Continuing Education Activity

Hand, foot, and mouth disease (HFMD) is a common viral illness usually affecting infants and children but can affect adults. The infection usually involves the hands, feet, mouth, and sometimes, even the genitals and buttocks. The cause of hand, foot, and mouth disease is coxsackievirus A type 16 in most cases, but the infection can also be caused by many other strains of coxsackieviruses and Enteroviruses. The coxsackievirus is a member of the Picornaviridae family, which includes non-enveloped single-stranded RNA viruses. This activity reviews the pathophysiology and clinical presentation of HFMD and highlights the role of the interprofessional team in managing patients with this disease.

Objectives:

• Identify the etiology of HFMD.
• Describe the presentation of a patient with HFMD.
• Outline the management options available for HFMD.
• Describe interprofessional team strategies for improving care coordination and communication to advance the management of HFMD and improve outcomes.

Introduction

Hand, foot, and mouth disease (HFMD) is a common viral illness usually affecting infants and children but can affect adults. The infection usually involves the hands, feet, mouth, and sometimes, even the genitals and buttocks. The cause of hand, foot, and mouth disease is coxsackievirus A type 16 in most cases, but the infection can also be caused by many other strains of coxsackievirus. In the western Pacific, hand, foot, and mouth disease has been linked to enterovirus. The coxsackievirus is a member of the Picornaviridae family, which includes non-enveloped single-stranded RNA viruses.[1][2][3]

Etiology

Hand, foot, and mouth disease is a viral exanthem, and it is most commonly caused by the coxsackievirus of the Enterovirus family. Coxsackievirus A16 and enterovirus A71 are the serotypes most commonly implicated as causative agents.[4][5][6] Coxsackievirus A6 has recently emerged as another cause of HFMD in the USA and worldwide.[7] Coxsackievirus A10 has been implicated in severe disease.[8] Coxsackievirus A4 to A7, A9, B1 to B3, and B5 have also been less commonly associated with HFMD.[9]

Epidemiology

This viral infection is not indigenous to one area in particular but occurs worldwide. As children (particularly those younger than seven years of age) tend to be infected at a higher rate than adults, you can see outbreaks in daycares, summer camps, or within the family. Large-scale surveillance from China demonstrated that more than 90% of HFMD cases occurred in children less than five years of age, mortality was around 0.03%, and that cases tended to occur more frequently during late spring and early summer.[10] A study from Vietnam showed a positive correlation between an increase in environmental temperature and humidity and an increase in the incidence of HFMD.[11]

In 2021, French surveillance found a rapid increase in HFMD cases, with more than 3400 cases. Although more than 90% of sequenced cases were found to be linked to Enterovirus, atypical cases were found to be associated with Coxsackievirus A6 and A16.[12] Coxsackievirus A6 remains the dominant cause of HFMD in the United States.[7] 

Pathophysiology

The spread of the human enterovirus is mediated by oral ingestion of the shed virus from the gastrointestinal or upper respiratory tract of infected hosts or via vesicle fluid or oral secretions.[13] Patients tend to be most infectious in the first week of the disease, with an incubation period ranging between 3 to 6 days.[13] After ingestion, the virus replicates in the lymphoid tissue of the lower intestine and the pharynx and spreads to the regional lymph nodes. This can be spread to multiple organs, including the central nervous system, heart, liver, and skin.

History and Physical

Hand, foot, and mouth disease can start with a low-grade fever, reduced appetite, and general malaise. The most common hand, foot, and mouth disease presenting symptom is usually mouth or throat pain secondary to the enanthem. The presence of vesicles is surrounded by a thin halo of erythema, eventually rupturing and forming superficial ulcers with a grey-yellow base and erythematous rim. The exanthem can be macular, papular, or vesicular. The lesions are about 2 mm to 6 mm in size, are non-pruritic, and are typically not painful. They last about ten days, tend to rupture, and result in painless and shallow ulcers that do not leave a scar. The exanthem can involve the dorsum of the hand, feet, buttocks, legs, and arms. Oral lesions commonly involve buccal and tongue ulcers but may also involve the soft palate.[13]

HFMD can also present with atypical features like concomitant aseptic meningitis. Enterovirus infections that cause hand, foot, and mouth disease are notorious for involving the central nervous system (CNS) and may cause encephalitis, polio-like syndrome, acute transverse myelitis, Guillain-Barre syndrome, benign intracranial hypertension, and acute cerebellar ataxia.[13]

Evaluation

The diagnosis of hand, foot, and mouth disease is usually made clinically. The virus can be detected in the stool for about six weeks after infection; however, shedding from the oropharynx is generally less than four weeks. Light microscopy of biopsies or scrapings of vesicles will differentiate HFMD from varicella-zoster virus and herpes simplex virus. While serology is not sensitive to making a diagnosis of HFMD, levels of IgG can be used to monitor recovery.

In some centers, serology is used to differentiate enterovirus 71 from coxsackievirus, as this has prognostic significance. Today, polymerase chain reaction assays are available in most centers to confirm the diagnosis of coxsackievirus. A swab of the lesion can detect coxsackievirus or enterovirus using real-time PCR assays.[14][7]

Treatment / Management

Hand, foot, and mouth disease is a mild clinical syndrome and will resolve within 7 to 10 days. Treatment is primarily supportive. Pain and fever can be managed with NSAIDs and acetaminophen. Making sure the patient remains well-hydrated is important. Additionally, a mixture of liquid ibuprofen and liquid diphenhydramine can be used to gargle, which helps coat the ulcers, easing the pain.[15][16] Steroids were found to increase the risk of severe HFMD.[17]

Over the past decade, researchers have developed specific treatments to manage enterovirus 71-induced hand, foot, and mouth disease because of its severe neurological complications. So far, no drug has been approved, but promising novel agents include molecular decoys, translation inhibitors, receptor antagonists, and replication inhibitors. An antiviral agent that has shown promise in the treatment of enterovirus 71 is pleconaril, an anti-picornaviral agent. However, there are currently no licensed antivirals for the treatment of HFMD.[18] Anecdotal reports have shown some clinical response to acyclovir, but large-scale trials have not established this.[19]

Several vaccine candidates have been developed against HFMD and Enteroviruses. Currently, strain-specific inactivated whole-virus aluminum-adjuvant vaccines have been developed in China and are approved for widespread use.[10] In a study with 10,077 participants, a three-dose regimen of the EV71 C4a vaccine showed an overall efficacy of 94.7% (95% CI 87.8–97.6), with protection lasting for around two years.[20] virus-like particles (VLPs) vaccines, DNA vaccines, peptide vaccines, and subunit vaccines have been developed but are in various stages of clinical trials.[21]

Differential Diagnosis

The differential diagnosis for HFMD should include conditions that present with maculopapular or vesicular rashes with or without oral lesions.[13] These conditions include:

• Erythema multiforme

• Herpangina

• Herpes simplex

• Herpes zoster

• Kawasaki disease

• Toxic epidermal necrolysis(TEN)

• Viral pharyngitis

• Rocky Mountain spotted fever

• Varicella zoster infection (chickenpox)

• Steven-Johnson syndrome

• Monkeypox - In the context of an ongoing outbreak, it becomes important to consider the difficulty in clinically differentiating between monkeypox and HFMD[22]

Prognosis

The prognosis for most patients with hand, foot, and mouth disease is excellent. Most patients recover within a few weeks without any residual sequelae. Acute illness usually lasts 10 to 14 days, and the infection rarely recurs or persists. However, some patients with hand, foot, and mouth disease may develop serious complications, which include the following:

• Persistent stomatitis is associated with painful ulcers. The pain can be severe enough to limit food intake, and dehydration can result, especially in young children.
• Aseptic meningitis can occur, but this is more common with enterovirus 71. This particular virus is associated with a higher rate of neurological involvement compared to coxsackievirus. The individual may develop acute cerebellar ataxia, polio-like syndrome, encephalitis, benign intracranial hypertension, and Guillain-Barre syndrome. The virus is believed to induce damage to the gray matter, resulting in motor dysfunction.[23]
• Coxsackievirus can rarely cause interstitial pneumonia, myocarditis, pancreatitis, and pulmonary edema.[24]
• Some studies indicate that coxsackievirus infections may also be associated with spontaneous abortions.[25]

Complications

Pneumonia, myocarditis, pancreatitis, and pulmonary edema, as well as serositis involving other major organs, are rarely associated with HFMD.[24] A large meta-analysis of children with HFMD suggested that lethargy, pneumo-edema/pneumorrhagia, seizures, dyspnoea, and coma were risk factors for death in HFMD.[26] The case fatality rate associated with enterovirus 71 was found to be 1.7% in a systematic review and meta-analysis.[27]

Deterrence and Patient Education

Patient/parental education is paramount in reducing the transmission of HFMD among children and also between children and adults. Handwashing has been proven to be an effective strategy in the prevention of HFMD transmission.[28] A community intervention study showed that intensive education on hand hygiene techniques led to an improvement in the personal hygiene of both parents and children. This subsequently reduced the incidence of HFMD in the study population.[29] The parents should also be advised to keep the child away from immunosuppressed individuals due to the potential risk of serious illness. 

Pearls and Other Issues

The majority of patients with coxsackievirus-induced hand, foot, and mouth disease are treated as outpatients, but those who have CNS involvement may require admission for close monitoring. These patients often require imaging studies of the brain to guide treatment and recovery. Infants may develop dehydration, especially if they develop painful oral ulcers and may require Intravenous hydration. Admission is highly recommended for any infant with hand, foot, and mouth disease who shows signs of severe disease and lethargy. The virus is shed in the stools for a few weeks; hence, patients should be educated about hand washing and maintenance of good personal hygiene.

Enhancing Healthcare Team Outcomes

Cases of HFMD are on the rise, and clinicians need to know how to make the diagnosis. Because many recent cases have involved the brain, a neurological consult may be necessary. An interprofessional team that includes clinicians (MDs, DOs, NPs, or PAs), specialists (neurologist, pediatrician, internist, infectious disease expert), nursing staff, and a pharmacist should be involved. Clinicians will diagnose and initiate therapy and decide which referrals may be necessary. Pharmacists can assist with medication management, perform medication reconciliation, and answer questions about the agents used. Nurses will coordinate activities with other interprofessional team members, help with patient examination, and counsel patients and/or parents. Everyone on the team must communicate openly with the rest of the care team to ensure the best care leading to optimal outcomes. [Level 5]

The outcomes for most patients with HFMD are excellent, with full recovery occurring within 7 to 21 days. [Level 1]