Lower-extremity nodules in a 2-year-old girl

The case

A previously healthy 2-year-old girl, born at term by cesarean delivery due to breech presentation, with an uncomplicated postnatal course, presented to the outpatient clinic with a chief complaint of 2 days of itchy, bilateral leg rash. Her mother stated that each of her daughter’s legs had 5 or 6 quarter-size “bruises,” which felt like “hard welts” and were warm to the touch; some were dark purple, and others appeared redder. According to her mother, the patient had no fever, upper respiratory symptoms, abdominal pain, vomiting, diarrhea, discolored urine, blood in stool, change in gait, weakness, or joint swelling. She was fully immunized and had had no respiratory illnesses or fevers during the previous month. Her oral intake, urine output, and ambulation were normal, and she was otherwise her active, playful self.

The patient had no sick contacts, known bugbites, or recent exposure to outdoor pool or reservoir water. She had traveled to Michigan 2 months prior for a camping trip, during which she ran around in fields and forested areas. After returning home, her father checked her for ticks and found none. She had no other recent travel.

The patient lived with her mother and father, with 1 dog in the home and no smokers. The patient attended daycare 3 days a week with 10 other children and did not take any medications.

History and physical examination

The patient’s symptoms began 2 days prior to presentation, with worsening itching and rash on her bilateral lower extremities. Her mother stated that she initially thought that the girl had bruises on her shins from playing, but the bruises grew larger, more numerous, and warm to the touch. The parents applied eczema cream and ice packs, which slightly improved the rash. The patient’s father had recently put new sheets on the girl’s bed, so the parents wondered if the symptoms might be an allergic reaction to the material. The patient’s family history is significant for Hodgkin lymphoma in the mother, who is also concerned about a possible malignancy in her daughter.

Figure 1

On examination, the patient appeared well, with no fever and no acute distress. Her growth parameters were normal for her age. Her vital signs were all within normal limits. She had moist mucous membranes without petechiae or exudates and normal lips, tongue, gingiva, and dentition. She had no enlargement of or exudate on the tonsils, no lymphadenopathy, and no pallor or cyanosis of the skin, and her respiratory and cardiac examinations were benign. Her abdomen was soft, nontender, and nondistended, with no hepatosplenomegaly or masses. She had no swelling, deformity, or pain in her extremities. Her skin exam was significant for multiple raised, blanching, erythematous, nonulcerated, immobile nodules on her lower extremities bilaterally (Figures 1 and 2).

Figure 2

Consultation­

After initial presentation to the outpatient clinic, the patient was prescribed ibuprofen 7.5 mL every 6 hours and advised to rest and keep her legs elevated. Pediatric infectious disease was consulted for evaluation of erythema nodosum (EN), with abnormal laboratory results showing elevated WBC.

The infectious disease consult determined that the etiology of this patient’s EN was likely infectious, and additional laboratory tests were ordered. These tests included CRP to assess for worsening inflammation, lactate dehydrogenase (LDH) level to rule out malignancy, QuantiFERON-TB Gold to rule out tuberculosis, and Mycoplasma pneumoniae antibodies to rule out that infection. The results, completed 3 days after initial presentation, were the following:

• Uric acid: 3.5 mg/dL (normal, 2.6-6.4 mg/dL)
• LDH: 198 units/L (normal, 220-462 units/L)
• CRP: 3.1 mg/L
• M pneumoniae antibodies, IgM: 1234 U/mL (normal, < 770 U/mL)
• M pneumoniae antibodies, IgG: ­ 0.90 (normal ­ 0.90)
• QuantiFERON-TB Gold: negative

Differential diagnosis

The initial differential diagnosis included several infectious and noninfectious etiologies that could account for the findings of the patient’s skin lesions and laboratory results (Box). Erythema nodosum is a type of skin inflammation that particularly affects subcutaneous fat, which typically results in painful erythematous nodules at the front of the legs below the knees. These lesions do not ulcerate and usually resolve without atrophy or scarring.¹ Lesions typically appear red at onset and, after a few days, evolve into a deep purple color, which may appear similar to a deep bruise.² These nodules may be preceded by fever, malaise, arthralgias, or upper respiratory symptoms, and joint swelling or pain may emerge at the same time the skin nodules do. Erythema nodosum can be the first sign of a systemic illness such as tuberculosis and other bacterial or fungal infections, inflammatory bowel disease, sarcoidosis, or cancer, although in many cases, no cause of EN can be found.^1,3-7 The most common cause of EN in children is idiopathic, followed by infection, sarcoidosis, and use of antibiotic drugs.^1,6,8 Among infectious etiologies of EN in children, the most common are streptococcal pharyngitis, Yersinia, Mycoplasma, Chlamydia, histoplasmosis, coccidioidomycosis, and Mycobacterium.^1,6-8

Laboratory results

Diagnostic evaluation of EN includes a comprehensive history and physical exam as well as a complete blood cell count with differential, ESR, and CRP level.^1,3 An individual patient’s presentation might warrant further evaluation, including testing for streptococcal infection, chest radiography, stool cultures, or testing for infection with tuberculosis.¹ Although EN is often self-limited, any identified underlying disorder should be treated appropriately. Pain from the lesions of EN can be treated with nonsteroidal anti-inflammatory drugs.^1,2,4

This patient’s initial presentation was most consistent with an idiopathic etiology. She lacked prodromal symptoms of fever, malaise, and arthralgias, and she had no preceding upper respiratory symptoms. The absence of fever, sore throat, and accompanying respiratory symptoms made it less likely that her EN was secondary to infection with Streptococcus or Mycobacterium tuberculosis. Additionally, she had no sick contacts or known exposure to tuberculosis-positive individuals. She received a QuantiFERON-TB Gold­ Plus test to rule out M tuberculosis infection, which was negative.

Her absence of gastrointestinal symptoms made it less likely that her skin findings were secondary to Yersinia enterocolitica­ or Yersinia pseudotuberculosis. Similarly, a negative family history of irritable bowel disease and lack of gastrointestinal disturbances pointed away from Crohn disease or ulcerative colitis as possible etiologies. The patient lacked any respiratory symptoms of sarcoidosis and denied abdominal pain, vision changes, fever, fatigue, or weight loss. Furthermore, her below-normal LDH levels effectively ruled out a malignant process, as elevated LDH is a well-known indicator of malignancy.^9,10

Recent case reports have indicated the possibility of EN in individuals with COVID-19 infections,^11,12 but such cases have not yet been documented in children, and data are still emerging regarding dermatological manifestations of COVID-19.

Differential diagnosis

Although this patient showed no respiratory symptoms or signs of systemic illness, her laboratory results were positive for M pneumoniae IgM, indicating a recent infection. Using this serological evidence of infection combined with her elevated inflammatory markers at presentation, it was determined that the most likely etiology of her EN was subclinical infection with M pneumoniae.

Discussion

M pneumoniae is a significant cause of upper and lower respiratory tract infection in both adults and children, constituting up to 40% of community-acquired pneumonias.¹³ Most infected individuals experience mild disease, which often resolves without complication. The most common symptoms of M pneumoniae infection in children include low-grade fever, cough, nausea/vomiting, and skin rash.¹⁴

Atypical pneumonia caused by M pneumoniae is most prevalent in school-aged children, with studies showing that just 13% to 18% of infected children actually develop symptoms. Estimations indicate that among individuals infected with M pneumoniae, 50% of adults and 20% of children are entirely asymptomatic.¹⁵

In this patient, the only symptom of infection was dermatologic. Skin changes associated with M pneumoniae infection have been reported in up to 25% of cases.^4,16 Skin findings range from mild erythematous maculopapular or vesicular rash to bullous purpuric lesions and even a Stevens-Johnson–like syndrome involving mucosal surfaces, known as M pneumoniae–induced rash and mucositis.¹⁷

Case reports of erythema nodosum (EN) in the context of M pneumoniae infection in children are limited. The first documented case was in 2001: A case series of 35 children with erythema nodosum reported that 3 of them had antibodies indicative of recent Mycoplasma infection. In these 3 cases, 1 child had respiratory involvement, 1 had associated fever, and the third had no other symptoms.¹⁸ In a later study by Aydin-Teke et al, 39 patients with EN were retrospectively evaluated, with streptococcal infections identified as the most common cause, and only 2 of those patients were identified as having M pneumoniae infections.¹⁹ In each case, M pneumoniae infection was diagnosed using IgM positive serology. The first systematic review of EN and M pneumoniae infection in children was completed in 2015 by Greco et al, which concluded that the pathogenesis of EN is not yet fully understood. The investigators noted that further clinical and immunologic studies are needed to better understand the connection between EN and M pneumoniae in the pediatric population.²⁰

Multiple diagnostic methods exist for the detection of M pneumoniae, each with its own advantages and disadvantages. Molecular polymerase chain reaction (PCR)–based testing has high sensitivity, high specificity, and rapid results, usually available in less than 1 day. However, PCR assays are expensive, often requiring specialized equipment and expertise.²¹ Serology-based testing has lower specificity but costs less and can be done via commercially available kits. Serology testing may require multiple patient visits to collect acute and convalescent samples, as a single elevated M pneumoniae antibody titer may not be definitive for distinguishing between active disease and an asymptomatic carrier state.²²

Culture is rarely used to detect M pneumoniae infection because isolation of the organism can take up to 3 weeks and requires a specialized medium to grow.²³ Additionally, cold agglutinin antibody titers are not recommended because the formation of cold agglutinins is neither sensitive nor specific for infection with M pneumoniae.²³ In current clinical practice, serology and molecular testing remain the most commonly used methods for detecting M pneumoniae infection.²⁴

This case demonstrates the importance of serologic testing for M pneumoniae infection in the case of pediatric erythema nodosum, even in the absence of pulmonary symptoms or radiologic findings.

Managing symptoms

M pneumoniae infection is usually mild and self-limited, not warranting specific treatment. In cases of pneumonia due to M pneumoniae infection, the most widely accepted treatment in children involves macrolide antibiotics, such as erythromycin, clarithromycin, and azithromycin.²⁵ M pneumoniae has no cell wall, making ß-lactam antibiotics ineffective. Furthermore, macrolides have a more favorable adverse effect profile in children compared with alternative drugs such as tetracyclines and fluoroquinolones. In children who are nonresponsive to antibiotic treatment, treatment with additional corticosteroids has been shown to be effective.²⁵

Complications of M pneumoniae infection are rare in children but include development or exacerbation of obstructive airway disease and asthma, alveolar hemorrhage, and acute respiratory distress syndrome. Morbidity and mortality are higher in smokers or individuals with underlying health conditions.²⁶

Patient outcome

The prescribed regimen of ibuprofen, rest, and leg elevation failed to improve the patient’s skin findings. Pediatric infectious disease consult resulted in evidence of recent infection with M pneumoniae, which was subclinical. The patient never developed systemic illness, but the erythema nodosum continued, with a new lesion on the proximal medial-anterior left thigh 12 days after her initial skin symptoms began. She had no pain at the new lesion’s site and remained afebrile, with no gastrointestinal disturbances or respiratory symptoms.

She completed a 5-day course of azithromycin (10 mg/kg, day 1; 5 mg/kg, days 2-5) according to recommendations from the consulting infectious disease physician. Her parents were counseled that the leg lesions should continue to resolve on their own, but they should manage the child’s pain and swelling with ibuprofen and cold compresses as needed. The patient remained well with gradual improvement of the pretibial lesions. Approximately 6 months later, at her 3-year-old well child visit, the patient had normal skin findings with no reported recurrence of the erythema nodosum.

References

1. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695-700.

2. Requena L, Sánchez Yus E. Erythema nodosum. Semin Cutan Med Surg. 2007;26(2):114-125. doi:10.1016/j.sder.2007.02.009

3. Mert A, Kumbasar H, Ozaras R, et al. Erythema nodosum: an evaluation of 100 cases. Clin Exp Rheumatol. 2007;25(4):563.

4. Requena L, Yus ES. Erythema nodosum. Dermatol Clin. 2008;26(4):425-v. doi:10.1016/j.det.2008.05.014

5. Diaconescu S, Strat S, Balan GG, et al. Dermatological manifestations in pediatric inflammatory bowel disease. Medicina (Kaunas). 2020;56(9):425. doi:10.3390/medicina56090425

6. García-Porrúa C, González-Gay MA, Vázquez-Caruncho M, et al. Erythema nodosum: etiologic and predictive factors in a defined population. Arthritis Rheum. 2000;43(3):584-592. Published correction appears in Arthritis Rheum. 2000;43(5):1061.

7. Mert A, Kumbasar H, Ozaras R, et al. Erythema nodosum: an evaluation of 100 cases. Clin Exp Rheumatol. 2007;25(4):563-570.

8. Baldock NE, Catterall MD. Erythema nodosum from Yersinia enterocolitica. Br J Dermatol. 1975;93(6):719-720. doi:10.1111/j.1365-2133.1975.tb05127.x

9. Liu R, Cao J, Gao X, et al. Overall survival of cancer patients with serum lactate dehydrogenase greater than 1000 IU/L. Tumour Biol. 2016;37(10):14083-14088. doi:10.1007/s13277-016-5228-2

10. Goldman RD, Kaplan NO, Hall TC. Lactic dehydrogenase in human neoplastic tissues. Cancer Res. 1964;24:389-399.

11. Suter P, Mooser B, Pham Huu Thien HP. Erythema nodosum as a cutaneous manifestation of COVID-19 infection. BMJ Case Rep. 2020;13(7):e236613. doi:10.1136/bcr-2020-236613

12. Sipfle N, Bridwell RE, Roper J. Erythema nodosum-like rash in a COVID-19 patient: a case report. Am J Emerg Med. 2021;40:227.e1-227.e2. doi:10.1016/j.ajem.2020.07.063

13. Waites KB, Balish MF, Atkinson TP. New insights into the pathogenesis and detection of Mycoplasma pneumoniae infections. Future Microbiol. 2008;3(6):635-648. doi:10.2217/17460913.3.6.635

14. Søndergaard MJ, Friis MB, Hansen DS, Jørgensen IM. Clinical manifestations in infants and children with Mycoplasma pneumoniae infection. PLoS One. 2018;13(4):e0195288. doi:10.1371/journal.pone.0195288

15. Brunner H. Mycoplasma pneumoniae infections. Isr J Med Sci. 1981;17(7):516-523.

16. Gordon O, Oster Y, Michael-Gayego A, et al. The clinical presentation of pediatric Mycoplasma pneumoniae infections-a single center cohort. Pediatr Infect Dis J. 2019;38(7):698-705. doi:10.1097/INF.0000000000002291

17. Vujic I, Shroff A, Grzelka M, et al. Mycoplasma pneumoniae-associated mucositis—case report and systematic review of literature. J Eur Acad Dermatol Venereol. 2015;29(3):595-598. doi:10.1111/jdv.12392

18. Kakourou T, Drosatou P, Psychou F, Aroni K, Nicolaidou P. Erythema nodosum in children: a prospective study. J Am Acad Dermatol. 2001;44(1):17-21. doi:10.1067/mjd.2001.110877

19. Aydın-Teke T, Tanır G, Bayhan GI, Metin O, Oz N. Erythema nodosum in children: evaluation of 39 patients. Turk J Pediatr. 2014;56(2):144-149.

20. Greco F, Catania R, Pira AL, et al. Erythema nodosum and Mycoplasma pneumoniae infections in childhood: further observations in two patients and a literature review. J Clin Med Res. 2015;7(4):274-277. doi:10.14740/jocmr2011w

21. Xu D, Li S, Chen Z, Du L. Detection of Mycoplasma pneumoniae in different respiratory specimens. Eur J Pediatr. 2011;170(7):851-858. doi:10.1007/s00431-010-1360-y

22. Spuesens EB, Fraaij PL, Visser EG, et al. Carriage of Mycoplasma pneumoniae in the upper respiratory tract of symptomatic and asymptomatic children: an observational study. PLoS Med. 2013;10(5):e1001444. doi:10.1371/journal.pmed.1001444

23. Bradley JS, Byington CL, Shah SS, et al. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):617-630. doi:10.1093/cid/cir625

24. Mycoplasma pneumoniae infections: diagnostic methods. Centers for Disease Control and Prevention. Updated June 5, 2020. Accessed September 12, 2021. https://www.cdc.gov/pneumonia/atypical/mycoplasma/hcp/diagnostic-methods.html

25. Youn YS, Lee KY. Mycoplasma pneumoniae pneumonia in children. Korean J Pediatr. 2012;55(2):42-47. doi:10.3345/kjp.2012.55.2.42

26. Bajantri B, Venkatram S, Diaz-Fuentes G. Mycoplasma pneumoniae: a potentially severe infection. J Clin Med Res. 2018;10(7):535-544. doi:10.14740/jocmr3421w