An old virus with atypical presentation - Tomato flu?

While the world is still under the COVID-19 variants’ threat and actively monitors the evolution of Monkeypox, India alerted about the appearance of a febrile exanthem in Kerala on May 6, 2022.¹ The characteristic red blister of this condition earned it the name “Tomato Flu or Tomato Fever” because rash appears as tomato red color and size of small tomato.² Limited to Kerala for three months, the outbreak is now spreading in the neighboring state of Tamil Nadu and two farther ones: Odisha and Haryana. This situation raised concern about its propagation speed across borders and motivated preventive measures from the Kerala Health department to prevent further spread to other states. For example, the border districts of Kerala like Kannada, Udupi, Kodagu, Chamarajanagar, and Mysuru have been on a daily alert since May with the orientation to monitor children for any symptoms of tomato flu (TF).³ Up to July 26, 82 under-five cases have been reported in Kerala.¹ In Odisha, 26 children from one to nine years old diagnosed with TF have been recently identified, according to the Regional Medical Research Center in Bhubaneswar.¹ The spread of the virus in Odisha also has the particularity to show an evolution of the group at risk, reaching children over five years old.¹

Since the apparition of the Kerala outbreak, there has been a debate about whether an emergent virus provoked the disease or not. The possibility of an entirely new virus was explored in the early days and then abandoned.⁴ Another hypothesis explored the possibility that the disease may have arisen as an after-effect of a Chikungunya or a Dengue infection.⁵ Did this theory consider it a complication of those diseases or a health condition of its own whose occurrence may be favored by the previous illness with Chikungunya or Dengue fever? This information was never specified, and this hypothesis was also considered unlikely. Nevertheless, the more recent and accepted explanation present TF as a variant of the Hand Foot Mouth disease (HFMD) caused by a virus from the Enterovirus family, the Coxsackie virus A-16.⁵ The HFMD is a well-known contagious viral exanthem affecting mainly the under-five. This disease can spread anytime during the year, but with a seasonal peak during summer and fall.⁶ Despite the atypical presentation of the cutaneous lesions of the Kerala outbreak, is it justified to rename the disease as a new one or consider it a variant of the HDFM as we are all used by now to the many variants of COVID-19? In his correspondence on 8/26/2022, Lucey argues against the use of a new name for a well-known virus.⁷ Still, the atypical presentation described in India raised question about the clinical difference between TF and HFMD. Therefore, studies and investigations about the biological and environmental conditions that may influence that change coupled with active surveillance of the disease symptomatology should bring more evidence.

Disease transmission and symptoms

The first evidence showed that TF, as the HFMD, is a very contagious disease transmitted by close contact making under-five children a particular group at risk. Infants can be infected mainly through nappies or if they touch unclean surfaces or put infected objects directly into the mouth.⁸

The main symptoms of TF are described as high fever, intense arthralgias with sometimes joint swelling, and a rash localized in the mouth (tongue, gums, inside of the cheek), palms, and soles.⁴ Doctors now report some atypical localization of the lesions; they can also be found on the buttocks or even the shedding of nails.⁴ The lesions are described as red, painful, growing blisters.

Additional symptoms like many viral infections include nausea, vomiting, diarrhea, dehydration, fatigue, body aches, and influenza-like symptoms.¹ The symptoms may have different presentations or intensity from one child to another, as illustrated by the two cases diagnosed in the United Kingdom a week after returning from a trip to Kerala.⁹ The two siblings, a five-year-old boy and a 13-month-old girl presented a vesicular rash without fever or other systemic symptoms. The girl's rash was more florid, and she gave two days after painful oral lesions while his brother was in a healing process. After six days, the boy's lesion completely healed without scarring, while his sister had to wait until 16 days for the same result.⁹ The Enterovirus PCR was positive for both children, and the EV typing by sequencing showed Coxsackie A-16,⁹ another finding in favor of the likeliness of the tomato flu as an atypical presentation of the HFMD.

Differential diagnosis

As with many other febrile rashes, the diagnosis of TF is not straightforward because of the similarity of its main symptoms with other diseases. When considering the exanthem, the most common differential diagnoses are HFMD, Monkeypox, and Varicella. The intense generalized pain and Flu-like symptoms brought to eliminate Dengue, also Dengue present with fever initially but rash appears in the late stage of disease,¹⁰ Chikungunya, Zika, or COVID-19, as shown in Table 1.

Table 1.

Differential diagnosis of tomato flu (HFMD).

Differential Diagnosis	Virus	Cutaneous lesions	Other clinical features	Remarks
Hand foot mouth syndrome/tomato flua,b,c	Coxsackievirus A16, A6, A5, A7, A9, A10, B2, B5, EV-71, and Echovirus	Localized vesicles and painful ulcerations are limited to the oral cavity, followed by grayish vesicles with erythema in the palms and soles. The lesions can also be localized on the buttocks, genitalia, legs, and arms. /Red and painful blisters throughout the body gradually enlarge to the size of a tomato.	High fever, sore mouth or sore throat, malaise. Vomiting is rare. /High fever, rashes, intense pain in joints, fatigue, nausea, vomiting, diarrhea, fever, dehydration, swelling of joints, body aches	HFMD caused by multiple Enterovirus (EV) serotypes mainly coxsackievirus A6 (CVA6), coxsackievirus A16(CVA16) and Enterovirus 71 (EV71) in India.b,c The disease arising from EV71 and CVA16 infections; has received noticeable attention since 2008 due to increasing evidence that the clinical, epidemiologic, and etiologic characteristics of HFMD are currently quite different from those initially thought. CVA6-associated atypical HFMD is characterized with aggressive clinical presentation like crusted lesions, an eczema-form rash affecting the arms, trunk, buttocks and legs, onychomadesis with a greater disease severity were genetically different from other earlier characterized CVA6 isolates.c This unusual clinical presentation has been demonstrated the role of virus recombination or mutations in the viral genome of various geographical regions leading to emergence of new strains with altered phenotypes. Urgent laboratory testing of more samples and genotyping of the virus is therefore needed to confirm the etiology to facilitate proper treatment.
Chikungunyad	Chikungunya virus	Maculopapular rash diffuse and erythematous of the trunk and extremities, palms, or soles accompanied by a flushed appearance of the face and trunk	High fever, sore throat, headache, abdominal pain, constipation, retro-orbital pain, conjunctivitis, intense migratory and polyarticular arthralgia
Zika	Zika virus	Maculopapular dermatitis starts on the trunk and descends to the lower extremities.	Fever, pain in minor joints, conjunctivitis, intraocular headache
COVID-19	Novel Coronavirus	–	Fever, fatigue, Body aches, cough, dyspnea, diarrhea, vomiting
Monkey poxe	Human monkeypox virus	Rash progresses to several stages: macules, papules, vesicles, and pustules.	Fever, chills, headaches, lethargy, asthenia, lymph node swellings, back pain, and myalgia
Varicella/chickenpoxf	varicella-zoster virus	Erythematous small macules on the scalp, face, trunk and proximal limbs progress to papules, then clear vesicles and pustules. The vesicles present a central umbilication and crust formation, characteristic of chickenpox.	Low fever, nausea, myalgia, anorexia, and headache.

^aKnöpfel N, Noguera-Morel L, Latour I, Torrelo A. Viral exanthems in children: A great imitator. Clin Dermatol. 2019; 37 (3):213–226. https://doi.org/10.1016/j.clindermatol.2019.01.009.

^bGopalkrishna V, Ganorkar N. Epidemiological and molecular characteristics of circulating CVA16, CVA6 strains and genotype distribution in hand, foot and mouth disease cases in 2017 to 2018 from Western India. J Med Virol. 2021 Jun; 93 (6):3572–3580. https://doi.org/10.1002/jmv.26454. Epub 2020 Oct 1. PMID: 32833231.

^cGanorkar NN, Patil PR, Tikute SS, Gopalkrishna V. Genetic characterization of enterovirus strains identified in Hand, Foot and Mouth Disease (HFMD): Emergence of B1c, C1 subgenotypes, E2 sublineage of CVA16, EV71 and CVA6 strains in India. Infect Genet Evol. 2017; 54:192–199. https://doi.org/10.1016/j.meegid.2017.05.024.

^dNatesan SK. Chikungunya Virus Clinical Presentation: History, Physical Examination, Diagnostic Criteria for Chikungunya Fever. Published February 17, 2022. Accessed August 26, 2022. https://emedicine.medscape.com/article/2225687-clinical.

^eMoore MJ, Rathish B, Zahra F. Monkeypox. In: StatPearls. StatPearls Publishing; 2022. Accessed August 25, 2022. http://www.ncbi.nlm.nih.gov/books/NBK574519/.

^fPapadopoulos AJ. Chickenpox Clinical Presentation: History, Physical Examination. Accessed August 26, 2022. https://emedicine.medscape.com/article/1131785-clinical#.

Treatment and prognosis

As a non-life-threatening disease, TF or even HFMD treatment is so far supportive. It focuses on bed rest, hydration, paracetamol for the fever and pain, and other supportive therapy as needed. Isolation of the infected person for five to seven days from the onset of the symptoms is recommended to prevent the spread of the disease. The hygiene and sanitization of the contact surface and environment also help prevent transmission.

Yet, there is no antiviral treatment for TF, as none is used for HFMD. There are no vaccines developed as well. Severe complications or fatalities are not reported; Tomato Fever is described so far as a self-limiting illness. However, continuous monitoring is required to understand the disease's evolution and the need for additional healthcare interventions.

Conclusion

Enterovirus serotypes mainly CA 6 and CA 16 has variety of clinical presentation. Even if TF was described as a rare non-life-threatening disease considered endemic in India, with a potential epidemic, recent evidence showed it could be a variant of an old disease, the HFMD. As an atypical manifestation was described, the disease's geographical spreading and clinical evolution should be closely monitored, as recent outbreaks of other viral diseases urge caution. More information is therefore needed with more samples from endemic region is required to be sequenced to generate more scientific evidence, regional and central WHO office should clear the misconception around the virus and the diseases. Its similarity with other viral exanthems may lead to an under or late diagnosis of those latter. If delayed or non-diagnosed, those other viral infections could seriously affect children and families as some of them, such as measles, may have severe complications. Therefore, frontline healthcare providers should be aware of these various viral rash differentials and informed of the new scientific evidence and epidemiologic distribution of TF for their daily practice. Family and communities should increase surveillance of children in shared spaces during outbreaks and apply preventive measures dictated by health authorities based on scientific evidence.

Contributors

RS, VJD, PS design and write the draft, PM, AD, AM, RPP, SS and BKP review the literature and edit the manuscript. All authors read and agreed for the final manuscript.

Declaration of interests

Authors declare no conflicts of interest.