The Enterics for Global Health (EFGH) Shigella Surveillance Study in Pakistan

Abstract

Background

The Enterics for Global Health (EFGH) Shigella surveillance study is a longitudinal multicountry study that aims to estimate incidence rates and document consequences of Shigella diarrhea within 7 countries in Africa, Asia, and Latin America. In addition to a high incidence of childhood diarrhea, Pakistan is facing a problem of antimicrobial resistance in urban and peri-urban areas of Karachi.

Methods

In Pakistan, EFGH will be conducted in Karachi, which is one of the metropolitan cities bordering the Arabian Sea and has a diverse population of 1.6 million according to the 2017 population census. The study aims to enroll 1400 children aged 6–35 months over 2 years (2022–2024) from 6 health care facilities (Abbasi Shaheed Hospital, Khidmat-e-Alam Medical Centre, Sindh Government Hospital Korangi 5, Sindh Government Hospital Ibrahim Hyderi, Ali Akbar Shah VPT Center, and Bhains Colony VPT Center) situated in Nazimabad and Bin-Qasim town. Moreover, population enumeration and health care utilization surveys from a defined catchment area of health facilities will be conducted to estimate the Shigella diarrhea incidence rates.

Conclusions

The study will provide critical data to policy-makers about the burden of Shigella and antimicrobial resistance, which is essential for planning Shigella vaccine trials.

This paper describes the country profile, terrain, health indicators, healthcare seeking and management of diarrheal disease. Pakistan is one of the consortium members in EFGH study and has high burden of childhood diarrheal diseases.

PAKISTAN COUNTRY PROFILE

Pakistan is a developing country that falls into the low- to medium-resource category according to World Bank income classification [1]. According to the 2017 national census, the population of the country is 207 million, with a population growth rate of 2.40; it is the fifth most populous country in the world [2]. The country is situated in the South Asia region, bordering India on the east, Iran and Afghanistan on the west, and China in the north. It is administratively divided into 4 provinces (Baluchistan, Khyber Pakhtunkhwa, Punjab, and Sindh) and a federally administered capital territory. The southern provinces of the country, including Sindh and Baluchistan, border the Arabian Sea, which is an important geographical feature of the country [3]. The climate of the country varies according to the topography and generally is dry and hot along the coastal lines and southern parts, compared with the northern parts, which remain cold [4]. The average daytime temperature is 35°C in the lower terrain during the hotter months of May to July, followed by the monsoon season during July to September [4, 5]. The country is vulnerable to climate change and has faced disastrous events such as heatwaves, droughts, and floods that have resulted in a significant number of mortalities, economic losses, and infrastructure damage [6].

The country has a poor health system infrastructure, with a gross domestic product (GDP) allocation that was <1% in 2008 and has been consistently low over the years [7]. The government provides health care through a 3-tiered health care delivery system that includes primary, secondary, and tertiary levels, along with other vertical programs such as immunization, maternal and child health, and infectious and communicable diseases. Health care delivery to the end user is systemized through preventive and promotional services provided at basic and rural health centers and strengthened through an outreach service by lady health visitors (LHVs), lady health workers (LHWs), and community midwives (CMWs). The secondary level covers referrals, acute care, and ambulatory care through district headquarters hospitals. The tertiary care includes teaching hospitals that are responsible for providing curative and rehabilitative services [8, 9].

Allocation of budgets to health has been consistently low over the years, and with the dismal performance of public health care services, the private sector emerged as the health care provider at all tiers. Almost 80% of health care funding is through out-of-pocket payments, and the rest is provided by government funding through taxes, private insurance, external funding, and semigovernment institutions for their own employees and families [8].

In recent years, the government introduced the social health protection initiative “Sehat Sahulat [health convenience] Program” for the entire population of at least 2 provinces (Punjab and Khyber Pakhtunkhwa [KPK]) of the country. The program allowed the underprivileged population to access quality care at a reasonable cost of 1 million Pakistani rupees for each household each year [10]. Despite the plans to extend this to other provinces, the program has faced setbacks with the unstable political condition of the country.

The country is far behind in meeting the health indicators of neighboring countries and in achieving the Sustainable Development Goals (SDGs) for 2015–2030 [11]. According to the Pakistan Demographic and Health Survey (PDHS) of 2017–2018, there has been significant improvement in childhood immunization, antenatal and neonatal care, and under-5 mortalities. The neonatal mortality rate is 42, the infant mortality rate is 62, and the under-5 mortality rate is 74 deaths per 1000 live births, respectively [12]. One-fifth of the children have a weight of <2.5 kg at the time of birth; 38% of children under 5 years old are stunted, 7% are wasted, and 3% are overweight [12]. Moreover, only 95% of households have access to a safe source of drinking water. Out of these, only 7% of households follow the appropriate way of treating the water before drinking, with the majority in urban areas rather than rural areas. Almost 70% of households have sanitation facilities that are not shared with other households; however, only 25% have flush toilets linked to the septic tank, and 13% have no toilet facilities, particularly in rural areas [12].

Despite improvements in the provision of safe drinking water and sanitation, each year more than 50 thousand children in Pakistan die due to diarrhea. Moreover, the presence of diarrhea, poor sanitation conditions, and food insecurity is strongly associated with stunting among children [13, 14]. According to PDHS, the community-based prevalence of diarrhea among children aged <5 years was 19% in 2017–2018 [12]. Moreover, the coronavirus disease 2019 pandemic halted progress toward achieving the targets of health indicators related to maternal and child health due to a lack of accessibility to health care facilities [10].

CHILDHOOD IMMUNIZATION SCHEDULE, PROGRESS, AND CHALLENGES

Pakistan launched the Expanded Program on Immunization (EPI) in 1978 to safeguard children with immunization against vaccine-preventable diseases, which included childhood tuberculosis, measles, diphtheria, poliomyelitis, pertussis, and tetanus. The program made significant progress in achieving the targets of immunizing children with an expansion and timely inclusion of vaccines, including Haemophilus influenzae type b (Hib), hepatitis B, and pneumococcal vaccine (PCV). Since 2015, inactivated polio vaccine has been added to the EPI schedule, along with rotavirus and typhoid conjugate vaccine (TCV) in subsequent years. The rotavirus vaccine and TCV were implemented in the provinces, including Sindh and Punjab, and in the federal capital city of Islamabad 2 years ago, in 2021 [15–17]. The EPI vaccine schedule [17] is shown in Table 1.

Table 1.

Schedule of Routine Immunization in Pakistan^a

When	Age of Administration	Vaccines
At birth	At birth	BCG, OPV0, HepB
2nd visit	6 wk	OPV1, rotavirus1, PCV1, pentavalent1
3rd visit	10 wk	OPV2, rotavirus2, PCV2, pentavalent2
4th visit	14 wk	OPV3, IPV1, PCV3, pentavalent3
5th visit	9 mo	Measles1, IPV2, typhoid
6th visit	15 mo	Measles2

^aImmunization Schedule, Federal Directorate of Immunization, Government of Pakistan.

In addition to routine immunization, supplementary immunization activities (SIAs) have been implemented in collaboration with the Global Polio Eradication Program (GPEI), a drive toward a polio-free Pakistan. Despite these incremental efforts, Pakistan ranks third, after India and Nigeria, in the highest number of unvaccinated children and the highest mortality among children under 5 years of age [16].

The results of local studies and surveys have demonstrated that vaccine compliance decreases at 14 weeks to as low as 39% and 42% for pentavalent and inactive polio vaccine (IPV), respectively [18]. According to PDHS, only 66% of children aged 12 to 23 months received essential vaccines at the time of survey in 2017 (ie, 1 dose of BCG at the time of birth, measles, and 3 doses of polio and diphtheria-tetanus-pertussis vaccines); moreover, 51% received all age-appropriate vaccinations, and 4% did not receive any vaccine [12]. Vaccination coverage has been suboptimal, as reported in various surveys and studies from different areas of the country [19, 20].

There are several factors affecting vaccine uptake in the community, including personal beliefs, fears related to side effects of vaccines, accessibility of vaccine centers, and past experiences of inappropriate behavior by health care professionals [21–23]. Moreover, inaccessible conflict areas, poor public health facilities, a lack of consensus by political leadership, a lack of liaison between government and community stakeholders, and misinformation and rumors spread by the media are among the causes of low vaccine coverage and uptake [24–26]. Conversely, better education status of parents, high socioeconomic status, women's empowerment, and visits by lady health visitors have been shown to positively impact vaccine uptake [20, 27, 28].

The use of multicomponent interventions such as identifying and involving relevant stakeholders, educating parents and health providers, community mobilization, appropriate use of social media, and targeted community-based campaigns has been proven to be an effective strategy in the successful rollout of newly introduced vaccines. The same was applied in the case of implementing the TCV vaccine a few years ago, and the results were phenomenal. The interventions included raising awareness among community members and health care professionals through school-based campaigns and involving influential and religious leaders in the community. All the strategies aimed to allow the community to engage in a process of building trust and help them make decisions [29].

THE ENTERICS FOR GLOBAL HEALTH (EFGH)–SHIGELLA SURVEILLANCE STUDY

Pakistan is a low- and middle-income country with a high burden of medically attended diarrhea among children aged <5 years [30]. It is 1 of the 7 participating countries in the Enterics for Global Health (EFGH) Shigella surveillance study. The study aims to enroll 1400 children over a 2-year period to establish incidence estimates and consequences of Shigella-associated diarrhea among enrolled children aged 6–35 months and to prepare sites for potential selection in future Shigella vaccine trials. The methodology and other study procedures are detailed elsewhere [31].

The site has been part of 2 previous major studies: the Global Enteric Multicenter Study (GEMS) [32] and the Antibiotics for Children with Severe Diarrhea (ABCD) Trial [33]. In the EFGH study, there are 6 recruitment centers, consisting of a mix of primary and tertiary care and public and private health care centers. The study was approved by the Ethics Review Committee (ERC), Aga Khan University, Karachi, Pakistan (Ref: 2021-6932-19680)

OVERVIEW OF RECRUITMENT FACILITIES

Karachi is one of the megacities in Pakistan. It accommodates almost 10% of the population and is considered the economic hub for generating a major portion of the revenue for the entire country. According to the 2017 census report, the population of Karachi is >16 million and is expected to reach 23 million in the next 15 years [2, 12]. Climate change, unplanned population growth, poor health care infrastructure, and unhealthy water and sanitation conditions provide conducive environments for neglected tropical diseases such as mosquito-borne arbovirus infections, bacterial diseases (typhoid, paratyphoid, etc.), and diarrheal diseases (including Shigella) among children [34].

The average household income is very low, with almost three-quarters of the adult population earning <$5 per day [35]. Moreover, because of the lack of affordable housing, >50% of the population lives in informal squatter settlements known as “katchi abadis” in Urdu, the local language. These settlements are usually several kilometers away from the main city. The residents of these settlements belong to low socioeconomic strata of the population and lack health care facilities, sanitation, education, and transportation to access the facilities located at the center of the city. Moreover, the health status of the population varies, and the gap is mostly filled by nongovernmental organizations depending on the acceptability of the community [34, 35].

Karachi is administratively divided into 6 districts and 18 towns, along with cantonment areas. In the EFGH study, 6 hospitals and primary health centers (PHCs) were selected from Bin Qasim and Nazimabad towns of Karachi with a defined catchment area (Figure 1). These centers offer health care services to a population of ∼1.3 million people. The sites from Bin Qasim town include Sindh Government Hospital Korangi 5 (SGHK5), Sindh Government Hospital Ibrahim Hyderi (SGHIH), Bhains Colony (BHC), and Ali Akbar Shah VPT Center (AAS) (Table 2).

Figure 1.

Study catchment area and surveillance sites.

Table 2.

Overview of Study Sites and Catchment Populations

Town	EFGH Health Care Facilities	Catchment Populationa	Distance From AKU, km	Sustenance
Nazimabad	Khidmat-e-Alam Abbasi Shaheed Hospital	∼822 961	∼5	Office workers/small business owners
Bin Qasim	Ali Akbar Shah VPT Center (AAS)	∼476 376	∼13	Industrial/fishing
	Sindh Government Hospital Korangi 5	…	∼11
	Sindh Government Hospital Ibrahim Hyderi	…	∼11
	Bhains Colony VPT Center (BHC)	∼32 857	∼20	Agriculture/port

Abbreviations: Aga Khan University (AKU), ; EFGH, Enterics for Global Health (EFGH)–Shigella surveillance study.

^aWorldPop Spatial Demographic Data and Research (Open Spatial Demographic Data and Research—WorldPop).

The 2 primary health care centers, BHC and AAS, are in a low-income peri-urban area of Karachi and were part of the GEMS study. These centers provide free primary health care services to children under 5 years of age. In addition, these centers also provide facilities for routine immunization for children in collaboration with the local government and expanded programs on immunization (EPI). The catchment populations of BHC and AAS are predominantly low- and middle-income groups. There is also a demographic surveillance system (DSS) established in the catchment populations of BHC and AAS that maintains population censuses, pregnancies, births, and deaths at regular intervals. The estimated <5 population was 25 558, and the <5 mortality rate was 52 and 46 deaths per 1000 live births in 2022 at AG and BHC, respectively. These centers are run by the Department of Pediatrics and Child Health at Aga Khan University and are staffed with a physician and lady health workers (LHWs).

The 2 Sindh government hospitals are public secondary care hospitals located in proximity to the Aga Khan University (AKU)-run PHCs. These public hospitals are working in collaboration with nongovernmental organizations (NGOs), and they also provide health care services to low-income communities. SGHK5 has a well-functioning pediatric emergency room and an inpatient facility, both run by 2 different NGOs in collaboration with the provincial government. The center also provides vaccination services to children through the EPI. In contrast, SGHIH provides only out-patient services with vaccination facilities in collaboration with the EPI.

The sites from Nazimabad town include Khidmat-e-Alam (KEA) Medical Centre and Abbasi Shaheed Hospital (ASH). ASH is a public tertiary care, 850-bed teaching hospital offering a wide variety of services in almost every specialty. The hospital falls under the administration of the city district government and is supported by NGOs [36]. The hospital has a pediatric emergency room as well as a parallel emergency room run by an NGO. KEA is a primary health care center that provides health care services to underprivileged communities. The center offers outpatient, pharmacy, and laboratory services, along with charitable activities.

These sites were selected based on a high patient volume of children presenting with diarrhea, a reasonably well-defined catchment population, an expected good working environment, collaboration with these sites, and health care–seeking trends for diarrhea during the study period.

ADHERENCE TO DIARRHEA MANAGEMENT GUIDELINES

During the preparatory phase of the study, a summary from the World Health Organization (WHO), Integrated Management of Childhood Illnesses (IMCI), and local country-specific guidelines on the clinical management of diarrhea in children were discussed. Table 3 describes the clinical management of diarrhea according to Pakistan Ministry of Health Guidelines in healthy as well as malnourished children.

Table 3.

Site-Specific Diarrhea Management Guideline^a

Dehydration Management (Without Severe Acute Malnutrition)
Dehydration level	Site-Specific Guideline
Severe	Give 20-mL/kg bolus of normal saline, then check vitals after 1 h; if there are no improvements, give another 20-mL/kg bolus of normal saline; repeat bolus 1 last time if no improvement is observed on reassessment. Start IV fluid immediately. If the child can drink, give ORS by mouth while the drip is set up. Give 100 mL/kg of Ringer's lactate (or, if not available, normal saline). Reassess the child every 2 h. If hydration status is not improving, give the IV drip more rapidly in the range of (100 mL/kg over 4–6 h). Also give ORS (about 5 mL/kg/h) as soon as the child can drink. Reassess an infant after 6 h and a child after 3 h. Classify dehydration. Then choose the appropriate plan (A, B, or C) to continue treatment. Follow up after 2 d in Morning Consultant OPD from 8 am to 12 pm. Return to ER if vomiting, dull/lethargic, not feeding well, fast breathing, decreased urine output. Fluid resuscitation is done mostly via Ringer’s lactate/Hartmann solution OR 0.9% NS (Site-Khidmat e Alam center).
Some	In the clinic, give recommended amount of ORS over 4-h period. AFTER 4 H: Reassess the child and classify the child for dehydration. Select the appropriate plan to continue treatment. Begin feeding the child in clinic. Advise the mother to continue breastfeeding. Advise mother when to return immediately. Follow-up in 5–7 d if not improving.
None	Give extra fluids (as much as the child will take). Advice to the mother/caregiver: Breastfeed frequently and for longer at each feed. If the child is exclusively breastfed, give ORS or clean water in addition to breastmilk. If the child is not exclusively breastfed, give 1 or more of the following: ORS, KYB, probiotics, or clean water.
Dehydration Management (Severe Acute Malnutrition & No Shock)
Dehydration	Site-Specific Guideline
Severe	Give 20-mL/kg bolus of half strength (0.45%) dextrose saline, then check vitals after 1 h; if there are no improvements, give another 20-mL/kg bolus of half-strength dextrose saline; repeat bolus one last time if no improvement is observed on reassessment. Weight (kg) Amount of fluid ml/kg/day Choice of fluid First 10 kg 50-75 0.45% D/S 11-20 kg 25 0.45% D/S 21 kg onwards 10 0.45% D/S Resomal when available; otherwise, ORS. 5 mL/kg every 30 min for the first 2 h. If there is resolution of the signs of diarrhea and weight gain, stop ReSoMal and start the child on F75. After 2 h, make a thorough assessment: If there is continued weight loss, increase rate of administration of ReSoMal by 10 mL/kg/h; reassess after 1 h. If there is no weight gain, increase the rate of ReSoMal by 5 mL/kg/h. If rehydration is still required at 10 h, give starter F75 instead of ReSoMal at the same time.
	In child with suspected cholera, use standard ORS.
Zinc
Population	Site-Specific Guideline
All children	Zinc supplementation (syrup 20 mg/5 mL): 2 m up to 6 m 2.5 mL daily for 14 d. 6 m or more 5 mL daily for 14 d.
Antibiotics
Population	Site-Specific Guideline
Dysentery or Shigella upon culture confirmation	For dysentery, first-line antibiotic: oral ciprofloxacin; second line: azithromycin. All health facilities follow the WHO-indicated Management Plan. Age Ciprofloxacin Give 15 mg/kg two times daily for 3 days 250 mg tablet or Syrup 500 mg tablet or Syrup < 6 months 1/2 tablet 1/4 6 m up to 5 y 1 1/2
Suspected cholera (age ≥2 y + severe dehydration + cholera present in area)	First-line antibiotic: Oral ciprofloxacin 15 mg/kg twice daily for 3 d.

Abbreviations: ER, emergency room; KYB, rice, yogurt, and banana; IV, intravenous; NS, Normal Salina; OPD, Out Patient department; ORS, oral rehydration salts; ReSoMal, rehydration solution fo malnourished; WHO, World Health Organization.

^aWorld Health Organization [37]. World Health Organization [38]. World Health Organization [39]. Pakistan Demographic and Health Survey [40].

Adherence to IMCI guidelines has been suboptimal throughout the country. According to recent PDHS data, there has been a decline in the community-based prevalence of diarrhea among children aged <5 years, from 23% in 2013 to 19% in 2018. However, in parallel, the practice of seeking treatment also increased to 71%. Only 37% of children who experienced diarrhea in the last 2 weeks received oral rehydration salts (ORS), and only 8% received zinc along with ORS, indicating low compliance with the recommended guideline. Among surveyed children who suffered from diarrhea in the last 2 weeks, 84% received care at the private facility, and 30% received appropriate antibiotics [12].

The rate of treatment advice sought improved, but still, progress is stagnant. The diarrhea treatment guidelines chalked out nationally still need a push, along with other measures such as improving the coverage of rotavirus vaccine, improving practices in water, sanitation, and hygiene, and providing essential medicines such as zinc and ORS. According to PDHS, most treatment is sought at private health care facilities. Paying out of pocket is a significant barrier to treatment; thus people prioritize living over health care [41]. Maternal knowledge about ORS and zinc, food abstinence during diarrhea, and food insecurity inflicted by poverty lead to a low level of compliance with the diarrhea management guidelines [42].

SHIGELLA INCIDENCE, PREVALENCE, AND ANTIMICROBIAL RESISTANCE

The case–control, health care facility–based GEMS study measured Shigella-attributed moderate to severe diarrhea (MSD) that led to care-seeking and ≥1 of the following: dehydration, dysentery, or hospital admission in children under 5 years of age. The incidence varied by age group across the 7 field sites in Sub-Saharan Africa and South Asia. When the results were extrapolated to the catchment population, the estimated incidences were 2.0 (95% CI, 1.4–2.6), 7.0 (95% CI, 5.0–9.0), and 2.3 (95% CI, 1.2–3.4) Shigella-attributed moderate to severe (MSD) cases per 100 child-years in children aged 0–11, 12–23, and 24–59 months, respectively, based on diagnosis using quantitative polymerase chain reaction. The incidences using a culture technique were 1.2, 2.8, and 1.1 Shigella-attributed MSD cases per 100 child-years in these same age cohorts [32].

According to the WHO, Shigella is one of the driving forces behind the rise in antimicrobial resistance (AMR) problems in low- and middle-income countries (LMIC) due to the failure to treat the disease successfully with available antibiotics [43]. It has been identified as a priority pathogen that requires intervention and preventable measures, including vaccines, safe drinking water, etc., to contain this potentially life-threatening global issue. The WHO recommends ciprofloxacin for the treatment of dysentery as the first-line treatment in addition to hydration, probiotics, and zinc supplementation [44]. Unfortunately, there is a rising burden of quinolone-resistant Shigella strains in Pakistan and other low-income settings due to inappropriate and irrational prescribing and overuse of antimicrobial drugs in acute watery diarrhea [45, 46]. Several studies conducted in Pakistan have demonstrated that from 1996 to 2007, 2.4% of Shigella isolates were cephalosporin-resistant, whereas in 2012 and 2014, this percentage increased to 19.5% and 20%, respectively, and the isolates became resistant to ≥1 of the third-generation cephalosporins [47–49]. Similarly, resistance to second-line antibiotics that include third-generation cephalosporins and azithromycin has also been observed in various other countries in Southeast Asia (2.0%–5.2%), India (16.8%), China (18%), and Iran (18.75%) [50–54]. The presence of this pressing issue of AMR, which has a wide-ranging impact on morbidity, mortality, and health care costs, particularly in developing countries where the health care system relies on out-of-pocket payments for health expenditures, further complicates the management of Shigella in Pakistan [43, 55].

CARE-SEEKING FOR DIARRHEA

Care-seeking for diarrhea and associated life-saving therapies is suboptimal in Pakistan. Studies have reported that care-seeking for diarrhea by caregivers of children under 5 years has been low; self-treatment at home with ORS, medicines such as zinc and antibiotics, and homemade local foods such as “khichri” (a traditional food that is a mixture of rice and pulses) delays health care seeking [56, 57]. The other factors affecting health care utilization are lack of transportation, support to take care of other children at home, and the high cost of antibiotic therapy [58]. Moreover, the cultural practices of a lack of the mother's role in decision-making, lack of knowledge, and reliance on home remedies result in delayed health care–seeking and increased chances of mortality and morbidity due to diarrhea [56–58].

Although it has been reported that mothers have adequate knowledge about the use of ORS and diarrhea case management, this does not always translate into the prevention of diarrhea or the recognition of danger signs. Moreover, knowledge about oral rehydration could be linked to media campaigns or LHWs in the community. However, it has been reported that these LHWs have not been approached very frequently to seek advice, and often the mothers prefer a physician over a lady health worker to seek treatment [59]. The data from PDHS suggests that the practice of seeking advice or treatment for diarrhea improved from 61% in 2012–2013 to 71% in 2017–2018 [12]. However, engaging the community in appropriate case management of diarrhea is an uphill task.

TRAINING AND CAPACITY BUILDING

The team consists of people from diverse backgrounds and is enriched with expertise ranging from clinicians to project managers. The diversity adds to the success of the project and provides opportunities to grow. The Pakistan EFGH team consists of infectious disease consultants, epidemiologists, laboratory scientists, and data managers. The team has been provided with opportunities for self-development and career growth. Junior investigators have been provided leading roles in the substudies and mentorship to secure funding. Moreover, the midcareer investigators have been involved in the manuscript writing as co-first authors to enhance their skills, give them the opportunity to network with consortium members, and help them grow as leaders.