PEDIATRICS Vol. 119 No. 4 April 2007, pp. e1002-e1005 (doi:10.1542/peds.2006-2401)
EXPERIENCE & REASON |
Mycoplasma pneumoniae and Atypical Stevens-Johnson Syndrome: A Case Series
a Division of Infectious Diseases
b Division of Emergency Medicine, Department of Pediatrics
c Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
d Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin
ABSTRACT
Mycoplasma pneumoniae is a common cause of community-acquired respiratory illness in the adolescent population. Stevens-Johnson syndrome is an extrapulmonary manifestation that has been associated with M pneumoniae infections. Three adolescent males presented within a 1-month period with M pneumoniae respiratory illnesses and severe mucositis but without the classic rash typical of Stevens-Johnson. Diagnosis was facilitated by the use of a polymerase chain reaction–based assay. This case series highlights the potential for M pneumoniae–associated Stevens-Johnson syndrome to occur without rash and supports the use of polymerase chain reaction for early diagnosis.
Key Words: Stevens-Johnson syndrome • Mycoplasma pneumoniae • mucositis
Abbreviations: SJS, Stevens-Johnson syndrome • PCR, polymerase chain reaction • PCP, primary care provider • HSV, herpes simplex virus
Mycoplasma pneumoniae is a well-recognized cause of community-acquired pneumonia. Most cases are mild and can be managed on an ambulatory basis. However, some M pneumoniae infections can be complicated by extrapulmonary disease. These manifestations occur in <10% of cases and include hemolytic anemia, hepatitis, arthritis, meningitis, and Stevens-Johnson syndrome (SJS).1 In children, M pneumoniae is the most commonly identified infectious cause of SJS.2 The classic rash and mucosal involvement of SJS typically accompany the signs and symptoms of an M pneumoniae respiratory infection. However, in recent literature, sporadic cases of M pneumoniae pneumonia with mucositis but lacking the typical target lesions and blisters of SJS have been described.3,4 In the following case series is described a cluster of 3 cases of SJS associated with M pneumoniae infection in which the classic rash was absent. All 3 cases were confirmed with polymerase chain reaction (PCR) technology, which facilitated rapid diagnosis and treatment of M pneumoniae.
CASE REPORTS
Case 1.
In December, an 11-year-old previously healthy boy returned from Boy Scout camp with complaints of a sore throat and low-grade fever. He was seen by his primary care provider (PCP), given a diagnosis of streptococcal pharyngitis by rapid antigen testing, and treated with penicillin. The fever persisted, and he developed a cough with shortness of breath over the next few days. On the day before admission, he was noted to have an urticarial rash on his trunk. Because of concern for a drug allergy, he was given diphenhydramine, and treatment was changed to azithromycin. On the following day he developed a fever of 103°F, red eyes, swelling, and peeling of his lips and was admitted to the hospital. He was found to be hypoxic, with an oxygen saturation of 85% on room air, and hypotensive, with diastolic blood pressure measurements (mmHg) in the 50s in the emergency department. He was admitted to the PICU.
On physical examination, his oral temperature was 38.2°C, heart rate was 135 beats/minute, blood pressure was 100/66 mmHg, and respiratory rate was 40 breaths/minute. He had bilateral subconjunctival hemorrhages, cracked erythematous lips with friable, erythematous mucosa, shotty anterior cervical adenopathy, and coarse crackles and wheezes bilaterally on auscultation. There were several small, erythematous macules on his shoulders. His laboratory workup results included an erythrocyte sedimentation rate of 47 mm/hour and a C-reactive protein level of 9.8 mg/dL. His chest radiograph showed bilateral infiltrates. He was diagnosed with mucositis and pneumonia.
He received fluid resuscitation, epinephrine, steroids, and oxygen supplementation by face mask. He was initially started on ceftriaxone and clindamycin, in addition to azithromycin, for treatment of the pneumonia, and erythromycin ophthalmic ointment was prescribed for the conjunctivitis. His antibiotic regimen was changed to levofloxacin on day 3 of hospitalization. Throat-swab results for M pneumoniae PCR collected at that time were positive. He was discharged on the fifth hospital day to complete a 14-day course of levofloxacin.
Case 2.
A 14-year-old previously healthy boy developed a fever of 102.6°F and myalgias thought to be caused by influenza virus in January. Approximately 1 week later, he began to have cough and congestion. A prescription for amoxicillin-clavulanate was telephoned in for him by his PCP. At a follow-up visit with his PCP 2 days later, he was found to have continued fever, worsening cough, and ulcerations of his oral mucosa. A chest radiograph showed a left lower lobe infiltrate, and his antibiotic was changed to clarithromycin. He was admitted to the general pediatric floor later that day because of an episode of hematemesis.
On physical examination, his axillary temperature was 38.1°C, heart rate was 111 beats/minute, respiratory rate was 22 breaths/minute, and blood pressure was 117/66 mmHg, and his oxygen saturation was 94% on room air. His physical examination showed bilateral injected conjunctiva, friable, erythematous lesions on his lips and soft palate, decreased breath sounds at the left base on auscultation, and an erythematous, ulcerated lesion on the penile meatus. His laboratory workup included a white blood cell count of 12.0/mm3, normal liver-function test results, and negative heterophile antibody test and urinalysis results. He was given a diagnosis of mucositis and pneumonia (see Fig 1).
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The patient was started on acyclovir, because of concerns for possible herpes simplex virus (HSV), in addition to azithromycin and cefuroxime. Results of swabs from his mouth and penis, collected for viral cultures, were negative. Throat-swab results for M pneumoniae PCR collected on the day of admission were positive. He improved clinically and was discharged on hospital day 3 to complete a 5-day course of azithromycin.
Case 3.
A 16-year-old previously healthy boy developed a sore throat and erythematous conjunctiva in January. He was seen by his PCP and had a negative rapid antigen detection test result for group A streptococcus. Polymyxin B and trimethoprim ophthalmic drops were prescribed for his conjunctivitis. Four days later, he was noted to have ulcerations of his oral mucosa, and oral acyclovir was prescribed. The following day, his sore throat worsened, and clarithromycin was prescribed. His fever increased to 103°F, and he was evaluated by an otolaryngologist. The patient was then referred to the emergency department for hydration and management of suspected HSV gingivostomatitis.
His physical examination showed a heart rate of 120 beats/minute and blood pressure of 96/53 mmHg, bilateral conjunctivitis, swollen, erythematous lips, diffuse friable oral mucosa, and an ulceration of the penile meatus. A chest radiograph showed a right middle lobe infiltrate. He was diagnosed with mucositis and pneumonia. Results of a rapid HSV-antigen test on his oral mucosa were negative, and he was started on ceftriaxone and azithromycin for treatment of the pneumonia. Throat-swab results for M pneumoniae PCR collected on the day of admission were positive. The patient subsequently required placement of a percutaneous intravenous central catheter line for parenteral nutrition and patient-controlled analgesia with morphine because of continued severe mouth and pharyngeal pain. He was discharged on hospital day 13 after improvement of his symptoms and completion of 5 days of treatment with ceftriaxone and azithromycin.
DIAGNOSIS WITH M pneumoniae PCR
Throat-swab specimens were obtained from each of the 3 patients and tested for M pneumoniae by a multiplex PCR-based assay as described previously.5,6 Throat-swab specimens from each of the patients included in this series tested positive for both M pneumoniae DNA targets in duplicate reactions, and there was no evidence of PCR inhibition. Positive and negative controls also yielded expected results (see Fig 2).
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SJS AND M pneumoniae
In a 1-month period of time, 3 adolescent boys were hospitalized at Children's Hospital of Pittsburgh with M pneumoniae pneumonia associated with SJS but lacking the classic rash. Making the diagnosis of SJS in the absence of the classic rash is clinically challenging, given that a number of other disease processes can manifest with mucosal changes, including infections, autoimmune diseases, and drug reactions. The exact pathophysiology of SJS is unclear but most likely involves immunologic response to reactive drug metabolites or infectious pathogens.7 The earliest histologic finding in skin lesions is a perivasculitis of superficial dermal vessels associated with an inflammatory cell infiltrate.7 Identification and withdrawal of the precipitating agent of SJS is important in management of the disease and may prevent additional episodes.8
In children, infections are the most commonly identified cause of SJS, with M pneumoniae implicated most frequently.2,3 Other associated infections include HSV, Mycobacterium tuberculosis, group A streptococci, hepatitis B virus, Epstein-Barr virus, enteroviruses, Yersinia enterocolitica, Histoplasma capsulatum, and Coccidioides immitis.8 HSV has been shown to have a stronger relationship with erythema multiforme minor than with SJS.8 Drugs are also an important cause of SJS and include penicillins, tetracyclines, cephalosporins, aspirin, and nonsteroidal antiinflammatory drugs. Systemic diseases such as inflammatory bowel disease may also precipitate SJS.3,7
Clinical features of SJS usually occur 1 to 3 weeks after the drug or infectious exposure. Patients present with mucosal erosions, skin lesions, and, occasionally, constitutional symptoms. Mucosal erosions typically occur at 2 or more sites such as oral, ocular, or genitourinary. Prodromal target lesions followed by skin detachment are the dominant clinical findings.7 Typical target lesions have 3 rings (a bright-pink or red inner ring, a lighter-pink outer ring, and a darker-pink outermost ring) and characteristically occur symmetrically on the extensor surfaces of the extremities and the gluteal area; the trunk and flexor surfaces are less likely to be involved.3,7 Small blisters or purpuric macules may occur, and the skin lesions are frequently pruritic and painful.9 Respiratory or gastrointestinal lesions occur in 10% to 30% of cases. Painful erosions may extend into the esophagus and cause difficulty with swallowing. Ocular complications can include keratitis and corneal scarring.
The adolescents described in this case series had unusual presentations of SJS. Although they all had severe oral mucositis, they lacked typical skin manifestations. The patient in the first case initially had a rash, but it never progressed to blisters or target lesions and quickly resolved. In this case, other etiologies of illness were initially considered, including streptococcal toxic shock syndrome and atypical Kawasaki disease. However, the patient's symptoms persisted despite appropriate antibiotic therapy for streptococcal disease, and he did not meet the criteria for diagnosis of Kawasaki disease. In addition, the finding of bilateral infiltrates on his chest radiograph was suggestive of atypical bacterial pneumonia as the cause of his illness.
A retrospective review of cases of SJS at Children's Hospital in Bordeaux, France, demonstrated that M pneumoniae infection was identified in 5 of 17 cases of SJS and strongly suspected in another 5 cases.2 There have also been sporadic reports in the literature of cases of severe mucositis without accompanying skin lesions associated with M pneumoniae infection.3,4 In 2005, Letko et al7 published a comprehensive review of the literature on SJS in which they demonstrated that, historically, there has been little agreement on diagnostic criteria; however, a majority of the case reports included a description of target lesions. In addition, a number of authors consider SJS to fall within a spectrum of diseases that affect the skin and mucous membranes, including erythema multiforme minor, erythema multiforme major (a term sometimes used interchangeably with SJS), and toxic epidermal necrolysis.7,8
Mycoplasmas are among the smallest, free-living microorganisms. After an incubation period of 1 to 4 weeks, infection typically presents with cough, coryza, fever, and malaise, which may progress to pneumonia in 
10% of patients.10 The rate of M pneumoniae pneumonia has been shown to be highest in school-aged children between 5 and 14 years of age.10 Extrapulmonary manifestations of M pneumoniae infection are unusual and include mucocutaneous eruptions, nervous system disease, hemolytic anemia, and arthritis.11
Mycoplasmas lack a cell wall and are slow-growing in culture, requiring 10 to 14 days of incubation, a characteristic that has made rapid diagnosis challenging.10 The association of serum cold hemagglutinin titers of 
1:32 in 50% to 75% of patients with M pneumoniae pneumonia infection has been used to assist with diagnosis.1,12 The test is more specific when serologic titers are higher. In addition, a variety of other respiratory tract pathogens can also cause a modest increase in cold hemagglutinin titers.1 Immunofluorescence and enzyme immunoassay tests detect immunoglobulin M and G antibodies specific for M pneumoniae.10 After infection, immunoglobulin M antibodies can remain elevated for a period of weeks to months. Consequently, although they can confirm recent infection, they may not signify current infection.12
PCR is a rapid, specific, and sensitive method of diagnosis of M pneumoniae infections.5,6 Although previously used mainly in research settings, PCR for M pneumoniae detection is now more widely available. The multiplex PCR assay used by our laboratory is specific and considerably more rapid than culture or serology. The assay can detect a single copy of M pneumoniae DNA in a PCR. Recent studies have validated the PCR technique, and results compare favorably to culture and serologic testing.13,14 Sensitivity and specificity of PCR-based assays have been shown to range from 78% to 100%.10,15 The sensitivity of serology on a single specimen is much less, ranging from 50% to 66%.16 Although the sensitivity of serology improves when paired sera samples are examined, this lengthens the time to confirmed diagnosis considerably.
CONCLUSIONS
Mucositis, with or without accompanying skin lesions, is a recognized extrapulmonary manifestation of infection with M pneumoniae. Accordingly, cases of severe mucositis, within the context of respiratory illness, should prompt testing for M pneumoniae as a potential causative agent. The use of real-time and multiplex PCR enables a rapid diagnosis, reducing the need for additional laboratory testing, and facilitates early initiation of treatment, thereby potentially decreasing the duration of illness in these patients.
FOOTNOTES
Accepted Oct 18, 2006.
Address correspondence to Karen A. Ravin, MD, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583. E-mail: karen.ravin{at}chp.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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