj and Umrah 2018 -An overview[END_REF]. Despite the risk of acquisition of S. pneumoniae during the Hajj, there is currently no consistent guideline on the use of pneumococcal vaccine for Hajj pilgrims across pilgrim countries of origin [START_REF] Al-Tawfiq | Prevention of pneumococcal infections during mass gathering[END_REF][START_REF] Ridda | Pneumococcal infections at Hajj: current knowledge gaps[END_REF]. Thus, and because many of the Hajj pilgrims are elderly and have chronic illnesses and underlying risk conditions for which pneumococcal vaccination is recommended [START_REF] Al-Tawfiq | Prevention of pneumococcal infections during mass gathering[END_REF], the SCIPV also recommended, in its 2016 pneumococcal vaccination guidelines, pneumococcal vaccination of the at-risk population at the appropriate time before the Hajj, using the 2 types of pneumococcal vaccines that are currently available: the 23-valent polysaccharide pneumococcal vaccine (PPSV23) and the 13-valent conjugate vaccine (PCV13) [START_REF] Alharbi | The Saudi Thoracic Society pneumococcal vaccination guidelines-2016[END_REF]. However, it did not recommend providing a pneumococcal vaccine routinely to healthy persons aged less than 50 years, because of lack of evidence. In addition, it has been well demonstrated that the conjugate vaccine against S. pneumoniae targets the most virulent serotypes associated with Invasive Pneumococcal Diseases (IPD) that are also associated with antibiotic resistance [START_REF] Leangapichart | Emergence of drug resistant bacteria at the Hajj: A systematic review[END_REF]. These arguments reinforce the need for compliance with current recommendations for vaccinating at-risk Hajj pilgrims against IPD and influenza [START_REF] Leangapichart | Emergence of drug resistant bacteria at the Hajj: A systematic review[END_REF].

Respiratory tract infections, including influenza, continue to be a major concern during the Hajj. Both cohort-and hospital-based studies provide complementary data and potentially useful information, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during this mass gathering. Large multinational follow-up studies are thus recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. Matched cohorts ensure better comparability across studies, particularly in terms of origin of pilgrims and possible travelling conditions. However, the study design and data collection procedures should be standardized, to facilitate reporting and to achieve comparability between studies. Furthermore, the definition of ILI, and of most common symptoms used to define respiratory infections (e.g., URTI), needs to be precisely defined and consistently used. Future studies need to address the potential effects of influenza and pneumococcal vaccine in the context of the Hajj pilgrimage. Moreover, because of the mismatching between circulating and vaccine strains that has frequently occurred since 2003 [START_REF] Alfelali | Mismatching between circulating strains and vaccine strains of influenza: Effect on Hajj pilgrims from both hemispheres[END_REF], Alfelali et al. recommends, when the composition of influenza vaccines differs and whenever logistically feasible, taking into consideration the dual vaccination of Hajj pilgrims with both the southern and northern hemispheres' vaccines. However, such strategy is impaired by the frequent unavailability of the southern hemisphere influenza vaccine in the northern hemisphere. Despite the risk of acquisition of S. pneumoniae during the Hajj, there is currently no consistent guideline on the use of pneumococcal vaccine for Hajj pilgrims across pilgrim countries of origin [START_REF] Al-Tawfiq | Prevention of pneumococcal infections during mass gathering[END_REF][START_REF] Ridda | Pneumococcal infections at Hajj: current knowledge gaps[END_REF]. Thus, and because many of the Hajj pilgrims are elderly and have chronic illnesses and underlying risk conditions for which pneumococcal vaccination is recommended [START_REF] Al-Tawfiq | Prevention of pneumococcal infections during mass gathering[END_REF], the SCIPV also recommended, in its 2016 pneumococcal vaccination guidelines, pneumococcal vaccination of the at-risk population at the appropriate time before the Hajj, using the 2 types of pneumococcal vaccines that are currently available: the 23-valent polysaccharide pneumococcal vaccine (PPSV23) and the 13-valent conjugate vaccine (PCV13) [START_REF] Alharbi | The Saudi Thoracic Society pneumococcal vaccination guidelines-2016[END_REF]. Also, it did not recommend providing a pneumococcal vaccine routinely to healthy persons aged less than 50 years, because of lack of evidence.

Respiratory tract infections, including influenza, continue to be a major concern during the Hajj. Both cohort-and hospital-based studies provide complementary data and potentially useful information, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during this mass gathering. Large multinational follow-up studies are thus recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. Matched cohorts ensure better comparability across studies, particularly in terms of origin of pilgrims and possible travelling conditions. However, the study design and data collection procedures should be standardized, to facilitate reporting and to achieve comparability between studies. Furthermore, the definition of ILI, and of most common symptoms used to define respiratory infections (e.g., URTI), needs to be precisely defined and consistently used. Future studies need to address the potential effects of influenza and pneumococcal vaccine in the context of the Hajj pilgrimage.

[44]

1 ILI was defined according to the presence measured fever of ≥ 38 C°, and cough; with onset within the last 10 days.

2 Influenza-like illness (ILI) was defined according to the presence of the triad of cough, subjective fever and sore throat.

3 ILI was defined as subjective (or proven) fever plus one respiratory symptom (e.g. dry or productive cough, runny nose, sore throat, shortness of breath).

4

ILI was defined as subjective (or proven) fever and at least one respiratory symptom such as cough, sore throat and rhinorrhea.

5

ILI was defined as symptoms and signs such as: sudden headache, dry cough, high grade fever, myalgia, coryza, malaise and loss of appetite with an abnormal general appearance.

6

Upper respiratory tract infections (URTI) was defined as any person who reported having developed at least one of the constitutional symptoms (fever, headache, myalgia) and one of the local symptoms (running nose, sneezing, throat pain, cough with /or without sputum) after reaching Mecca for the Hajj or within 2 weeks from return to Riyadh.

7

Acute febrile respiratory infection (AFRI) was defined as the presence of subjective fever plus at least one respiratory symptom (cough, sore throat, runny nose or breathlessness).

8

Two travelers who reported ''bronchitis'' as a symptom were also included.

9

ILI was defined as fever plus sore throat and/or coughing.

10

Common cold was defined as sore throat with coryzal symptoms, and low grade fever.

11 ILI was defined as fever >38.5°C, myalgia, low back pain, coryzal symptoms and cough.

12 Acute respiratory infection (ARI) was defined as one of the constitutional symptoms (fever, headache, myalgia) along with one of the local symptoms (running nose, sneezing, throat pain, cough with/without sputum, difficulty breathing).

13 ARI was defined as any person suffering from at least one of the constitutional symptoms (fever, headache, myalgia) along with one of the local symptoms (runny nose, sneezing, throat pain, cough with/without Sputum, difficulty in breathing) developing after reaching Makkah for the Hajj.

14 ILI was defined as cough and fever >38°C with or without the coryzal symptoms and myalgia.

15 ARI was defined as any person suffering from at least one of the constitutional symptoms (fever, headache, myalgia) along with one of the local symptoms (runny nose, sneezing, throat pain, cough with/without Sputum, difficulty in breathing) developing after reaching Mecca for the Hajj.

16

ILI was defined as sore throat with either temperature ≥38.8°C or cough.

# 1 :

 1 Hajj OR hadj OR pilgrim OR pilgrims OR pilgrimage #2: Respiratory #3: Infection OR infections #4: ILI OR URTI OR URTIs OR URI OR URIs OR LRTI OR LRTIs OR LRI OR LRIs #5: Pneumonia OR Streptococcus pneumoniae OR pneumococcus OR pneumococcal #6: #1 AND ((#2 AND #3) OR (#4) OR (#5))

17

 17

  Cough or sore throat or rhinorrhea or muscle ache or headache.

Table 2 .

 2 Studies conducted among ill Hajj pilgrims at health care facilities

	Hajj	Study population	Recrutement	Proportion of ill patients with	Proportion of ill	Study	Ref.
	season			respiratory symptoms globally	patients with
				(%)	pneumonia (%)
	2012-	185 Turkish patients (87.5%	15 referral Turkish centers with	URTI 1 : 33.1%	50.3%	Erdem et al.,	[64]
	2014	were pilgrims) returning to	infectious diseases departments	Acute tracheobronchitis 2 : 13.6%		2016 (Eur J Clin
		Turkey from the Arabian	(inpatients)	Acute exacerbation of COPD 3 :		Microbiol Infect
		Peninsula countries		8.9%		Dis)
	2008	4136 patients (94.9% were	13 randomly selected Mina	Common cold: 20.6%	0.2%	Alzahrani et al.,	[59, 60]
		pilgrims) from 82 nationalities	primary health care centers	Pharyngitis: 23.7%		2012 (J Infect
			(outpatients)	Bronchitis: 9.6%		Public Health)
				Tonsillitis: 4.2%		Alzahrani et al.,
						2009 (Saudi
						Epidemiology
						Bulletin)
	2009-	452 pilgrims from over 40	Intensive care unit of 15	Not specified	27.2%	Mandourah et al.,	[65]
	2010	nationalities	hospitals in Mecca, Mina,			2012 (BMC Infect
			Arafat, and Medina (inpatients)			Dis)
	2009	3087 Saudi and non-Saudi	Ear, nose, and throat clinic at Al-	Pharyngitis: 45.7%	Not specified	Alherabi et al.,	[58]

Table 3 .

 3 Prevalence of cough, influenza-like illness, upper respiratory tract infection and pneumonia reported in the included studies

	Symptoms

Was not defined.

Acknowledgments

None.

Funding

None.

Conflicts of interest

The authors have no conflicts of interest to declare.


Robert Winkler

Stéphane Pellet-Rostaing

Guilhem Arrachart
email: guilhem.arrachart@cea.fr

Tailored structuring of functionalized silsesquioxanes in an one-step approach

The silica hybrid materials prepared from tailor-made precursors with different headgroups in several experimental conditions (acid or base catalysis in water or THF) were studied in order to identify the structure directing mechanisms. By infrared spectroscopy and small-angle X-ray scattering and thermogravimetric analysis, it was found that the molecular interactions such as Coulomb interactions, vdW forces, hydrogen bonds and sterical factors that are strongly influenced by the experimental conditions, orient the main structural features. Secondarily, the chemically directed connectivity of the growing Si-O-Si network nuances the final structure. Finally, on heating to 130 °C, lamellar structures remained stable whereas the deformation of hexagonal and cubic stuctures shows metastability. The results can be regarded as an interaction tool box for "all-in-one" material chemists.

Introduction

Inorganic-organic hybrid materials advantageously combine the properties of modulable organic moieties and robust inorganic matrices. [START_REF] Soler-Illia | Multifunctional Hybrids by Combining Ordered Mesoporous Materials and Macromolecular Building Blocks[END_REF] To successfully tailor physical and chemical properties of the material, the efficient incorporation of the required organic moiety and the controlled formation of the inorganic matrix are crucial. To this end, the sol-gel process of silica materials has become a considerable tool due to the, often, mild reaction conditions and convenient reaction kinetics. Adapting the nature of the precursor and the reaction conditions (solvent, temperature, catalyst...) the synthesis of a wide variety of silica hybrid materials (SHMs) is possible. Classically, it is done in a two-or multi-step procedure. In most cases, first, the inorganic matrix is created by applying the principles of soft matter structuring to control porosity and wall properties. In a second step, the structure directing template molecule is removed by thermal or chemical treatment or washing. Finally, the organic function is introduced by post-functionalization. Although well-studied and, thus, effective, this approach has several disadvantages. The synthesis of the inorganic matrix is associated to a large production of waste like the template surfactant and the washing solutions. This includes the thermic cost of template removal by combustion. Despite the fact that these disadvantages might be outsourced by buying a commercially available product, for example, SBA-15, their negative impact persists and the client loses the access to a tailor-made product. Moreover, during the post-grafting step, several problems can occur such as the pore clogging due to the limited accessibility of molecules to the pore wall surface [START_REF] Lim | Comparative Studies of Grafting and Direct Syntheses of Inorganic-Organic Hybrid Mesoporous Materials[END_REF][START_REF] Calvo | Chemical Reactivity of Amino-Functionalized Mesoporous Silica Thin Films Obtained by Co-Condensation and Post-Grafting Routes[END_REF][START_REF] Rébiscoul | Impact of Silica Surface Nanoconfinement on the Microstructure of Alkoxysilane Layers Grafted by Supercritical Carbon Dioxide[END_REF] , the inhomogeneity of the grafting [START_REF] Rébiscoul | Impact of Silica Surface Nanoconfinement on the Microstructure of Alkoxysilane Layers Grafted by Supercritical Carbon Dioxide[END_REF][START_REF] Brunel | Preferential Grafting of Alkoxysilane Coupling Agents on the Hydrophobic Portion of the Surface of Micelle-Templated Silica[END_REF] and a wall-facing functional group orientation [START_REF] Yokoi | Synthesis of Amino-Functionalized MCM-41 via Direct Co-Condensation and Post-Synthesis Grafting Methods Using Mono-, Di-and Tri-Amino-OrganoalkoxysilanesElectronic Supplementary Information (ESI) Available: XRD Patterns of (A) x-DNN-MCM-41 and (B) x-DNNN[END_REF] . An alternative approach for the synthesis of tailor-made SHMs is a unimolecular "all-in-one" approach. It consists in combining the required components -silica precursor, template molecule, organic moiety -into one single precursor molecule -the organosilane precursor -that forms the desired material under the right reaction conditions. Ultimately, this approach has the potential to eliminate all of the mentioned disadvantages of the classical multistep approach. No sacrificial template molecule is used that needs subsequent removal. The structuring is piloted by the interactions between the precursors that are conditioned by the reaction parameters. The porosity of such a material will not be clogged in a postfunctionalization step since the organic moiety is already incorporated. Hence, inhomogeneous grafting and wall-facing groups are avoided. In the last decade, this concept was explored to form a variety of original bridged silsesquioxanes [START_REF] Besnard | Self-Assembly of Condensable "Bola-Amphiphiles" in Water/Tetraethoxysilane Mixtures for the Elaboration of Mesostructured Hybrid Materials[END_REF][START_REF] Besnard | Tuning the Nanostructure of Highly Functionalized Silica Using Amphiphilic Organosilanes: Curvature Agent Effects[END_REF][START_REF] Besnard | Ion Extraction Applications of Bilayer-Structured Hybrid Silicas[END_REF][START_REF] Besnard | Structural Study of Hybrid Silica Bilayers from "Bola-Amphiphile" Organosilane Precursors: Catalytic and Thermal Effects[END_REF][START_REF] Besnard | Tuning the Morphology of Functionalized Silica Using Amphiphilic Organosilanes[END_REF][START_REF] Alauzun | Synthesis of New Lamellar Materials by Self-Assembly and Coordination Chemistry in the Solids[END_REF][START_REF] Alauzun | Reversible Covalent Chemistry of CO2: An Opportunity for Nano-Structured Hybrid Organic-Inorganic Materials[END_REF][START_REF] Alauzun | An Original Synthesis of Highly Ordered Organosilica with a High Content of Thiol Groups[END_REF][START_REF] Voss | Synthesis and Characterization of Highly Amine Functionalized Mesoporous Organosilicas by an "All-in-One" Approach[END_REF][START_REF] Moreau | New Approach for the Organisation and the Shaping of Organo-Bridged Silicas: An Overview[END_REF][START_REF] Moreau | Nanostructuring Organo-Silicas: Combination of Intermolecular Interactions and Molecular Recognition Properties to Generate Self-Assembled Hybrids with Phenylene or Adenine⋯thymine Bridging Units[END_REF] by playing with several parameters of which the interactions such as π-stacking, hydrophobic interactions or hydrogen bonding. Following the same unimolecular all-in-one approach, the aim of this study is to work towards the generalization of the effects of different reaction parameters on the resulting material structure. To this end, several home-made organosilane precursors [START_REF] Winkler | Efficient and Multi-Function Compatible Click-Reaction of Organosilanes[END_REF] (see Figure 1) with amine or alkyl groups and functional groups effective at rare earth extraction [START_REF] Ogata | Immobilization of Diglycol Amic Acid on Silica Gel for Selective Recovery of Rare Earth Elements[END_REF][START_REF] Ogata | Adsorption Mechanism of Rare Earth Elements by Adsorbents with Diglycolamic Acid Ligands[END_REF] were polymerized under different reaction conditions and, then, thermally treated (see Figure 2). The reactions to form the silsesquioxanes were carried out in aqueous solution or in tetrahydrofuran (THF) under acidic or basic catalysis. More information is provided in the ESI or in literature. [START_REF] Ogata | Adsorption Mechanism of Rare Earth Elements by Adsorbents with Diglycolamic Acid Ligands[END_REF] Using thermogravimetric analysis (TGA), infrared spectroscopy (FT-IR) and small angle X-ray scattering (SAXS), three different factors driving the properties of the sol and the final materials were considered: (i) the silica condensation mechanism of the inorganic part of the precursors as a function of pH and the solvent; (ii) the organic functional group of the precursors and their steric and electronic properties and (iii) the interactions between the organosilanes driven by the functional group, the pH and the solvent.

Results and Discussion

This section is separated into three parts that thoroughly investigate the material structure in a hierarchical manner. Beginning with the composition and the molecular structure, going to the supramolecular organization, this section ends with the morphology at the mesoscale. Afterwards, the results are discussed along the lines of the three mentioned factors in order to propose the material formation mechanisms.

Composition and molecular structure

The material composition was investigated using FT-IR and TGA. Figure shows the FT-IR spectra of the resulting materials before (black) and after thermal treatment (coloured). Some data was already published in another context. [START_REF] Winkler | Selective Extraction of REEs Thanks to One-Pot Silica Hybrid Materials[END_REF] In all spectra, characteristic peaks of the present SHMs are found (ν1-ν6). They are common to all materials such as the C-H stretching mode of the triazole moiety (~3130 cm -1 , ν1), the asymmetric (~2920 cm -1 , ν2) and symmetric (~2850 cm -1 , ν3) CH2 stretching modes, the C=C stretching mode of the triazole moiety (~1460 cm -1 , ν4) that is split for P3 due to conjugation with C=O (ν4a, ν4b), the Si-CH2-stretching mode (~1210 cm -1 , ν5), and the various Si-OH stretching modes (~1020-930 cm -1 , ν6). [START_REF] Al-Oweini | Synthesis and Characterization by FTIR Spectroscopy of Silica Aerogels Prepared Using Several Si(OR)4 and R′′Si(OR′)3 Precursors[END_REF][START_REF] Arkles | Silicon Compounds: Silanes & Silicones[END_REF][START_REF] Murugavel | Crystal Structure Analysis, Spectral Investigations (NMR, FT-IR, UV), DFT Calculations, ADMET Studies, Molecular Docking and Anticancer Activity of 2-(1-Benzyl-5-Methyl-1H-1,2,3-Triazol-4-Yl)-4-(2-Chlorophenyl)-6-Methoxypyridine -A Novel Poten[END_REF] These peaks confirm the retention of the Si-C bond and the triazole moiety. For P3-TB/-Δ, the broad peaks between 3400 and 2400 cm -1 around the C=O mode, and at 1400 cm -1 reveal the formation NH4Cl due to an unintended addition HCl to the sol that was not properly removed. In the following, the results data for this material are, nonetheless, presented but not discussed. After the thermal treatment, an expected attenuation (sometimes even disappearance) of the Si-OH peaks is observed. andd). The grey insets highlight the regions were the characteristic signals for ladder or cage-like supramolecular structures are found. Some of the data was already published in a different context. [START_REF] Ogata | Adsorption Mechanism of Rare Earth Elements by Adsorbents with Diglycolamic Acid Ligands[END_REF] This process indicates the advancing condensation of the Si-O-Si network. Consistently, the intensity of the peaks in the region between 1200 and 1000 cm -1 that are assigned to the Si-O-Si stretching modes increases. Furthermore, some precursor specific peaks are observed corresponding to the N-H bending mode of the primary amine of P1 (~1660 cm -1 , δ1) and the C=O stretching modes for P3, P4 and P5 in the region comprised between 1800 and 1600 cm -1 . For the latter, the different carbonyl functions are identified. P3 materials show a single peak that is assigned to the methyl ester and for P4 the large peak is composed of the 3° and 2° amide. No change is observed after thermal treatment. For P5 the situation is more complex. A zoom on the region (see Figure S1 ESI) reveals three different peaks. The ester peak at ~1740 cm -1 shows an intensity decrease after the thermal treatment. The other two peaks are both attributed to the 2° amide. The reason for this splitting may be the formation of hydrogen bonds that typically lead to a red-shift. For the fresh material, this leads to a shifted peak at 1650 cm -1 It is probably overlapped by the bending mode of residual water. After thermal treatment, this peaks intensity strongly decreases for the benefit of the free 2° amide peak (1690 cm -1 ). The region between 3600 and 2800 cm -1 contains the merged peaks of several X-H (X = H-O, N, Si-O) bonds. For all materials, the intensity of this region decreases after the thermal treatment due to the evaporation of residual water and the condensation of free Si-OH bonds. In this region, a peak of low intensity residual intensity is observed in the cases of P1, P4 and P5 due to the N-H bonds. It should be noted that for the acid catalysed fresh materials from P1 (P1-HA, P1-TA) a particular peak between 3000 and 2800 cm -1 is observed. This peak disappears after the washing with a basic solution. The simultaneous absence of δ1 indicates the formation of a primary ammonium group. Another particular feature is the sharpness of the broad peak for the fresh P5 materials at 3280 cm -1 that indicates water hydrogen bonding. [START_REF] Athokpam | Effect of Hydrogen Bonding on the Infrared Absorption Intensity of OH Stretch Vibrations[END_REF][START_REF] Philippe | An FTIR/ATR in Situ Study of Sorption and Transport in Corrosion Protective Organic Coatings: 1. Water Sorption and the Role of Inhibitor Anions[END_REF][START_REF] Crupi | Vibrational Properties of Water Molecules Adsorbed in Different Zeolitic Frameworks[END_REF] This supports the presence of hydrogen bonding in the fresh materials P5-HB and P5-TB between residual water and the 2° amide.

TGA results in Figure were used to assess the Si-O-Si network condensation and to calculate the molecular weight of the final material. For all materials, the weight loss occurs in consecutive but indistinguishable steps beginning around 200 to 300 °C which is characteristic for the decomposition of the triazole group. [START_REF] Katritzky | Benzotriazole Is Thermally More Stable than 1,2,3-Triazole[END_REF] The absence of weight loss at lower temperatures which would be typical for water evaporation or Si-OH condensation, confirms the effective network consolidation. After 600 °C, the residual mass remains constant indicating the complete decomposition of the organic part. FT-IR investigations after the measurement (see Figure S2 ESI) show that the material heated to 1000 °C is ssentially SiO2. [START_REF] Murugavel | Crystal Structure Analysis, Spectral Investigations (NMR, FT-IR, UV), DFT Calculations, ADMET Studies, Molecular Docking and Anticancer Activity of 2-(1-Benzyl-5-Methyl-1H-1,2,3-Triazol-4-Yl)-4-(2-Chlorophenyl)-6-Methoxypyridine -A Novel Poten[END_REF] Exploiting the molar equivalence of silicon in the residual and the thermally treated material using (1)

𝑀 𝑇𝐺𝐴 = 100 * 𝑀 𝑆𝑖𝑂 2 𝑤 700°𝐶 = 316 ± 20 𝑔 𝑚𝑜𝑙 -1 (1)
where MTGA is the molecular weight of the material as determined by TGA, MSiO2 the molecular weight of silica (60.09 g mol -1 ) and w700°C the residual mass percentage at 700 °C, the molecular weight was calculated. The results are shown in Table 1. For all materials, the calculated molecular weights are in good agreement with the theoretical data. A small tendency towards overestimation is noticed which might be due to incomplete condensation of the Si-OH groups.

Concluding the first part, the molecular structure of the synthesized silsesquioxanes was confirmed for all obtained materials by the identification of all relevant peaks in the FT-IR spectra. Concerning the composition, an incomplete condensation is observed for the fresh materials by the presence of the Si-OH peak. After thermal treatment, the attenuation of this peak indicates the Si-O-Si network condensation. Moreover, the molecular weights obtained by TGA confirm this observation. Finally, some particularities are observed in the FT-IR spectra that are discussed in a later context.

Supramolecular organization

FT-IR data (see Figure ) were used to determine the arrangement of the monomers inside the silsesquioxanes as described in literature. [START_REF] Wong | Pressure Effects on the Infrared Spectrum of 1,2-dipalmitoyl Phosphatidylcholine Bilayers in Water[END_REF][START_REF] Vaia | Interlayer Structure and Molecular Environment of Alkylammonium Layered Silicates[END_REF][START_REF] Bantignies | Insights into the Self-Directed Structuring of Hybrid Organic -Inorganic Silicas through Infrared Studies[END_REF][START_REF] Singh | Variable Temperature FT-IR Studies of n-Alkyl Modified Silica Gels[END_REF] First, the position of the asymmetric CH2 stretching mode (ν2) and the intensity ratio of the asymmetric to the symmetric mode 𝑅 𝑎𝑙𝑘𝑦𝑙 = 𝐼(𝜈 2 ) 𝐼(𝜈 3 ) ⁄ gives information on the alkyl chain conformation. Second, the two broad peaks between 1200 and 1000 cm -1 give information on the geometry of the Si-O-Si bridges that relates to the overall structure of the inorganic phase. In silsesquioxanes, they are typically assigned to cage-like motifs (PC, ~1110 cm -1 ) and open chain or ladder-like motifs (PL, ~1020 cm -1 ). [START_REF] Bantignies | Insights into the Self-Directed Structuring of Hybrid Organic -Inorganic Silicas through Infrared Studies[END_REF][START_REF] Orel | Hydrolysis and Solvolysis of Methyltriethoxysilane Catalyzed with HCl or Trifluoroacetic Acid: IR Spectroscopic and Surface Energy Studies[END_REF] Their ratio 𝑅 𝑆𝑖𝑂𝑆𝑖 = 𝐼(𝑃 𝐶 ) 𝐼(𝑃 𝐿 ) ⁄ indicates the predominant motif. The values for the materials prepared from P3 need to be taken with care and those for P4 and P5 were not calculated because of the overlay with carbonyl related peaks. The obtained values are shown in Table 2. Table 1. Residual masses and the corresponding molecular weights of the obtained materials after thermal treatment as determined by TGA. The last column shows the calculated theoretical molecular weight of the completely condensed precursor.

All materials show an extended all-trans configuration of the alkyl chains (Pos(ν2) ≈ 2920 cm -1 , 1.2<Ralkyl<1.4) except one. For P4-HB-Δ the ratio is superior indicating a (partially) collapsed alkyl chain.

Concerning the Si-O-Si geometry, the tendencies vary between the precursors. For the materials synthesized from P1, the synthesis in THF yields higher shares of cage-like motifs than synthesis in aqueous conditions. In both cases base catalysis yields the highest share of cage-like motifs. For P2, synthesis in THF leads to overall higher shares of ladder-like motifs without a clear distinction of acid or base catalysis. Under aqueous conditions, the share of cage-like motifs is higher, especially with base catalysis. For P3-HA-Δ, P3-HB-Δ and P3-TA-Δ, a dominance of ladder-like structures is observed. The share of cage-like motifs is slightly higher for P3-TB-Δ.

Major influences on the ratio of cage-to ladder-like motifs are the precursor and the water concentration and the pH during the sol-gel process. [START_REF] Lee | Higher Yielding Synthetic Route towards Dodecaphenyl Cage Silsesquioxanes: Synthesis and Mechanistic Insights[END_REF][START_REF] Lee | Hydrolysis Kinetics of a Sol-Gel Equilibrium Yielding Ladder-like Polysilsesquioxanes[END_REF][START_REF] Issa | Kinetics of Alkoxysilanes and Organoalkoxysilanes Polymerization: A Review[END_REF] Under basic conditions, coherent with the known strong ramification, a tendency to cage-like motifs is observed. The degree depends on the solvent and the precursor. For P2, the influence of precursor solubility and water concentration are coherent with literature. The higher solubility of the hydrophobic precursor in THF than in water and the lower water concentration in THF lead to a higher share of ladder-like motifs. For the precursors P3 and P1 the difference is less obvious because of the more complicated molecular structure. Precursor-specific effects arise from the interactions between the functional groups and the solvent. This is complicated further by the protonation and the bola-amphiphilic character in some cases. A more thorough discussion is given ulteriorly.

Mesoscale structuring

Lastly, the morphology at the mesoscale is characterized. To this end, SAXS as performed. The results are shown in Figure .

For all materials, at q < 1 nm -1 , a slope proportional to q -α where α is comprised between 3 and 4 is observed. This indicates solid materials varying between smooth (α = 4) and rough (α = 3) surfaces. At higher q, several Bragg peaks can be observed, that allow the assignment of different mesophases. For the materials synthesized from P1, the assignment is possible for the materials P1-HB/-Δ and P1-TA/-Δ. The equidistant positions of the Bragg peaks (qX00) indicate a lamellar structure. After the thermal treatment, the Bragg peaks shift to higher q and a repeat unit length of 3.6 nm is found that corresponds to two extended precursor molecules. [START_REF] Besnard | Structural Study of Hybrid Silica Bilayers from "Bola-Amphiphile" Organosilane Precursors: Catalytic and Thermal Effects[END_REF] The shift indicates a material contraction and is more distinct for the materials synthesized under basic conditions. A possible explanation is the release of CO2 due to the thermal decomposition of carbamates that are formed in situ, as reported in an earlier study. [START_REF] Besnard | Structural Study of Hybrid Silica Bilayers from "Bola-Amphiphile" Organosilane Precursors: Catalytic and Thermal Effects[END_REF] For P1-TA-Δ the repeat unit length is confirmed by TEM (see Figure S3 a and b) ESI). For the other materials, a structure assignment is ambiguous. For P1-TB/-Δ the presence of two peak no structure can be identified which is confirmed by TEM (see Figure S3 c) ESI). For P1-HA/-Δ, a lamellar structure is suspected but the peak width and the absence of higher order peaks impedes a conclusion. For all P2-materials, the Bragg peaks allow the assignment of a lamellar structure. The increasing peak sharpness and the visibility of higher order peaks indicate increasing lamellar characteristics in the order P2-TA ≈ P2-TB < P2-HB << P2-HA. For these materials, a peak attenuation for even-order peaks is observed that is due to a particularity in the scattering length density (SLD) distribution. [START_REF] Dourdain | Caractérisation Structurale Poreuse Mécanique de Films Minces de Silice Mésoporeuse[END_REF][START_REF] Skoulios | Organisation et Problèmes Structuraux de Copolymères Séquencés[END_REF] After thermal treatment, some peak smoothing is observed and a loss of long-range can be concluded. An exception is the material P1-HB where the intensity of peak q100 increases. This is explained by the high share of cagelike motifs. Indeed, these motifs act as defects in the lamellar structure. Upon further condensation during the thermal treatment, their SLD increases and thus the peak intensity. In the other materials, less cage-like motifs are observed by FT-IR rendering the effect invisible. For the materials synthesized from P3, the larger repertory of structures is found. Thanks to the presence of high-order Bragg peaks a lamellar structure for P3-HA, a D-bicontinous mesophase in a cubic lattice for P3-HB [START_REF] Hyde | Identification of Lyotropic Liquid Crystalline Mesophases[END_REF] , and a 2D hexagonal structuring are concluded. After thermal treatment, P3-HA-Δ shows a contraction to a repeat unit length of 4 nm that corresponds to two extended precursor molecules. At the same time, some peak smoothing is observed that indicates the loss of long-range order. For the other materials, a significant loss of order is observed that is categorized as amorphization. For P4-HB/-Δ, a single large peak at ~4 nm -1 is observed. The absence of further peaks indicates an amorphous structure. For the materials prepared from P5, the interpretation of the scattering patterns is not straightforward due to the complexity of the SLD profile. For P5-HB/-Δ, the Bragg peaks noted qH1 to qH5 are at positions that are characteristic of a 2D hexagonal structure. The first peak at q ≈ 1 nm -1 (6-7 nm real space) is hard to distinguish due to its position on the slope. After the thermal treatment, the broadening peaks indicate increasing disorder. Finally, for P5-TB/-Δ, a qualitative fit was done in order to interpret the patterns (see Figure 6). This simple fit simulates a lamellar structure of condense d precursor double layers. It does not claim a remodelling of the exact structure but serves as a guide to identify at least the second order peak (q200) and its position using reasonable SLDs and SLD changes.

The peak shift indicates a dilation of the lamellar structure from 6 to 6.7 nm after the thermal treatment. Knowing from FT-IR that the alkyl chains are in an extended configuration, this corresponds to a change from intercalated to end-to-end arrangement of the lamellae. On a final note, it is mentioned that, both, P5-HB and P5-TB show several Bragg peaks in the WAXS region (q > 10 nm -1 ) of the pattern (see Figure S4 ESI). They are more pronounced for P5-TB but disappear for both materials after the thermal treatment.

Discussion

Regarding the obtained results, several SHM formation mechanisms are proposed taking the factors introduced earlier into account. They are (i) the silica condensation mechanism depending on pH and solvent, (ii) the organic functional group and its steric and electronic properties, and (iii) the interactions between the precursors driven by their molecular structure, the pH and the solvent. An overview of the results is shown in Figure 7.

In the case of P1, the share of ladder-or cage-like motifs is mostly directed by the silica condensation mechanism. Whatever the solvent, base catalysis leads to a higher share of cage-like motifs than acid catalysis. Intermolecular coulomb interactions could come into play in a mesoscale structuredetermining mechanism: The lamellar character of the materials is most pronounced for P1-TA/-Δ and P1-HB where the latter and the subsequent amorphization is largely explained by a mechanism described in literature. [START_REF] Besnard | Structural Study of Hybrid Silica Bilayers from "Bola-Amphiphile" Organosilane Precursors: Catalytic and Thermal Effects[END_REF] For P1-TA/-Δ, the proposed mechanism is organised by the charge-forming protonation of the amine group. Indeed, the acid induced protonation creates a charged ammonium headgroup that, in THF, tends to form counter-ion pairs. A hydrated, hydrophilic pseudophase is thus created with several of the precursor molecules. The, thereby, induced local proximity of the silanol groups gives place to lamellae after condensation as displayed in Figure 8. This effect is less structuring in aqueous solution where a less organized structure is observed.

For P2, the silica condensation mechanism leads to more ladder-like structures under acidic conditions compared to basic conditions. Otherwise, the only potentially strong interactions are vdW forces between the precursors in solution. They have stronger effects in water than in THF. A combination of both factors allows the explanation of the lamellar characteristics in the order P2-TA ≈ P2-TB < P2-HB << P2-HA. The solvent nature divides the less structured (THF) from the more structured (water) lamellar morphologies by the effect of vdW forces. The silica condensation mechanism, then, separates depending on the catalysis conditions.

In THF this effect is insignificant. In water, however, this leads to different shares of of ladder-and cage like motifs. Under acidic conditions, P2 assembles in an extended ladder-like fashion, which finally favours the formation of lamellae. This is illustrated in Figure 9. The materials prepared from P3 show less impact of the catalysis conditions on the share of ladderor cage-like motifs. The effects of vdW forces between and the steric hindrance of the precursors show a stronger impact. Like observed for P2, in aqueous solution, the vdW forces of the rather hydrophobic P3 lead to highly structured morphologies. In the SAXS patterns, this is highlighted by the sharp peaks of the materials before thermal treatment.

The observed D-cubic bicontinous and hexagonal phases (see Figure 10) are induced by the branched methyl ester head group that is rigid due to its conjugation with the triazole group. During self-assembly, this steric hindrance, in analogy to surfactant-based soft matter structures, leads to structures with a mean curvature κ < 0. This is energetically favourable. [START_REF] Evans | The Colloidal Domain[END_REF] It is important to note that, for bicontinous phases, the average curvature remains close to zero. This explains the possibility a lamellar phase with the same precursor under different conditions. After the thermal treatment, only the lamellar structure, however contracted, remains observable. The curved structures are severely deformed due to the condensation of the free silanol groups.

Lastly, for the diglycolic acid derivatives (P5), hydrogen bonding is suspected to be responsible for the observed mesophases. As discussed for the scattering patterns (see Figure 5), a headgroup intercalation occurs that disappears together with the residual water after the thermal treatment. A clear link can be established using the peak shift and the hydrogen bonding evidence in the FT-IR spectra. Indeed, it can be supposed that the formation of hydrogen bonds involving residual water and the carbonyl functions is the driving force for the intercalation.

The Bragg peaks observed in the WAXS patterns support the existence of such an ordered phase. Mechanistically, the different mesophases may be caused by the persistence of hydrogen bonds in organic solvents up to high dilution in the form of agglomerates. In THF, these agglomerates would be formed by the intercalating headgroups and the limited quantity of water (r ≈ 40) that probably would be energetically favoured in that configuration. Due to the geometric constraints, the silanols, then, polymerizes to form a lamellar structure (see Figure 11). In water, a large excess of hydrogen bond donors is present and, thus, the headgroup hydration is assured. This can lead to an apparent increase of the packing parameter [START_REF] Besnard | Tuning the Nanostructure of Highly Functionalized Silica Using Amphiphilic Organosilanes: Curvature Agent Effects[END_REF] and, consequently, a 2D hexagonal phase. After freeze drying, the hydrogen bonds persist thanks to residual water. Once this required residue is evaporated, the intercalation disappears as well. For P4, this mechanism, a priori, would be possible but is not observed. This might be due to the steric demand of the diethyl amide group.

Conclusion

The present work gives, for the first time, a comprehensive overview of the complex interplay between the factors that come into play during the all-in-one synthesis of SHMs. This includes strong interactions such as Coulomb interactions, vdW forces and hydrogen bonds, and steric hinderance direct the structuring that can be inherent, like the steric demand (P3), or caused by the reaction conditions, protonation of P1 or the H-bonding for P5. Secondarily, the chemically directed connectivity of the growing Si-O-Si network nuances the obtained structure. Observations are e.g. the varying lamellar character for P2 or the structure change for P3. The factors act simultaneously and are responsible for the resulting morphology. Generally, non-lamellar structures (hexagonal, cubic) are possible in a metastable state. After the thermal treatment, the advancing condensation leads to their deformation. For further studies, a generalisation of the identified interactions can be envisaged by exploring the effects of precursor chain length or branched headgroups. Another level of complexity is possible by introducing a second silane group.

Figure 1 .

 1 Figure 1. Organosilane precursor molecules used in the present work.

Figure 2 .

 2 Figure 2. Overview of the silsesquioxane precursors, the experimental conditions used to prepare the SHMs with their references where X is 1, 2, 3, 4 or 5 depending on the precursor.

Figure 3 .

 3 Figure 3. FT-IR spectra of the obtained materials before (PX-YY) and after thermal treatment (PX-YY-Δ). The left-hand side (a) and c)) show the materials prepared from aqueous solution while the right-hand side (b) and d)) shows the materials prepared in THF. Catalysis was acidic for the materials shown in a) and b) and basic for the materials shown in c)and d). The grey insets highlight the regions were the characteristic signals for ladder or cage-like supramolecular structures are found. Some of the data was already published in a different context.[START_REF] Ogata | Adsorption Mechanism of Rare Earth Elements by Adsorbents with Diglycolamic Acid Ligands[END_REF]

Figure 4 .

 4 Figure 4. TGA weight loss curves for the obtained materials after thermal treatment sorted by precursor. The dashed line highlights the final residual mass.

Figure 5 .

 5 Figure 5. SAXS patterns of the obtained materials before (PX-YY) and after thermal treatment (PX-YY-Δ). The left-hand side (a) and c)) show the materials prepared from aqueous solution while the right-hand side (b) and d)) shows the materials prepared in THF. Catalysis was acidic for the materials shown in a) and b) and basic for the materials shown in c) and d). The highlighted q values show Bragg-peaks that indicate the mesostructure as discussed in the text. The colour of these highlights indicates their assignment to the untreated (black) or the thermally treated samples (coloured).

Figure 6 .

 6 Figure 6. Scheme of the modelled evolution of material P5-TB upon thermal treatment. The centre figure is calculated using the fit parameters that produced the fits in Figure c).

Figure 7 .

 7 Figure 7. An overview of the discussed material morphologies and the required conditions to synthesize them.

Figure 8 .

 8 Figure 8. Schematic representation of the structural organization determined for the material P1-TA/-Δ.

Figure 9 .

 9 Figure 9. Schematic representation of the structural organization determined for the material P2-HA/-Δ.

Figure 10 .

 10 Figure 10. Schematic representation of the structural organization determined for the materials a) P3-HB and b) P3-TA.

Figure 11 .

 11 Figure 11. Schematic representation of the structural organization determined for the material P5-TB.

Table 2 .

 2 Data of the FT-IR analyses concerning the supramolecular organisation. The columns list the position of the asymmetric CH2 stretching mode, the ratio Ralkyl and the ratio RSiOSi.

Winkler, R.; Pellet-Rostaing, S.; Arrachart, G. Selective Extraction of REEs Thanks to One-Pot Silica Hybrid Materials. Appl. Sci.

2020, 10 (21), 7558.

Acknowledgements

The authors thank Cyrielle Rey and Bruno Corso for technical support with TGA and SAXS analysis, and Diane Rébiscoul, for fruitful discussions.

Conflicts of interest

"There are no conflicts to declare".

Electronic Supplementary Information for

Tailored structuring of functionalized silsesquioxanes in an one-step approach Robert Table S1. Fit parameters for the qualitative fit P5-TB/-Δ.

Material synthesis

The silica hybrid material (SHM) synthesis was adapted from literature. [START_REF] Soler-Illia | Multifunctional Hybrids by Combining Ordered Mesoporous Materials and Macromolecular Building Blocks[END_REF] In a typical synthesis, 1.5 mmoles of organosilane precursor PX were added to 50 mL of water and the pH was adjusted to basic (NH4OH, pH 9) or acidic (HCl, pH 1.5) conditions. After stirring for two weeks in a sealed flask, the obtained precipitate was dried by freeze drying and washed with 60 mL (3x20 mL) EtOH/water (1/1) followed by 60 mL (3x20 mL) of EtOH and analysed. Afterwards, the materials were heated to 130 °C for 24 h to promote the condensation and washed in the same order to remove possible degradation products. Table S1. Fit parameters for the qualitative fit P5-TB/-Δ.