Mucositis and rash in a 9-year-old boy

THE CASE

The anxious parents of a 9-year-old boy bring him to clinic for the evaluation of progressive sores in his mouth for 2 days and a rash that erupted last night. Nine days earlier, he had felt warm and had a cough with wheezing and abdominal pain. At that time, he was taken to an acute care center where he was diagnosed with pneumonia and prescribed amoxicillin. Overnight, his symptoms worsened, and he was admitted to the hospital. The amoxicillin was discontinued and albuterol, azithromycin, and oral steroids were started. He did well and was discharged after 4 days. Shortly afterward, the mother noted a few blisters on his upper lip.

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Physical exam

The boy’s past medical history was negative. With the exception of slight tachycardia, his vital signs were within normal limits. He was drooling and had hemorrhagic crusted bullae with ulcerations on his lips that crossed the vermillion zone to the oral mucosa. His mucous membranes were slightly dry but his tongue and the remainder of the oropharynx were unremarkable. He had 2 quarter-sized erythematous annular plaques on his left forearm and erythema with slight swelling of his fingertips. The bullous lesion of his right ear exhibited a positive Nikolsky sign (after slight pressure was applied to the lesion, it expanded at the border and the surface, became wrinkled and peeled off like tissue paper). No conjunctivitis or lymphadenopathy was noted and the remainder of his examination was normal. He was readmitted to the hospital for further evaluation.

Differential diagnosis

The patient now had an almost 2-week history of a subjective fever, a 2-day history of mucositis, and a 1-day history of a rash on his arm and right ear. Possible etiologies of fever, mucositis, and rash (Table 1) include herpetic gingivostomatitis with erythema multiforme (EM); Kawasaki disease (KD); Mycoplasma pneumoniae (M pneumoniae); Stevens-Johnson syndrome (SJS); and toxic epidermal necrolysis.

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The initial concern was herpetic gingivostomatitis with EM. The majority of EM cases follow herpes labialis infections, usually by 3 to 14 days, but concurrent infection and EM have been noted. The rash in EM is characterized by symmetric eruption of red papules and/or urticarial plaques that enlarge centrifugally over 2 to 3 days, forming the classic “target” lesions often with a central bulla.¹ It has a predilection for the palms and soles and extensor surfaces of the extremities. However, the patient’s lesions were not present in these areas and the characteristic concentric rings of EM were absent. Erythema multiforme as a single diagnosis was not considered in this patient because of the severity of his mucositis.

Kawasaki disease, also known as mucocutaneous lymph node syndrome, was considered. Although the etiology remains elusive, infectious causes have been reported. One theory is that bacterial toxins acting as superantigens activate T cells with subsequent cytokine release. Gram-negative bacteria, Mycoplasma, Rickettsia, Staphylococcus, and Streptococcus species have been implicated. One case-controlled study suggested that some cases of KD are associated with M pneumoniae infection.² There is no single pathognomonic finding or laboratory test for KD; the diagnosis is based on clinical features. Criteria include at least 4 days of fever and at least 4 of the 5 signs listed in Table 2 without alternative explanation for the findings.³

Because the patient had a history of a subjective fever, mucous membrane changes, peripheral extremity changes, and a rash, incomplete KD was considered. Although atypical KD is more common in younger children, “the epidemiologic case definition also allows diagnosis of KD when a person has fewer than 4 principle clinical criteria in the presence of coronary artery aneurysms.”³

Although the rash in KD can be EM-like, lesions tend to be truncal and cutaneous, and oral bullae and ulcerations have not been described in KD. Moreover, a Nikolsky sign would not be consistent with KD. Therefore, without fulfilling the diagnostic criteria for classic KD, alternative explanations were explored.

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Because the patient had been diagnosed with pneumonia, M pneumoniae-induced rash and mucositis were considered. The rash can be vesicobullous, targetoid, or macular, but unlike EM where the target lesions occur on the hands and feet, these lesions are predominantly located on the extremities and trunk. However, the skin lesions, as in this patient, can be limited. A 90-year systematic review found that these findings can be mislabeled as EM or SJS but that patients with an M pneumoniae-induced rash and mucositis are younger, have more severe mucositis, have less cutaneous involvement, and experience a milder disease course with less hepatic and renal involvement.⁴ Before the patient developed his rash, his isolated mucosal involvement might have been attributed to Fuchs syndrome or incomplete SJS.

In addition, because the patient had a history of antibiotic use (1 dose of amoxicillin and 5 doses of azithromycin), SJS was considered. Stevens-Johnson syndrome often is triggered by drugs and less commonly by infections. It is a clinical diagnosis suggested by fever and malaise followed by an extensive painful, nonblanching, macular rash that commonly progresses to blistering or sloughing, and mucositis. Less than 10% of the total body surface area has epidermal detachment.

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This patient’s rash progressed to blistering and sloughing and exhibited a positive Nikolsky sign. His lesions were slightly elevated, consistent with SJS, and lacked the characteristic concentric rings of EM. Also, the lesions of SJS are more commonly located on the trunk and 2 or more mucosal surfaces are involved. Although the patient had no truncal lesions, he had at least 1 (oral) and possibly 2 (respiratory epithelial mucosa) altered mucosal surfaces. However, because SJS rarely occurs within the first few days of drug administration, the timing of the patient’s mucositis and rash (9 days after a single dose of amoxicillin and 2 days after completing a course of azithromycin) made a diagnosis of SJS secondary to medication less likely. It is thought that the reaction follows drug therapy by 1 to 3 weeks, allowing time for the antigenic stimulus to cause the host immune response.

Although the most common triggers for SJS are medications, M pneumoniae infection is the most likely infectious trigger. A case series of children with SJS showed that most had a positive M pneumoniae-polymerase chain reaction (PCR); none had preceding medication exposure; and all had radiographic pneumonia.⁵ A case-controlled study comparing children with SJS (with and without evidence of M pneumoniae infection) showed that M pneumoniae-associated SJS episodes were more likely to have pneumonia (odds ratio [OR], 10.0), preceding respiratory symptoms (OR, 30.0), an erythrocyte sedimentation rate 35 mL/hr or greater (OR, 22.8), and fewer than 3 affected skin sites (OR, 4.5) than non-M pneumoniae-associated SJS episodes.⁵

Laboratory testing

Laboratory tests were ordered to diagnose identifiable causes of mucositis and rash, electrolyte abnormalities, and any hepatic or renal complications. Negative results were reported for the herpes simplex virus types 1 and 2 PCR. Tests for influenza virus types A and B, parainfluenza virus types 1, 2, and 3, and respiratory syncytial virus also were negative. Both immunoglobulin (Ig) M and IgG antibodies for M pneumoniae were elevated. The patient’s complete blood count, basic metabolic panel, liver profile, and urinalysis were normal. Abnormal results are shown in Table 3. A chest radiograph showed mild perihilar infiltrates.

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Further investigation

Because atypical or incomplete KD was considered, pediatric cardiology was consulted and an echocardiogram was ordered. Mild dilatation of the right coronary artery (RCA) and left main coronary artery (LMCA) were noted as 3.3 mm and 4 mm, respectively. No aneurysms were seen. Coronary artery (CA) abnormalities are classified as: an internal lumen diameter greater than 3 mm in children aged 4 years and younger, and greater than 4 mm in children aged 5 years and older; the internal diameter of a segment measures 1.5 times larger than that of the adjacent segment; or a coronary lumen that is clearly irregular.⁶

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Other criteria consider an echocardiogram positive if any of 3 conditions are met: z score of left anterior descending (LAD) or RCA equal to or greater than 2.5; CAs meet Japanese Ministry of Health criteria for aneurysms; or more than 3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased left ventricle function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2 to 2.5.³ However, dilatation occurs in other inflammatory and infectious diseases, and the distribution of CA dimensions for children with febrile illnesses other than KD has not been established.⁷ The pathogenesis may be related to higher myocardial oxygen demand caused by fever and tachycardia or pathogenic proteins that bind to the endothelial cells, activating common immune response pathways that produce cytokines and further cell damage.

Diagnosis

Although there is much clinical overlap between the various illnesses in the differential diagnosis for the patient and a lack of laboratory confirmation for most concerns, the patient’s high M pneumoniae IgM and IgG titers make M pneumoniae-induced rash and mucositis the most likely diagnosis. Given the patient’s CA dilatation and evidence that M pneumoniae is associated with KD and SJS leads to presumptive treatment for both. Fortunately, both have been shown to respond to intravenous immunoglobulin (IVIG).

Treatment and management

The patient was treated for Mycoplasma pneumonia during his first hospitalization.  During his second hospitalization, he was treated for KD. Intravenous immunoglobulin and aspirin are best initiated within the first 10 days. He received a 1-time dose of IVIG at 2 g/kg and aspirin at 80 mg/kg was started. A moisturizing ointment also was used for symptomatic relief of his oral lesions. The patient improved and was discharged home after 5 days to continue on aspirin. Two months later, a repeat echocardiogram showed resolution of his CA dilatation and the aspirin was discontinued. No desquamation was ever noted. Because recurrences of KD, M pneumoniae, and M pneumoniae-induced rash and mucositis are possible, close long-term follow-up is planned.

REFERENCES

1. Soukup S. Painful lesions target girl’s hands, feet, and mouth. Contemp Pediatr. 2015;32(7);38-40.

2. Lee MN, Cha JH, Ahn HM, et al. Mycoplasma pneumonia infection in patients with Kawasaki disease. Korean J Pediatr. 2011;54(3):123-127.

3. Newburger JW, Takahashi M, Gerber MA, et al; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young. American Heart Association. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular in the Young, American Heart Association. Pediatrics. 2004;114(6):1708-1733.

4. Canavan TN, Mathes EF, Frieden I, Shinkai K. Mycoplasma pneumonia-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systemic review. J Am Acad Dermatol. 2015;72:239-245.

5. Olson D, Watkins LK, Demirjian A, et al. Outbreak of Mycoplasma pneumoniae-associated Stevens-Johnson syndrome. Pediatrics. 2015;136(2):e386-e394.

6. Research Committee on Kawasaki Disease. Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Tokyo, Japan: Japanese Ministry of Health and Welfare; 1984.

7. Muniz JC, Dummer K, Gauvreau K, Colan SD, Fulton DR, Newburger JW. Coronary artery dimensions in febrile children without Kawasaki disease. Circ Cardiovasc Imaging. 2013;6(2):239-244.

Dr Mazur is professor of pediatrics at the University of Texas, Houston. Ms Rosas is a first-year medical student at the University of Texas Medical School at Houston. Ms Little is a fourth-year medical student at the University of Texas Medical School. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.