Emerging Hand Foot Mouth Disease in Bangladeshi Children- First Report of Rapid Appraisal on Pocket Outbreak: Clinico-epidemiological Perspective Implicating Public Health Emergency

Set up, patients and research design

Utilizing a pre-set syndromic approach based on case-definition following the WHO’s HFMD guidelines¹ this rapid appraisal (descriptive study) was conducted among 143 children attending Pabna Medical College and General Hospital (PMC-GH) from its catchment areas between September and November, 2017. PMC-GH is a 250-bed secondary care hospital serving a targeted population of nearly 2.81 million from its 2,371.5 km²³⁰ catchment area situated in a small poverty-stricken north-western flood-prone plain land on the Ganges Delta basin in Bangladesh.

Research instruments used

Clinical diagnostic tool. Prepared based on syndromic case-definition following the WHO’s HFMD guidelines¹, similar to a prior study conducted in Thailand²⁹. Most of the contents of this tool have been shown in Figure 4 (4 A), showing the algorithm of Clinical diagnosis of HFMD¹.

Clinical case management protocol. This was prepared incorporating a history of disease, onset, chief complaints and duration of illness, clinical diagnosis and therapeutic intervention. We ascertained clinical outcome by through post-treatment follow-up in the outpatient department of PMC-GH or through cellphone-based enquiry. We performed the clinical diagnosis following WHO guidelines¹, predominantly based on three main signs/symptoms: fever, oral ulcers and rash in extremities. Fever was graded into moderate-to high (38.5°C) and none-to-low (37-38.4°C), oral ulcers were grouped into three stages- more painful, less painful and painless; and, rashes in extremities into three types: painful and itchy, painless and itchy; and painful but not itchy.

Pain assessment/scoring

Since pain remains subjective in younger children in expressing pain intensity properly, we arbitrarily categorized the pain intensity based on following clinical grounds:

Therapeutic index

A therapeutic index was prepared to treat childhood HFMD cases following standard therapeutic plan consisting of: antipyretic/analgesics, antihistamines, anesthetic-cream for topical applications. These aforementioned three clinical diagnostic tools (moderate-to-high fever, painful oral ulcers and painful rash in extremities) have been prepared adopting the WHO clinical management and public health response for HFMD¹ with a little modifications to suit our short-term comprehensive study (Figure 4 (4 A)).

Epidemiological tool

This tool consisted of socio-demographic variables and household (HH) income. We categorized the income of children’s family following World Bank Data Help Desk 2016³¹ as follows:

We calculated income scale using the USD rate: 1US $ = 84.31 BDT as of 11 June 2018.

Records on seasonal data on local weather/climate (average temperature and rain precipitation) were collected from Pabna Meteorology Dept., Bangladesh over the period of September through November 2017. In Bangladesh, early autumn runs from September to mid-October, followed by late autumn/fall from mid-October to mid-November. All tools were pre-tested for this rapid-appraisal (small-scale disease surveillance)^1,2.

Data analysis

Crosschecked data were subjected to Pearson’s chi-squared test, Fisher’s exact test and Spearman correlation analysis using SPSS for Windows v.21, taking P<0.05 as indicating statistical significance (at 95% CI).

Inclusion criteria/patient enrolment

Any child, irrespective of age and sex, attending PMC-GH between September and November 2017 with suspected HFMD (meeting WHOs¹ recommended criteria) were included in this study. Suspected cases having other serious disease/co-morbidities were excluded, although patients were referred to concerned department for proper clinical management.

Ethical considerations

Following standard procedure of ethical issues³², written informed consent was obtained from the parents of children with suspected HFMD prior to enrolment. We detailed the parents/guardian of all children on the purpose and procedures of this study. We also informed the parents on the lack of risk of harm/damage involved in procedures and did not collect body fluids or other biological samples. We informed the parents that they could remove their child at any stage of the study. Complete privacy and anonymity of clinical data was ensured, including its protected use research purposes only. This study had prior approval through the Ethical Committee of Pabna Medical College and General Hospital, Government of the Peoples’ Republic of Bangladesh (Memo No. 1577, dated: 26/08/2017).

Demographic information

The mean (±SD) age of the 143 children was 2.9±2.3 years; 80 (56%) were boys and 63 (44%) were girls. Of the total, 70% were under 5 years old. Age did not differ with sex (P=0.98). Data on HH structure yielded an average size of children’s family as 5.5±6.9 persons/per HH. Of them, 62% having only one (no siblings) and 38% two (first sibling) children, (Table 1).

Following Word Bank, (2016) standard³¹ family/HH income-group evidenced that majority families (85%) belonged to middle-income HH/families (34% belonged to upper-middle and 51% to lower-middle income-groups living with a modest HH budget). The rest (14.7%) belonged to low-income groups lived with a tight HH-budget. Notably, children from mid-income-HHs contracted significantly more HFMD which was more among the first siblings (P<0.01), (Table 1).

Assessment of symptoms

Child’s age was significantly associated with three major clinical signs/symptoms. Younger children (under 5 years old) suffered more (74/91, 81%) with moderate-to-high fever than older children (17/91, 19%; p<.04). Similarly, painful oral ulcers (82/111, 74%) and painful itchy rash in extremities (92/116, 79%) were more common in younger than older children (p<0.03 and p<0.01, respectively). Notably, characteristics of skin rash in extremities of younger children’s were more predominantly papulo-vesicular (59/68, 87%) than chicken-pox-like (43/75, 57%), (P<0.01). However, sex did not differ with other signs/symptoms except oral ulcers: boys had less painful ulcers (23/32, 72%) than girls (9/32, 28%), (P<0.04), (Table 2).

None of the three major signs/symptoms of HFMD (fever, oral-ulcers/blisters and extremity rash) was associated with seasonal variations except fever and characteristics of rash. Moderate-to high fever (57/91, 63%) was observed more in fall/late-autumn (mid-October through mid-November) than in early autumn (September through mid-October), yielding 37% of cases (34/91), (p<0.01). Similarly, papulo-vascular rashes were more common in fall (42/68, 62%) than in early autumn (26/68, 38%) (P<0.03; Table 3).

The three major sign/symptoms among these HFMD contracted children were more prevalent on days where 0.0 mm precipitation was recorded. Rain had no significant impact on any of the three major sign/symptoms, unlike on dry days with no rainfall (0.0 mm). Similarly, all major sign/symptoms prevailed more in hot and humid days when the ambient temperature was recorded at ≥30°C (up to a maximum of 36.2°C), with no significant difference among three major sign/symptoms (Table 3).

Findings of post-treatment clinical outcome was associated with age. More younger children (<5 years) recovered in <5 days (63/74, 85%) than older peers (≥5 years) (47/69, 69%) who were more likely to recover in >5 days) (P<0.05). However, clinical disease/outcome was not associated with children’s sex, although boys were more likely to suffer with the illness for 6–7 days, whereas girls tended to recover within 5 days. However, this was only marginally significant (P<0.05; Table 4).

Basis of this rapid appraisal on HFMD outbreak

We conducted an extensive review on HFMD in the latest literature. Clinico-epidemiological insight from these articles augmented by our careful observations and intensive appraisal on WHO’s “Clinical management and public health response for HFMD”¹ enabled us to establish a primary clinical diagnosis of childhood HFMD on an unusual events of febrile-rash cases (M.A.H.K., unpublished observations, June–July 2017). Concurrent agreement from similar reports attested our HFMD diagnosis among those febrile illness and rash syndrome cases in children as correct^1–3. Gauging the potential of a sudden upsurge in childhood HFMD cases (during July 2017) attending PMC-GH from its catchment area made us aware that we faced an upcoming localized outbreak. A strategic plan was thus urgently adopted to conduct this rapid appraisal (short-term standardized surveillance)¹ on childhood HFMD utilizing a pre-set case-definition/syndromic approach based on the WHO’s HFMD guidelines¹. This study is comparable with a study conducted in Thailand²⁹.

The main objective of this descriptive study (rapid appraisal) was to create awareness on childhood HFMD as a newly emerged disease in Bangladesh and tended to stir-up country’s public health emergency squad in getting alert to combat similar upcoming-HFMD outbreaks. In conducting this study, we were also able to assess the clinical skill, diagnostic potential and epidemiological insight of PMC-GH team along with instant local support, which will also prove helpful. The findings of our study will help to show how skillfully the clinicians at the mid-level secondary-care hospitals remain capable in combating localized HFMD outbreaks quite confidently. They accomplished it utilizing own resources and work force, without seeking additional assistance. Credit goes to concerned physicians (dermatologist and/or pediatricians) in establishing correct diagnosis of childhood-HFMD based on strong yet rational suspicions, as reported by others^12,13,23 along with institution of supportive therapy. Every issue was addressed and resolved successfully despite huge constraints in manpower, funding and gross lack in diagnostic facilities, though laboratory-test is reportedly not essential, often^14,19,25.

Potentials and dynamics of HFMD outbreaks

HFMD has emerged as a major public health problem in recent years^2,10. HFMD was first recognized in the Western world^1,2 during the mid-1970s². It was then spread out in the Asia-Pacific region since the mid-1990s^3,6,9, mostly in four countries (Malaysia, Taiwan, China and Singapore)^3,6,9,11. HFMD outbreaks were also reported in the Indian districts of Orissa¹² and Calcutta¹³, bordering with Bangladesh. It is therefore strange that no data or published reports exist in Bangladesh yet then, as Prabir et al. commented rightly and in-time²³. Despite epidemiological forecasts that HFMD outbreaks occur in a 2–3-year cyclical pattern¹¹, two large epidemics broke out in 2 consecutively years: one in Malaysia during 1997 and the other in Taiwan, the following year⁹.

All these facts and figures, including epidemiological hunches and variabilities support our strong speculation of this localized outbreak of HFMD in Pabna that we could combat boldly. Based on such experience, we do suspect that HFMD might have emerged in Bangladesh earlier, but, swept on unnoticed. HFMD often remains ‘underestimated’ due to its benign nature and self-limiting clinical features^6,8. These facts led us to suspect that latent HFMD cases or small localized outbreaks might remained under-reported or un-reported (Kazi Selim Anwar and Md. Abid Hossain Mollah, personal observation, June 2017).

Clinico-epidemiological perspectives

Using observations of clinical course, disease progression, short-term suffering and disease outcome confirms that childhood-HFMD remains a benign and self-limiting disease, observations that are consistent with several other studies^6–8. We attest that HFMD can be diagnosed accurately once there is a strong suspicion^13,14. The presenting signs and symptoms can be the sole diagnostic modality, too¹². We diagnosed these HFMD cases based on a patient’s history, onset and the presented clinical features^6,19. In addition, we considered the patient’s socio-demographic characteristics^12,14, and a positive history of similar sign/symptoms in child’s family, nursery and/or in schools^12,14. However, our data does not agree to such higher incidences of sever disease (8.5%) that was reported from Vietnam⁸, rather it goes in favor of ‘no’ or ‘rare fatalities’ contrararily^5,6.

Our data yielded a significant association between age groups and three major clinical signs/symptoms. Moderate-to-high fever, painful oral ulcers and itchy-painful rashes were directly proportional to younger children which was consistent with several other findings^4–6,8,9. Moderate-to-high fever remains an important, but not mandatory or principal sign of HFMD, as the WHO’s guidelines for clinical and public health response indicate¹, in agreement with our findings. Oral and/or axillary temperature in 64% of cases revealed a moderate fever (38.5°C), ranging mostly between 37.5°C and 38.2°C; the rest (36%) had no or a low-grade fever (ranging between 37.0 to 38.4°C). This variation in body temperature led us to postulate that fever itself can never be considered as the sole symptom in confirming HFMD diagnosis. Our observation on ‘fever’ though remain consistent with several authors, such as Van Pham et al.⁸, and other studies reported high patient body temperatures in HFMD-cases^5,9.

The most important characteristic symptoms for HFMD remains papulo-vesicular rash, often manifesting as painful chicken-pox-like rashes. We observed that this papulo-vesicular rash (Figure 3) was painful in 60% of cases and was less painful/painless in 40% of cases. Since pain remains subjective in younger children in expressing pain intensity, we categorized HFMD based on no recent history of pain status, facial expression of child having body rash/oral ulcer on touch/other sensitizations and impression of child’s mother and the clinician’s rational judgements. Our findings on rashes and its types in patients with childhood HFMD remain consistent with other reports^1,4, particularly its distributions in knees or buttocks^{1,2,7,13,14,17}. We observed itchy rashes in child’s extremities, forming small pustules that were filled with turbid fluid (Figure 1) and in some cases it consequently crusted off⁶ after 3–4 days. These rash symptoms remain consistent with several prior reports^1,4,13,14.

Figure 1. Multiple vesicular lesions containing turbid fluid seen in right knee of 4-year old girl.

Most of the children under 5 years (78%) suffering from HFMD had characteristic oral ulcers and/or painful blisters in tongue/mouth (Figure 2), symptoms cited in several reports^{1,4,7,14,16,17}. However, we found less painful/painless oral ulcers/blisters in 22% HFMD cases. Although the exact reason for these less pain/painless oral ulcers remain unclear, we postulate that it could be due to a varied perception and/or different tolerability level by those children. Of course, being unwilling to mention or disclose about their tolerable/bearable little pain feeling shy or even being scared of cannot be ruled-out, either. Some of these children may have taken analgesics at home before coming to hospital, which they did not disclose despite repeated questioning. Notably, we did not find any sign/symptom that significantly differed with sex of children except oral ulcers. More boys had less painful ulcers than girls (P<0.04). Our findings that revealed a sex differences for some specific clinical sign/symptom remain unique, though findings from a study in India reported an overall male-female ratio of 21:17¹³.

Figure 2. An oral ulcer on tongue with surrounding erythema of a 5-year old boy.

Figure 3. Papulo-vesicular lesions surrounded by erythematous zones on the left palm of a 1.5-year-old boy.

Figure 4. Decision tree for the clinical diagnosis and management of hand, foot and mouth disease.

Differential Diagnosis of HFMD

We performed a thorough DD to make the clinical diagnosis of HFMD as perfect as practicable. We performed the DD to differentiate HFMD from closely similar diseases, like varicella/chicken-pox, scabies, measles, erythema multiforme, herpangina, herpetic gingivitis, drug eruptions, as several reports have mentioned^1,6–8,22. Mosquito bite was also included in the DD as it was reported in a recent study in India, underlining this simple yet valuable DD-point¹³. Particular attention in the DD was paid to the characteristics of skin lesions where macules and papules quickly evolve into vesicles. Characteristically, the lesions in these children occurred on their palms, soles, and buttocks²². We observed vesicles in majority of these children that ruptured with the formation of erosions and crusts. However, Sharma et al. observed in Indian patients that it starts with small (1–5 mm) erythematous maculopapular lesions that rapidly enlarged to 3–15 mm lesions, progressing to vesicular eruption with prominent erythematous halo^13,14. We observed this common dermatological phenomenon in some of our studied children with HFMD. Nonetheless, our observation remains similar to that of Bhumesh et al. from India that oral lesions begins as erythematous macules and then evolved into vesicles (measuring 2–3 mm) on an erythematous base²¹.

Laboratory diagnosis for HFMD

Laboratory diagnosis is usually not essential^12,23 to confirm a readily diagnosed HFMD case based on rational judgement of existing clinical features. Even, lab diagnosis often remains unnecessary¹⁹. Laboratory tests, such as serotyping, molecular, PCR and genotyping³ and virus culture^1,13,24, may not be feasible, available and more importantly not affordable in resource-constrained countries^12,13 like Bangladesh, particularly in hard-to-reach/remote areas. Although few studies report high WBC count or blood glucose, as associated with HFMD severity^{13–19,23,24}, it remains scarcely seen in recent literature. Furthermore, rise in blood glucose level may be due to other viral diseases rather than HFMD, and may well remain confounded by a wide range of infections and/or inflammatory processes. Moreover, in some pediatric cases, it may not be practically possible to collect intravenous blood from younger children, who possess thin veins, particularly at the primary care health centers in grass-root level. Children often become too agitated when attempts are made to draw blood, as we observed, with their parents distressed, and the children non-compliant and non-cooperative. However, we observed this was more an issue among less-educated and low-income group families.

Latest literature shows that virological diagnosis remains the main diagnostic tool. Of the four species in the family of Picornaviridae (groups EV-A, B, C and D) that cause HFMD in children, chiefly remain EV 71 and coxsackie-virus A-6, A-10 and A16^3,7,8,10,24. More crucial is that these viruses are transmitted rapidly^15,17 through direct contact, respiratory droplets, via feces/blister-fluid and contaminated environment¹⁸.

Specific treatment for HFMD viruses

There is no specific treatment^22,25 or pharmacological intervention⁴ available for HFMD yet. Since it largely remain supportive^19,25 we prepared a standardized therapeutic index involving our clinical experts that we followed as therapeutic measure among childhood cases of HFMD in this study. It consisted of: i) antipyretic/analgesics, ii) antihistamines, and iii) anesthetics drugs (oral gel or ointment). Skin lesions in those cases (observed in only two cases) healed within 3–4 days; we did not prescribe any acyclovir due to the highly reported adverse effects (nephropathy and neurotoxicity). Since oral acyclovir is poorly absorbed, we prescribed it as an exception in recommended dosage of oral syrup (20 mg/kg body-weight) for 5 days only in eight severe cases (mean age, 2.4 years). However, children with profuse skin-lesions with severe pain responded dramatically, with early recoveries. Reasons for this mechanism or the basis of its pathogenicity and the pharmaco-dynamics of acyclovir are not fully understood, which necessitates further investigation.

Vaccination of HFMD

Though no effective vaccine available yet against HFMD-viruses^1,2,7. Scientists have been attempting to develop a vaccine against HFMD in Malaysia (since 2010)³³, in China (since 2012)³⁵, and in Taiwan (since 2014)^36,37. Cai et al. demonstrated how active immunization with an experimental inactivated CA16 vaccine can confer full protection- which provided a solid foundation for developing inactivated whole-virus vaccines against CA16 infection in humans³⁵. Similarly, Chih-Wei Lin et al.³⁶ found some ‘prospect and challenges’ with critical bottlenecks in the development of multivalent HFMD vaccines. They demonstrated how combined vaccine would reduce number of injections simplifying WHOs ongoing child immunization schedule to protect against several viruses, like H5N1, EV71 and JEV at the same time³⁶. Yican Cui et al. attempted to develop a combined bivalent-vaccine comprising EV71 and A16 to give balanced protective immunity³⁷. There is also evidence for the further development of multivalent vaccines for broader protection against HFMD³⁷.

Due to a lack of available vaccines against viruses that cause HFMD^15,17,18, preventive measures remain the primary way of circumventing HFMD. Prevention methods includes good personal hygiene, proper hand washing²⁶ pollution free environment^12,18, sewage²⁷, and germ-free water and food¹⁸. Although avoiding person-to-person contact² through isolation remain justified, it may often not be practical in unprivileged low-income communities and/or resource-constrained healthcare settings like Bangladesh. It is imperative to increase mass awareness among such communities more.

Clinical outcome

In agreement with other studies^4,6, our data also revealed that younger children (<5 years old) recovered more quickly (in <5 days) than their elder peers (>5 years old) who recovered in 6-7 days (>5 days) (P<0.05). There was a marginal significant difference in sexes, since boys had seemingly quicker recovery than peer girls did (P<0.05). Nevertheless, according to latest literature, most childhood HFMD-cases resolve themselves within 7–10 days^5,8,9. These findings remain consistent with that of other reports from Asia-pacific countries^4–8, including India^12,13,14,18.

Complications

Complications of childhood HFMD remain few, although younger children may develop them more often^7,17,21. We found three cases (2.09 %) of such complications (mild-to-moderate severity) who we had to pay a special attention to. The first case (a 4-year-old girl) was a case of pneumonia, who we treated with IV antibiotics and discharged following recovery after 2 days. The second one was an admitted case of pyoderma (a 5-year-old boy), who received appropriate antibiotics and was discharged on after 3 days. We diagnosed a third case of a 1.5-year-old girl with a case of post-HFMD Onychomadesis³⁸, who had clinically diagnosed HFMD 25 days before, who had shedding of skin on her right little finger since last few days. On repeated observations (weekly) her nail resumed in original position after 3 weeks of her development of a nail problem without any medication. This scenario remains comparative to a report from South Korea³⁸. However, the mechanisms of Onychomadesis and its association with HFMD is not yet fully understood as literature shows³⁸ and that, some viruses are responsible for onychomadesis as a temporal variation.

Although CA16 and EV71² are mostly associated with neuro-respiratory syndromes^1,4, we did not observe serious complications, nor encountered any death in the children with HFMD, a finding that remain consistent with several reports^5,6,9,15.

HFMD cases and local weather/climate

Several studies carried out in the Asia-Pacific region reported an association of HFMD cases with a wide range of meteorological findings (weather, climate, ambient temperature, humidity, rain, etc.)^{5–10,15,17,18}. Meteorological factors reportedly remain associated with HFMD outbreaks in Asia-Pacific regions^5,17, like Singapore^9,15, China¹⁰ and Hong Kong²⁰. The rainy season⁸ and short-term variations in temperature^20,28 had an impact on HFMD occurrence⁵ in this region. This includes atmospheric pressure, relative humidity and rain precipitation⁹ as well which peaks in summer and early autumn¹⁸. We conducted this study during autumn, that runs in Bangladesh from early September through November in two phases: early autumn from September to mid-October, while its next phase (late autumn/fall) from mid-October to November.

One limitation is that we could not conduct a proper meteorological study as reported from some Asian countries^9,10,15,20. As a small part of our study, we only tried to find out briefly if local weather has any impact on HFMD just to acquire a preliminary idea in this aspect. However, the literature did not reveal any such study/report detailing the symptom-specific association of HFMD with seasons, as we have tried to. Some of our overall findings remain comparable with that of others^5,6,9,10. Our data from the rapid appraisal of short-term surveillance demonstrated certain seasonal characteristics of local weather were associated with HFMD, like fever and rash characteristics. Moderate-to high fever (63%) was observed more often in fall/late-autumn (mid-October to November) than in early autumn (September to mid-October), yielding 37% cases (P<0.01). A similar result was obtained for papulo-vascular rashes, which predominantly occurred in fall (62%) rather than in early autumn (38%), (P<0.03).

However, our data did not support an impact of rainfall/precipitation or ambient temperature on any of the three major signs/symptoms we have evaluated. We observed that childhood HFMD cases occurred mostly in dry weather with no rainfall (0.0 mm). Similarly, the three major symptoms of HFMD were more likely to be observed during hot/humid days, with no difference in disease severity. These findings on climatic factors or locally prevailed weather did not corroborate with the findings of others^5,9,10.

Socio-demographic characteristics and Household economy of victim’s families

One of the other unique strength of our study was to dig out an association of socio-demographic and/or HH economy of children’s families with that of childhood HFMD. The age group of victimized children (mean ± SD, 2.9± 2.3 years) remained similar to several reports^{1,2,7,8,14–21}. However; the age of children did not differ significantly with sex. The HH structure revealed an average size of children’s family containing 5.5±0.7 persons/HH, 62% of who were the first child and 38% were the second children. The HH income scale/grades, following the World Bank standard family/HH income-groups³¹, highlighted that the majority of families (85%) belonged to middle-income HHs living on a modest budget. While 34.3% had upper-mid incomes, 51% had lower-mid levels of income. However, 14.7% belonged to the low-income group, who were to live on a very tight HH budgets. Notably, but logically (based on ecology, environment, health care facilities, etc.) HFMD infection was observed more among first siblings and from families significantly associated with living on tight/low HH-budget than in second sibling (P<0.01). This finding should be noteworthy as one of our unique findings associating among family size, child’s-sibs and HH-budget/family-economy. These findings might have several multifaceted reasons, but our postulation go in favor of gross inadequacy in health care expenditure by individual families, the distance of PMC-GH from respective HHs and of course, total family income as one of the major concerns. Although such socio-economic parameters and public health issues demand to be explored further, some studies highlighted that the occurrence of HFMD is associated with patients’ personal hygiene, post-defecation hand-washing, water and sanitation²⁶. Surrounding environment, like food and drinking water¹⁸, including the contaminated sewage water²⁷ also have a particular role in transmitting HFMD viruses amidst surrounding communities.

Insights on principal findings