Hand, foot, and mouth disease (HFMD) is a prevalent viral infection, commonly affecting infants and young children, though it can occur in adults. Characterized by distinctive lesions, HFMD typically manifests on the hands, feet, and mouth, and may extend to the genitals and buttocks. The primary etiological agent is coxsackievirus A type 16, but a spectrum of coxsackieviruses and Enteroviruses can induce the condition. Belonging to the Picornaviridae family, these viruses are non-enveloped, single-stranded RNA viruses. This article provides an in-depth review of HFMD, emphasizing diagnostic approaches and clinical recognition, crucial for effective patient management.
Delving into the Etiology of HFMD
Hand, foot, and mouth disease is classified as a viral exanthem, predominantly triggered by coxsackieviruses within the Enterovirus genus. Specifically, Coxsackievirus A16 and enterovirus A71 are frequently identified as the causative serotypes. Notably, Coxsackievirus A6 has emerged as a significant etiological agent in recent years, contributing to HFMD cases globally, including in the USA. Coxsackievirus A10 has also been associated with more severe manifestations of the disease. Less frequently, HFMD can be linked to Coxsackieviruses A4 through A7, A9, B1 through B3, and B5.
Epidemiological Insights into HFMD
HFMD exhibits a worldwide distribution, affecting diverse geographical locations. Children, particularly those under the age of 7, are disproportionately affected, leading to outbreaks in settings like daycare centers, summer camps, and within households. Surveillance data from China indicates that over 90% of HFMD cases occur in children younger than 5 years, with a mortality rate around 0.03%. The incidence tends to peak in late spring and early summer. Research in Vietnam has shown a positive correlation between increased environmental temperature and humidity and a rise in HFMD cases. In 2021, French surveillance reported a surge in HFMD cases, exceeding 3400. While Enterovirus was implicated in over 90% of sequenced cases, atypical presentations were associated with Coxsackievirus A6 and A16. In the United States, Coxsackievirus A6 remains the predominant cause of HFMD.
Pathophysiology of Hand, Foot, and Mouth Disease
Transmission of human enteroviruses occurs primarily through the fecal-oral route, via ingestion of viral particles shed from infected individuals’ gastrointestinal or upper respiratory tracts. It can also spread through direct contact with vesicle fluid or oral secretions. Patients are most contagious during the first week of illness, with an incubation period ranging from 3 to 6 days. Following ingestion, the virus replicates in the lymphoid tissue of the lower intestine and pharynx, disseminating to regional lymph nodes. From there, the virus can spread to various organs, including the central nervous system, heart, liver, and skin.
Clinical Presentation: History and Physical Examination in HFMD Diagnosis
The onset of HFMD may be marked by nonspecific prodromal symptoms such as low-grade fever, reduced appetite, and malaise. However, the hallmark presenting symptom is typically mouth or throat pain resulting from the enanthem. Intraoral examination often reveals vesicles surrounded by a thin halo of erythema. These vesicles subsequently rupture, forming superficial ulcers with a grey-yellow base and an erythematous rim.
The exanthem of HFMD can manifest as macular, papular, or vesicular lesions, typically ranging from 2 mm to 6 mm in size. Characteristically, these lesions are non-pruritic and generally not painful. They typically persist for about 10 days, eventually rupturing and evolving into painless, shallow ulcers that heal without scarring. The exanthem distribution commonly involves the hands, feet, buttocks, legs, and arms, particularly on the dorsum. Oral lesions frequently affect the buccal mucosa and tongue, manifesting as ulcers, but may also involve the soft palate.
Atypical presentations of HFMD can occur, including concomitant aseptic meningitis. Enteroviruses, known to cause HFMD, have a propensity for central nervous system involvement, potentially leading to encephalitis, polio-like syndrome, acute transverse myelitis, Guillain-Barre syndrome, benign intracranial hypertension, and acute cerebellar ataxia. Therefore, a thorough neurological assessment is crucial in patients presenting with HFMD, especially in cases with unusual or severe symptoms.
Image alt text: Clinical presentation of Hand, Foot, and Mouth Disease showing characteristic rash on hand with vesicles and erythema, crucial for hand foot and mouth diagnosis.
Evaluation and Diagnostic Modalities for HFMD
The diagnosis of HFMD is primarily clinical, based on the characteristic history and physical examination findings. While viral shedding in stool can be detected for up to 6 weeks post-infection, oropharyngeal shedding typically lasts less than 4 weeks. Light microscopy of vesicle biopsies or scrapings can aid in differentiating HFMD from varicella-zoster virus and herpes simplex virus infections, especially in atypical presentations. Serology is not typically sensitive for acute HFMD diagnosis, but IgG levels can be used to monitor recovery in research settings. In specialized centers, serology may be used to distinguish enterovirus 71 from coxsackievirus infections due to prognostic implications.
Currently, polymerase chain reaction (PCR) assays are widely available to confirm coxsackievirus or enterovirus infection. Real-time PCR assays performed on lesion swabs offer a rapid and sensitive method for definitive laboratory confirmation of HFMD etiology, especially in cases requiring differential diagnosis or epidemiological surveillance.
Treatment and Management Strategies for HFMD
HFMD is generally a self-limiting illness, resolving spontaneously within 7 to 10 days. Treatment is largely supportive, focusing on symptom management. Pain and fever can be effectively managed with over-the-counter analgesics such as NSAIDs and acetaminophen. Maintaining adequate hydration is crucial, particularly in young children who may experience reduced oral intake due to painful mouth ulcers. A gargle solution composed of ibuprofen and diphenhydramine can provide local relief by coating the oral ulcers and alleviating pain. It is important to note that steroid use has been associated with an increased risk of severe HFMD and should be avoided.
In recent years, research has focused on developing specific antiviral treatments for enterovirus 71-induced HFMD due to its potential for severe neurological complications. While no drugs are currently approved specifically for HFMD, promising agents under investigation include molecular decoys, translation inhibitors, receptor antagonists, and replication inhibitors. Pleconaril, an anti-picornaviral agent, has shown some promise against enterovirus 71. However, there are no licensed antiviral medications specifically for routine HFMD treatment. Anecdotal evidence suggests potential clinical response to acyclovir, but this has not been substantiated in large-scale clinical trials.
Vaccine development for HFMD and Enteroviruses has progressed significantly. Strain-specific inactivated whole-virus aluminum-adjuvant vaccines have been developed and approved for widespread use in China. Clinical trials have demonstrated high efficacy, with a 3-dose regimen of the EV71 C4a vaccine showing 94.7% efficacy and protection lasting approximately 2 years. Other vaccine modalities, including virus-like particles, DNA, peptide, and subunit vaccines, are in various stages of clinical trials, offering hope for future preventative strategies.
Differential Diagnosis of Hand, Foot, and Mouth Disease
The differential diagnosis for HFMD encompasses conditions presenting with maculopapular or vesicular rashes, with or without oral lesions. These include:
- Erythema multiforme
- Herpangina
- Herpes simplex
- Herpes zoster
- Kawasaki disease
- Toxic epidermal necrolysis
- Viral pharyngitis
- Rocky Mountain spotted fever
- Varicella zoster infection (chickenpox)
- Steven-Johnson syndrome
- Monkeypox – Particularly relevant in the context of ongoing outbreaks, as clinical differentiation between monkeypox and HFMD can be challenging.
Prognosis and Expected Outcomes in HFMD
The prognosis for the vast majority of patients with HFMD is excellent. Most individuals recover fully within a few weeks without any lasting sequelae. The acute illness typically resolves within 10 to 14 days, and recurrent or persistent infections are rare.
Potential Complications of HFMD
Although uncommon, serious complications can arise from HFMD, including pneumonia, myocarditis, pancreatitis, pulmonary edema, and serositis affecting major organs. Meta-analyses have identified risk factors for severe outcomes and mortality in HFMD, such as lethargy, pneumo-edema/pneumorrhagia, seizures, dyspnea, and coma. The case fatality rate associated with enterovirus 71 infection has been reported to be around 1.7% in systematic reviews.
Deterrence and Patient Education for HFMD Prevention
Patient and parental education is paramount in limiting HFMD transmission, both among children and between children and adults. Handwashing is a proven effective measure to prevent HFMD spread. Community intervention studies have demonstrated that intensive hand hygiene education improves personal hygiene practices in parents and children, leading to a reduction in HFMD incidence within the population. Parents should be advised to keep infected children away from immunosuppressed individuals due to the potential for more severe illness in vulnerable populations.
Clinical Pearls and Key Considerations in HFMD Management
Most patients with coxsackievirus-induced HFMD can be managed as outpatients. However, those exhibiting central nervous system involvement may require hospitalization for close monitoring and potential neurological imaging. Infants are at risk for dehydration, especially if oral ulcers impede oral intake, and may require intravenous hydration. Hospital admission is strongly recommended for infants with HFMD who present with signs of severe disease or lethargy. Given the prolonged viral shedding in stools, emphasizing hand hygiene and good personal hygiene practices remains crucial in preventing further transmission.
Enhancing Healthcare Team Outcomes in HFMD Management
With HFMD cases on the rise, healthcare professionals need to be adept at accurate and timely diagnosis. Neurological consultation may be warranted in cases with neurological manifestations. Optimal management of HFMD benefits from an interprofessional team approach, including physicians (MDs, DOs, NPs, or PAs), specialists (neurologist, pediatrician, internist, infectious disease expert), nursing staff, and pharmacists. Clinicians are responsible for diagnosis, initiating treatment, and determining necessary referrals. Pharmacists play a vital role in medication management, medication reconciliation, and addressing medication-related inquiries. Nurses are essential for coordinating care, assisting with examinations, and providing patient and parent education. Open communication and collaboration among all team members are crucial to ensure comprehensive patient care and achieve optimal outcomes in HFMD management. The prognosis for most patients remains excellent, with full recovery typically within 7 to 21 days.
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