Pneumoniae Infections and Stevens-Johnson Syndrome
Mycoplasma
Report of Eight Cases and Review of the Literature Maurice
Levy, MD, M.Sc.*, Neil H. Shear, MD*†
On the basis of a literature review and eight cases of our own, we analyzed 37 cases of Mycoplasma pneumoniae (MP) infection and Stevens-Johnson syndrome (SJS). Our clinical and laboratory findings do not differ from those reported in the literature for MP infection with no exanthem or for SJS of various etiologies. Eighty percent of the children presented with symptoms of upper respiratory tract infection (URTI) (cough, fever, sore throat, malaise, headache), with a mean of 10 days (range 1 to 30) before skin rash broke out. Skin manifestations occurred in 94.2% of the patients after 3 to 21 days (mean 10.3 days) of fever. The exanthem, composed predominantly of maculopapular and vesicular, was distributed chiefly on the trunk and extremities and lasted less than 14 days in 87.8% of the patients. Stomatitis was observed in 91.6% of the patients and conjunctivitis in 50%. No consistent pattern seems to emerge by which one could predict the existence of MP infection causing SJS. The complications of SJS associated with MP seem less frequent (2.7%) and much less severe than in cases where SJS arises from other reported causes. Because coincidence cannot be excluded from the assessments of the degree and rate of improvement for the few patients treated with corticosteroid, from the low frequency of complications, and from the mortality rate of zero in this series of patients, the use of corticosteroids for SJS associated with MP infection is questionable.
*From the Division of Clinical Pharmacology (Department of Paediatrics), The Hospital for sick Children and the Division of Dermatology (Department of Medicine), Sunnybrook Health Science Centre, and the University of Toronto, Toronto, Canada.
tDr. Shear is a recipient of a career scientist award from the Ontario Ministry of Health. Correspondence to: Dr. Maurice Levy, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario Canada M5G 1X8.
42
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The Stevens-Johnson
syndrome (SJS),
or
erythema
multiforme (EM) major, is a well-defined systemic disease that can develop into a life-threatening illness. It is generally manifested in skin lesions, such as erythematous paules, plaques, vesicles, bullae and target-like, annular lesions (concentric rings resembling the iris of the eye).’ If these follow the pattern of toxic epidermal necrolysis (Lyell’s syndrome, a severe form of SJS), the mortality rate can reach 50%.2 Mucosal lesions occur and include mouth and genital ulcers. The conjunctiva may be affected, resulting in opacifications, decreased visual activity, and adhesions immobilizing the eye.3-5 Gastrointestinal, renal and musculoskeletal manifestations, although less frequent, include intrahepatic cholestasis,6 hepatitis,’ gastrointestinal bleeding (from erosions and sloughing),’-&dquo; and nephritis.11,11 Arthritis, arthralgia, myalgia, and fever are other
symptoms. the various causes and precipitating factors,’I EM has been associated with infectious processes, largely with herpes simplex infections SJS has also been described in case reports of adenovirus infection,’4 varicella, 155 infectious mononucleosis,’6 influenza B,&dquo; Legionnaires’ disease,&dquo; bacterial endotoxin,19 BCG vaccination,2° pseudomonas,2’ and parasites.22 One of the more common infectious causes of SJS is Mycoplasma pneumoniae (MP). Although an association has been documented for over 30 years, most papers describe only one to five case reports. This paper reports eight cases observed in our hospitals between 1974 and 1989 among 110 pediatric patients diagnosed with EM. It also analyzes the literature in order to identify the clinical characterisitics, pathogenesis and diagnostic criteria of MP-associated SJS in children.
Among
of referee);
prodromal symptoms (fever, malaise, cough, throat, rhinorrhea) and their duration; patient’s general condition on admission; description and distributions of skin lesions and mucous membrane involvement (i.e., conjunctivitis, nasal involvement, genital-anal lesions); course and associated complications: ocular, hepatic, renal, hematologic, pulmonary, gastrointestinal problems); sore
skin condition (mainly necrolysis), electrolyte imbalance and septic complications; laboratory data, including complete blood cell count with differential, erythrocyte sedimentation rate (ESR), serum cold agglutinin titer, mycoplasma complement fixation test (MCFT), liver and kidney function test results, as well as results of cultures (blood, urine, throat swabs, stool, skin lesion); chest (physical findings and x-ray results); results of skin biopsy and autopsy; etiological factors associated with EM and appropriate diagnostic test results; duration of hospitalization and treatment administered. For this paper, we carefully studied the patients with SJS in association with MP infection, comparing their characteristics with similar cases reported in the literature.24-39 Only the cases with positive MCFT (complement fixation titers as described below) accompanied by positive or negative serum cold agglutinins titer result and/or positive or negative nasopharyngeal and skin cultures for the MP organism were included. Of the 34 patients with positive MCFT, four had a single high titer done. The other 30 patients showed fourfold or more of increasing titer. Cold agglutinin titers were done in 31 patients, and titers were increased and positive in only 12 patients.
Results
General Data Patients and Methods The data for this study were retrieved from the charts of patients admitted to The Hospital for Sick Children, Toronto, between 1974 and 1989. Charts of all patients discharged with a diagnosis of EM minor or EM major SJS were reviewed. Patients meeting three of the following criteria were included in the study: (1) the skin lesions described were clearly typical of EM, although the patient may not have been evaluated by a dermatologist; (2) mucosal inflammation and erosion of the nasopharynx, and either conjunctivitis or genito-urinary involvement, were present; (3) skin biopsy revealed characteristic EM histopathology;23 (4) the diagnosis was made by a der-
matologist. The following information was retrieved: general data (i.e., age, sex, weight, seasonal incidence, initial diagnosis
Of the 316,500 children admitted to The Hospital for Sick Children between 1974 and 1989,110 were discharged with a diagnosis of either EM minor or Stevens-Johnson syndrome. Among the latter, eight cases (7.3%) were associated with MP infection. When these cases were added to those reported in the literature, the number of detailed cases of MP associated with a clinical description of SJS totalled 37. Twenty-five patients were males and 12 females. Their mean age was 12.2 years (range 5 to 19 years). Tables 1 and 2 present the summarized clinical and laboratory data of the patients. The seasonal incidence, reported in 16 of the 37 cases, indicated that the cases occur mainly between July and February and sporadically throughout the year. Sixteen out of 26 patients (62%) received early antibiotic treatment for fever, cough, malaise, sore throat, and
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TABLE 1. Incidence of Clinical Data in Children with
Mycoplasma Pneumoniae Infection and Stevens-Johnson Syndrome.
development of SJS. Nine of them given penicillin, seven erythromycin, one Septra and one clindamycin with ampicillin. Two patients had been in contact for three to five weeks otitis before the full were
with relatives who had symptoms of a flu-like illness (fever, cough, sore throat). These patients had a high titer of complement-fixing antibodies for MP and a positive throat swab culture. Two other patients had been in contact for two weeks with relatives who had flu-like
symptoms, but in their cases infection was documented.
no
serological evidence
of
Prodromal Symptoms and Patient’s Condition Admission
on
The characteristic manifestations of MP infection associated with SJS were often preceded by fever, cough and malaise. Sore throat, sore eyes and nasal discharge were less frequent but associated prodromal complaints.
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TABLE 2.
Laboratory Data in Children with Mycoplasma Pneumoniae Infection and Stevens-Johnson Syndrome
aThirty patients showed fourfold ranging from 1/128 to 1/1024
or more
of
increasing MCFT titer from
bTiter rises ranged from 1/4 to 1/1792. WBC=white blood cell, PMN=polymorphonuclear, fixation titer
1/4 to 1/8000. Four had
a
high single titer done
ESR=erythrocyte sedimentation rate, MCFT=mycoplasma complement
Fever was observed in 26 out of 32 (81.2%) patients. Its patient’s admission was 10.1 1 +7.4 dayss (range 1 to 30 days). Cough was observed in 25 of the 32 (78.1 %) patients. It preceded the skin rash by a mean of 10.5 +7.8 days (range 2 to 30 days). Malaise and headache (noted in 14 of 32 patients), sore throat (13/30), sore eyes (5/32) and nasal discharge (5/32) were other prodromal symptoms observed between 1 to 30 days before admission. The general condition of the patients on admission was described as very ill, and in 11 cases, as acutely ill. One patient was described as encephalopathic, with hallucinations and combative behavior. Three patients suffered from respiratory distress. Five were listed as in a fair, stable condition on admission and in 13 other cases, this condition might be presumed since nothing to the contrary was noted. In 10 cases no reports on general condition were available.
mean duration until
Types of Lesions Eye lesions. Eye lesions were observed in 19 of 323 (59.3%) patients. Nine patients had bilateral conjunctivitis, which was purulent in four cases. Associated swollen eyelids and photophobia were each documented in four patients, subconjunctival hemorrhage and hemorrhagic
conjunctivitis in three, conjunctival ulceration in two, and severe blepharitis and mild iritis in one patient each. Sore eyes were an initial complaint in five patients, Complications were noted in only one of them (case no. 33), who presented with bilateral purulent conjunctivitis, swelling red eyelids with crusting, and pinpoint lesions the cornea. Genital or anal lesions. These were observed in 21/32 (65.6%) of the patients. These included vesicobullous lesions and ulceration of the vulva, vagina and the glans penis, near the meatus or in the scrotum, sometimes in the absence of a generalized skin rash (5/30). Urethritis and purulent urethral discharge were documented in five patients, dysuria and increased urinary frequency in four (none of whom had urinary retention), and anal lesions in three. Oral lesions. Oral lesions, documented in 33 of 36 patients (91.6%), varied from isolated lesions to involvement of the whole buccal mucosa, pharynx, tongue and lips. Ulcerative stomatitis was found in 23 of 36 patients. Vesicles or bullae were documented in five patients, tonsillitis or pharyngitis in four. Lip lesions, observed in 12 patients, included ulcers (n=4), swelling (n=5), bleeding, peeling and crusting (n=3) vesicles and blisters (n=3). Two patients had associated gum involveover
ment.
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Skin manifestations. In 33 of 35
(94.2%) patients, skin
manifestations, became evident after 3 to 21 days of fever (mean 10.3 days). In two patients who had no fever no
temporal association could be made. Although
in ten exanthem was documented with fever on admission, it is possible that fever precedes it. In one patient, fever appeared after the vesicobullous rash. The predominant components of the exanthem were maculopapular and vesicular. Target lesions were observed in 43.7% of cases (14/32). Vesicular bullous exanthems were observed in female and males both. The distribution of the rash was variable but predominated on the extremities and trunk. Its duration was less than 14 days in 33/37 patients (89.1 %). Vesicles or bullae contents occasionally became hemorrhagic. Crops of lesions appeared for some days and different stages of rash
patients
were
an
visible
simultaneously.
Laboratory data (n=19) on admission was 11.47±5.03x109/ L(6.0 24.0x 1 0~/L). The mean percentage of polymorphonuclear was 67.0± 16.5 (range 20 to 86%), lymphocytes 18.5+13.8% (5 to 63%), monocytes 6.76+2.46% (2 to 10%), eosinophils 2.5+2.8% (range 0.7 to 7%). Mean ESR on presentation (n=10) was 44.3+34.6 mm/ hour (range 21 to 126 mm/hour). Mean WBC to
MCFT titer determination was positive and documented in 34/37 patients. In four of them, measurements of a single titer ranged from 1/128 to 1/1024; the other 30 showed a variable titer rise, ranging from 1/4 on the day of admission to 1/8000 five weeks later. Serum cold agglutinin studies were positive in 12/311 (38.7%) cases. Cold agglutinin titerrises ranged from less than 1/4 to 1/1792. Of the 16 nasopharyngeal cultures done, nine grew MP. Cultures from skin blisters were positive in three of the four cases done. Additional positive laboratory findings included the following: Recovery of herpes simplex from scraping of skin lesions (n=1), skin lesion culture for Staphylococcus epidermidis (n=1), sputum culture yield Staphylococcus aureus (n=l), Hemophilus parainfluenzae (n=l), throat culture for Beta-hemolytic streptococcus (n=I), alpha hemolytic and non-hemolytic (n=I), eye swabs yield Staphylococcus aureus culture from a purulent discharge (n=I). Liver enzymes (serum glutamic oxaloacetic
transaminase, serum glutamic pyruvic transaminase) were elevated in two
In one patient C-reactive protein was strongly positive on admission and negative 14 days later. Splenomegaly was an associated physical finding in two patients and dysphagia in another two. cases.
Chest, physical and x-ray findings. Of the 27 results of initial chest x-rays reported, 17 (63%) showed positive findings, and in 10 of these cases positive physical findings were also reported. In 16 of the 29 cases (55.1 %) in which physical findings were reported, the findings were normal.
Treatment Antibiotic and/or corticosteroids were given to 23 patients. In the remaining cases, treatment was not documented. Antibiotics alone (erythromycin, penicillin, tetracycline) were given to 15 patients, antibiotics and corticosteroids to three, and corticosteroids alone to five. Treatment with antibiotics ranged in duration from 7 to 36 days, treatment with corticosteroids from 12 to 43 days. In the patients treated with corticosteroids alone, lesions healed and patients recovered within two weeks. The three who received steroid therapy and antibiotics showed significant improvement after one, two and seven days of administration. Evidence of improvement consisted in rapid resolution of fever, malaise, and pruritus, absence of new skin lesions, healing of existing exanthem, and reduced conjunctival inflammation. Complications and recurrences No deaths occurred as a result of SJS associated with MP infection, and in only two cases were there serious complications. One patient, a 15-year-old boy, presented with pharyngitis, conjuctivitis, high fever, and respiratory distress, preceded by an URTI of one week. Respiratory distress and extension of oral swelling necessitated a tracheostomy; however, the patient improved gradually with no other complications. In another patient the hospital course was complex and prolonged. This patient had complete sloughing of conjunctival epithelia and epidermis of the face, trunk and upper legs. It was associated with major problems in pain control as well as caloric intake. In the fifth week of hospitalization the patient developed restrictive lung disease. Hypopigmentation and hyperpigmentation of skin lesions were long-term
sequelae. Eye complications included subconjunctival hemorrhage (n=1) and hemorrhagic conjunctivitis (n=2), conjunctival ulceration (n=2), mild iritis (n= 1), pinpoint lesions over the cornea (n=1), and conjunctival shrinkage (n=1). Increased liver enzymes were noted in two patients, urethritis in five and transient decrease in urine output in one. Two patients were reported to have an associated loss of fingernails. Two patients had associated hemolysis, and one required blood transfusions as a result. Recurrence of the symptomatology and characteristic features of EM
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was documented in 6 of 30 patients. In one, symptoms recurred within two weeks following withdrawal of systemic steroid therapy and MP grew again from a nasopharyngeal culture. The second had a recurrence after two years; a third had recurring skin manifestations with fever, malaise and documented MP infection. No details were available in the remaining three cases of recurrence. Table 1 summarizes the clinical characteristics of SJS associated with MP infection.
Discussion
Mycoplasma pneumoniae is a common respiratory tract pathogen responsible for 10% to 20% of all cases of pneumonia.4° Symptoms outside the pulmonary tract associated with it include abnormalities of the central system (e.g. meningitis, encephalitis), cardiac manifestations (e.g., myocarditis, pericarditis), hemolytic anemia, arthritis, gastrointestinal inflammations (hepatitis, pancreatitis), and mucocutaneous reactions .4 Extensive studies of children have found a 3% to 33% incidence of protean cutaneous manifestations associated with MP infection.4° Erythema multiforme and SJS, although not the most common cutaneous manifestations of MP, are those most often reported. Our review of hospital records between 1974 and 1989 indicated that the annual incidence of EM is one case in every 205 medical admissions (0.48%). This figure is similar to the incidence estimated by Hellgren, which was less than 1 % but greater than 0.01 %.42 Judging from the 27 cases of SJS associated with MP infections reported in the literature and the eight cases in our hospital, SJS associated with or due to MP is predominantly a disorder of children and young adults. This mean age of the patients was 12.2 years (range 5 to 19 years). Perhaps this merely reflects the tendency of MP to cause pneumonia in children and younger adolescents, but because we were interested in children with MP and SJS we omitted the few cases reported beyond 19 years of age. These have mainly involved adults between 22 and 28 years,43-46 but in one case reported recently, the patient was a 45-year-old man. 47 Two-thirds of the patients were male. A higher incidence in males of SJS of various etiology has been reported in both children and adults, ’,9 but the gender incidence reported for MP-associated infections is highly variable. 41 Mucocutaneous reactions, including SJS, seem more frequent in males, according to Cherry et al,41 who investigated exanthems associated with MP infections. Clinically, 80% of the children exhibited upper respiratory tract symptoms in the 11 days (mean) before the nervous
of rash. A similar incidence was found in reports of children with SJS of various etiology’ and of adults,’,&dquo; in which 30-50% patients with SJS had symptoms suggestive of an upper respiratory infection preceding skin problems. These symptoms (cough, fever, malaiseheadache, sore throat) were similar to those of patients with MP infections without exanthems. 40 The incidence of positive chest auscultatory findings observed in the patients in our study (55.1 %) differed substantially from that reported elsewhere4° in patients with SJS (75%). Chest x-ray findings were positive in 63% of onset
our cases.
No significant differences were observed in our patients from reports in the literature in terms of mucocutaneous lesions of SJS observed in children9 and adults.’ None of the patients had a skin rash prior to fever or other prodromal upper respiratory tract symptoms. The rash was mainly maculopapular and vesicular, but could also be petechial, urticarial or bullous. Contrary to a previous study,4’ vesicular exanthem was observed not only in males but also in females among our patients and in others.34,40 A varicella-like rash was observed among the patients and reported in an adult with MP infections and SJS.47 The frequency of eye lesions observed in this series of patients with MP infection and SJS (59.3%) was similar to the finding (about 50%) reported by Fransen et al49 in patients with MP pneumonia infections without associated SJS, and in sharp contrast to a 3% incidence in the study group of Jansen et al.5o No differences were noted between the results of the routine laboratory tests (WBC, ESR) performed on our patients and those reported in children with EM, 51 in children with MP infections without SJS,=~9 and in a study of 224 patients with EM.4’ Only 50% had leukocytosis, and 70% had increased ESR. Our cold agglutinin study results, which were positive in only 38.7% of cases, contrasted with those in the report of Lind, 51 who studied mucocutaneous reactions during MP infection. Lind’s report concluded that symptoms of the skin and mucous membranes, particularly SJS, are more likely to occur in cold-agglutinin associated respiratory infections caused by MP than in infections caused by other pathogens. Contrary to the severe complications and the relatively high incidence of long-term sequelae usually reported in patients with SJS, 1-9-53 none of our patients died, and only one suffered severe eye impairment and sloughing of the skin and developed restrictive lung disease, a known complication of MP.~9 Except for one patient who developed restrictive lung disease, requiring tracheostomy,
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and another with hemolysis (a well-known complication of MP infection with or without associated SJS), hepatitis was mild and infrequent and renal complications were few. The pathogenesis of SJS is unclear. Whether MP directly causes the syndrome or triggers it indirectly remains to be determined. Although immune complexes have been found in the serum of patients with SJS and herpes simplex54,55 and immune complexes and complement cleavage products in blister fluid of several patients with SJS,56 their significance is unknown. It is unclear whether previous antibiotic exposure affects the development of mucocutaneous lesions,51 by intensifying the dermosensitive potential of MP infection agents in a manner similar to that noted between Epstein-Barr virus and ampicillin in infectious mononucleosis. Although 62% of our patients received antibiotics (mainly penicillin and erythromycin) for a prodrome resembling URTI, many other children receive similar antibiotics for suspicion of MP pneumonia and yet do not develop any mucocutaneous reaction. The fact that viable MP was cultured from the skin lesion of these patients suggests a dissemination of the organism and a true dermal infection. Because of the nonspecific nature of the increases in cold agglutinin (lower incidence) and MCFT titers, the use of nasopharyngeal and skin lesion cultures should be emphasized, even though their sensitivity to the organism is unclear. Although we did not compare a group of patients with MP infection and SJS to a group of patients with no SJS, from the reported literature it seems that there is no pattern that can be used to predict the existence of MP infections causing SJS. Cough and pneumonia coupled with SJS rather than EM alone, however, should raise the suspicion of coexistent MP infection. The patient’s contact with a person exhibiting similar URTI symptomatology with positive chest x-ray and serology should also be noted in the medical history. Although a variety of therapeutic regimens has been employed, particularly antibiotics and/or corticosteroids, no firm conclusions can be drawn because of the low number of patients receiving corticosteriods; coincidence obviously cannot be excluded from the assessments of the degree and rate of improvement. However, the use of corticosteroid in the treatment of MP infection associated with SJS is very controversial. Because of the mortality rate of zero in this series of patients and that reported in some studies,58 most authoritiessg~’9 now feel that corticosteroids do not alter the course of the
disease and may be associated with
an
increased risk of
complications.
Acknowledgment This paper was prepared with the assistance of Medical
Publications, The Hospital for Sick Children, Toronto, Ontario.
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Mycoplasma
Report of Eight Cases and Review of the Literature Maurice
Levy, MD, M.Sc.*, Neil H. Shear, MD*†
On the basis of a literature review and eight cases of our own, we analyzed 37 cases of Mycoplasma pneumoniae (MP) infection and Stevens-Johnson syndrome (SJS). Our clinical and laboratory findings do not differ from those reported in the literature for MP infection with no exanthem or for SJS of various etiologies. Eighty percent of the children presented with symptoms of upper respiratory tract infection (URTI) (cough, fever, sore throat, malaise, headache), with a mean of 10 days (range 1 to 30) before skin rash broke out. Skin manifestations occurred in 94.2% of the patients after 3 to 21 days (mean 10.3 days) of fever. The exanthem, composed predominantly of maculopapular and vesicular, was distributed chiefly on the trunk and extremities and lasted less than 14 days in 87.8% of the patients. Stomatitis was observed in 91.6% of the patients and conjunctivitis in 50%. No consistent pattern seems to emerge by which one could predict the existence of MP infection causing SJS. The complications of SJS associated with MP seem less frequent (2.7%) and much less severe than in cases where SJS arises from other reported causes. Because coincidence cannot be excluded from the assessments of the degree and rate of improvement for the few patients treated with corticosteroid, from the low frequency of complications, and from the mortality rate of zero in this series of patients, the use of corticosteroids for SJS associated with MP infection is questionable.
*From the Division of Clinical Pharmacology (Department of Paediatrics), The Hospital for sick Children and the Division of Dermatology (Department of Medicine), Sunnybrook Health Science Centre, and the University of Toronto, Toronto, Canada.
tDr. Shear is a recipient of a career scientist award from the Ontario Ministry of Health. Correspondence to: Dr. Maurice Levy, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario Canada M5G 1X8.
42
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The Stevens-Johnson
syndrome (SJS),
or
erythema
multiforme (EM) major, is a well-defined systemic disease that can develop into a life-threatening illness. It is generally manifested in skin lesions, such as erythematous paules, plaques, vesicles, bullae and target-like, annular lesions (concentric rings resembling the iris of the eye).’ If these follow the pattern of toxic epidermal necrolysis (Lyell’s syndrome, a severe form of SJS), the mortality rate can reach 50%.2 Mucosal lesions occur and include mouth and genital ulcers. The conjunctiva may be affected, resulting in opacifications, decreased visual activity, and adhesions immobilizing the eye.3-5 Gastrointestinal, renal and musculoskeletal manifestations, although less frequent, include intrahepatic cholestasis,6 hepatitis,’ gastrointestinal bleeding (from erosions and sloughing),’-&dquo; and nephritis.11,11 Arthritis, arthralgia, myalgia, and fever are other
symptoms. the various causes and precipitating factors,’I EM has been associated with infectious processes, largely with herpes simplex infections SJS has also been described in case reports of adenovirus infection,’4 varicella, 155 infectious mononucleosis,’6 influenza B,&dquo; Legionnaires’ disease,&dquo; bacterial endotoxin,19 BCG vaccination,2° pseudomonas,2’ and parasites.22 One of the more common infectious causes of SJS is Mycoplasma pneumoniae (MP). Although an association has been documented for over 30 years, most papers describe only one to five case reports. This paper reports eight cases observed in our hospitals between 1974 and 1989 among 110 pediatric patients diagnosed with EM. It also analyzes the literature in order to identify the clinical characterisitics, pathogenesis and diagnostic criteria of MP-associated SJS in children.
Among
of referee);
prodromal symptoms (fever, malaise, cough, throat, rhinorrhea) and their duration; patient’s general condition on admission; description and distributions of skin lesions and mucous membrane involvement (i.e., conjunctivitis, nasal involvement, genital-anal lesions); course and associated complications: ocular, hepatic, renal, hematologic, pulmonary, gastrointestinal problems); sore
skin condition (mainly necrolysis), electrolyte imbalance and septic complications; laboratory data, including complete blood cell count with differential, erythrocyte sedimentation rate (ESR), serum cold agglutinin titer, mycoplasma complement fixation test (MCFT), liver and kidney function test results, as well as results of cultures (blood, urine, throat swabs, stool, skin lesion); chest (physical findings and x-ray results); results of skin biopsy and autopsy; etiological factors associated with EM and appropriate diagnostic test results; duration of hospitalization and treatment administered. For this paper, we carefully studied the patients with SJS in association with MP infection, comparing their characteristics with similar cases reported in the literature.24-39 Only the cases with positive MCFT (complement fixation titers as described below) accompanied by positive or negative serum cold agglutinins titer result and/or positive or negative nasopharyngeal and skin cultures for the MP organism were included. Of the 34 patients with positive MCFT, four had a single high titer done. The other 30 patients showed fourfold or more of increasing titer. Cold agglutinin titers were done in 31 patients, and titers were increased and positive in only 12 patients.
Results
General Data Patients and Methods The data for this study were retrieved from the charts of patients admitted to The Hospital for Sick Children, Toronto, between 1974 and 1989. Charts of all patients discharged with a diagnosis of EM minor or EM major SJS were reviewed. Patients meeting three of the following criteria were included in the study: (1) the skin lesions described were clearly typical of EM, although the patient may not have been evaluated by a dermatologist; (2) mucosal inflammation and erosion of the nasopharynx, and either conjunctivitis or genito-urinary involvement, were present; (3) skin biopsy revealed characteristic EM histopathology;23 (4) the diagnosis was made by a der-
matologist. The following information was retrieved: general data (i.e., age, sex, weight, seasonal incidence, initial diagnosis
Of the 316,500 children admitted to The Hospital for Sick Children between 1974 and 1989,110 were discharged with a diagnosis of either EM minor or Stevens-Johnson syndrome. Among the latter, eight cases (7.3%) were associated with MP infection. When these cases were added to those reported in the literature, the number of detailed cases of MP associated with a clinical description of SJS totalled 37. Twenty-five patients were males and 12 females. Their mean age was 12.2 years (range 5 to 19 years). Tables 1 and 2 present the summarized clinical and laboratory data of the patients. The seasonal incidence, reported in 16 of the 37 cases, indicated that the cases occur mainly between July and February and sporadically throughout the year. Sixteen out of 26 patients (62%) received early antibiotic treatment for fever, cough, malaise, sore throat, and
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TABLE 1. Incidence of Clinical Data in Children with
Mycoplasma Pneumoniae Infection and Stevens-Johnson Syndrome.
development of SJS. Nine of them given penicillin, seven erythromycin, one Septra and one clindamycin with ampicillin. Two patients had been in contact for three to five weeks otitis before the full were
with relatives who had symptoms of a flu-like illness (fever, cough, sore throat). These patients had a high titer of complement-fixing antibodies for MP and a positive throat swab culture. Two other patients had been in contact for two weeks with relatives who had flu-like
symptoms, but in their cases infection was documented.
no
serological evidence
of
Prodromal Symptoms and Patient’s Condition Admission
on
The characteristic manifestations of MP infection associated with SJS were often preceded by fever, cough and malaise. Sore throat, sore eyes and nasal discharge were less frequent but associated prodromal complaints.
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TABLE 2.
Laboratory Data in Children with Mycoplasma Pneumoniae Infection and Stevens-Johnson Syndrome
aThirty patients showed fourfold ranging from 1/128 to 1/1024
or more
of
increasing MCFT titer from
bTiter rises ranged from 1/4 to 1/1792. WBC=white blood cell, PMN=polymorphonuclear, fixation titer
1/4 to 1/8000. Four had
a
high single titer done
ESR=erythrocyte sedimentation rate, MCFT=mycoplasma complement
Fever was observed in 26 out of 32 (81.2%) patients. Its patient’s admission was 10.1 1 +7.4 dayss (range 1 to 30 days). Cough was observed in 25 of the 32 (78.1 %) patients. It preceded the skin rash by a mean of 10.5 +7.8 days (range 2 to 30 days). Malaise and headache (noted in 14 of 32 patients), sore throat (13/30), sore eyes (5/32) and nasal discharge (5/32) were other prodromal symptoms observed between 1 to 30 days before admission. The general condition of the patients on admission was described as very ill, and in 11 cases, as acutely ill. One patient was described as encephalopathic, with hallucinations and combative behavior. Three patients suffered from respiratory distress. Five were listed as in a fair, stable condition on admission and in 13 other cases, this condition might be presumed since nothing to the contrary was noted. In 10 cases no reports on general condition were available.
mean duration until
Types of Lesions Eye lesions. Eye lesions were observed in 19 of 323 (59.3%) patients. Nine patients had bilateral conjunctivitis, which was purulent in four cases. Associated swollen eyelids and photophobia were each documented in four patients, subconjunctival hemorrhage and hemorrhagic
conjunctivitis in three, conjunctival ulceration in two, and severe blepharitis and mild iritis in one patient each. Sore eyes were an initial complaint in five patients, Complications were noted in only one of them (case no. 33), who presented with bilateral purulent conjunctivitis, swelling red eyelids with crusting, and pinpoint lesions the cornea. Genital or anal lesions. These were observed in 21/32 (65.6%) of the patients. These included vesicobullous lesions and ulceration of the vulva, vagina and the glans penis, near the meatus or in the scrotum, sometimes in the absence of a generalized skin rash (5/30). Urethritis and purulent urethral discharge were documented in five patients, dysuria and increased urinary frequency in four (none of whom had urinary retention), and anal lesions in three. Oral lesions. Oral lesions, documented in 33 of 36 patients (91.6%), varied from isolated lesions to involvement of the whole buccal mucosa, pharynx, tongue and lips. Ulcerative stomatitis was found in 23 of 36 patients. Vesicles or bullae were documented in five patients, tonsillitis or pharyngitis in four. Lip lesions, observed in 12 patients, included ulcers (n=4), swelling (n=5), bleeding, peeling and crusting (n=3) vesicles and blisters (n=3). Two patients had associated gum involveover
ment.
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Skin manifestations. In 33 of 35
(94.2%) patients, skin
manifestations, became evident after 3 to 21 days of fever (mean 10.3 days). In two patients who had no fever no
temporal association could be made. Although
in ten exanthem was documented with fever on admission, it is possible that fever precedes it. In one patient, fever appeared after the vesicobullous rash. The predominant components of the exanthem were maculopapular and vesicular. Target lesions were observed in 43.7% of cases (14/32). Vesicular bullous exanthems were observed in female and males both. The distribution of the rash was variable but predominated on the extremities and trunk. Its duration was less than 14 days in 33/37 patients (89.1 %). Vesicles or bullae contents occasionally became hemorrhagic. Crops of lesions appeared for some days and different stages of rash
patients
were
an
visible
simultaneously.
Laboratory data (n=19) on admission was 11.47±5.03x109/ L(6.0 24.0x 1 0~/L). The mean percentage of polymorphonuclear was 67.0± 16.5 (range 20 to 86%), lymphocytes 18.5+13.8% (5 to 63%), monocytes 6.76+2.46% (2 to 10%), eosinophils 2.5+2.8% (range 0.7 to 7%). Mean ESR on presentation (n=10) was 44.3+34.6 mm/ hour (range 21 to 126 mm/hour). Mean WBC to
MCFT titer determination was positive and documented in 34/37 patients. In four of them, measurements of a single titer ranged from 1/128 to 1/1024; the other 30 showed a variable titer rise, ranging from 1/4 on the day of admission to 1/8000 five weeks later. Serum cold agglutinin studies were positive in 12/311 (38.7%) cases. Cold agglutinin titerrises ranged from less than 1/4 to 1/1792. Of the 16 nasopharyngeal cultures done, nine grew MP. Cultures from skin blisters were positive in three of the four cases done. Additional positive laboratory findings included the following: Recovery of herpes simplex from scraping of skin lesions (n=1), skin lesion culture for Staphylococcus epidermidis (n=1), sputum culture yield Staphylococcus aureus (n=l), Hemophilus parainfluenzae (n=l), throat culture for Beta-hemolytic streptococcus (n=I), alpha hemolytic and non-hemolytic (n=I), eye swabs yield Staphylococcus aureus culture from a purulent discharge (n=I). Liver enzymes (serum glutamic oxaloacetic
transaminase, serum glutamic pyruvic transaminase) were elevated in two
In one patient C-reactive protein was strongly positive on admission and negative 14 days later. Splenomegaly was an associated physical finding in two patients and dysphagia in another two. cases.
Chest, physical and x-ray findings. Of the 27 results of initial chest x-rays reported, 17 (63%) showed positive findings, and in 10 of these cases positive physical findings were also reported. In 16 of the 29 cases (55.1 %) in which physical findings were reported, the findings were normal.
Treatment Antibiotic and/or corticosteroids were given to 23 patients. In the remaining cases, treatment was not documented. Antibiotics alone (erythromycin, penicillin, tetracycline) were given to 15 patients, antibiotics and corticosteroids to three, and corticosteroids alone to five. Treatment with antibiotics ranged in duration from 7 to 36 days, treatment with corticosteroids from 12 to 43 days. In the patients treated with corticosteroids alone, lesions healed and patients recovered within two weeks. The three who received steroid therapy and antibiotics showed significant improvement after one, two and seven days of administration. Evidence of improvement consisted in rapid resolution of fever, malaise, and pruritus, absence of new skin lesions, healing of existing exanthem, and reduced conjunctival inflammation. Complications and recurrences No deaths occurred as a result of SJS associated with MP infection, and in only two cases were there serious complications. One patient, a 15-year-old boy, presented with pharyngitis, conjuctivitis, high fever, and respiratory distress, preceded by an URTI of one week. Respiratory distress and extension of oral swelling necessitated a tracheostomy; however, the patient improved gradually with no other complications. In another patient the hospital course was complex and prolonged. This patient had complete sloughing of conjunctival epithelia and epidermis of the face, trunk and upper legs. It was associated with major problems in pain control as well as caloric intake. In the fifth week of hospitalization the patient developed restrictive lung disease. Hypopigmentation and hyperpigmentation of skin lesions were long-term
sequelae. Eye complications included subconjunctival hemorrhage (n=1) and hemorrhagic conjunctivitis (n=2), conjunctival ulceration (n=2), mild iritis (n= 1), pinpoint lesions over the cornea (n=1), and conjunctival shrinkage (n=1). Increased liver enzymes were noted in two patients, urethritis in five and transient decrease in urine output in one. Two patients were reported to have an associated loss of fingernails. Two patients had associated hemolysis, and one required blood transfusions as a result. Recurrence of the symptomatology and characteristic features of EM
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was documented in 6 of 30 patients. In one, symptoms recurred within two weeks following withdrawal of systemic steroid therapy and MP grew again from a nasopharyngeal culture. The second had a recurrence after two years; a third had recurring skin manifestations with fever, malaise and documented MP infection. No details were available in the remaining three cases of recurrence. Table 1 summarizes the clinical characteristics of SJS associated with MP infection.
Discussion
Mycoplasma pneumoniae is a common respiratory tract pathogen responsible for 10% to 20% of all cases of pneumonia.4° Symptoms outside the pulmonary tract associated with it include abnormalities of the central system (e.g. meningitis, encephalitis), cardiac manifestations (e.g., myocarditis, pericarditis), hemolytic anemia, arthritis, gastrointestinal inflammations (hepatitis, pancreatitis), and mucocutaneous reactions .4 Extensive studies of children have found a 3% to 33% incidence of protean cutaneous manifestations associated with MP infection.4° Erythema multiforme and SJS, although not the most common cutaneous manifestations of MP, are those most often reported. Our review of hospital records between 1974 and 1989 indicated that the annual incidence of EM is one case in every 205 medical admissions (0.48%). This figure is similar to the incidence estimated by Hellgren, which was less than 1 % but greater than 0.01 %.42 Judging from the 27 cases of SJS associated with MP infections reported in the literature and the eight cases in our hospital, SJS associated with or due to MP is predominantly a disorder of children and young adults. This mean age of the patients was 12.2 years (range 5 to 19 years). Perhaps this merely reflects the tendency of MP to cause pneumonia in children and younger adolescents, but because we were interested in children with MP and SJS we omitted the few cases reported beyond 19 years of age. These have mainly involved adults between 22 and 28 years,43-46 but in one case reported recently, the patient was a 45-year-old man. 47 Two-thirds of the patients were male. A higher incidence in males of SJS of various etiology has been reported in both children and adults, ’,9 but the gender incidence reported for MP-associated infections is highly variable. 41 Mucocutaneous reactions, including SJS, seem more frequent in males, according to Cherry et al,41 who investigated exanthems associated with MP infections. Clinically, 80% of the children exhibited upper respiratory tract symptoms in the 11 days (mean) before the nervous
of rash. A similar incidence was found in reports of children with SJS of various etiology’ and of adults,’,&dquo; in which 30-50% patients with SJS had symptoms suggestive of an upper respiratory infection preceding skin problems. These symptoms (cough, fever, malaiseheadache, sore throat) were similar to those of patients with MP infections without exanthems. 40 The incidence of positive chest auscultatory findings observed in the patients in our study (55.1 %) differed substantially from that reported elsewhere4° in patients with SJS (75%). Chest x-ray findings were positive in 63% of onset
our cases.
No significant differences were observed in our patients from reports in the literature in terms of mucocutaneous lesions of SJS observed in children9 and adults.’ None of the patients had a skin rash prior to fever or other prodromal upper respiratory tract symptoms. The rash was mainly maculopapular and vesicular, but could also be petechial, urticarial or bullous. Contrary to a previous study,4’ vesicular exanthem was observed not only in males but also in females among our patients and in others.34,40 A varicella-like rash was observed among the patients and reported in an adult with MP infections and SJS.47 The frequency of eye lesions observed in this series of patients with MP infection and SJS (59.3%) was similar to the finding (about 50%) reported by Fransen et al49 in patients with MP pneumonia infections without associated SJS, and in sharp contrast to a 3% incidence in the study group of Jansen et al.5o No differences were noted between the results of the routine laboratory tests (WBC, ESR) performed on our patients and those reported in children with EM, 51 in children with MP infections without SJS,=~9 and in a study of 224 patients with EM.4’ Only 50% had leukocytosis, and 70% had increased ESR. Our cold agglutinin study results, which were positive in only 38.7% of cases, contrasted with those in the report of Lind, 51 who studied mucocutaneous reactions during MP infection. Lind’s report concluded that symptoms of the skin and mucous membranes, particularly SJS, are more likely to occur in cold-agglutinin associated respiratory infections caused by MP than in infections caused by other pathogens. Contrary to the severe complications and the relatively high incidence of long-term sequelae usually reported in patients with SJS, 1-9-53 none of our patients died, and only one suffered severe eye impairment and sloughing of the skin and developed restrictive lung disease, a known complication of MP.~9 Except for one patient who developed restrictive lung disease, requiring tracheostomy,
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and another with hemolysis (a well-known complication of MP infection with or without associated SJS), hepatitis was mild and infrequent and renal complications were few. The pathogenesis of SJS is unclear. Whether MP directly causes the syndrome or triggers it indirectly remains to be determined. Although immune complexes have been found in the serum of patients with SJS and herpes simplex54,55 and immune complexes and complement cleavage products in blister fluid of several patients with SJS,56 their significance is unknown. It is unclear whether previous antibiotic exposure affects the development of mucocutaneous lesions,51 by intensifying the dermosensitive potential of MP infection agents in a manner similar to that noted between Epstein-Barr virus and ampicillin in infectious mononucleosis. Although 62% of our patients received antibiotics (mainly penicillin and erythromycin) for a prodrome resembling URTI, many other children receive similar antibiotics for suspicion of MP pneumonia and yet do not develop any mucocutaneous reaction. The fact that viable MP was cultured from the skin lesion of these patients suggests a dissemination of the organism and a true dermal infection. Because of the nonspecific nature of the increases in cold agglutinin (lower incidence) and MCFT titers, the use of nasopharyngeal and skin lesion cultures should be emphasized, even though their sensitivity to the organism is unclear. Although we did not compare a group of patients with MP infection and SJS to a group of patients with no SJS, from the reported literature it seems that there is no pattern that can be used to predict the existence of MP infections causing SJS. Cough and pneumonia coupled with SJS rather than EM alone, however, should raise the suspicion of coexistent MP infection. The patient’s contact with a person exhibiting similar URTI symptomatology with positive chest x-ray and serology should also be noted in the medical history. Although a variety of therapeutic regimens has been employed, particularly antibiotics and/or corticosteroids, no firm conclusions can be drawn because of the low number of patients receiving corticosteriods; coincidence obviously cannot be excluded from the assessments of the degree and rate of improvement. However, the use of corticosteroid in the treatment of MP infection associated with SJS is very controversial. Because of the mortality rate of zero in this series of patients and that reported in some studies,58 most authoritiessg~’9 now feel that corticosteroids do not alter the course of the
disease and may be associated with
an
increased risk of
complications.
Acknowledgment This paper was prepared with the assistance of Medical
Publications, The Hospital for Sick Children, Toronto, Ontario.
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