Hand Foot and Mouth Disease (HFMD)
Hand Foot and Mouth Disease (HFMD)

Hand Foot and Mouth Disease (HFMD)

Hand foot and mouth disease (HFMD) is a common infection caused by a group of enteroviruses. HFMD is a communicable disease mostly affects infants and children but can also occur in adolescents and adults.

CONTENTS:

1. INTRODUCTION

Hand-Foot-and-Mouth Disease (HFMD) is one such common childhood disease (Solomon, T, Lewthwaite).

HFMD is mild, but highly contagious viral disease. It usually affects children below 10 years (can also affect older children and adults). The infection usually involves the hands, feet, mouth, and sometimes even the genitals and buttocks (Xing, W, Liao).

HISTORY :

HFMD cases were first described clinically in Canada and New Zealand in 1957. It was first discovered by Daldrof and Sickles (Robinson, CR, Doane, 1958). The disease was termed “Hand Foot and Mouth Disease”, by Thomas Henry Flewett .

It can be considered as the oldest viral infection – as it was mentioned in 1400 BC in Europe.

2. ETIOLOGICAL AGENTS

HFMD is caused by virus belong to Family Picornaviridae

This family includes viruses like : Poliovirus

                                                 Coxsackievirus (A-16)

                                                 Echovirus

                                                 Enterovirus 71 (EV-71)

Coxsackievirus A16 and Enterovirus 71  are most commonly implicated as the causative agents of HFMD.

Fig : EV-71

CV-A16, isolated in 1958 was the first identified HFMD pathogen, followed by EV71- which was isolated in the USA in 1969 (Racaniello, VR. Picornarviridae ,2013).

HFMD caused by EV71 is of particular concern as it is more likely associated with severe complications (such as viral meningitis, encephalitis and poliomyelitis-like paralysis) and even death.

Molecular Characterization of Enterovirus:

EV comprises more than 100 serotypes. Virus under this Genus are: Icosahedral shaped, Non-enveloped, and contains a single positive RNA genome of about 7,400 nucleotides (nt).

Its open reading frame encodes 4 structural proteins: viral protein 1 (VP1), (VP2), (VP3), (VP4)

Also encodes 7 non structural proteins: 2A, 2B, 2C, 3A, 3B, 3C, and 3D

VP1 is the immunodominant protein of the Picornaviridae capsid and contains serotype-specific information. Thus, the VP1 has been used for virus serotype identification and molecular epidemiology.

Molecular structure of Enterovirus

3. EPIDEMIOLOGY

(A) Geographical Distribution :

Hand foot and mouth disease (HFMD) is a major emerging infection in India, it was first reported in West Bengal in 2007. HFMD has become an endemic childhood disease in East and Southeast Asia. More than 80,000 cases presenting with HFMD are reported each year.

In China, HFMD has been prevalent since 2007. During 2008–2015, ≈13 million HFMD cases were reported, including 123,261 severe cases and 3,322 deaths in mainland China (China, HMoPsRo. ,2008).

Fig : Annual distribution of HFMD confirmed cases in
 Guangzhou ,Southern China ( 2008-2012)
Fig : HFMD epidemiological status &  relationship with meteorological variables in Guangzhou, Southern China, 2008-2012

 Outbreaks of HFMD :

The outbreaks of HFMD are usually during the summer and early autumn when there is summer camps.

             YEAR OF OUTBREAK                           PLACE
1957New Zealand & Canada
1959USA
1960UK, New Zealand & USA
1970Hungary
1975Bulgaria
1978Japan
1997 Sarawak, Malaysia
2008 & 2009Mainland China
2011Vietnam

(B)  Host Range :

The majority of people infected with Coxsackievirus are children under the age 10.

It occurs at an equal frequency in  both genders, but some epidemiological data suggest that the frequency of infection is slightly higher in males.

                                                                                                                    Fig : Overall cases of HFMD in Shandong province, 2009–2016 & Sex distribution of probable and laboratory-confirmed cases.

4. MODE OF TRANSMISSION

HFMD is a contagious disease that is spread from person to person by :

  • Close personal contact
  • Nasopharyngeal secretion
  • Contact with feces (fecal-oral transmission)
  • Contact with contaminated objects and surfaces
  • Contaminated water

Factors affecting the transmission:

  • Level of hygiene
  • Water quality
  • Extent of crowding
  • Seasonal variations

Tropical and subtropical: Circulation of virus with more outbreaks in rainy season

Temperate regions: Autumn and spring

5. PATHOGENESIS

The pathogenesis of HFMD caused by EV-71 includes:

  1. EV-71 replicates in the lymphoid tissues of the oropharyngeal cavity(tonsils), small bowel (payer’s patches) and regional lymph nodes (deep cervical and mesenteric nodes) leading to a mild viremia.
  2. Most of the viruses are destroyed in these lymphatic tissues and the patients remain asymptomatic.
  3. Patients present with clinical symptoms when the virus disseminates to other organs like reticuloendothelial system (liver, spleen, bone marrow, lymph node) heart, lung, pancreas, skin, mucous membranes and CNS.
  4. The virus is typically shed for between two and four weeks, and sometimes for as long as 12 weeks post-infection.
  5. Replication also occurs in the upper respiratory tract and the virus has been recovered from throat swabs for up to two weeks post-infection.

Complication of HFMD:

Cox A16: May develop Myocarditis with intractable shock, deaths

EV 71:  May develop Meningitis, Encephalitis & Neurogenic Pulmonary Edema

EV 71 infection can be classified into 4 stages :

 Stage 1 : Development of Oral ulcer & vesicular rashes.

Stages 2 : CNS involvement ( Aseptic meningitis, Encephalitis, Encephalomyelitis or Poliomyelitis like )

 Stage 3 :  Cardiopulmonary failure, Pulmonary edema or Hemorrhage, LVF

 Stage 4 : Convalescence

6.  CLINICAL SIGNS

Other Symptoms includes :

  • Headache
  • Loss of apatite
  • Sore throat
  • Irritability in infants & toddlers
  • Malaise

The incubation period is three to six days.

7. DIAGNOSIS

A doctor can often diagnose HFMD simply by performing a physical examination from blisters & rashes. Cases of HFMD relies on laboratory identification of the virus.

Ranges of samples for virus isolation includes :

  • Throat swab
  • Rectal swab
  • Stool sample
  • Serum
  • CSF
                             SAMPLES                POSITIVE RESULT (%)
Throat swab49%
Vesicle swab48%
Throat + Vesicle swab67%
Rectal & Ulcer swab8%
Flowchart of Clinical specimen collection, Handling & Transportation

8. RAPID MOLECULAR DETECTION METHOD

Historically, Enterovirus serotype were identified  by serological neutralization. Because neutralization methods are labour-intensive, they have been replaced by Molecular methods based on the correlation between the serotype and the genotype determined by sequencing of the structural region of the genome.

The most commonly-used method of Enterovirus genotyping targets the 1D gene (∼900 nt in length) that encodes the VP1 capsid protein, which contains the major neutralizing epitopes.

Human Enterovirus 71 (EV-71) have been classified primarily into six genogroups [A to F] (based on gene, which encodes the VP1 capsid protein).

  • Genogroup C evolved in 1960
  • Indian genogroup (D)
  • African genogroups (E and F)
Genogroups of EV-71

RT-PCR:     

Specific TaqMan real-time RT-PCR assay by analyzing VP1 gene sequences of strains. The method also used during outbreak in Yunnan, China in 2009.

                                

Cytokine & Chemokine profiling:

There is a differential cytokine and chemokine profiles in the patients infected with CA6 in comparison to those infected with EV71.

  • EV-A71 & CV-A6 infected HFMD patients had  reduced levels of sera: IL-1α, MIF, IL-1β, IL-2, IL-8, IL-15, FGF-basic, GM-CSF, MCP-1, MIP-1 & MIP-1β. •
  • Increased levels of sera: IL-16, IL-18, CTACK, β-NGF, SDF-1α, IL-5, IL-7, IL-13, IP-10, and PDGF-ββ.

9. TREATMENT

Presently, there is no specific effective antiviral drugs & vaccine available for the treatment of HFMD. HFMD actually go away on its own after 7 to 14 days if proper medication is started earlier. Mild HFMD cases only need symptomatic treatment. Parents and care takers should be educated on hygiene and measures that they should take to prevent transmission to other children.

Symptoms can be treated by :

  • Fever can be treated with antipyretics.
  •  Pain can be treated with Acetaminophen, Ibuprofen or other pain relievers.
  •  Mouthwashes, spray or gargle solutions can be used to reduce mouth ulcer pain.
  • Fluid intake should be enough to prevent dehydration.

Severe Complications are rare but can develop if HFMD is left untreated in certain individuals, this can lead to:

                Meningitis

                Encephalitis

                Acute flaccid paralysis

10. CONTROL

 

DIFFERENCE BETWEEN HFMD & FMD:

Hand Foot and Mouth Disease (HFMD) Foot and Mouth Disease (FMD)
Host: Human (especially children)Host: Animals (especially cloven hoof footed, e.g. cattle, pig, goat etc.)
Causative agent:
                     Family – Picornaviridae
                 Genus – Enterovirus
Causative agent:
                    Family – Picornaviridae
                Genus – Aphthovirus
Vaccination: No vaccine is availableVaccination: Animal vaccine is available
HFMD

FMD

References:

  1. Solomon, T, Lewthwaite, P and Perera, Det al.Virology, epidemiology, pathogenesis, and control of enterovirus 71.LancetInfect Dis2010;10: 778–90.

2. Xing, W, Liao, Q and Viboud, Cet al.Hand, foot, and mouthdisease in China, 2008–12: an epidemiological study.LancetInfect Dis2014;14: 308–18.

3. Robinson, CR, Doane, FW and Rhodes, AJ. Report of an out-break of febrile illness with pharyngeal lesions and exanthem:Toronto, summer 1957; isolation of group A Coxsackie virus.Can Med Assoc J1958;79: 615–21.

4. Racaniello, VR. Picornarviridae: the viruses and their repli-cation. In David, PMH and Knipe, M (eds).Fielda Virol-ogy, 6th edn. Philadelphia: Lippincott Williams & Wilkins,2013.

5. China, HMoPsRo. Guidelines for Hand-foot-mouth disease prevention and control (2008).National Health and Family Plan-ning Commission of the People’s Republic of China, 2008.

6. Wong, KT, Munisamy, B and Ong, KCet al.The distribution of inflamma-tion and virus in human enterovirus 71 encephalomyelitis suggests possi-ble viral spread by neural pathways.J Neuropathol Exp Neurol2008;67:162–9.67.

7. WHO.A Guide to Clinical Management and Public Health Response for Hand,Foot and Mouth Disease (HFMD). 2011.

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