Annals of B-Pod: Connect the Dots - A Tale of Two Rashes
/Case 2
HISTORY OF PRESENT ILLNESS
The patient is a previously healthy African female in her late twenties who presents with a chief complaint of productive cough and a rash. She was seen in the ED three days ago for her cough and was diagnosed with community acquired pneumonia, for which she was prescribed doxycycline and azithromycin. She has been compliant with her antibiotic regimen, however notes she has developed a desquamating rash, purulent drainage from her lips and mouth, and erythema and purulent drainage from bilateral eyes. The rash has progressed to form papules over bilateral upper and lower extremities. She denies fever, chest pain, shortness of breath, nausea, vomiting, and abdominal pain. The patient has recently moved to the United States from Western Africa three months prior to her presentation.
PHYSICAL EXAM
VITALS: T 39.1 HR 118 BP 106/60 RR 27 SpO2 96% on RA
The patient is an awake, alert, ill-appearing female. She exhibits desquamation of the upper and lower lips with purulent drainage from her oral mucosa, as well as bilateral conjunctival injection with purulent drainage. An erythematous, maculopapular rash is present on the upper and lower extremities. Many lesions have necrotic centers, and some lesions appear to be pustular. One erythematous lesion is present at the left lower quadrant of the abdomen, and scattered lesions are present on the patient’s back. Genitalia exhibits erythema and purulent drainage, but no pustules or necrolysis. Lung sounds are diminished throughout, with wheezes auscultated at the right middle lobe. Cardiovascular, abdominal, and neurologic exams are within normal limits.
HOSPITAL COURSE
Basic laboratory studies were unremarkable. HIV screening was negative. Sputum culture and blood cultures showed no growth. Urine legionella antigen and mycoplasma pneumonia DNA studies were negative. Chest x-ray was within normal limits.
The patient’s initial presentation was concerning for Stevens Johnson syndrome versus an infectious etiology of her rash, including mycoplasma pneumonia-associated mucositis given her recent history of pneumonia. Dermatology, burn surgery and ophthalmology were consulted during the patient’s hospital course to assist with management.
Upon admission, the patient was treated with IV fluids, levofloxacin, and standard wound care. A respiratory viral panel and quantiferon gold testing were negative. Mycoplasma IgM resulted positive, supporting a diagnosis of mycoplasma pneumonia-associated mucositis. Ophthalmology evaluated the patient on hospital day three and noted pseudomembranes and new staining of the bulbar conjunctiva in bilateral eyes. Ophthalmic moxifloxacin was started and the patient was taken to the operating room for bilateral amniotic membrane graft placements and symblepharon ring placement. Following the procedure, she was started on daily prednisone 60 mg. She required multiple days to heal from an ophthalmologic standpoint, however was ultimately discharged on hospital day 15 with a prednisone taper, and bacitracin and clioxan ointment to bilateral eyes. At discharge, her rash was noted to have eroded and crusted over, and she was discharged with topical application of mild barrier cream for moisturization.
The patient followed up in ophthalmology clinic two days after discharge and was noted to have almost complete resolution of bilateral conjunctival staining. She also reported significant improvement in her skin lesions.
Case 1
HISTORY OF PRESENT ILLNESS
The patient is a male in his early thirties with a past medical history of celiac disease and herpes simplex virus induced-erythema multiforme who presents to the emergency department (ED) with a chief complaint of a progressive, painful rash that has been worsening over the past three days. The patient’s symptoms began with a cold sore on his lip, followed by lesions on his bilateral upper extremities. The lesions then spread to his palms, soles, trunk, back, neck, periorbital and perioral regions. He reports subjective fevers, odynophagia, and a tingling sensation of the left eye. He denies visual changes, eye pain, shortness of breath, abdominal pain, vomiting, urinary or bowel symptoms, or genital lesions. He denies recent tick exposure.
The patient was seen an outside ED on day two of symptoms, where he was treated with methylprednisolone, cetirizine and encouraged to follow up as an outpatient. His symptoms continued to worsen, so he presented to the same ED later that evening, where he was treated with dexamethasone and hydrocortisone cream and discharged. Despite these therapies, he has had no relief and now complains of severe pain and worsening lesions, particularly in his mouth and on his hands.
PHYSICAL EXAM
VITALS: T 36.3 HR 54 BP 129/75 RR 12 SpO2 94% on RA
The patient is a well-appearing male who appears uncomfortable but is in no distress. There are diffuse 0.5-3 cm variable eruptions, including tender papules and vesicles, over the trunk and extremities. The rash involves the palms and soles, and targetoid papules are noted on bilateral hands. There are also many scattered pigmented macules from older lesions. On the posterior scalp, there is a large 8x8 cm irregular pink plaque. No perianal lesion is noted, but there is an eruption on the right lateral penis with white scale. There is mucosal involvement of the anterior gingiva and palate. Ophthalmologic, cardiovascular, pulmonary, abdominal, and neurologic exams are within normal limits.
HOSPITAL COURSE
The patient’s initial presentation was consistent with erythema multiforme major as a leading diagnosis. Basic laboratory studies were unremarkable, and additional labs were sent to assess for drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, human immunodeficiency virus (HIV), syphilis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency, which were negative. The patient was treated with intravenous (IV) fluids and pain medication in the ED, and dermatology was consulted for recommendations on management. Based on his prior medical history of erythema multiforme secondary to herpes simplex virus, he was clinically diagnosed with erythema multiforme and biopsy was deferred. He was prescribed topical steroids and valacyclovir in the inpatient setting, and dressings were used to cover his lesions. He remained stable and was discharged home in stable condition with valacyclovir, topical clobetazole, ibuprofen, acetaminophen and tramadol with follow up in dermatology clinic.
The patient was seen in dermatology clinic three weeks later,and his active cutaneous lesions had been replaced by scattered dyspigmented patches over this palms, soles, extremities and trunk. Clobetasol ointment was discontinued given that he no longer had active lesions, and he was started on a suppressive dose of valacyclovir.
DISCUSSION
Erythema multiforme (EM - Case 1), mycoplasma pneumonia-associated mucositis (MPAM - Case 2), and Stevens-Johnson Syndrome (SJS) present with similar clinical features and are often considered to be varying points along the same disease spectrum. Mycoplasma pneumonia is known to be a cause of all three disease processes, but some studies argue that there are subtle, yet important, differences in pathogenesis, presentation, and disease course between the three disease processes. [1]
Epidemiology and Clinical Presentation
Erythema Multiforme (EM)
Erythema multiforme is an immune-mediated condition characterized by cutaneous targetoid lesions, primarily on the face and extremities. [2] The disease occurs mostly in adolescents and young adults, with a male to female ratio of 3:2.2 The etiology of EM is almost always infectious, with the herpes simplex virus and Mycoplasma pneumoniae being two major causes. Less commonly, EM is caused by other infectious pathogens or drugs, such as adenovirus, cytomegalovirus, Epstein-barr virus, varicella zoster virus, viral hepatitis, non-steroidal anti-inflammatory drugs (NSAIDs), sulfonamides, and other antibiotics. [2]
The classic EM rash presents with asymptomatic targetoid lesions with or without mucosal involvement. There are two classifications of EM: EM major, which develops in approximately twenty percent of EM cases and signifies mucosal involvement, and EM minor, which involves only cutaneous symptoms.3 Although the majority of patients will have asymptomatic cutaneous lesions, some patients, such as the one described above, do report pain or pruritus associated with dermatologic findings. The disease is usually self-limited and resolves within a few weeks, and very rarely does it recur or persist. [2] In severe cases, complications can occur, such as cutaneous scarring or ocular scarring with subsequent visual impairment.
Mycoplasma Pneumonia-Associated Mucositis (MPAM)
Mycoplasma pneumonia associated mucositis is an immune-mediated condition that is different from erythema multiforme in that cutaneous involvement is often sparse or nonexistent. [4] It is most common in children and adolescents, [5] with 66% of documented cases occurring in males. [6] It occurs in less than 10% of patients who acquire a Mycoplasma pneumoniae infection. [7]
MPAM primarily presents with involvement of oral and/or ocular mucosa. When cutaneous lesions are present, they are commonly maculopapular or vesicular and present on the trunk and extremities. [8] Prodromal symptoms, including respiratory symptoms, are almost always present, [1] and while upper respiratory tract disease is more common, pneumonia may occur as well. [9] Ocular complications, such as those present in the patient described here, are some of the most common sequelae of mycoplasma mucositis and can cause scarring and visual impairment. More rarely, CNS complications may ensue. These are relatively more common in children and include aseptic meningitis, meningoencephalitis, seizures, peripheral neuropathy, transverse myelitis, cognitive abnormalities, and cerebellar ataxia. [10,11] MPAM may also be associated with esophagitis and erosive bronchitis. [2] The disease course is most often mild but depends on severity of lesions and degree of ocular involvement. [1]
Mycoplasma pneumoniae is a documented cause of mucositis regardless of preceding antibiotic administration, but the large number of cases in which patients were receiving antibiotics at the presentation of mucocutaneous disease increases the suspicion that antibiotics “intensify the dermatosensitive potential of Mycoplasma pneumoniae,” [8] such as in the patient case presented above.
Diagnosis
EM and MPAM are primarily clinical diagnoses based on patient history and visual assessment of lesions. The differential diagnosis of these presentations will therefore include other skin conditions, including SJS, toxic epidermal necrolysis (TEN), urticaria, erythema nodosum, bullous pemphigoid, or dermatitis herpetiformis. [12] As discussed previously, EM will typically present with an acral distribution of papular targetoid cutaneous lesions, while MPAM will typically present with mucosal lesions with possible cutaneous involvement. Although atypical lesions may also occur, the typical target EM lesion is characterized by a “dusky central disk” with a more peripheral “infiltrated pale ring” and surrounding “erythematous halo.” [2] Atypical EM lesions may include two rings only, or may be vesicles overlying a darker center and surrounded by erythema. However, EM lesions will always be papules, not macules. [2] Knowledge of HSV infection should increase suspicion for EM.
In cases of diagnostic uncertainty, biopsy of skin lesions, direct immunofluorescence, herpes serology, and serum antibodies may be used. [2] Cold agglutination studies may also assist with a diagnosis of MPAM. While these studies may not be necessary in a patient who will be discharged from the emergency department, they can assist admitting teams and consulting services in gaining a clearer picture of the patient’s disease process.
Treatment
Management of patients with EM and MPAM will depend on the specific signs and symptoms exhibited by each patient, but generally entails supportive care. Both diseases are generally self-limited and do not have a specific cure.
Erythema Multiforme (EM)
While some physicians advocate for the use of systemic corticosteroids for severe cases of EM, there is insufficient evidence proving efficacy, and there is a significant risk of adverse side effects. [2] Three case reports did show significant improvement in duration of fever and vesicular eruptions with use of IV methylprednisolone, and another two cases demonstrated that IV methylprednisolone stopped disease progression and prevented recurrences. Other larger studies, however, linked corticosteroid treatment to longer hospital stays and increased complications. [13] Since EM can be managed with supportive care only, the possible benefits of steroid use have not been demonstrated to sufficiently outweigh the risks.
Since EM is an immune-mediated process, another possible treatment option for severe cases is intravenous immunoglobulin (IVIg). While evidence regarding its use in EM is limited, one case study demonstrated 80% improvement without significant adverse effects in a patient with persistent, severe EM that had been unresponsive to multiple rounds of steroids, acyclovir, and azathioprine. [14] Furthermore, IVIg has been shown to be effective in treating SJS and TEN, [15] therefore providers may consider empiric IVIg therapy if there is any diagnostic uncertainty.
Although anti-HSV drugs have no effect on an active episode of EM, they can prevent recurrences in HSV-associated EM. [2] A double-blind, placebo-controlled study demonstrated that a six-month course of acyclovir 400 mg twice daily achieved successful suppression of recurrent EM. [16] Valacyclovir and famciclovir have greater oral bioavailability than acyclovir and can be tried as alternatives to the above regimen. The goal of using antiviral agents is to achieve a recurrence-free period of several months at which point the dosage can be reduced and, hopefully, eventually discontinued. [17] When anti-HSV drugs have not worked to prevent recurrences, azathioprine and thalidomide have been found to be helpful. [2]
Mycoplasma Pneumonia-Associated Mucositis (MPAM)
For MPAM in particular, there are no evidence-based guidelines regarding management. [1] As such, current guidelines recommend discontinuation of the culprit drug, if that is the etiology of disease onset, and supportive management. . This includes standard wound care such as topical corticosteroids for cutaneous lesions, and oral antihistamines, topical corticosteroid gel, or mouthwash containing lidocaine for painful oral lesions. Ophthalmology consultation should be obtained for any ocular involvement in order to prevent long term sequelae.
Benefit of antibiotic use in mucocutaneous presentations may be limited, however use can often prevent neurologic and pulmonary complications later in the disease course, thus is commonly prescribed. Studies of steroid use in MPAM show similar conclusions as those studying steroids for EM: fever and hospital course are decreased, but complications may be increased. Similarly, there is limited evidence that IVIg is beneficial, but may be more helpful in cases with severe mucositis, such as cases so severe as to cause respiratory distress. [18]
Most patients with the above pathologies can be safely discharged. However, if symptoms are severe, or if there is any concern for SJS/TEN, a burns specialist or dermatologist should be consulted. [19] In severe cases, patients may have electrolyte abnormalities and should be corrected as needed. These patients will require hospital admission.
SUMMARY
EM and MPAM are two clinically diagnosed conditions that are frequently thought to be along the same spectrum of dermatologic pathologies. However, there are some key differences that aid in diagnosis: EM is primarily a dermatologic condition, while MPAM is predominantly a mucositis. EM may be infectious or drug-induced, while MPAM is always associated with Mycoplamsa pneumoniae, and therefore respiratory symptoms are essentially universal. Both conditions focus on supportive care and discontinuing culprit drug use, if indicated, for management, however may require specialty care involvement, such as ophthalmology, dermatology, pulmonology, or intensivists, depending on extent of systemic dissemination of the disease process. In severe cases, corticosteroids and IVIg may be beneficial, however more definitive research need to be conducted to support routine use in these conditions.
REFERENCES
Caravan, T. N., et al. Mycoplasma pneumoniae - induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: A systematic review. Journal of the American Academy of Dermatology. Volume 72, Issue 2, Pages 239-245. February 2015.
Roujeau JC. Erythema multiforme. In: Fitzpatrick's Dermatology in General Medicine, Wolff K, Goldsmith LA, Katz SI, et al (Eds), McGraw-Hill Companies, Inc, 2012. Chapter 39.
Huff, J. C., Weston, W. L., Tonnesen M.G. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. Journal of American Academy of Dermatology. 1983. 8:763.
Canavan TN, Mathes EF, Frieden I, Shinkai K. Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review. J Am Acad Dermatol 2015; 72:239.
Meyer Sauteur PM, Goetschel P, Lautenschlager S. Mycoplasma pneumoniae and mucositis--part of the Stevens-Johnson syndrome spectrum. J Dtsch Dermatol Ges 2012; 10:740.
Bukhari, E., et al. Mycoplasma pneumoniae-associated mucositis syndrome: A rare and clinically challenging disease in a Saudi child. Journal of Taibah University Medical Sciences. August 2017. Volume 12, Issue 4, p. 356-359.
Figueroa, F. MPAM-Mycoplasma pneumonia associated mucositis: A diagnostic challenge. Cardiovascular Pharmacology Open Access. Volume 7. 2018.
Cherry JD. Anemia and mucocutaneous lesions due to Mycoplasma pneumoniae infections. Clin Infect Dis 1993; 17 Suppl 1:S47.
Mansel, JK, et al. Mycoplasma pneumoniae pneumonia. Chest. March 1989. 95(3):639-46.
Candler, PM, Dale, RC. Three cases of central nervous system complications associated with Mycoplasma pneumoniae. Pediatric Neurology. August 2004. 31(2): 133-8.
Smith, R., Eviatar, L. Neurologic manifestations of Mycoplasma pneumoniae infections: diverse spectrum of disease. A report of six cases and review of the literature. Clinical Pediatrics (Phila). April 2000. 39(4): 195-201.
Erythema Multiforme. NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/erythema-multiforme/. Accessed January 25, 2020.
Yeung, A.K., Goldman, R.D. Use of steroids for erythema multiforme in children. Canadian Family Physician. November 2005. 51(11): 1481–1483.
Momin, SB, et al. Review of Intravenous Immunoglobulin in the Treatment of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Journal of Clinical and Aesthetic Dermatology. February 2009. 2(2): 51–58.
Singh, MN, et al. Severe erythema multiforme responding to high dose intravenous immunoglobulin therapy. Journal of the American Academy of Dermatology. March 2004. Volume 50, Issue 3, Supplement, Page P95
Tatnall, FM, et al. A double-blind, placebo controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. British Journal of Dermatology. February 1995. 132(2):267-70.
Lamoreux, MR, et al. Erythema Multiforme. American Family Physician. December 2006. 74(11):1883-1888.
Parris, RS, et al. More than Meets the Eye. A 23-Year-Old Woman with Rapidly Progressive Respiratory Failure, Mucositis, and Rash. Annals of the American Thoracic Society. December 2015. Vol 12, No 12.
Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol 2016; 174:1194.
Aurelian, L., et al. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatology Online Journal. February, 2003. 9(1):1.
Sandhu R, Mareddy C, Itskowitz M, Mount CE, Bhanot N, Min Z. Mycoplasma-induced rash and mucositis in a young patient with red eyes, oral mucositis, and targetoid cutaneous vesicles. The Lancet Infectious Diseases. 2017;17(5):562.
