Hand-foot-and-mouth disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2], Yamuna Kondapally, M.B.B.S[3], Aravind Kuchkuntla, M.B.B.S[4]

Hand foot and mouth disease (HFMD) is a common, contagious viral illness of infants and children younger than 5 years old, but can also occur in older children and adults. It is is caused by a number of enteroviruses, including Coxsackie A16 and Enterovirus 71 (EV71) in the family Picornaviridae. It is characterized by fever, sores in the mouth, and a rash with blisters on hands and feet.^[1][2][3][4]

Notable outbreaks have occurred in Malaysia, Taiwan and China in the past. Hand, foot and mouth disease infected 1,520,274 people with 431 deaths reported up to end of July in 2012 in China. ^[5].

Hand-foot-and-mouth disease may be classified according to international classification of diseases-10 (ICD-10) into B08.4 Enteroviral vesicular stomatitis with exanthem.^[6]

Hand-foot-and-mouth disease usually affects infants and children, and is quite common. It is highly contagious and is spread through direct contact with the mucus or feces of an infected person. It typically occurs in small epidemics in nursery schools or kindergartens, usually during the summer and autumn months.

Hand-foot-and-mouth disease may be caused by the following viral organisms Coxsackie viruses (Coxsackievirus A2, A4 to A10, A16, B2, B3, B5), Echoviruses (Echovirus 1, 4, 7, 19) and Enteroviruses (A71).

Herpes simplex virus infections, chicken pox and measles present similar to hand-foot-and-mouth disease, and needs to be differentiated from each other clinically using appropriate diagnostic tests.

Individual cases and outbreaks of hand-foot-and-mouth disease occur worldwide, more frequently in summer and early autumn. In the recent past, major outbreaks of hand-foot-and-mouth disease attributable to enterovirus 71 have been reported in some South East Asian countries (Malaysia, 1997; Taiwan, 1998)

The risk factors predisposing for hand foot mouth disease include: close contact with infected patient, attendance at a kindergarten/child care center, residence in rural areas and poor hygiene.

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for hand-foot-and-mouth disease.

It is characterized by fever, sores in the mouth, and a rash with blisters. Hand-foot-and-mouth disease begins with a mild fever, poor appetite, malaise and frequently a sore throat.

Hand-foot-and-mouth disease is one of many infections that result in mouth sores. Another common cause is oral herpesvirus infection, which produces an inflammation of the mouth and gums. Usually, the physician can distinguish between hand-foot-and-mouth disease and other causes of mouth sores based on the age of the patient, the pattern of symptoms reported by the patient or parent, and the appearance of the rash and sores on examination. A throat swab or stool specimen may be sent to a laboratory to determine which enterovirus caused the illness. Since the testing often takes 2 to 4 weeks to obtain the results, it is therefore not done.

Physical examination is usually diagnostic for hand foot and mouth disease. However, throat swabs, swabs from the lesion and Tzanck test can be used in diagnosing hand-foot-and-mouth disease.

There are no EKG findings associated with hand-foot-and-mouth disease.

There are no X-Ray findings associated with hand-foot-and-mouth disease.

There are no CT findings associated with hand-foot-and-mouth disease.

There are no MRI findings associated with hand-foot-and-mouth disease.

There are no ultrasound findings associated with hand-foot-and-mouth disease.

Hand foot mouth disease is a clinical diagnosis, there is no need for performing diagnostic tests, however molecular testing can be done to identify the serotype of enterovirus.

No specific treatment is available for this or other enterovirus infections. Symptomatic treatment is given to provide relief from fever, aches, or pain from the mouth ulcers.

Surgical intervention is not recommended for the management of hand foot mouth disease.

Specific prevention for hand-foot-and-mouth diseaseor other non-polio enterovirus infections is not available, but the risk of infection can be lowered by good hygienic practices. Preventive measures include frequent handwashing, especially after diaper changes, cleaning of contaminated surfaces and soiled items first with soap and water, and then disinfecting them by diluted solution of chlorine-containing bleach (made by mixing approximately ¼ cup of bleach with 1 gallon of water. Avoidance of close contact (kissing, hugging, sharing utensils, etc.) with children with hand-foot-and-mouth disease may also help to reduce of the risk of infection to caregivers.

Secondary prevention measures are the same as the primary preventive measures that should be followed for hand foot mouth disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Notable outbreaks have occurred in Malaysia, Taiwan and China in the past. Hand, foot and mouth disease infected 1 520 274 people with 431 deaths reported up to end of July in 2012 in China. ^[1].

• In 1997, 34 children died in an outbreak in Sarawak, Malaysia.
• In 1998, there was an outbreak in Taiwan, affecting mainly children^[2]. There were 405 severe complications, and 78 children died^[3]. The total number of cases in that epidemic was estimated to be 1.5 million^[3].
• In 2006, 7 people died in what seemed to be a new outbreak in Kuching Sarawak (according to the New Straits Times, 14th of March).
• In 2006, after the outbreak of Chikungunya in Southern and some Western parts of India cases of HFMD were reported. ^[4]
• In 2007, during the week of April 15-21 alone, Singapore recorded 688 cases of the disease. ^[5]
• In 2007, 30th May, outbreak in the Maldives was reported. ^[6]
• In 2008, an outbreak in China, beginning in March in Fuyang, Anhui, led to 25,000 infections, and 42 deaths.^{[7][8][9][10][11][12]} Similar outbreaks were reported in Singapore (more than 2,600 cases as of April 20, 2008), Vietnam (2,300 cases, 11 deaths), Mongolia (1,600 cases),^[13] and Brunei (1053 cases from June–August 2008)^{[14] [15]}
• In 2009, 17 children died in an outbreak during March and April 2009 in China’s eastern Shandong Province, and 18 children died in the neighboring Henan Province.^[16] Out of 115,000 reported cases in China from January to April, 773 were severe and 50 were fatal.^[17]
• In 2010, in China, an outbreak occurred in southern China’s Guangxi autonomous region as well as Guangdong, Henan, Hebei and Shandong provinces. Until March 70,756 children were infected and 40 died from the disease. By June, the peak season for the disease, 537 had died. ^[18]
• In 2010 in Vietnam, by 04.09 the disease was reported to have claimed 98 lives, 75% of whom were children under 3 years old. Although there was no official declaration of an outbreak, over 42,000 cases were reported. Over 10,000 new cases were recorded in the second half of August alone.^[19]
• The World Health Organization between January to October 2011, (1,340,259) states the number of cases in China dropped by approx 300,000 from 2010 (1,654, 866) cases, with new cases peaking in June. 437 deaths, down from 537 deaths in 2010. ^[20][21]
• In Cambodia, 52 of 59 reviewed cases of children reportedly dead (as of 09 July 2012) due to a mysterious disease was diagnosed to be caused by a virulent form of HFMD. ^[22] Although a significant degree of uncertainty exists with reference to the diagnosis, WHO report states, “Based on the latest laboratory results, a significant proportion of the samples tested positive for enterovirus 71 (EV-71), which causes hand foot and mouth disease (HFMD). The EV-71 virus has been known to generally cause severe complications amongst some patients.” ^[23][24]

• In 2012 in Alabama, United States there was an outbreak of an unusual type of the disease. It occurred in a season it is not usually seen and affected teenagers and older adults. There were some hospitalizations due to the disease but no reported deaths.^[25]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

HFMD usually affects infants and children, and is quite common. It is highly contagious and is spread through direct contact with the mucus or feces of an infected person. It typically occurs in small epidemics in nursery schools or kindergartens, usually during the summer and autumn months.

• HFMD outbreaks typically occur during summer and autumn months in the United states.^[1]

Mode of transmission

• HFMD is a contagious disease that is spread from person to person by:^{[1][2][3][4][5]}

• Close personal contact
• Nasopharyngeal secretions
• Contact with feces (fecal-oral transmission)
• Contact with contaminated objects and surfaces
• Contaminated water (Swimming pools not properly treated with chlorine)

• The virus can be isolated from the following sources:

• Nose and throat secretions (such as saliva, sputum, or nasal mucus)
• Blister fluid
• Feces (stool)

• Following the disease, the infected person (symptomatic or asymptomatic) is most contagious during the first week of illness but can spread disease for days or weeks after symptoms go away.
• Hand foot and mouth disease is not transmitted to or from pets or other animals.
• Factors affecting the transmission:

• Level of hygiene
• Water quality
• Extent of crowding
• Seasonal variations
  • Tropical and subtropical: Circulation of virus tends to be year long, with more outbreaks in rainy season
  • Temperate regions: Autumn and spring

The exact pathogenesis of HFMD is not fully understood.The pathogenesis of HFMD caused by EV71 includes:^[6][7]

• EV71 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.
• Most of the viruses are destroyed in these lymphatic tissues and the patients remain asymptomatic.
• 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.
• The virus is typically shed for between two and four weeks, and sometimes for as long as 12 weeks post-infection.
• Replication also occurs in the upper respiratory tract and the virus has been recovered from throat swabs for up to two weeks post-infection.
• The relationship between pathogenesis and distribution of viral entry receptors (scavenger receptor B2, P-selectin glycoprotein ligand-1 and sialic acid-linked glycans) and host factors, such as gender and age group, is unknown.
• The pathogenesis of EV71 depends on following factors:

Viral factors Viral virulence factors are still unknown. Host factors

• Inflammatory factors: High levels of following factors are seen in pulmonary edema.

• Interleukin 6 (IL-6)
• Tumor necrosis factor alpha
• Interleukin-1 beta (IL-12)
• Interleukin-10(IL-10)
• Monocyte chemo attractant protein (MCP-1)
• Monokine induced by interferon gamma (MIG)

• Cell mediated immunity

• Reduction in T-lymphocytes and NK cells

• Human Leukocyte antigen(HLA)

• HLA-A33: Associated with increased susceptibility of EV71 in Asian population
• HLA-A2: Increased risk of cardiopulmonary complications

• Microscopic examination of the vesicular lesions will demonstrate loose strands of fibrin, lymphocytes and neutrophils in the vesicular fluid. The presence of acantholysis in the epidermis and perivascular infiltration of leukocytes is seen in hand foot and mouth disease. The absence of intracelluar inclusion bodies differentiates it from the herpes simplex infection.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Yamuna Kondapally, M.B.B.S[3], Aravind Kuchkuntla, M.B.B.S[4]

Hand-foot-and-mouth disease should be differentiated from other conditions that cause maculopapular or vesicular rash which includes herpes simplex virus infections, herpangina, chicken pox and measles.

Hand-foot-and-mouth disease should be differentiated from other conditions that cause maculopapular or vesicular rash include:

• Herpes simplex virus infections
• Herpangina
• Chicken pox
• Measles
• Aphthous ulcers/ Gingivitis
  • The ulcers are on the mucosal surface of the mouth and is not associated with fever, malaise or rash.
• Stevens-Johnson syndrome/ Erythema multiforme
• Henoch-Schönlein purpura
• Kawasaki disease
• Other rare conditions in children:
  • Behcet’s disease
  • Pemphigus vulgaris

The following table is a list of differential diagnosis and their features:

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh ≤1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals[1][2] Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles
Herpangina	Sudden fever Sore throat and dysphagia– These can occur several hours(up to 24 hours), before the appearance of the enanthem. Vomiting Abdominal pain Myalgia Headache Pharyngeal lesions	Attendance at a kindergarten/child care center Contact with herpangina cases Residence in rural areas Overcrowding Poor hygiene Low socioeconomic status	Clincial diagnosis Pharyngeal viral and bacterial cultures can be taken to exclude HSV infection and streptococcal pharyngitis.	Skin Oral Cavity	Characteristic enanthem- Punctate macule which evolve over a period of 24 hours to 2-4mm erythematous papules which vesiculate, and then centrally ulcerate. The lesions are usually small in number, and evolve rapidly. The lesions are seen more commonly on the soft palate and uvula. The lesions can also be seen on the tonsils, posterior pharyngeal wall and the buccal mucosa.
Primary herpetic gingivoestomatitis[3]	Pin-head vesicles rupture to form painful irregular ulcerations covered by yellow-grey membrane Severe pain Submandibular lymphadenopathy Halitosis It involves buccal mucosa, tongue, posterior pharynx, and gingival and palatal mucosa	Direct contact HIV infection	Tzanck test demonstrates multinucleated epithelial giant cells[4] Viral culture is the gold standard for diagnosis Direct immunofluorescence	Oral cavity Mucous membranes	Ulcers are common on lips, gums, throat, front of tongue, inside of the cheeks and roof of the mouth Treatment is with antiviral agents such as Valacyclovir and Famciclovir

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Individual cases and outbreaks of HFMD occur worldwide, more frequently in summer and early autumn. In the recent past, major outbreaks of HFMD attributable to enterovirus 71 have been reported in some South East Asian countries (Malaysia, 1997; Taiwan, 1998).^[1]

• In the Western Pacific Region, widespread epidemics have been reported in many countries, including Australia, Brunei Darussalam, China, Japan, Malaysia, Mongolia, the Republic of Korea, Singapore, and Vietnam.
• The epidemiology data on the hand foot mouth disease is limited in countries outside the Western Pacific Region.^[2]

• In China, a total of 38,654 cases of hand foot mouth disease including deaths were reported in the month of February 2017.^[2]
• In Japan, 333 cases of hand foot mouth disease were reported in the month of February 2017.
• In Vietnam, 705 cases of hand foot mouth disease were reported in the month of February 2017.
• In Singapore, 855 cases of hand foot mouth disease were reported in the month of February 2017.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

The risk factors predisposing for hand foot mouth disease include: close contact with infected patient, attendance at a kindergarten/child care center, residence in rural areas and poor hygiene.

The risk factors for development of hand foot mouth disease include:

• Close contact with infected patient
• Attendance at a kindergarten/child care center
• Residence in rural areas
• Overcrowding
• Poor hygiene
• Low socioeconomic status
• Sharing toys with other children^[1]
• Not washing hands before meal and after using the toilet^[1]
• Risk factors predisposing the patients for the developing severe manifestations of hand foot mouth disease include:^[2][3][4]
  • Infection in children age of less than one year
  • Body temperature greater than 39.0°C
  • Duration of fever greater than three days
  • Absence of skin lesions, diarrhea, dyspnea, and hyperglycemia
  • Vomiting
  • Increased neutrophil count^[5]
  • Respiratory rate greater than 24/minute^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2], Aravind Kuchkuntla, M.B.B.S[3]

The outbreaks of hand foot mouth disease occur during the period of warm temperatures of spring, summer, and fall, showing a strong seasonal pattern. Hand foot mouth disease affects infants and children, and is quite common.The symptoms appear within 3 days to 1 week after the infection with mild fever, poor appetite, malaise and sore throat, followed by development of painful sores develop in the mouth. It is a self limiting condition but few patients might develop complications such as pulmonary hemorrhage and meningitis.

The outbreaks of hand foot mouth disease occur during the period of warm temperatures of spring, summer, and fall, showing a strong seasonal pattern.^[1] Hand foot mouth disease affects infants and children, and is quite common. It is highly contagious and is spread through direct contact with the mucus or feces of an infected person. Transmission is by direct contact with nose and throat discharges, saliva, fluid from blisters, or stools of an infected person. It typically occurs in small epidemics in nursery schools or kindergartens, usually during the summer and autumn months.The symptoms appear within 3 days to 1 week after the infection with mild fever, poor appetite, malaise and sore throat, followed by development of painful sores develop in the mouth. The mouth ulcers are usually seen on the tongue, gums, and inside of the cheeks. The skin rash develops over 1 to 2 days as a flat red patch with blisters on the palms and foot. Hand foot mouth disease usually resolves in a week to 10 days, but very rarely complications such as meningitis and acute flaccid paralysis can occur.

Complications of hand foot and mouth disease include:

• Viral or aseptic meningitis, it presents with fever, headache, stiff neck, or back pain.^[2]
• Encephalitis
• A polio-like paralysis
• Fingernail and toenail loss, usually occurs mostly in children within 4 weeks of having hand foot and mouth disease. However, the nail loss has been temporary and nail growth resumed without medical treatment.^[3][4]
• Acute flaccid paralysis)
• Cardiopulmonary failure^[5]
• Pulmonary edema or pulmonary hemorrhage^[6][7]
• Acute pancreatitis^[8]

Hand foot mouth disease is a self limiting disease and complete recovery occurs in 5 to 7 days. In very few patients prognosis is poor with the development of pulmonary hemorrhage, hypotension and elevated serum lactate.^[9]

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